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1.  Adipose-tissue-derived Stem Cells Enhance the Healing of Ischemic Colonic Anastomoses: An Experimental Study in Rats 
This experimental study verified the effect of adipose-tissue-derived stem cells (ASCs) on the healing of ischemic colonic anastomoses in rats.
ASCs were isolated from the subcutaneous fat tissue of rats and identified as mesenchymal stem cells by identification of different potentials. An animal model of colonic ischemic anastomosis was induced by modifying Nagahata's method. Sixty male Sprague-Dawley rats (10-week-old, 370 ± 50 g) were divided into two groups (n = 30 each): a control group in which the anastomosis was sutured in a single layer with 6-0 polypropylene without any treatment and an ASCtreated group (ASC group) in which the anastomosis was sutured as in the control group, but then ASCs were locally transplanted into the bowel wall around the anastomosis. The rats were sacrificed on postoperative day 7. Healing of the anastomoses was assessed by measuring loss of body weight, wound infection, anastomotic leakage, mortality, adhesion formation, ileus, anastomotic stricture, anastomotic bursting pressure, histopathological features, and microvascular density.
No differences in wound infection, anastomotic leakage, or mortality between the two groups were observed. The ASC group had significantly more favorable anastomotic healing, including less body weight lost, less ileus, and fewer ulcers and strictures, than the control group. ASCs augmented bursting pressure and collagen deposition. The histopathological features were significantly more favorable in the ASC group, and microvascular density was significantly higher than it was in the control group.
Locally-transplanted ASCs enhanced healing of ischemic colonic anastomoses by increasing angiogenesis. ASCs could be a novel strategy for accelerating healing of colonic ischemic risk anastomoses.
PMCID: PMC3398108  PMID: 22816056
Colonic anastomosis; Ischemia; Anastomotic healing; Adipose-tissue-derived stem cell; Angiogenesis
2.  A novel colonic anastomosis technique involving fixed polyglycolic acid mesh 
Background: Polyglycolic acid mesh (PAM) reinforcement of colonic anastomoses were evaluated. Methods: Twenty female albino rabbits were divided into two groups. Each rabbit underwent segmental colonic resection with single-layer anastomosis. In one group of rabbits, PAM of length equal to the circumference of the anastomosis was applied. Rabbits were sacrificed on postoperative day 10 and peritoneal adhesions, anastomosis burst pressure, and anastomosis histopathological characteristics were evaluated. Results: The average burst pressure for the control and PAM groups was 149±15.95 mmHgand 224±124.5 mmHg, respectively (p=0.578). All control anastomoses burst, whereas only five (50%) PAM anastomoses burst (p<0.03). There was no anastomotic leakage in the control group, whereas three PAM group anastomoses leaked (p=0.210). The collagen fiber density and amount of neovascularization were lower in the PAM than the control group (p=0.001 and p=0.002, respectively). The average peritoneal adhesion value was 1.6±0.51 in the control group and 2.9±0.31 in the PAM group (p<0.0001). Conclusion: The new fixed PAM-reinforced anastomosis technique resulted in an increased risk of anastomosis leakage and peritoneal adhesion, but also higher in non-burst anastomoses.
PMCID: PMC2971543  PMID: 21072268
Anastomosis; polyglycolic acid; colon; mesh; novel; technique
3.  Effect of preoperative chemotherapy on postoperative liver regeneration following hepatic resection as estimated by liver volume 
In order to analyze postoperative liver regeneration following hepatic resection after chemotherapy, we retrospectively investigated the differences in liver regeneration by comparing changes of residual liver volume in three groups: a living liver donor group and two groups of patients with colorectal liver metastases who did and did not undergo preoperative chemotherapy.
This study included 32 patients who had at least segmental anatomical hepatic resection. Residual liver volume, early postoperative liver volume, and late postoperative liver volume were calculated to study the changes over time. From the histopathological analysis of chemotherapy-induced liver disorders, the effect on liver regeneration according to the histopathology of noncancerous liver tissue was also compared between the two colorectal cancer groups using Kleiner’s score for steatohepatitis grading {Hepatology, 41(6):1313–1321, 2005} and sinusoidal obstruction syndrome (SOS) grading for sinusoidal obstructions {Ann Oncol, 15(3):460–466, 2004}.
Assuming a preoperative liver volume of 100%, mean late postoperative liver volumes in the three groups (the living liver donor group and the colorectal cancer groups with or without chemotherapy) were 91.1%, 80.8%, and 81.3%, respectively, with about the same rate of liver regeneration among the three groups. Histopathological analysis revealed no correlation between either the Kleiner’s scores or the SOS grading and liver regeneration.
As estimated by liver volume, the level of liver regeneration was the same in normal livers, tumor-bearing livers, and post-chemotherapy tumor-bearing livers. Liver regeneration was not adversely affected by the extent to which steatosis or sinusoidal dilatation was induced in noncancerous tissue by chemotherapy in patients scheduled for surgery.
PMCID: PMC3621216  PMID: 23497123
4.  Proximal enterectomy provides a stronger systemic stimulus to intestinal adaptation than distal enterectomy. 
Gut  1987;28(Suppl):165-168.
Enteroglucagon has been implicated as a tropic hormone in the control of intestinal adaptation. Because cells producing enteroglucagon are located mainly in the distal small bowel (and colon), ileal resection might be expected to produce less adaptive change than a jejunal resection of equivalent length. This hypothesis was tested in male Sprague-Dawley rats (n = 40) weighing 184.0 +/- 7.3 g and receiving a Thiry-Vella fistula (TVF) of the mid-60% of the small intestine. One group had concomitant resection of the jejunum proximal to the TVF (n = 12), another had resection of the ileum distal to the TVF (n = 13), while controls had a TVF alone (n = 15). When killed 10 days postoperatively rats with ileal resection weighed only 81% of controls (p less than 0.001) and 85% of those with jejunal resection (p less than 0.01). Jejunal resection produced an 81% increase in crypt cell production rate (measured by a stathmokinetic technique) over control values (28.5 +/- 4.2 v 15.8 +/- 2.3 cells/crypt/h: p = 0.025), whereas ileal resection had no demonstrable effect (17.5 +/- 2.3 cells/crypt/h). Adaptive hyperplasia in isolated small bowel is modulated by factors localised to the distal small intestine, enteroglucagon being a plausible candidate.
PMCID: PMC1434573  PMID: 3692304
5.  The effect of preconditioning on liver regeneration after hepatic resection in cirrhotic rats 
The Korean Journal of Hepatology  2011;17(2):139-147.
Ischemic preconditioning (IP) decreases severity of liver necrosis and has anti-apoptotic effects in previous studies using liver regeneration in normal rats. This study assessed the effect of IP on liver regeneration after hepatic resection in cirrhotic rats.
To induce liver cirrhosis, thioacetamide (300 mg/kg) was injected intraperitoneally into Sprague-Dawley rats twice per week for 16 weeks. Animals were divided into four groups: non-clamping (NC), total clamping (TC), IP, and intermittent clamping (IC). Ischemic injury was induced by clamping the left portal pedicle including the portal vein and hepatic artery. Liver enzymes alanine transaminase (ALT) and aspartate aminotransferase (AST) were measured to assess liver damage. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining for apoptosis and proliferating cell nuclear antigen (PCNA) staining for cell replication were also performed.
Day-1 ALT and AST were highest in IP, however, levels in NC and IC were comparably low on days 1-7. There was no significant correlation of AST or ALT with experimental groups (P=0.615 and P=0.186). On TUNEL, numbers of apoptotic cells at 100× magnification (cells/field) were 31.8±24.2 in NC, 69.0±72.3 in TC, 80.2±63.1 in IP, and 21.2±20.8 in IC (P<0.05). When regeneration capacity was assessed by PCNA staining, PCNA-positive cells (cells/field) at 400× were 3.4±6.0 in NC, 16.9±69 in TC, 17.0±7.8 in IP and 7.4±7.6 in IC (P<0.05).
Although regeneration capacity in IP is higher than IC, the liver is vulnerable to ischemic damage in cirrhotic rats. Careful consideration is needed in applying IP in the clinical setting.
PMCID: PMC3304634  PMID: 21757985
Liver cirrhosis; Ischemic preconditioning; Liver regeneration; Hepatectomy; Apoptosis
6.  Locally applied molgramostim improves wound healing at colonic anastomoses in rats after ligation of the common bile duct 
Canadian Journal of Surgery  2005;48(3):213-218.
Several systemic factors, including jaundice, long-term corticosteroid therapy, diabetes and malnutrition, increase the risk of anastomotic dehiscence. The local application of molgramostim (recombinant human granulocyte-macrophage colony stimulating factor) has been reported to improve impaired dermal wound healing. Since jaundice, one of the systemic risk factors for anastomotic dehiscence, causes significant impairment of anastomotic healing, we hypothesized that locally injected molgramostim could improve the healing of bowel anastomoses in bile-duct-ligated rats used as an experimental model for jaundice.
Eighty-six Sprague–Dawley rats were randomized into 4 groups of 20–22 animals each as follows: group 1 — colonic anastomosis only; group 2 — laparotomy followed 7 days later by colonic anastomosis; group 3 — common-bile-duct ligation (CBDL) followed 7 days later by colonic anastomosis (control group); group 4 — CBDL followed by colonic anastomosis with locally applied molgramostim. Laparotomy was performed under anesthesia in group 2 rats. In groups 3 and 4, laparotomy was followed by ligation and dissection of the common bile duct. After 7 days, colonic anastomosis was performed; in group 4 rats, molgramostim (50 μg) was injected into the perianastomotic area. On postoperative day 3, rats were killed, and the bursting pressures and hydroxyproline levels measured. Two rats from each group were selected for histopathological examination.
The mean bursting pressure in group 4 was significantly higher than that in group 3 (37.8 v. 30.5 mm Hg [p < 0.01]). The mean hydroxyproline level in group 3 was significantly lower than that of the other groups (2.7 v. 3.1–3.5 mg/g tissue [p < 0.01]). On histopathological examination, specimens from group 4 rats showed an increased mononuclear cell population and a smaller gap on the anastomotic line than those from group 3.
The local injection of molgramostim improves healing of the impaired wound in rats subjected to CBDL.
PMCID: PMC3211557  PMID: 16013625
The Journal of surgical research  2012;178(1):280-287.
This study examines the effects of types of liver resection on the growth of liver and lung metastasis.
Materials and Methods
Experimental liver metastases were established by spleen injection of the Colon 26 murine adenocarcinoma cell line expressing GFP into transgenic nude mice expressing RFP. Experimental lung metastases were established by tail vein injection with Colon 26-GFP. Three days after cell injection, groups of mice underwent liver resection (35%+35% [repeated minor resection] vs. 70% [major resection]). Metastatic tumor growth was measured by color-coded fluorescence imaging of the GFP-expressing cancer cells and RFP-expressing stroma.
Although major and repeated minor resection removed the same volume of liver parenchyma, the two procedures had very different effects on metastatic tumor growth: major resection, stimulated liver and lung metastatic growth as well as recruitment of host-derived stroma compared to repeated minor resection. Repeated minor resection did not stimulate metastasis or stromal recruitment. There was no significant difference in liver regeneration between the two groups. Host-derived stroma density, which is stimulated by major resection compared to repeated minor resection, may stimulate growth in the liver-metastatic tumor. TGF-β is also preferentially stimulated by major resection and may play a role in stroma and metastasis stimulation.
The results of this study indicate that when liver resection is necessary, repeated minor liver resection is superior to major liver resection, since major resection, in contrast to repeated minor resection, stimulates metastasis, which should be taken into consideration in clinical situations indicating liver resection.
PMCID: PMC3396724  PMID: 22487397
Nude mice; liver resection; lung metastasis; liver metastasis; stroma; green fluorescent protein; red fluorescent protein; color-coded imaging
8.  Incidence and detection of occult hepatic metastases in colorectal carcinoma. 
Isotope liver scan, ultrasonography, and computed tomography of the liver were performed during the postoperative period in 43 consecutive patients undergoing laparotomy for colorectal carcinoma. Obvious hepatic metastases were detected in six patients at the time of surgery. Eleven patients considered to have a disease-free liver at laparotomy developed hepatic metastases during the two-year follow-up period. These patients were considered to have had occult hepatic metastases at the time of surgery. Postoperative isotope liver scan, ultrasonography, and computed tomography detected the presence of overt metastases in four, five, and six patients respectively. Of the 11 patients with occult metastases, isotope liver scan, ultrasonography, and computed tomography detected one, three, and nine respectively. These observations suggest that 29% of patients undergoing apparently curative resection for colorectal carcinoma possess occult hepatic metastases and that computed tomography is superior to ultrasonography and isotope liver scan in detecting them.
PMCID: PMC1496421  PMID: 6802235
9.  The effects of carnosine in an experimental rat model of septic shock 
To examine the effect of carnosine on liver function and histological findings in experimental septic shock model, 24 Sprague-Dawley rats were used.
Rats were divided into control, septic shock, and carnosine-treated septic shock groups. Femoral vein and artery catheterization were performed on all rats. Rats in the control group underwent laparotomy and catheterization; in the test groups, cecal ligation-perforation and bladder cannulation were added. Rats in the treatment group received a single intraperitoneal (IP) injection of 250 mg/kg carnosine 60 minutes after cecal ligation-perforation. Rats were monitored for blood pressure, heart rate, and body temperature to assess the postoperative septic response, and body fluids were replaced as necessary. At the end of 24 hours, rats were sacrificed and liver samples were collected.
Statistically significant improvements were observed in liver function, tissue and serum MDA levels, and histological findings in rats treated with carnosine, compared to rats with untreated sepsis. HB and HCT values did not change significantly during the course of the experiment. Rats exposed to septic shock and treated with carnosine exhibited decreased sinusoidal dilatation and cellular inflammation into the portal region, compared to the sepsis group; the livers of rats in this group had near-normal histological structure.
We conclude that carnosine may be an effective treatment for oxidative damage due to liver tissue perfusion defects in cases of septic shock.
PMCID: PMC3940703  PMID: 23396325
carnosine; septic shock; rat; liver
10.  Ultrastructural view of colon anastomosis under propolis effect by transmission electron microscopy 
AIM: To evaluate the effect of propolis administration on the healing of colon anastomosis with light and transmission electron microscopes.
METHODS: Forty-eight Wistar-Albino female rats were divided into two groups and had colon resection and anastomosis. In group I, rats were fed with standard rat chow pre- and postoperatively. The rats in group II were fed with standard rat chow and began receiving oral supplementation of propolis 100 mg/kg per day beginning 7 d before the operation and continued until they were sacrificed. Rats were sacrificed 1, 3, 7 and 14 d after operation, and anastomotic bursting pressures measured. After the resection of anastomotic segments, histopathological examination was performed with light and transmission electron microscopes by two blinded histologists and photographed.
RESULTS: The colonic bursting pressures of the propolis group were statistically significantly better than the control group. Ultrastructural histopathological analysis of the colon anastomosis revealed that propolis accelerated the phases of the healing process and stimulated mature granulation tissue formation and collagen synthesis of fibroblasts.
CONCLUSION: Bursting pressure measurements and ultra structural histopathological evaluation showed that administration of propolis accelerated the healing of colon anastomosis following surgical excision.
PMCID: PMC2739337  PMID: 18720536
Propolis; Wound healing; Colon anastomosis; Histopathology; Transmission electron microscope
11.  Fibrinogen and thrombin concentrations are critical for fibrin glue adherence in rat high-risk colon anastomoses 
Clinics  2014;69(4):259-264.
Fibrin glues have not been consistently successful in preventing the dehiscence of high-risk colonic anastomoses. Fibrinogen and thrombin concentrations in glues determine their ability to function as sealants, healers, and/or adhesives. The objective of the current study was to compare the effects of different concentrations of fibrinogen and thrombin on bursting pressure, leaks, dehiscence, and morphology of high-risk ischemic colonic anastomoses using fibrin glue in rats.
Colonic anastomoses in adult female Sprague-Dawley rats (weight, 250-350 g) treated with fibrin glue containing different concentrations of fibrinogen and thrombin were evaluated at post-operative day 5. The interventions were low-risk (normal) or high-risk (ischemic) end-to-end colonic anastomoses using polypropylene sutures and topical application of fibrinogen at high (120 mg/mL) or low (40 mg/mL) concentrations and thrombin at high (1000 IU/mL) or low (500 IU/mL) concentrations.
Ischemia alone, anastomosis alone, or both together reduced the bursting pressure. Glues containing a low fibrinogen concentration improved this parameter in all cases. High thrombin in combination with low fibrinogen also improved adherence exclusively in low-risk anastomoses. No differences were detected with respect to macroscopic parameters, histopathology, or hydroxyproline content at 5 days post-anastomosis.
Fibrin glue with a low fibrinogen content normalizes the bursting pressure of high-risk ischemic left-colon anastomoses in rats at day 5 after surgery.
PMCID: PMC3971357  PMID: 24714834
Wound Healing; Colonic Anastomosis; Fibrin Glue; Ischemia
12.  Human Adipose Tissue Derived Stem Cells Promote Liver Regeneration in a Rat Model of Toxic Injury 
Stem Cells International  2013;2013:534263.
In the light of the persisting lack of donor organs and the risks of allotransplantations, the possibility of liver regeneration with autologous stem cells from adipose tissue (ADSC) is an intriguing alternative. Using a model of a toxic liver damage in Sprague Dawley rats, generated by repetitive intraperitoneal application of retrorsine and allyl alcohol, the ability of human ADSC to support the restoration of liver function was investigated. A two-thirds hepatectomy was performed, and human ADSC were injected into one remaining liver lobe in group 1 (n = 20). Injection of cell culture medium performed in group 2 (n = 20) served as control. Cyclosporine was applied to achieve immunotolerance. Blood samples were drawn weekly after surgery to determine liver-correlated blood values. Six and twelve weeks after surgery, animals were sacrificed and histological sections were analyzed. ADSC significantly raised postoperative albumin (P < 0.017), total protein (P < 0.031), glutamic oxaloacetic transaminase (P < 0.001), and lactate dehydrogenase (P < 0.04) levels compared to injection of cell culture medium alone. Transplanted cells could be found up to twelve weeks after surgery in histological sections. This study points towards ADSC being a promising alternative to hepatocyte or liver organ transplantation in patients with severe liver failure.
PMCID: PMC3839126  PMID: 24312129
13.  Liver transplantation in a patient with cholangiocarcinoma and ulcerative colitis. 
A 39 year-old patient with cholangiocarcinoma and pre-existing ulcerative colitis was successfully treated by orthotopic liver transplantation. He was given low doses of prednisone and azathioprine and survived for more than 9 months, dying with tumour metastases, thrombosis of the inferior vena cava and an intra-abdominal abscess. At autopsy the homograft showed little evidence of rejection. Preoperatively the patient had septicemia. Removal of his liver was difficult. The discrepancy between donor and recipient in size of blood vessels and the presence of two hepatic arteries in the donor caused problems during the vascular anastomoses. During the operation cardiac arrest occurred. Postoperatively there were several medical and surgical problems, including intraperitoneal and gastrointestinal hemorrhage, paralysis of the right dome of the diaphragm, sinus bradycardia, massive diuresis, peroneal nerve palsy, and one major and three minor episodes of rejection, which were reversed by giving pulse doses of methylprednisolone intravenously.
PMCID: PMC1878766  PMID: 184908
14.  Hepatic Colorectal Metastases Involving Infra-Hepatic Inferior Vena Cava in High Risk Patients for Extended Resection: An Alternative Method for Achieving Radical Resection in Patient with Borderline Liver Remnant 
The Indian Journal of Surgery  2012;75(3):220-225.
Resection is the only chance of cure for isolated liver metastases from colorectal cancer. In the case of extended parenchymal resections, one crucial point is the ischemic damage to the remnant liver. We report an alternative technique for extremely extended liver resections without total hilar clamping for borderline liver remnants. Two patients presented with invasion of the infrahepatic vena cava, both with an estimated live remnant ≤20 %. The crucial point of the technique is the absence of a portal triad clamping in under beating heart-extracorporeal circulation. In both patients resection margins were free of disease. No signs of liver insufficiency were noted. Survival was more than 2 years in both cases. We believe that aggressive treatment of liver colorectal metastases should be given to all suitable patients. This operation may be added to the techniques that can be offered to these patients.
PMCID: PMC3689385  PMID: 24426431
Liver metastases; Colorectal cancer; Caval invasion; Extracorporeal circulation; Small liver remnant
15.  Splenectomy affects the balance between hepatic growth factor and transforming growth factor-β and its effect on liver regeneration is dependent on the amount of liver resection in rats 
Small-for-size syndrome (SFSS) is a major problem in liver surgery, and splenectomy has been used to prevent SFSS. However, it is unknown whether splenectomy has the same effect on liver regeneration in both standard and marginal hepatectomy. The aim of this study is to see a difference in effect of splenectomy on liver regeneration according to the amount of liver resection.
Thirty male Sprague-Dawley rats (220 to 260 g) were divided into the following five groups: control (n = 6), 70% hepatectomy (n = 6), 70% hepatectomy with splenectomy (n = 6), 90% hepatectomy (n = 6), and 90% hepatectomy with splenectomy (n = 6). The animals were euthanized 24 hours after surgery and liver specimens were obtained. To assess liver regeneration, we performed immunohistochemistry of liver tissue using 5-bromo-2-deoxyuridine (BrdU) labeling and Western blot analysis of hepatic growth factor (HGF) and transforming growth factor-β (TGF-β) in the liver tissue.
The splenectomized subgroup had a higher BrdU-positive cell count in the 90% hepatectomy group, but not in the 70% hepatectomy group (P < 0.001). Splenectomy significantly decreased TGF-β expression (P = 0.005) and increased the HGF to TGF-β ratio (P = 0.002) in the 90% hepatectomy group, but not in the 70% hepatectomy group.
The positive effect of splenectomy on liver regeneration was greater in the group with the larger liver resection. This phenomenon may be related to the relative balance between HGF and TGF-β in the liver.
PMCID: PMC3319778  PMID: 22493765
Liver regeneration; Splenectomy; Hepatectomy; HGF; Transforming growth factor beta
16.  Hepatic 31P MRS in rat models of chronic liver disease: assessing the extent and progression of disease 
Gut  2003;52(7):1046-1053.
Background: Hepatic adenosine triphosphate (ATP) levels are an accurate reflection of functioning hepatic mass following surgical resections and acute liver injury.
Objective: To determine whether hepatic ATP levels can serve as a non-invasive means of documenting progression of chronic liver disease to cirrhosis.
Methods: In vivo phosphorus-31 magnetic resonance spectroscopy (31P MRS) was performed in three animal models of chronic liver disease. Sixty six adult Sprague- Dawley rats were subjected to either thioacetamide, carbon tetrachloride (CCl4), or common bile duct ligation (CBDL) to induce liver disease (n=35, 21, and 10, respectively). Serial MRS examinations, blood samples, and liver biopsies (when appropriate) were obtained throughout and/or on completion of the study.
Results: Over the course of the chronic liver disease, a progressive decrease in hepatic ATP levels was consistently observed in each model. The findings were most striking when end stage liver disease (cirrhosis) was established. The reduction in hepatic ATP levels correlated with significant changes in serum albumin concentrations (CCl4 and CBDL models) and the extent of hepatocyte loss seen histologically (all models).
Conclusion: The results of this study indicate that during progression of chronic liver disease to cirrhosis, there is a progressive reduction in hepatic ATP levels. In addition, changes in hepatic ATP levels correlate with changes in liver function and histology. Thus hepatic 31P MRS provides a non-invasive means of documenting the severity and progression of parenchymal and cholestatic models of chronic liver disease in rats.
PMCID: PMC1773729  PMID: 12801965
liver; magnetic resonance spectroscopy; liver disease; cirrhosis; rat
17.  Perioperative ischaemia-induced liver injury and protection strategies: An expanding horizon for anaesthesiologists 
Indian Journal of Anaesthesia  2013;57(3):223-229.
Liver resection is an effective modality of treatment in patients with primary liver tumour, metastases from colorectal cancers and selected benign hepatic diseases. Its aim is to resect the grossly visible tumour with clear margins and to ensure that the remnant liver mass has sufficient function which is adequate for survival. With the advent of better preoperative imaging, surgical techniques and perioperative management, there is an improvement in the outcome with decreased mortality. This decline in postoperative mortality after hepatic resection has encouraged surgeons for more radical liver resections, leaving behind smaller liver remnants in a bid to achieve curative surgeries. But despite advances in diagnostic, imaging and surgical techniques, postoperative liver dysfunction of varied severity including death due to liver failure is still a serious problem in such patients. Different surgical and non-surgical techniques like reducing perioperative blood loss and consequent decreased transfusions, vascular occlusion techniques (intermittent portal triad clamping and ischaemic preconditioning), administration of pharmacological agents (dextrose, intraoperative use of methylprednisolone, trimetazidine, ulinastatin and lignocaine) and inhaled anaesthetic agents (sevoflurane) and opioids (remifentanil) have demonstrated the potential benefit and minimised the adverse effects of surgery. In this article, the authors reviewed the surgical and non-surgical measures that could be adopted to minimise the risk of postoperative liver failure following liver surgeries with special emphasis on ischaemic and pharmacological preconditioning which can be easily adapted clinically.
PMCID: PMC3748674  PMID: 23983278
Ischaemia; liver resection; perioperative; protection
18.  Myofibroblasts and colonic anastomosis healing in Wistar rats 
BMC Surgery  2011;11:6.
The myofibroblasts play a central role in wound healing throughout the body. The process of wound healing in the colon was evaluated with emphasis on the role of myofibroblasts.
One hundred male Wistar rats weighing 274 ± 9.1 g (mean age: 3.5 months) were used. A left colonic segment was transected and the colon was re-anastomosed. Animals were randomly divided into two groups. The first group experimental animals (n = 50) were sacrificed on postoperative day 3, while the second group rats (n = 50) were sacrificed on postoperative day 7. Healing of colonic anastomosis was studied in terms of anastomotic bursting pressure, as well as myofibroblastic reaction and expression of α-smooth muscle actin (α-SMA), adhesion formation, inflammatory reaction and neovascularization.
The mean anastomotic bursting pressure increased from 20.6 ± 3.5 mmHg on the 3rd postoperative day to 148.8 ± 9.6 Hg on the 7th postoperative day. Adhesion formation was increased on the 7th day, as compared to the 3rd day. In addition, the myofibroblastic reaction was more profound on the 7th postoperative day in comparison with the 3rd postoperative day. The staining intensity for α-SMA was progressive from the 3rd to the 7th postoperative day. On the 7th day the α-SMA staining in the myofibroblats reached the level of muscular layer cells.
Our study emphasizes the pivotal role of myofibroblasts in the process of colonic anastomosis healing. The findings provide an explanation for the reduction in the incidence of wound dehiscence after the 7th postoperative day.
PMCID: PMC3053216  PMID: 21366898
19.  Curative Resection of Hepatocellualr Carcinoma Using Modified Glissonean Pedicle Transection versus the Pringle Maneuver: A Case Control Study 
Objective: The Glissonean pedicle transection method of liver resection has been found to shorten operative time and minimize intraoperative bleeding during liver segmentectomy. We have compared the feasibility, effectiveness, and safety of the Glissonean pedicle transection method with the Pringle maneuver in patients undergoing selective curative resection of large hepatocellualr carcinoma (HCC).
Methods: Eligible patients with large (> 5 cm) nodular HCC (n = 50) were assigned to undergo curative hepatectomy using the Glissonean pedicle transection method (n = 25) or the Pringle maneuver (n = 25). Partial interruption of the infrahepatic inferior vena cava was incorporated to further reduce bleeding from liver transection. The primary outcome measure was postoperative changes in liver function from baseline. Secondary outcomes included operating time, volume of intraoperative blood loss/transfusion, and time to resolution of ascites.
Results: The two groups were comparable in age, sex, site and size of the liver tumor, segment or lobe intended to be resected, and liver function reserve, and the results were not significant statistically. All patients underwent successful major hepatectomies using the assigned method, with the extent of major hepatectomy comparable in the two groups (P = 0.832). The Glissonean approach was associated with shorter hepatic inflow interruption (30.0 ± 12.0 min vs. 45.0 ± 13.0 min, P < 0.001), lower volume of blood loss (145.0 ± 20.0 mL vs. 298.0 ± 109.0 mL, P < 0.001), reduced requirement for transfusion (0.0 ± 0.0 mL vs. 200.0 ± 109.0 mL, P < 0.0001), and more rapid resolution of ascites (9.5 ± 1.2 d vs. 15.3 ± 2.4 d, P < 0.001). Postoperative liver function measures were comparable in the two groups, and the results were not significant statistically.
Conclusion: The Glissonean pedicle transection method is a feasible, effective, and safe technique for hepatic inflow control during the curative resection of large nodular HCCs.
PMCID: PMC3498749  PMID: 23155358
Hepatocellualr carcinoma, large nodular; Pringle maneuver; Glissonean pedicel transection; Partial interruption of inferior vena cava; Surgical outcomes.
20.  Effect of different liver resection methods on liver damage and regeneration factors VEGF and FGF-2 in mice 
Canadian Journal of Surgery  2012;55(6):389-393.
Different approaches to study liver regeneration in murine models have been proposed. We investigated the effect of different liver resection models on liver damage and regeneration parameters in mice.
We compared the technical aspect of the 2 most commonly used techniques of 50% and 70% liver resection. Liver damage, as determined by the change in serum alanine aminotransferase and aspartate aminotransferase, as well as the regeneration parameters VEGF and FGF-2 were analyzed at 6 time points. A postoperative vitality score was introduced.
Cholestasis was not observed for either technique. Both resection techniques resulted in full weight recovery of the liver after 240 hours, with no significant difference between sham and resection groups. Postoperative animal morbidity and total protein levels did not differ significantly for either method, indicating early and full functional recovery. However, comparing the mitogenic growth factors FGF-2 and VEGF, a significant increase in serum levels and, therefore, increased growth stimulus, was shown in the extended resection group.
Extended resection led to a greater response in growth factor expression. This finding is important since it shows that growth factor response differs acdording to the extent of resection. We have demonstrated the need to standardize murine hepatic resection models to adequately compare the resulting liver damage.
PMCID: PMC3506688  PMID: 22992401
21.  Serial Changes of Serum Growth Factor Levels and Liver Regeneration after Partial Hepatectomy in Healthy Humans 
This study aimed to investigate the associations of the serial changes of serum levels of various growth factors with liver regeneration after hepatectomy in healthy liver donors. Sixteen healthy liver donors who underwent conventional liver resection were included. Serum levels of various growth factors before hepatectomy and on postoperative day (POD) 1, 3, 5 and 7 were measured. Liver volume data calculated by multi-detector computed tomography using workstation. The ratio of remnant liver volume on POD 0 to liver volume before the operation was 51% ± 20%. The ratio of liver volume on POD 14 to liver volume on POD 0 were inversely correlated with remnant liver volume on POD 0 (r = −0.91). The ratio of liver volume on POD 14 to liver volume on POD 0 were significantly correlated with serum hepatocyte growth factor (HGF) levels on POD 1 (r = 0.54), serum leptin levels on POD 1 (r = 0.54), and serum macrophage colony-stimulating factor (M-CSF) levels on POD 5 (r = 0.76) and POD 7 (r = 0.80). These results suggest that early-phase elevation of serum levels of HGF, leptin and M-CSF may be associated with the acceleration of liver regeneration after hepatectomy in humans.
PMCID: PMC3821648  PMID: 24141186
hepatectomy; hepatocyte growth factor; human; leptin; liver regeneration; macrophage colony-stimulating factor
22.  Conversion to Resectability Using Hepatic Artery Infusion Plus Systemic Chemotherapy for the Treatment of Unresectable Liver Metastases From Colorectal Carcinoma 
Journal of Clinical Oncology  2009;27(21):3465-3471.
To determine the conversion to resectability in patients with unresectable liver metastases from colorectal cancer treated with hepatic arterial infusion (HAI) plus systemic oxaliplatin and irinotecan (CPT-11).
Patients and Methods
Forty-nine patients with unresectable liver metastases (53% previously treated with chemotherapy) were enrolled onto a phase I protocol with HAI floxuridine and dexamethasone plus systemic chemotherapy with oxaliplatin and irinotecan.
Ninety-two percent of the 49 patients had complete (8%) or partial (84%) response, and 23 (47%) of the 49 patients were able to undergo resection in a group of patients with extensive disease (73% with > five liver lesions, 98% with bilobar disease, 86% with ≥ six segments involved). For chemotherapy-naïve and previously treated patients, the median survival from the start of HAI therapy was 50.8 and 35 months, respectively. The only baseline variable significantly associated with a higher resection rate was female sex. Variables reflecting extensive anatomic disease, such as number of lesions or number of vessels involved, were not significantly associated with the probability of resection.
The combination of regional HAI floxuridine/dexamethasone and systemic oxaliplatin and irinotecan is an effective regimen for the treatment of patients with unresectable liver metastases from colorectal cancer, demonstrating a 47% conversion to resection (57% in chemotherapy-naïve patients). Future randomized trials should compare HAI plus systemic chemotherapy with systemic therapy alone to assess the additional value of HAI therapy in converting patients with hepatic metastases to resectability.
PMCID: PMC3646304  PMID: 19470932
23.  Adjuvant liver perfusion in colorectal cancer: initial results of a clinical trial. 
British Medical Journal  1977;2(6098):1320-1322.
Fifty consecutive patients with colorectal cancer but no evidence of secondary deposits in the liver were included in an ongoing controlled clinical trial of adjuvant liver perfusion aimed at reducing the incidence of hepatic metastases. All patients had their primary tumour resected in the standard way. Twenty-six of the patients served as controls, and 24 received fluorouracil, 1 g daily, as a continuous infusion into the portal venous system during the first seven days after operation. The patients were matched for age, sex, and site and stage of the disease. The immediate postoperative mortality and morbidity did not differ significantly between the two groups. During the follow-up period (mean duration 15.5 months), however, six deaths occurred in the control group and only one in the perfusion group. At necropsy four of the controls had multiple liver metastases. Two of the surviving controls developed evidence of liver metastases, and two had a local recurrence. No patient in the perfusion group developed evidence of hepatic metastases. These initial results suggest that adjuvant portal venous perfusion with fluorouracil may reduce the incidence of liver metastases in colorectal cancer.
PMCID: PMC1632555  PMID: 338105
24.  Hepatic resection for breast cancer metastases. 
INTRODUCTION: Hepatic resection is an established modality of treatment for colorectal cancer metastases. Resection of breast cancer liver metastases remains controversial, but has been shown to be an effective treatment in selected cases. This study reports the outcome of 8 patients with liver metastases from breast cancer. PATIENTS & METHODS: 8 patients with liver metastases from previously treated breast cancer were referred for hepatic resection between September 1996 and December 2002. Six were eligible for liver resection. The mean age was 45.8 years. The resections performed included 1 segmentectomy and 5 hemihepatectomies of which one was an extended hemihepatectomy. One patient had a repeat hepatectomy 44 months after the first resection. RESULTS: There were no postoperative deaths or major morbidity. The resectability rate was 75%. Follow-up periods range from 6 to 70 months with a median survival of 31 months following resection. There have been 2 deaths, one died of recurrence in the residual liver at 6 months and one died disease-free from a stroke. Of the remaining 4 patients, 1 has had a further liver resection at 44 months following which she is alive and 'disease-free' at 70 months. The one patient with peritoneal recurrence is alive 49 months after her liver resection with 2 patients remaining disease-free. CONCLUSION: Hepatic resection for breast cancer liver metastases is a safe procedure with low morbidity and mortality.
PMCID: PMC1963924  PMID: 15901375
25.  The effects of 5-fluorouracil and interferon-alpha on early healing of experimental intestinal anastomoses. 
British Journal of Cancer  1996;74(5):711-716.
The continuing search for effective adjuvant therapy after resection of intestinal malignancies has prompted a growing interest in both immediate post-operative regional chemotherapy and the combination of 5-fluorouracil (5-FU) and interferon-alpha as drugs of choice. We have compared the effects of both compounds, alone and together, on early healing of intestinal anastomoses. Four groups (n = 26 each) of rats underwent resection and anastomosis of both ileum and colon: a control group and three groups receiving intraperitoneal 5-FU, interferon-alpha or both on the day of surgery and the next 2 days. Animals were killed 3 or 7 days (n = 10 each) after operation in order to measure anastomotic strength and hydroxyproline content. The remaining six animals in each group were used to study anastomotic collagen synthetic capacity at day 3. Three days after operation, ileal anastomotic bursting pressure was lowered by 37% in the 5-FU/interferon-alpha group (P = 0.0104). At day 7, anastomotic breaking strength was reduced significantly in ileum (P = 0.0221) and colon (P = 0.0054) of the 5-FU/interferon-alpha group and in colon of the interferon-alpha group (P = 0.0221). Collagen synthetic capacity was strongly suppressed by 5-FU but not by interferon-alpha. However, no differences in anastomotic hydroxyproline content were observed between groups at both days 3 and 7. Thus, post-operative use of interferon-alpha, in particular in combination with 5-FU, may be detrimental to anastomotic repair in the intestine.
PMCID: PMC2074708  PMID: 8795572

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