Early derangement of INR predicts liver failure after liver resection for hepatocellular carcinoma.

BACKGROUND: Surgical resection, where appropriate, remains one of the best treatment options for hepatocellular carcinoma (HCC), however outcomes can be compromised by the development of liver failure. We reviewed our experience of liver resection for HCC patients to identify factors that may predict the development of post-hepatectomy liver failure (PHLF) and survival. METHODS: A single centre retrospective cohort study. Data was collected between 1999 and 2017 from all patients undergoing HCC resection in a tertiary university hospital from electronic medical records. PHLF was defined as per the International Study Group for Liver Surgery criteria. Variables with p < 0.15 on univariate analysis were included in a multivariate binary logistic regression model. Kaplan-Meier analyses were used to determine correlations with overall survival (OS) and disease-free survival (DFS), and variables with p < 0.15 on univariate analysis selected for a step-down Cox proportional hazard regression model. RESULTS: Overall, 120 patients underwent liver resection within the study period, of which 22 (18%) developed PHLF. Patients with normal INR ≤1.20 at day 2 did not develop PHLF whereas patients with INR >1.60 were at significant risk. Resection of multiple tumours (odds ratio 21.63, p = 0.002) and deranged postoperative day 2 INR>1.6 (odds ratio 21.05, p < 0.0001) were identified as independent prognostic markers of PHLF. CONCLUSION: The use of INR measurement at day 2 predicts PHLF and may enable us to objectively identify and stratify patients who may be eligible for enhanced recovery programs from those who will merit close monitoring in high dependency areas.

A rational approach to postoperative surveillance for resected non-functional pancreatic neuro-endocrine tumours.

BACKGROUND: Non-functional pancreatic neuroendocrine tumours (NF-PNETs) are rare and have highly variable outcomes. Current guidelines recommend surveillance for NF-PNETs <2 cm. Patients who ultimately have surgical resection are at risk of disease recurrence, and data to support postoperative surveillance protocols are lacking. The aims of this study were to i) identify post-operative predictors of recurrence and ii) risk stratify patients at risk of recurrence. METHODS: Consecutive patients who underwent surgery for NF-PNETs between 2002 and 2015 were identified retrospectively. Data were collected on demographics, pre-operative laboratory results and histopathological tumour characteristics. Statistical analyses were based on penalised Cox-regression modelling and a decision-tree model. Comparison of the variables identified was performed using ROC curves to identify the most sensitive and specific variable associated with disease recurrence. RESULTS: We identified 73 patients (38 males) with a median age of 61.5 years (range: 31-79). The median period of follow-up was 49 months (5-131). During follow up, 10 deaths (13.9%) were recorded and disease recurrence occurred in 12 patients (16.4%). The Kaplan-Meier predicted 1-,3- and 5-year recurrence-free survival rates were 98.6% (95% CI = 95.9, 100%), 85.4% (76.9-94.8%) and 72% (58.7-88.2%) respectively. Cox multivariate analysis identified poor tumour differentiation (WHO G3 grade) and lymph node ratio (LNR) as independent predictors for recurrence (p < 0.05). A simple criterion of 'tumour grade G3 or LNR ≥0.1' was found to be sensitive and specific in detecting disease recurrence. CONCLUSION: Our results have identified a simple and sensitive criterion for risk stratifying post-resection surveillance. Prospective validation in larger patient cohort is now warranted.

When one becomes more: minimum renal artery length in laparoscopic live donor nephrectomy.

BACKGROUND: Laparoscopic donor nephrectomy may convert short main arteries into multiple arteries, increasing the technical challenge of implantation. We evaluated our experience to identify factors predictive of multiple arteries after laparoscopic nephrectomy. METHODS: All laparoscopic nephrectomies from the start of our program in November 2002 until June 2013 were studied, and preoperative imaging reviewed for donor artery length and multiplicity together with operative findings. RESULTS: A total of 287 consecutive laparoscopic live donor nephrectomies (64 right and 223 left nephrectomies) were studied. Renal artery length was measured from preoperative donor magnetic resonance or computed tomography angiogram and nephrectomy performed using a laparoscopic stapling device. Nine left kidneys with a single artery (6, 7, 9, 10, 11, 12, 13, 14, and 16 mm in length) and five right kidneys with a single artery (5, 13, 15, 20, and 26 mm) on imaging resulted in multiple renal arteries at implantation. Complex renal vein anatomy was associated with multiple arteries following retrieval. CONCLUSION: A main renal artery length of more than 16 mm on the left and 26 mm on the right is unlikely to result in multiple arteries to implant. The possibility of multiple arteries should be borne in mind when the donor renal artery is short.

Abdominal aortic aneurysm surgery in renal, cardiac and hepatic transplant recipients.

With advancements in transplantation and improved long-term allograft survival, the once rare clinical scenario of an abdominal aortic aneurysm (AAA) in a patient with a functioning allograft has become much more frequent. In transplant recipients, AAA repair has the potential to cause irreversible ischaemic injury to the transplanted organ. Different case series and case reports have mentioned a variety of techniques to offer protection to the transplanted organs during aneurysm repair such as cold perfusion, shunting, temporary surgical bypass and extracorporeal circuits etc. Critical review of these adjuncts seems to suggest that that they do not give any better results than just using a "clamp and go" approach. Endovascular aneurysm repair (EVAR) may offer some advantages for transplant patients who have suitable anatomy for endovascular stent deployment. In addition to these surgical techniques, various aspects of medical management for renal, cardiac and hepatic transplant recipients undergoing AAA repair are discussed.

F18-FDG-PET evaluation of patients for resection of colorectal liver metastases.

BACKGROUND/AIMS: Liver resection is the only treatment which offers long-term survival for patients with colorectal liver metastases. However, the significant mortality and morbidity associated with hepatectomy makes accurate patient selection paramount. Current staging by CT and MRI has limitations, with these modalities delivering a sensitivity and specificity of only 70-80%. Thus some patients may be deprived of long-term survival, and others subjected to futile surgery. METHODOLOGY: We report our experience of the influence of F18-FDG-PET scanning in the management of 31 consecutive patients with colorectal liver metastases referred for liver resection. RESULTS: F18-FDG-PET scanning detected liver and pulmonary metastases with a sensitivity of 96% and 100% respectively, in comparison to corresponding figures of 70% and 83% for CT. Furthermore, the sensitivity of F18-FDG-PET scanning in identifying extra-hepatic and extra-pulmonary disease was 100% in comparison to 20% for CT. Overall, F18-FDG-PET scanning resulted in a significant alteration of management in 29% of patients. CONCLUSIONS: F18-FDG-PET scanning has an important clinical impact on the management of patients being considered for resection of colorectal liver metastases.

A novel human Wnt gene, WNT10B, maps to 12q13 and is expressed in human breast carcinomas.

Several members of the Wnt gene family have been shown to cause mammary tumors in mouse. Using degenerate primer polymerase chain reaction (PCR) on human genomic DNA, and specific PCR of cDNA libraries, we have isolated a WNT gene which has not previously been described in human. The gene is the human homologue of mouse Wnt10b, recently shown to be one of the oncogenes cooperating with FGF3 in the development of mouse mammary tumour virus (MMTV) induced mouse mammary carcinomas. The human WNT10B sequence was 88% and 95% identical to the murine gene at nucleotide and amino acid levels, respectively. YAC FISH mapping localises the gene to 12q13, a chromosomal region frequently rearranged in human tumours and also containing the WNT1 gene. In normal and benign proliferations of human breast tissue, WNT10B expression was not detected by ribonuclease protection assays but was found at low levels in RT-PCR experiments. In contrast, using both methods, WNT10B expression was found to be elevated in 3 of 50 primary breast carcinomas. Southern blot analysis of the carcinoma expressing the highest levels of WNT10B showed no amplification or rearrangement of the gene. The WNT10B gene was also expressed in some cancer and non cancerous breast cell lines. These findings suggest that the WNT10B gene may be involved in human breast cancer, and show that there is differential expression of the WNT10B gene in benign and malignant disease.

Compartment switching of WNT-2 expression in human breast tumors.

WNT-2 is a secreted polypeptide with mitogenic effects in murine mammary epithelial cells, but its role in human cancer is unknown. Using RNase protection analysis of primary cell preparations and in situ hybridization analysis, we report that WNT-2 is expressed at low levels in normal human breast fibroblasts but not in epithelial cells. WNT-2 was found to be expressed at high levels in both the epithelium and stroma of 5 of 11 infiltrating carcinomas and 2 of 6 fibroadenomas. The high level of WNT-2 expression in tumor epithelium suggests that tumorigenesis may involve the ectopic expression of WNT-2 and the creation of an autocrine Wnt signaling loop.

Regulation of Wnt5a mRNA expression in human mammary epithelial cells by cell shape, confluence, and hepatocyte growth factor.

The Wnts are a family of genes with a role in cell fate and morphological development in numerous embryonic and adult tissues. In mouse mammary tissue a subset of the Wnts have a function in the normal development of the gland, and aberrant expression of Wnts normally silent in this tissue causes mammary carcinomas. We have previously shown that Wnt5a expression is elevated in the epithelial component of proliferative lesions of human breast and have therefore examined the regulation of Wnt5a mRNA expression in the human mammary epithelial cell line HB2, which has a luminal phenotype and thus represents the most commonly transformed cell type in human breast cancer. Wnt5a was up-regulated 30-fold at confluence. This up-regulation was induced specifically by confluence and not by the growth arrest that accompanied it. In addition, Wnt5a was down-regulated 3-fold by changes in cell shape associated with the transition from growth on a two-dimensional surface (flat cell morphology) to growth in three-dimensional gels (spherical cell morphology). Cytoskeletal disruption with non-toxic doses of colchicine also induced a spherical morphology and brought about a dose-dependent down-regulation of Wnt5a. Wnt5a was also down-regulated 10-fold during the hepatocyte growth factor-induced branching of HB2 cell aggregates in collagen gels. The down-regulation of Wnt5a preceded the branching process. A similar result was obtained with primary human breast epithelial populations and the breast cancer cell line MDA468. We conclude that regulation of Wnt5a expression is a down-stream effect of signaling by hepatocyte growth factor. These results are consistent with a role for Wnt5a in mammary epithelial cell motility and are in accord with Xwnt5a's function in embryonal cell migration. If Wnt5a's function in human mammary epithelial cells is similar to that of Xwnt5a, its up-regulation at confluence may be a mechanism for inhibition of cell migration beyond confluence.

Wnt5a cloning, expression, and up-regulation in human primary breast cancers.

Wnt genes are involved in mouse mammary cancer, but their role in human cancer is unknown. Human Wnt5a was cloned from a placental cDNA library and used to assess expression by ribonuclease protection and in situ hybridization in human breast cell lines and in normal, benign, and malignant breast tissues. Human Wnt5a shows over 99% homology at amino acid level with mouse Wnt5a, and 90% with Xenopus Wnt5a. It was expressed only at low levels in breast cell lines and normal breast tissue. Benign proliferations and invasive cancer respectively showed 10-fold and 4-fold higher Wnt5a than normal breast tissues. The greater up-regulation in benign conditions suggests a role in aberrant differentiation. In situ hybridization localized the signal to the epithelial component. Wnt5a is the first member of the Wnt family to demonstrate overexpression in human breast cancer. It was not associated with factors known to affect breast cancer prognosis such as lymph node status or epidermal growth factor receptor status.

Differential expression of human Wnt genes 2, 3, 4, and 7B in human breast cell lines and normal and disease states of human breast tissue.

Wnt gene expression was investigated by ribonuclease protection analysis in human breast cancer, nontumorous breast tissue, and a variety of human breast cell lines. We report the expression of Wnt3, Wnt4, and Wnt7b in human breast cell lines and Wnt2, Wnt3, Wnt4, and Wnt7b in human breast tissues. Wnt3a and Wnt7a were absent in the cell lines and tissues tested. The level of expression of Wnt2 and Wnt4 was 10- to 20-fold higher in fibroadenomas than it was in normal or malignant breast tissue, and in 10% of tumors Wnt7b expression was 30-fold higher than in normal or benign breast tissues. In contrast to the mouse, in which Wnt1 and Wnt3 are involved in tumorigenesis, our results suggest that Wnt2, Wnt4, and Wnt7b may be associated with abnormal proliferation in human breast tissue.