Complete mesocolic excision for right hemicolectomy: an updated systematic review and meta-analysis.

PURPOSE: Complete mesocolic excision improves lymphadenectomy for right hemicolectomy and respects the embryological planes. However, its effect on cancer-free and overall survival is questioned. Therefore, we aimed to determine the potential benefits of the technique by performing a systematic review of the literature and meta-analysis of the available evidence. METHODS: Web of Science, PubMed/Medline, and Embase were searched on February 22, 2023. Original studies on short- and long-term oncological outcomes of adult patients undergoing right hemicolectomy with complete mesocolic excision as a treatment for primary colon cancer were considered for inclusion. Outcomes were extracted and pooled using a model with random effects. RESULTS: A total of 586 publications were identified through database searching, and 18 from citation searching. Exclusion of 552 articles left 24 articles for inclusion. Meta-analysis showed that complete mesocolic excision increased the lymph node harvest (5 studies, 1479 patients, MD 9.62, 95% CI 5.83-13.41, p > 0.0001, I2 84%), 5-year overall survival (5 studies, 2381 patients, OR 1.88, 95% CI 1.14-3.09, p = 0.01, I2 66%), 5-year disease-free survival (4 studies, 1376 patients, OR 2.21, 95% CI 1.51-3.23, p < 0.0001, I2 0%) and decreased the incidence of local recurrence (4 studies, 818 patients, OR 0.27, 95% CI 0.09-0.79, p = 0.02, I2 0%) when compared to standard right hemicolectomy. Perioperative morbidity was similar between the techniques (8 studies, 3899 patients, OR 1.04, 95% CI 0.89-1.22, p = 0.97, I2 0%). CONCLUSION: Meta-analysis of observational and randomised studies showed that right hemicolectomy with complete mesocolic excision for primary right colon cancer improves oncologic results without increasing morbidity/mortality. These results need to be confirmed by high-quality evidence and randomised trials in selected patients to assess who may benefit from the procedure.

Liver transplantation for "very early" intrahepatic cholangiocarcinoma: International retrospective study supporting a prospective assessment.

UNLABELLED: The presence of an intrahepatic cholangiocarcinoma (iCCA) in a cirrhotic liver is a contraindication for liver transplantation in most centers worldwide. Recent investigations have shown that "very early" iCCA (single tumors ≤2 cm) may have acceptable results after liver transplantation. This study further evaluates this finding in a larger international multicenter cohort. The study group was composed of those patients who were transplanted for hepatocellular carcinoma or decompensated cirrhosis and found to have an iCCA at explant pathology. Patients were divided into those with "very early" iCCA and those with "advanced" disease (single tumor >2 cm or multifocal disease). Between January 2000 and December 2013, 81 patients were found to have an iCCA at explant; 33 had separate nodules of iCCA and hepatocellular carcinoma, and 48 had only iCCA (study group). Within the study group, 15/48 (31%) constituted the "very early" iCCA group and 33/48 (69%) the "advanced" group. There were no significant differences between groups in preoperative characteristics. At explant, the median size of the largest tumor was larger in the "advanced" group (3.1 [2.5-4.4] versus 1.6 [1.5-1.8]). After a median follow-up of 35 (13.5-76.4) months, the 1-year, 3-year, and 5-year cumulative risks of recurrence were, respectively, 7%, 18%, and 18% in the very early iCCA group versus 30%, 47%, and 61% in the advanced iCCA group, P = 0.01. The 1-year, 3-year, and 5-year actuarial survival rates were, respectively, 93%, 84%, and 65% in the very early iCCA group versus 79%, 50%, and 45% in the advanced iCCA group, P = 0.02. CONCLUSION: Patients with cirrhosis and very early iCCA may become candidates for liver transplantation; a prospective multicenter clinical trial is needed to further confirm these results. (Hepatology 2016;64:1178-1188).

Effect of ischaemic preconditioning on recurrence of hepatocellular carcinoma in an experimental model of liver steatosis.

BACKGROUND: Livers with parenchymal abnormalities tolerate ischaemia-reperfusion (IR) injury poorly. IR injury is a risk factor for hepatocellular carcinoma (HCC) recurrence. This study assessed the link between liver parenchymal abnormalities and HCC recurrence, and evaluated the protective effect of ischaemic preconditioning. METHODS: C57BL/6 mice were fed a choline-deficient diet for 6 and 12 weeks, or standard chow. Hepatic IR and ischaemic preconditioning were achieved by clamping liver blood inflow. Hepa 1-6 HCC cells were inoculated through the spleen. Thereafter, tumour burden, serum α-fetoprotein and cancer cell aggressiveness were compared among groups. RESULTS: Hepatocellular damage and expression of inflammatory genes (encoding interleukin 6, tumour necrosis factor α, hypoxia inducible factor 1α and E-selectin) were exacerbated after IR injury in mice with severe steatosis. Compared with control livers or those with minimal steatosis, livers exposed to a prolonged choline-deficient diet developed larger tumour nodules and had higher serum α-fetoprotein levels. Non-ischaemic liver lobes from mice with steatosis were not protected from accelerated tumour growth mediated by IR injury. This remote effect was linked to promotion of the aggressiveness of HCC cells. Ischaemic preconditioning before IR injury reduced the tumour burden to the level of that in non-ischaemic steatotic controls. This protective effect was associated with decreased cancer cell motility. CONCLUSION: Livers with steatosis tolerated IR poorly, contributing to more severe HCC recurrence patterns in mice with increasingly severe steatosis. IR injury also had a remote effect on cancer cell aggressiveness. Ischaemic preconditioning before IR injury reduced tumour load and serum α-fetoprotein levels. SURGICAL RELEVANCE: Liver ischaemia-reperfusion (IR) injury is associated with organ dysfunction and surgical morbidity. Livers with steatosis tolerate IR injury poorly in the setting of both liver resection and liver transplantation. Ischaemic preconditioning is a simple method to mitigate IR injury. This study shows that ischaemic preconditioning of mouse livers with steatosis reduces ischaemia-mediated tumour growth acceleration. Liver parenchymal abnormalities such as warm IR injury and liver steatosis should be taken into account to predict accurately the risk of liver cancer recurrence after surgical management. Ischaemic preconditioning strategies may hold therapeutic potential not only to mitigate surgical morbidity but also to reduce postoperative recurrence of liver cancer.

Liver resection in patients with eight or more colorectal liver metastases.

BACKGROUND: Patients with large numbers of colorectal liver metastases (CRLMs) are potential candidates for resection, but the benefit from surgery is unclear. METHODS: Patients undergoing resection for CRLMs between 1998 and 2012 in two high-volume liver surgery centres were categorized according to the number of CRLMs: between one and seven (group 1) and eight or more (group 2). Overall (OS) and recurrence-free (RFS) survival were compared between the groups. Multivariable analysis was performed to identify adverse prognostic factors. RESULTS: A total of 849 patients were analysed: 743 in group 1 and 106 in group 2. The perioperative mortality rate (90 days) was 0.4 per cent (all group 1). Median follow-up was 37.4 months. Group 1 had higher 5-year OS (44.2 versus 20.1 per cent; P < 0.001) and RFS (28.7 versus 13.6 per cent; P < 0.001) rates. OS and RFS in group 2 were similar for patients with eight to ten, 11-15 or more than 15 metastases (48, 40 and 18 patients respectively). In group 2, multivariable analysis identified three preoperative adverse prognostic factors: extrahepatic disease (P = 0.010), no response to chemotherapy (P = 0.023) and primary rectal cancer (P = 0.039). Patients with two or more risk factors had very poor outcomes (median OS and RFS 16.9 and 2.5 months; 5-year OS zero); patients in group 2 with no risk factors had similar survival to those in group 1 (5-year OS rate 44 versus 44.2 per cent). CONCLUSION: Liver resection is safe in selected patients with eight or more metastases, and offers reasonable 5-year survival independent of the number of metastases. However, eight or more metastases combined with at least two adverse prognostic factors is associated with very poor survival, and surgery may not be beneficial.

Donor characteristics and risk of hepatocellular carcinoma recurrence after liver transplantation.

BACKGROUND: To date, studies assessing the risk of post-transplant hepatocellular carcinoma (HCC) recurrence have focused on tumour characteristics. This study investigated the impact of donor characteristics and graft quality on post-transplant HCC recurrence. METHODS: Using the Scientific Registry of Transplant Recipients patients with HCC who received a liver transplant between 2004 and 2011 were included, and post-transplant HCC recurrence was assessed. A multivariable competing risk regression model was fitted, adjusting for confounders such as recipient sex, age, tumour volume, α-fetoprotein, time on the waiting list and transplant centre. RESULTS: A total of 9724 liver transplant recipients were included. Patients receiving a graft procured from a donor older than 60 years (adjusted hazard ratio (HR) 1.38, 95 per cent c.i. 1.10 to 1.73; P = 0.006), a donor with a history of diabetes (adjusted HR 1.43, 1.11 to 1.83; P = 0.006) and a donor with a body mass index of 35 kg/m(2) or more (adjusted HR 1.36, 1.04 to 1.77; P = 0.023) had an increased rate of post-transplant HCC recurrence. In 3007 patients with documented steatosis, severe graft steatosis (more than 60 per cent) was also linked to an increased risk of recurrence (adjusted HR 1.65, 1.03 to 2.64; P = 0.037). Recipients of organs from donation after cardiac death donors with prolonged warm ischaemia had higher recurrence rates (adjusted HR 4.26, 1.20 to 15.1; P = 0.025). CONCLUSION: Donor-related factors such as donor age, body mass index, diabetes and steatosis are associated with an increased rate of HCC recurrence after liver transplantation.

Surgical management of patients with colorectal cancer and simultaneous liver and lung metastases.

BACKGROUND: The management of patients with colorectal cancer and simultaneously diagnosed liver and lung metastases (SLLM) remains controversial. METHODS: The LiverMetSurvey registry was interrogated for patients treated between 2000 and 2012 to assess outcomes after resection of SLLM, and the factors associated with survival. SLLM was defined as liver and lung metastases diagnosed 3 months or less apart. Survival was compared between patients with resected isolated liver metastases (group 1, control), those with resected liver and lung metastases (group 2), and patients with resected liver metastases and unresected (or unresectable) lung metastases (group 3). An Akaike test was used to select variables for assessment of survival adjusted for confounding variables. RESULTS: Group 1 (isolated liver metastases, hepatic resection alone) included 9185 patients, group 2 (resection of liver and lung metastases) 149 patients, and group 3 (resection of liver metastases, no resection of lung metastases) 285 patients. Ten variables differed significantly between groups and seven were included in the model for adjusted survival (age, number of liver metastases, synchronicity of liver metastases with primary tumour, carcinoembryonic antigen level, node status of the primary tumour, initial resectability of liver metastases and inclusion in group 3). Adjusted overall 5-year survival was similar for groups 1 and 2 (51·5 and 44·5 per cent respectively), but worse for group 3 (14·3 per cent) (P = 0·001). CONCLUSION: Patients who had resection of liver and lung metastases had similar overall survival to those who had undergone removal of isolated liver metastases.

Toward a better liver graft allocation that accounts for candidates with and without hepatocellular carcinoma.

In some countries where the Model for End-Stage Liver Disease (MELD) score is used for graft allocation, selected patients with hepatocellular carcinoma (HCC) receive a fixed number of exception points at listing, and increasing priority on the list by accruing additional exception points at regular time intervals. This system originally aimed at balancing the risks of HCC patients of developing contraindications and of non-HCC patients of dying before transplantation, is not ideal because it appears to offer an advantage to HCC patients, regardless of tumor characteristics and response to loco-regional treatment. Scores modulated by HCC characteristics have been proposed. They are based on a more refined estimate of the risk of pretransplant drop-out or of the posttransplant transplant benefit expressed as the life-years gained for each graft. This review describes the newly proposed systems, and discusses their advantages and drawbacks. We believe that the current exception points allocation should be revised and that drop-out-equivalent or transplant benefit-equivalent models should be studied further. As with all policy changes, these should be done under close monitoring that allows subsequent revisions.

Outcomes of combined liver-kidney transplantation in children: analysis of the scientific registry of transplant recipients.

Combined liver-kidney transplantation (CLKT) in children is uncommon and outcomes have not been well defined. Using the Scientific Registry of Transplant Recipients, data were analyzed on 152 primary pediatric CLKTs performed from October 1987 to February 2011, to determine their outcome in the largest series reported to date. Patient survival was 86.8%, 82.1% and 78.9% at 1, 5 and 10 years, liver graft survival was 81.9%, 76.5% and 72.6%, and kidney graft survival was 83.4%, 76.5% and 66.8%. By way of comparison, the Registry was queried for pediatric patient survival following isolated liver transplantation (LT) during the same time frame: 86.7%, 81.2% and 77.4% and following isolated kidney transplant (KT): 98.2%, 95.4% and 90% at 1, 5 and 10 years. In patients having undergone CLKT, primary hyperoxaluria was associated with reduced patient (p = 0.01), liver graft (p = 0.01) and kidney graft survival (p = 0.01). Furthermore, graft outcome following CLKT improved over the past decade (p = 0.04 for liver, p = 0.02 for kidney), but this did not translate into improved patient outcome (p = 0.2). All in all, our results confirmed that survival following LT was less than following KT, and that CLKT offered similar patient survival to isolated LT.

Systematic review and meta-analysis of percutaneous subclavian vein puncture versus surgical venous cutdown for the insertion of a totally implantable venous access device.

BACKGROUND: Totally implantable venous access devices (TIVADs) are commonly used in patients with cancer. Although several methods of implantation have been described, there is not enough evidence to support the use of a specific technique on a daily basis. The objective of this study was systematically to assess the literature comparing percutaneous subclavian vein puncture with surgical venous cutdown. METHODS: MEDLINE, Embase and the Cochrane Central Register of Controlled Trials were searched by two independent authors. No time limits were applied. A systematic review and meta-analysis was carried out according to the recommendations of the Cochrane Collaboration, including randomized clinical trials comparing primary percutaneous subclavian vein puncture with surgical venous cutdown. RESULTS: Six trials were included, with 772 patients overall. The primary implantation failure rate was significantly lower for the percutaneous approach compared with surgical cutdown (odds ratio (OR) 0.26, 95 per cent confidence interval (c.i.) 0.07 to 0.94; P = 0.039). There was no evidence supporting a significant difference in terms of risk of pneumothorax, haematoma, venous thrombosis, infectious events or catheter migration. After taking between-study heterogeneity into account by using a random-effects model, procedure duration was not significantly longer for surgical cutdown: weighted mean difference +4 (95 per cent c.i. -12 to 20) min (P = 0.625). CONCLUSION: Percutaneous subclavian vein puncture is associated with a higher TIVAD implantation success rate and a procedure duration similar to that of surgical cutdown. Pneumothorax develops exclusively after percutaneous puncture and requires special attention from clinicians dealing with TIVAD insertion.

Transplanted human pancreatic islets after long-term insulin independence.

Long-term insulin independence after islets of Langerhans transplantation is rarely achieved. The aims of this study were to identify the histological and immunological features of islets transplanted in a type 1 diabetic patient who died of a cerebral hemorrhage after >13 years insulin independence. Islets were pooled from two donors with respectively one and five HLA mismatches. Insulin-positive islets were found throughout the right and left liver, and absent in the pancreas. Two- and three-dimensional analysis showed that islets lost their initial rounded and compact morphology, had a mean diameter of 136 µm and were constituted of an unfolded epithelial band of 39.1 µm. Leukocyte phenotyping showed no evidence of a tolerogenic environment in the islet-containing portal spaces. Finally, HLA typing of microdissected islets showed HLA from the best matched donor in all 23 microdissection samples, compared to 1/23 for the least matched donor. This case report demonstrates that allogeneic islets can survive over 13 years while maintaining insulin independence. Allogeneic islets had unique morphologic features and implanted in the liver regardless of their size. Finally, our results suggest that, in this case, rejection had been prevalent over autoimmunity, although this hypothesis warrants further investigation.

Systematic review and meta-analysis of the effect of perioperative steroids on ischaemia-reperfusion injury and surgical stress response in patients undergoing liver resection.

BACKGROUND: Several therapeutic strategies, such as ischaemic preconditioning, intermittent or selective pedicle clamping and pharmacological interventions, have been explored to reduce morbidity caused by hepatic ischaemia-reperfusion injury and the surgical stress response. The role of steroids in this setting remains controversial. METHODS: A comprehensive literature search in MEDLINE, Embase and the Cochrane Register of Clinical Trials (CENTRAL) was conducted (1966 onwards), identifying studies comparing perioperative administration of intravenous steroids with standard care or placebo, in the setting of liver surgery. Randomized Controlled trials (RCTs) and non-RCTs were included. Critical appraisal and meta-analysis were carried out according to the Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA) statement. RESULTS: Six articles were included; five were RCTs. Pooling the results revealed that patients receiving intravenous glucocorticoids were 24 per cent less likely to suffer postoperative morbidity compared with controls (risk ratio 0.76, 95 per cent confidence interval 0.57 to 0.99; P = 0.047). The treated group experienced a significantly greater rise in early postoperative interleukin (IL) 10 levels compared with controls. In addition, steroids significantly reduced postoperative blood levels of bilirubin, and of inflammatory markers such as IL-6 and C-reactive protein. There was no evidence supporting a risk difference in infectious complications and wound healing between study groups. CONCLUSION: Perioperative steroids have a favourable impact on postoperative outcomes after liver resection.

Recurrence of type 1 diabetes after simultaneous pancreas-kidney transplantation in the absence of GAD and IA-2 autoantibodies.

We report herein the patterns of type 1 diabetes recurrence in a simultaneous pancreas-kidney transplant (SPK) recipient, in the absence of rejection. A 38-year-old female underwent SPK for end-stage nephropathy secondary to type 1 diabetes. Fasting blood glucose, HbA1c, fructosamine, C-peptide and autoantibodies (GAD-65, IA-2) were monitored throughout follow-up. At 3.5 years post-SPK, HbA1c and fructosamine increased sharply, indicating loss of perfect metabolic control, despite C-peptide levels in the normal-high range. Exogenous insulin was restarted 4 months later. C-peptide levels abruptly fell and became undetectable at 5.5 years. Autoantibody levels, which were undetectable at the time of SPK, never converted to positivity. Pancreas retranspantation was performed at 6 years. The failed pancreas graft had a normal macroscopic appearance. On histology, there were no signs of cellular or humoral rejection in the kidney or pancreas. A selective peri-islet lymphocytic infiltrate was observed, together with near-total destruction of ß cells. At 2.5 years post retransplantation, pancreatic graft function is perfect. This observation indicates unequivocally that pancreas graft can be lost to recurrence of type 1 diabetes in the absence of rejection. GAD-65 and IA-2 autoantibodies are not reliable markers of autoimmunity recurrence.

Liver transplantation for hepatocellular carcinoma: five steps to prevent recurrence.

Liver transplantation is the best treatment of patients with unresectable early hepatocellular carcinoma, allowing disease-free survival rates of 60-80% at 5 years. Despite these good results, some 10% of recipients experience a posttransplant HCC recurrence, which leads to death in almost all patients. Recurrence is either due to the growth of occult metastases or to the engraftment of circulating tumor cells. It can be hypothesized that strategies to decrease the engraftment of circulating tumor cells could decrease the risk of recurrence and, in addition, extend access to transplantation to patients with more advanced HCC. These potential strategies can be schematized into five steps, including (1) selecting recipients with low baseline levels of circulating HCC cells, by adding biological markers (such as alpha fetoprotein or molecular signatures) to the accepted combination of morphological criteria; (2) decreasing the perioperative release of HCC cells, with careful perioperative handling of the tumors; (3) preventing the engraftment of circulating HCC cells by decreasing liver graft ischemia-reperfusion injury, which has been shown to promote cancer cell engraftment and growth; (4) using anticancer drugs, including mammalian target of rapamycin inhibitors and (5) tuning immunity toward HCC clearance.

Eculizumab in acute recurrence of thrombotic microangiopathy after renal transplantation.

Renal thrombotic microangiopathy (TMA) is a severe complication of systemic lupus erythematosus (SLE), which is associated with the presence of antiphospholipid (aPL) antibodies. In its most fulminant form, TMA leads to a rapid and irreversible end-stage renal failure. Eculizumab, an anti-C5 monoclonal antibody, is a novel therapy of choice for patients with paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome. Here, we report the case of a 27-year-old woman, known for SLE and end-stage renal disease due to fulminant TMA. Both aPL antibodies and antinucleosome antibodies were positive. The patient underwent a living-related kidney transplantation with immediate production of urine. Although serum creatinine was remaining high, a graft biopsy, performed on day 6, demonstrated a TMA recurrence. Despite a treatment with plasma exchange, the situation got worse and dialysis was started. Eculizumab treatment was subsequently administered and renal function improved rapidly. Three months after transplantation, serum creatinine was at 100 µmol/L, without proteinuria. This case illustrates the benefit of eculizumab therapy in a fulminant recurrence of TMA after kidney transplantation, resistant to classical therapy.

A novel method for quantitative monitoring of transplanted islets of langerhans by positive contrast magnetic resonance imaging.

The Automatic Quantitative Ultrashort Echo Time imaging (AQUTE) protocol for serial MRI allows quantitative in vivo monitoring of iron labeled pancreatic islets of Langerhans transplanted into the liver, quantifying graft implantation and persistence in a rodent model. Rats (n = 14), transplanted with iron oxide loaded cells (0-4000 islet equivalents, IEQ), were imaged using a 3D radial ultrashort echo time difference technique (dUTE) on a Siemens MAGNETOM 3T clinical scanner up to 5 months postsurgery. In vivo 3D dUTE images gave positive contrast from labeled cells, suppressing liver signal and small vessels, allowing automatic quantification. Position of labeled islet clusters was consistent over time and quantification of hyperintense pixels correlated with the number of injected IEQs (R² = 0.898, p < 0.0001), and showed persistence over time (5 months posttransplantation). Automatic quantification was superior to standard imaging and manual counting methods, due to the uniform suppressed background and high contrast, resulting in significant timesavings, reproducibility and ease of quantification. Three-dimensional coverage of the whole liver in the absence of cardiac/respiratory artifact provided further improvement over conventional imaging. This imaging protocol reliably quantifies transplanted islet mass and has high translational potential to clinical studies of transplanted pancreatic islets.

Development and implementation of an assessment tool to evaluate technical skills in the insertion of implantable venous access devices, a Prospective Cohort Study.

OBJECTIVE: Based on the Competency Assessment Tool, herein we developed an assessment instrument suitable to evaluate the implantation of central intravenous devices. BACKGROUND: Surgical assessment is based mainly on the subjective impressions of the teacher. Based on the "Competency Assessment Tool" (CAT) developed for the evaluation of technical surgical skills in minimally invasive colorectal resection, we designed an assessment tool suitable to evaluate the implantation of central venous access devices performed by junior surgical trainees. METHODS: Four major assessments during the different steps of the intervention were used in this evaluation. Each of these tasks was divided into four sub-domains according to surgical skill. In addition to the CAT score, the apprentices' skills were evaluated using a visual assessment that was quantified using an analogue scale (value from 1 to 10). The candidates were classified into junior and senior trainees depending on the number of procedures they had already performed and on their surgical experience. RESULTS: 71 procedures were evaluated during the study period. Seven senior trainees conducted 43 procedures and five junior trainees performed 28 interventions. The senior trainees had significantly higher CAT scores than junior candidates, and the scores fluctuated according to surgical experience, usually reaching their peak after 10 procedures. CONCLUSIONS: The CAT model is well suited for the assessment of surgical trainees during central venous access device implantation. It enables a close assessment of the learning process and the technical skills of trainees, which helps them improving in a safe, standardized manner.