Rea D.,Animal Faculty Unit |
Rea D.,Instituto Nazionale Per Lo Studio E La Cura Dei Tumori Fondazione G Pascale |
Coppola C.,Cardiology Unit |
Barbieri A.,Animal Faculty Unit |
And 11 more authors.
In Vivo | Year: 2016
Background: In recent years, the development of more effective anticancer drugs has provided great benefits in patients' quality of life by improving both prognosis and disease-free survival. Nevertheless, the frequency and severity of side-effects, with particular reference to cardiac toxicity, have gained particular attention. The purpose of this study was to create a precise and sensitive preclinical model, able to identify early contractile dysfunction in mice treated with chemotherapy, through use of speckle-tracking echocardiography. Materials and Methods: We generated a mouse model of cardiotoxicity induced by doxorubicin. C57BL 6 mice were divided into two groups, treated for 7 days by intraperitoneal injections of placebo (vehicle) or doxorubicin (2.17 mg/kg), in order to characterize the cardiac phenotype in vivo. Results: We demonstrated that doxorubicin caused ealy remodeling of the left ventricle: after two days of therapy, the radial, circumferential and strain rates were reduced respectively by 35%, 34%, and 39% (p-value ≤0.001). Moreover, histological analysis revealed that doxorubicin treatment increased fibrosis, cardiomyocyte diameter and apoptosis. Conclusion: In a murine model of doxorubicin-induced cardiac injury, we detected left ventricular dysfunction followed by alterations in conventional echocardiographic indices. Our study suggests that a change in strain could be an effective early marker of myocardial dysfunction for new anticancer treatments and, in preclinical studies, it might also be a valuable indicator for the assessment of activity of cardioprotective agents.
Baddour N.,Alexandria University |
Farrag E.,Alexandria University |
Zeid A.,Hepatobiliary Unit |
Taher Y.,Hepatobiliary Unit
Chinese Journal of Cancer Research | Year: 2013
Objective and background: Although p21 ras has been reported to be upregulated in hepatocellular carcinoma complicating chronic hepatitis C type I, p21 ras has a different role in advanced stages, as it has been found to be downregulated. The goal of this study was to investigate the status of p21 ras in early-stage/low-grade and late-stage/high-grade hepatocellular carcinoma and its possible link to apoptosis. Material and methods: Thirty-five cases each of chronic HCV hepatitis type 4 (group I) and cirrhosis with hepatocellular carcinoma (HCC) complicating chronic HCV hepatitis (groups II and III) were immunohistochemically evaluated using a p21 ras polyclonal antibody. The apoptotic index was determined in histologic sections using the terminal deoxynucleotidyl transferase-mediated d-UTP biotin nick end labeling (TUNEL) assay. Results: Significant differences (P=0.001) were detected in p21 ras protein expression between the three groups. A near 2-fold increase in p21 ras staining was observed in the cirrhotic cases compared to the hepatitis cases, and p21 ras expression was decreased in the HCC group. p21 ras expression correlated with stage (r=0.64, P=0.001) and grade (r=-0.65, P=0.001) in the HCC group and grade in the HCV group (r=0.44, P=0.008). Both p21 ras expression and TUNEL-LI were significantly lower in large HCCs compared to small HCCs (P=0.01 each). The TUNEL values were negatively correlated with stage in the HCC group (r=-0.85, P=0.001). The TUNEL values were also negatively correlated with grade in both the HCV and HCC groups (r=0.89, P=0.001 and r=-0.53, P=0.001, respectively). The p21 ras scores were significantly correlated with the TUNEL-LI values in the HCC group (r=0.63, P=0.001) and HCV group (r=0.88, P=0.001). Conclusions: p21 ras acts as an initiator in HCC complicating type 4 chronic HCV and is downregulated with HCC progression, which most likely promotes tumor cell survival because it facilitates the downregulation of apoptosis with tumor progression. © Chinese Journal of Cancer Research. All rights reserved.
Lai Q.,Catholic University of Louvain |
Lai Q.,Azienda Universitario ospedaliera Pisana |
Castro Santa E.,Catholic University of Louvain |
Castro Santa E.,National Center for Liver Transplantation and Hepatobiliary Surgery |
And 5 more authors.
Transplant International | Year: 2014
There is increasing evidence that systemic inflammation markers like neutrophil (NLR) and platelet-to-lymphocyte ratios (PLR) may play a role in the outcome of hepatocellular cancer (HCC). Between January 1994 and March 2012, 181 patients with HCC were registered on the transplant waiting list: 35 (19.3%) patients dropped out during the waiting period and 146 (80.7%) patients underwent liver transplantation (LT). The median follow-up of this patient cohort was 4.2 years (IQR: 1.8-8.3). On c-statistics, the last NLR (AUROC = 67.4; P = 0.05) was the best predictor of dropout. The last PLR had an intermediate statistical ability (AUROC = 66.1; P = 0.07) to predict post-LT tumor recurrence. Patients with a NLR value >5.4 had poor 5-year intention-to-treat (ITT) survival rates (48.2 vs. 64.5%; P = 0.02). Conversely, PLR better stratified patients in relation to tumor-free survival (TFS) (80.7 vs. 91.6%; P = 0.02). NLR is a good predictor for the risk of dropout, while PLR is a good predictor for the risk of post-LT recurrence. Use of these markers, which are all available before LT, may represent an additional tool to refine the selection criteria of HCC liver recipients. © 2013 Steunstichting ESOT. Published by John Wiley & Sons Ltd.
Is Minimal, [Almost] Steroid-Free immunosuppression a safe approach in adult liver transplantation? :Long-term outcome of a prospective, double blind, placebo-controlled, randomized, investigator-driven study
Lerut J.P.,Catholic University of Louvain |
Pinheiro R.S.,Catholic University of Louvain |
Lai Q.,Catholic University of Louvain |
Stouffs V.,Catholic University of Louvain |
And 8 more authors.
Annals of Surgery | Year: 2014
Objective: To investigate the safety of minimal immunosuppression (IS) in liver transplantation (LT). Background: The lack of long-term follow-up studies, including pathologic data, has led to a protean handling of IS in LT. Methods: Between February 2000 and September 2004, 156 adults were enrolled in a prospective, randomized, double-blind, placebo-controlled minimization trial comparing tacrolimus placebo (TAC-PLAC) and TAC shortterm steroid (TAC-STER) IS. All patients had a minimum clinical, biochemical, and histological follow-up of 5 years. Results: Five-year actual patient and graft survival rates in TAC-PLAC and TAC-STER groups were 78.1% and 82.1% (P = 0.89) and 74.2% and 76.9% (P = 0.90), respectively. Five-year biopsies were available in 112 (89.6%) of 125 survivors. Twelve patients refused a biopsy because of their excellent evolution; tissue material was insufficient in 1 patient; 11 had normal liver tests; and 2 patients had developed alcoholic and secondary biliary cirrhosis. Histology was normal in 44 (39.3%) patients; 35 (31.3%) had disease recurrence. The remaining biopsies showed nonspecific chronic hepatitis (14.3%), mild inflammatory infiltrates (10.7%), and steatosis (3.5%). All findings were equally distributed between both groups. In each group, 3 patients (4.8%) presented with acute cellular rejection after the first year and only 1 (0.9%) TAC-PLAC patient developed chronic rejection after IS withdrawal because of pneumonitis. Arterial hypertension, diabetes mellitus, renal insufficiency, hypercholesterolemia, gout, and obesity were equally low in both groups. Conclusions: Excellent long-term results can be obtained under minimal IS and absence of steroids. TAC-based monotherapy is feasible in most adult liver recipients until 5 years of follow-up. Copyright © 2014 by Lippincott Williams & Wilkins.
Byrne B.E.,Hepatobiliary Unit |
Geddes T.,University of Bristol |
Welsh F.K.S.,Hepatobiliary Unit |
John T.G.,Hepatobiliary Unit |
And 2 more authors.
Colorectal Disease | Year: 2012
Aim Brain metastases from colorectal cancer are rare, with an incidence of 0.6-4%. The risk and outcome of brain metastases after hepatic and pulmonary metastasectomy have not been previously described. This study aimed to determine the incidence, predictive factors, treatment and survival of patients developing colorectal brain metastases, who had previously undergone resection of hepatic metastases. Method A retrospective review was carried out of a prospectively maintained database of patients undergoing liver resection for colorectal metastases. Results Fifty-two (4.0%) of 1304 patients were diagnosed with brain metastases. The annual incidence rate was 1.03% per person-year. In the majority of cases brain metastases were found as part of multifocal disease. Median survival was 3.2months (95% CI: 2.3-4.1), but was best for six patients treated with potentially curative resection [median survival=13.2 (range, 4.9-32.1) months]. Multivariate analysis showed that a lymph node-positive primary tumour [hazard ratio (HR)=2.7, 95% CI: 1.8-6.19; P=0.019], large liver metastases (>6cm) [HR=2.23, 95% CI: 1.19-2.33; P=0.012] and recurrent intrahepatic and extrahepatic disease [HR=2.11, 95% CI: 1.2-4.62; P=0.013] were independent predictors for the development of brain metastases. Conclusion The annual risk of developing brain metastases following liver resection for colorectal metastases is low, but highest for patients presenting with a Dukes' C primary tumour, large liver metastases or who subsequently develop disseminated disease. The overall survival from colorectal brain metastases is poor, but resection with curative intent offers patients their best chance of medium-term survival. © 2011 The Authors. Colorectal Disease © 2011 The Association of Coloproctology of Great Britain and Ireland.
Swan P.J.,Hepatobiliary Unit |
Welsh F.K.S.,Hepatobiliary Unit |
Chandrakumaran K.,Hepatobiliary Unit |
Rees M.,Hepatobiliary Unit
British Journal of Surgery | Year: 2011
Background: Long-term survival from metastatic colorectal cancer is partly dependent on favourable tumour biology. Large case series have shown improved survival following hepatectomy for colorectal liver metastases (CRLM) in patients diagnosed with metastases more than 12 months after index colorectal surgery (metachronous), compared with those with synchronous metastases. This study investigated whether delayed hepatic resection for CRLM affects long-term survival. Methods: Consecutive patients undergoing hepatic resection for CRLM in a single centre (1987-2007) were grouped according to the timing of hepatectomy relative to index bowel surgery: less than 12 months (synchronous; group 1), 12-36 months (group 2) and more than 36 months (group 3). Cancer-specific survival was calculated using Kaplan-Meier analysis. Results: There were 577 patients (48·0 per cent) in group 1, 467 (38·9 per cent) in group 2 and 158 (13·1 per cent) in group 3. The overall 5-year cancer-specific survival rate after liver surgery was 42·3 per cent, with no difference between groups. However, when measured from the time of primary colorectal surgery, group 3 showed a survival advantage at both 5 and 10 years (94·1 and 47·6 per cent respectively) compared with groups 1 (46·3 and 24·9 per cent) and 2 (57·1 and 35·0 per cent) (P = 0·003). Survival graphs showed a steeper negative gradient from 5 to 10 years for group 3 compared with groups 1 and 2 (-0·80 versus - 0·34 and - 0·37), indicating an accelerated mortality rate. Conclusion: Patients undergoing delayed liver resection for CRLM have a survival advantage that is lost during long-term follow-up. © 2011 British Journal of Surgery Society Ltd. Published by John Wiley and Sons Ltd.
Sidhu R.,Royal Hallamshire Hospital |
McAlindon M.E.,Royal Hallamshire Hospital |
Drew K.,Royal Hallamshire Hospital |
Hardcastle S.,Royal Hallamshire Hospital |
And 2 more authors.
European Journal of Gastroenterology and Hepatology | Year: 2012
OBJECTIVE: There are few centres that offer all forms of small-bowel endoscopic modalities [capsule endoscopy (CE), push enteroscopy (PE), double-balloon enteroscopy (DBE) or single-balloon enteroscopy and intraoperative enteroscopy (IOE)]. Previous investigators have suggested that DBE may be more cost-effective as the first-line investigation. We evaluated the relationship among four modalities of small-bowel endoscopy in terms of demand, diagnostic yield, patient management and tolerability. METHODS: Data were collected on patients who underwent PE and IOE since January 2002, CE since June 2002 and DBE since July 2006. These included age, sex, indication of referral, comorbidity, previous investigations and diagnosis obtained, including subsequent management change. RESULTS: Demand for CE and DBE increased every year. A total of 1431 CEs, 247 PEs, 102 DBEs and 17 IOEs were performed over 93 months. The diagnostic yield was 88% for IOE compared with 34.6% for CE, 34.5% for PE and 43% for DBE (P<0.001). Management was altered by CE in 25%, by PE in 19% and by DBE in 33% of patients. However, 44% of patients who underwent DBE found the procedure difficult to tolerate. In 2009, for every 17 CEs performed, one patient underwent DBE locally. CONCLUSION: This is the first series to report the clinical experience of four modalities of small-bowel endoscopy from a single centre. The use of CE as first-line investigation, followed by PE/DBE or IOE, is potentially both less invasive and tolerable. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.
PubMed | Hepatobiliary Unit
Type: Editorial | Journal: World journal of gastrointestinal surgery | Year: 2016
Gallbladder cancer is the most common tumor of the biliary tract and it is associated with a poor prognosis. Unexpected gallbladder cancer is a cancer incidentally discovered, as a surprise, at the histological examination after cholecystectomy for gallstones or other indications. It is a potentially curable disease, with an intermediate or good prognosis in most cases. An adequate surgical strategy is mandatory to improve the prognosis and an adjunctive radical resection may be required depending on the depth of invasion. If the cancer discovered after cholecystectomy is a pTis or a pT1a, a second surgical procedure is not mandatory. In the other cases (pT1b, pT2 and pT3 cancer) a re-resection (4b + 5 liver segmentectomy, lymphadenectomy and port-sites excision in some cases) is required to obtain a radical excision of the tumor and an accurate disease staging. The operative specimens of re-resection should be examined by the pathologist to find any residual tumor. The residual disease is the most important prognostic factor, significantly reducing median disease-free survival and disease-specific survival. The other factors include depth of parietal invasion, metastatic nodal disease, surgical margin status, cholecystectomy for acute cholecystitis, histological differentiation, lymphatic, vascular and peri-neural invasion and overall TNM-stage.
PubMed | Hepatobiliary Unit
Type: Journal Article | Journal: Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland | Year: 2012
Brain metastases from colorectal cancer are rare, with an incidence of 0.6-4%. The risk and outcome of brain metastases after hepatic and pulmonary metastasectomy have not been previously described. This study aimed to determine the incidence, predictive factors, treatment and survival of patients developing colorectal brain metastases, who had previously undergone resection of hepatic metastases.A retrospective review was carried out of a prospectively maintained database of patients undergoing liver resection for colorectal metastases.Fifty-two (4.0%) of 1304 patients were diagnosed with brain metastases. The annual incidence rate was 1.03% per person-year. In the majority of cases brain metastases were found as part of multifocal disease. Median survival was 3.2 months (95% CI: 2.3-4.1), but was best for six patients treated with potentially curative resection [median survival = 13.2 (range, 4.9-32.1) months]. Multivariate analysis showed that a lymph node-positive primary tumour [hazard ratio (HR) = 2.7, 95% CI: 1.8-6.19; P = 0.019], large liver metastases (> 6 cm) [HR = 2.23, 95% CI: 1.19-2.33; P = 0.012] and recurrent intrahepatic and extrahepatic disease [HR = 2.11, 95% CI: 1.2-4.62; P = 0.013] were independent predictors for the development of brain metastases.The annual risk of developing brain metastases following liver resection for colorectal metastases is low, but highest for patients presenting with a Dukes C primary tumour, large liver metastases or who subsequently develop disseminated disease. The overall survival from colorectal brain metastases is poor, but resection with curative intent offers patients their best chance of medium-term survival.
PubMed | Catholic University of the Sacred Heart and Hepatobiliary Unit
Type: Journal Article | Journal: World journal of surgery | Year: 2016
Primary intrahepatic lithiasis is defined by the presence of gallstones at the level of cystic dilatations of the intrahepatic biliary tree. Liver resection is considered the treatment of choice, with the purpose of removing stones and atrophic parenchyma, also reducing the risk of cholangiocarcinoma. However, in consequence of the considerable incidence of infectious complications, postoperative morbidity remains high. The current study was designed to evaluate the impact of preoperative bacterial colonization of the bile ducts on postoperative outcome.The clinical records of 73 patients treated with liver resection were reviewed and clinical data, operative procedures, results of bile cultures, and postoperative outcomes were examined.Left hepatectomy (38 patients) and left lateral sectionectomy (19 patients) were the most frequently performed procedures. Overall morbidity was 38.3 %. A total of 133 microorganisms were isolated from bile. Multivariate analysis identified previous endoscopic or percutaneous cholangiography (p = 0.043) and preoperative cholangitis (p = 0.003) as the only two independent risk factors for postoperative infectious complications.Postoperative morbidity was strictly related to the preoperative biliary infection. An effective control of infections should be always pursued before liver resection for intrahepatic stones and an aggressive treatment of early signs of sepsis should be strongly emphasized.