21 research outputs found
Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis (New EPOC): long-term results of a multicentre, randomised, controlled, phase 3 trial.
BACKGROUND: The interim analysis of the multicentre New EPOC trial in patients with resectable colorectal liver metastasis showed a significant reduction in progression-free survival in patients allocated to cetuximab plus chemotherapy compared with those given chemotherapy alone. The focus of the present analysis was to assess the effect on overall survival. METHODS: New EPOC was a multicentre, open-label, randomised, controlled, phase 3 trial. Adult patients (aged ≥18 years) with KRAS wild-type (codons 12, 13, and 61) resectable or suboptimally resectable colorectal liver metastases and a WHO performance status of 0-2 were randomly assigned (1:1) to receive chemotherapy with or without cetuximab before and after liver resection. Randomisation was done centrally with minimisation factors of surgical centre, poor prognosis cancer, and previous adjuvant treatment with oxaliplatin. Chemotherapy consisted of oxaliplatin 85 mg/m2 administered intravenously over 2 h, l-folinic acid (175 mg flat dose administered intravenously over 2 h) or d,l-folinic acid (350 mg flat dose administered intravenously over 2 h), and fluorouracil bolus 400 mg/m2 administered intravenously over 5 min, followed by a 46 h infusion of fluorouracil 2400 mg/m2 repeated every 2 weeks (regimen one), or oxaliplatin 130 mg/m2 administered intravenously over 2 h and oral capecitabine 1000 mg/m2 twice daily on days 1-14 repeated every 3 weeks (regimen two). Patients who had received adjuvant oxaliplatin could receive irinotecan 180 mg/m2 intravenously over 30 min with fluorouracil instead of oxaliplatin (regimen three). Cetuximab was given intravenously, 500 mg/m2 every 2 weeks with regimen one and three or a loading dose of 400 mg/m2 followed by a weekly infusion of 250 mg/m2 with regimen two. The primary endpoint of progression-free survival was published previously. Secondary endpoints were overall survival, preoperative response, pathological resection status, and safety. Trial recruitment was halted prematurely on the advice of the Trial Steering Committee on Nov 1, 2012. All analyses (except safety) were done on the intention-to-treat population. Safety analyses included all randomly assigned patients. This trial is registered with ISRCTN, number 22944367. FINDINGS: Between Feb 26, 2007, and Oct 12, 2012, 257 eligible patients were randomly assigned to chemotherapy with cetuximab (n=129) or without cetuximab (n=128). This analysis was carried out 5 years after the last patient was recruited, as defined in the protocol, at a median follow-up of 66·7 months (IQR 58·0-77·5). Median progression-free survival was 22·2 months (95% CI 18·3-26·8) in the chemotherapy alone group and 15·5 months (13·8-19·0) in the chemotherapy plus cetuximab group (hazard ratio [HR] 1·17, 95% CI 0·87-1·56; p=0·304). Median overall survival was 81·0 months (59·6 to not reached) in the chemotherapy alone group and 55·4 months (43·5-71·5) in the chemotherapy plus cetuximab group (HR 1·45, 1·02-2·05; p=0·036). There was no significant difference in the secondary outcomes of preoperative response or pathological resection status between groups. Five deaths might have been treatment-related (one in the chemotherapy alone group and four in the chemotherapy plus cetuximab group). The most common grade 3-4 adverse events reported were: neutrophil count decreased (26 [19%] of 134 in the chemotherapy alone group vs 21 [15%] of 137 in the chemotherapy plus cetuximab group), diarrhoea (13 [10%] vs 14 [10%]), skin rash (one [1%] vs 22 [16%]), thromboembolic events (ten [7%] vs 11 [8%]), lethargy (ten [7%] vs nine [7%]), oral mucositis (three [2%] vs 14 [10%]), vomiting (seven [5%] vs seven [5%]), peripheral neuropathy (eight [6%] vs five [4%]), and pain (six [4%] vs six [4%]). INTERPRETATION: Although the addition of cetuximab to chemotherapy improves the overall survival in some studies in patients with advanced, inoperable metastatic disease, its use in the perioperative setting in patients with operable disease confers a significant disadvantage in terms of overall survival. Cetuximab should not be used in this setting. FUNDING: Cancer Research UK
Orthotopic kidney transplantation in mice: technique using cuff for renal vein anastomosis.
Mouse renal transplantation is a technically challenging procedure. Although the first kidney transplants in mice were performed over 34 years ago and refined some years later, the classical techniques of mouse renal transplantation required clamping both vena cava and aorta simultaneously and carry out suture anastomoses of the renal artery and vein in a heterotopic position. In our laboratory, we have successfully developed mouse orthotopic kidney transplantation for the first time, using a rapid "cuffed" renal vein technique for vessel anastomosis, wherein the donor's renal vein was inserted through an intravenous catheter, folded back and tied. During grafting, the cuffed renal vein was directly inserted into the recipient's renal vein without the need for the clamping vena cava and suturing of renal vein. This technique allowed for the exact transplantation of the kidney into the original position, compared to the classical technique, and has significantly shortened the clamping time due to a quicker and precise anastomosis of renal vein as described. This also allowed for a quicker recovery of the lower extremity activity, reduction in myoglobinuria with resultant kidney graft survival of 88.9%. Thus we believe that the cuffed renal vein technique simplifies microvascular anastomoses and affords important additional benefits
Establishment of animal model of dual liver transplantation in rat.
The animal model of the whole-size and reduced-size liver transplantation in both rat and mouse has been successfully established. Because of the difficulties and complexities in microsurgical technology, the animal model of dual liver transplantation was still not established for twelve years since the first human dual liver transplantation has been made a success. There is an essential need to establish this animal model to lay a basic foundation for clinical practice. To study the physiological and histopathological changes of dual liver transplantation, "Y" type vein from the cross part between vena cava and two iliac of donor and "Y' type prosthesis were employed to recanalize portal vein and the bile duct between dual liver grafts and recipient. The dual right upper lobes about 45-50% of the recipient liver volume were taken as donor, one was orthotopically implanted at its original position, the other was rotated 180° sagitally and heterotopically positioned in the left upper quadrant. Microcirculation parameters, liver function, immunohistochemistry and survival were analyzed to evaluate the function of dual liver grafts. No significant difference in the hepatic microcirculatory flow was found between two grafts in the first 90 minutes after reperfusion. Light and electronic microscope showed the liver architecture was maintained without obvious features of cellular destruction and the continuity of the endothelium was preserved. Only 3 heterotopically positioned graft appeared patchy desquamation of endothelial cell, mitochondrial swelling and hepatocytes cytoplasmic vacuolization. Immunohistochemistry revealed there is no difference in hepatocyte activity and the ability of endothelia to contract and relax after reperfusion between dual grafts. Dual grafts made a rapid amelioration of liver function after reperfusion. 7 rats survived more than 7 days with survival rate of 58.3.%. Using "Y" type vein and bile duct prosthesis, we successfully established a novel rat model of dual right upper liver lobe transplantation
The cuffed renal vein technique significantly shortened the operation time.
<p><b>A</b>) Total operative time was reduced with the new cuffed renal vein technique, as evidenced by the significantly reduced times required to carry out the renal anastomoses (p<0.001,). <b>B</b>) The clamping times for vena cava and aorta were dramatically reduced in cuffed renal vein technique compared to the classical technique (p<0.001), and consequently the recovery of lower limb activity was significantly quicker with cuffed renal vein technique (p<0.001). <b>C</b>) The survival improved significantly from 75% with the classical technique to 93.3% with the cuffed renal vein technique (P < 0.001).</p
Orthotopic Kidney Transplantation in the Mice Using Cuff for Renal VeinAnastomosis.
<p>Top panel shows a classical kidney transplantation, lower panel illustrates the cuffed renal vein techniques. Left portrait is match with the right in vivo picture. A-aorta, V-vein, K- kidney, C-cuff.</p
The cuffed renal vein technique.
<p>The renal vein was cleaned for insertion through 22G intravenous catheter (outer diameter 1.1 mm), using a cuff length of about 0.7-0.9 mm and an equal vein length, which was folded back and tied. </p
Histology results by HE staining.
<p>A and D, Ninety minutes after reperfusion: right graft showed moderate sinusoidal congestion morphological changes(A), left graft shows moderafte-severe sinusoidal congestion and vacuolar changes in the cytoplasm of hepatocytes (D). B and E, 1 day after reperfusion: apoptosis of 3–4 hepatocyte in the right and left graft was seen. C and F, 3 days after reperfusion: normal liver architecture was found in right graft (C), and scatter necrosis can be seen in left graft(F), H&E staining magnification×80 for A and D, ×120 for B,C,E and F. The normal arrow pointed to the sinusoidal congestion, the dot arrow indicated the hepatocyte apoptosis(eosino-dying), the broken arrow displayed the necrosis.</p
Proliferation and apoptosis of Hepatocyte and contraction and relaxation of endothelium by immunostaining.
<p>A and B, PCNA staining in right and left grafts 1 day after reperfusion. C and D, TUNEL staining in right and left grafts 1 day after reperfusion. E and F, PCNA staining in right and left grafts 5 day after reperfusion. G and H, TUNEL staining in right and left grafts 1 day after reperfusion. I, Proliferation and apoptosis index ratio was significantly increased in right and left graft 1 day after reperfusion (p<0.05), compared to the sham group. No difference was found between right and left grafts. J and K, ET-1 staining in right and left grafts 90 minutes after reperfusion. L and M, eNOS staining in right and left grafts 90 minutes after reperfusion. N and O, ET-1 staining in right and left grafts 3 days after reperfusion. P and Q, eNOS staining in right and left grafts 3 days after reperfusion. R, ET-1 and eNOS balance ratio in right and left grafts were dramatically increased 90 minutes and 3 days after reperfusion compared to the sham group (p<0.01). No difference was found between right and left grafts. Brown stained cell is positive cells. ET-1, endothelin-1; eNOS, endothelial NO-synthase; ENBR, ET-1 and eNOS balance ratio; PAIR, proliferation and apoptosis index ratio; PCNA, proliferation cell nuclei antigen; TUNEL, terminal deoxynucleotidyl transferase-mediated nick-end labeling.</p
Electron microscopy results 1 day after reperfusion.
<p>A, In sham group, hepatocyte and sinusoidal cell had normal appearance. B, In right graft, The continuity of the endothelium was preserved except for minimal edema and defenestration. the liver architecture was maintained without obvious features of cellular destruction. C In left graft, integrity of endothelial cells was disrupted. Sinusoidal congestion and irregular large gap in the sinusoid lining cells were found. Mitochondrial swelling and vacuolar changes in cytoplasm of hepatocytes were obvious. The normal arrow indicated the endothelium, the dot arrow indicated mitochondrial vascuolar changes.</p