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Background: Mortality from colorectal cancer is mainly due to metastatic liver disease. Improved understanding of the molecular events underlying metastasis is crucial for the development of new methods for early detection and treatment of colorectal cancer. Loss of chromosome 8p is frequently seen in colorectal cancer and implicated in later stage disease and metastasis, although a single metastasis suppressor gene has yet to be identified. We therefore examined 8p for genes involved in colorectal cancer progression.Methods: Loss of heterozygosity analyses were used to map genetic loss in colorectal liver metastases. Candidate genes in the region of loss were investigated in clinical samples from 44 patients, including 6 with matched colon normal, colon tumour and liver metastasis. We investigated gene disruption at the level of DNA, mRNA and protein using a combination of mutation, semi-quantitative real-time PCR, western blotting and immunohistochemical analyses.Results: We mapped a 2 Mb region of 8p21-22 with loss of heterozygosity in 73% of samples; 8/11 liver metastasis samples had loss which was not present in the corresponding matched primary colon tumour. 13 candidate genes were identified for further analysis. Both up and down-regulation of 8p21-22 gene expression was associated with metastasis. ADAMDEC1 mRNA and protein expression decreased during both tumourigenesis and tumour progression. Increased STC1 and LOXL2 mRNA expression occurred during tumourigenesis. Liver metastases with low DcR1/TNFRSF10C mRNA expression were more likely to present with extrahepatic metastases (p = 0.005). A novel germline truncating mutation of DR5/TNFRSF10B was identified, and DR4/TNFRSF10A SNP rs4872077 was associated with the development of liver metastases (p = 0.02).Conclusion: Our data confirm that genes on 8p21-22 are dysregulated during colorectal cancer progression. Interestingly, however, instead of harbouring a single candidate colorectal metastasis suppressor 8p21-22 appears to be a hot-spot for tumour progression, encoding at least 13 genes with a putative role in carcinoma development. Thus, we propose that this region of 8p comprises a metastatic susceptibility locus involved in tumour progression whose disruption increases metastatic potential. [ABSTRACT FROM AUTHOR]

The purpose of this research was to investigate the diagnostic and prognostic value of circulating SFRP5 (cSFRP5) in colorectal cancer (CRC). We evaluated preoperative cSFRP5 levels in CRC patients and controls (n = 208). We found significantly higher cSFRP5 levels in CRC patients compared with non-CRC controls (p < 0.001). Levels of cSFRP5 were significantly lower in CRC patients with either vascular invasion (p = 0.001) or liver metastasis (p = 0.016). High cSFRP5 levels were associated with longer disease-free survival in both univariate (p = 0.024) and multivariate (p = 0.015) analyses. Analysis of an independent tissue cohort from The Cancer Genome Atlas database revealed significantly lower SFRP5 RNA expression in CRC tumor tissue compared with adjacent normal mucosa (n = 590 vs 47; p < 0.0001). Our findings confirm the role of cSFRP5 as a physiologic tumor suppressor and demonstrate its potential diagnostic and prognostic value in CRC.

Objective: Adipose tissue plays a key role in obesity-related metabolic dysfunction. MicroRNA (miRNA) are gene regulatory molecules involved in intercellular and inter-organ communication. It was hypothesized that miRNA levels in adipose tissue would change after gastric bypass surgery and that this would provide insights into their role in obesity-induced metabolic dysregulation., Methods: miRNA profiling (Affymetrix GeneChip miRNA 2.0 Array) of omental and subcutaneous adipose (n = 15 females) before and after gastric bypass surgery was performed., Results: One omental and thirteen subcutaneous adipose miRNAs were significantly differentially expressed after gastric bypass, including downregulation of miR-223-3p and its antisense relative miR-223-5p in both adipose tissues. mRNA levels of miR-223-3p targets NLRP3 and GLUT4 were decreased and increased, respectively, following gastric bypass in both adipose tissues. Significantly more NLRP3 protein was observed in omental adipose after gastric bypass (P = 0.02). Significant hypomethlyation of NLRP3 and hypermethylation of miR-223 were observed in both adipose tissues after gastric bypass. In subcutaneous adipose, significant correlations were observed between both miR-223-3p and miR-223-5p and glucose and between NLRP3 mRNA and protein levels and blood lipids., Conclusions: This is the first report detailing genome-wide miRNA profiling of omental adipose before and after gastric bypass, and it further highlights the association of miR-223-3p and the NLRP3 inflammasome with obesity., (© 2020 The Obesity Society.)

Obesity, particularly visceral adiposity, has been linked to mitochondrial dysfunction and increased oxidative stress, which have been suggested as mechanisms of insulin resistance. The mechanism(s) behind this remains incompletely understood. In this study, we hypothesized that mitochondrial complex II dysfunction plays a role in impaired insulin sensitivity in visceral adipose tissue of subjects with obesity. We obtained subcutaneous and visceral adipose tissue biopsies from 43 subjects with obesity (body mass index ≥ 30 kg/m 2 ) during planned bariatric surgery. Compared with subcutaneous adipose tissue, visceral adipose tissue exhibited decreased complex II activity, which was restored with the reducing agent dithiothreitol (5 mM) ( P < 0.01). A biotin switch assay identified that cysteine oxidative posttranslational modifications (OPTM) in complex II subunit A (succinate dehydrogenase A) were increased in visceral vs. subcutaneous fat ( P < 0.05). Insulin treatment (100 nM) stimulated complex II activity in subcutaneous fat ( P < 0.05). In contrast, insulin treatment of visceral fat led to a decrease in complex II activity ( P < 0.01), which was restored with addition of the mitochondria-specific oxidant scavenger mito-TEMPO (10 µM). In a cohort of 10 subjects with severe obesity, surgical weight loss decreased OPTM and restored complex II activity, exclusively in the visceral depot. Mitochondrial complex II may be an unrecognized and novel mediator of insulin resistance associated with visceral adiposity. The activity of complex II is improved by weight loss, which may contribute to metabolic improvements associated with bariatric surgery.

Biomarkers are urgently required to support current histological staging to provide additional accuracy in stratifying colorectal cancer (CRC) patients according to risk of spread to properly assign adjuvant chemotherapy after surgery. Chemotherapy is given to patients with stage III to reduce the risk of recurrence but is controversial in stage II patients. Up to 25% of stage II patients will relapse within 5 years after tumor removal and when this occurs cure is seldom possible. The aim of this study was to identify protein biomarkers to stratify risk of spread of CRC patients. Laser micro-dissection was used to isolate cancer cells from primary colorectal tumors of stage II patients which did or did not metastasize within 5 years after surgical resection. Protein expression differences between two groups of tumors were profiled by 2D-DIGE with saturation CyDye labeling and identified using MALDI-TOF mass spectrometry. Evaluation of protein candidates was conducted using tissue micro array (TMA) immunohistochemistry on 125 colorectal tumor tissue samples of different stages. A total of 55 differentially expressed proteins were identified. Ten protein biomarkers were chosen based on p value and ratio between non metastasized and metastazised groups and evaluated on 125 tissues using TMA immunohistochemistry. Expression of HLAB, protein 14-3-3β, LTBP3, ADAMTS2, JAG2 and NME2 on tumour cells was significantly associated with clinical parameters related to tumour progression, invasion and metastasis. Kaplan-Meier survival curve showed strong expression of six proteins was associated with good CRC specific survival. Expression of HLAB, ADAMTS2, LTBP3, JAG2 and NME2 on tumour cells, was associated with tumour progression and invasion, metastasis and CRC specific survival may serve as potential biomarkers to stratify CRC patients into low and high risk of tumour metastasis. Combined methods of laser microdissection, 2D DIGE with saturation labelling and MALDI-TOF MS proved to be resourceful techniques capable of identifying protein biomarkers to predict risk of spread of CRC to liver.

Objective: Extracellular microRNAs (miRNAs) represent functional biomarkers for obesity and related disorders; this study investigated plasma miRNAs in insulin resistance phenotypes in obesity., Methods: One hundred seventy-five miRNAs were analyzed in females with obesity (insulin sensitivity, n = 11; insulin resistance, n = 19; type 2 diabetes, n = 15) and without obesity (n = 12). Correlations between miRNA level and clinical parameters and levels of 15 miRNAs in a murine obesity model were investigated., Results: One hundred six miRNAs were significantly (adjusted P ≤ 0.05) different between controls and at least one obesity phenotype, including miRNAs with the following attributes: previously reported roles in obesity and altered circulating levels (e.g., miR-122, miR-192); known roles in obesity but no reported changes in circulating levels (e.g., miR-378a); and no current reported role in, or association with, obesity (e.g., miR-28-5p, miR-374b, miR-32). The miRNAs in the latter group were found to be associated with extracellular vesicles. Forty-eight miRNAs showed significant correlations with clinical parameters; stepwise regression retained let-7b, miR-144-5p, miR-34a, and miR-532-5p in a model predictive of insulin resistance (R 2  = 0.57, P = 7.5 × 10 -8 ). Both miR-378a and miR-122 were perturbed in metabolically relevant tissues in a murine model of obesity., Conclusions: This study expands on the role of extracellular miRNAs in insulin-resistant phenotypes of obesity and identifies candidate miRNAs not previously associated with obesity., (© 2017 The Obesity Society.)

The expression of HLA-G by tumour cells is an established mechanism to escape recognition and immune mediated destruction, allowing tumour survival, growth and metastasis. However, the prognostic value of soluble HLA-G (sHLA-G) remains unknown. Mucinous carcinoma (MC) is a distinct form of colorectal cancer (CRC) found in 10 to 15% of patients, which has long been associated with poor response to treatment. To investigate the prognostic value of plasma sHLA-G levels in CRC patients, preoperative plasma sHLA-G levels were determined by ELISA in CRC patients (n = 133). In addition, the local expression of HLA-G in tumour biopsies was assessed using tissue microarray analysis (n = 255). Within the high 33rd percentile of sHLA-G levels (265-890 U/mL; n = 44) we observed higher frequency of MC patients (p = 0.012; Chi-square), and higher sHLA-G levels in patients with vascular invasion (p = 0.035; two-tailed t-test). Moreover, MC patients had significantly higher sHLA-G levels compared to those with adenocarcinoma not otherwise specified (p = 0.036; two-tailed t-test). Surprisingly, while stage II patients showed negative correlation between sHLA-G levels and liver metastasis free survival (LMFS) (p = 0.041; R = -0.321), in stage III patients high sHLA-G levels were associated with significantly longer LMFS (p = 0.002), and sHLA-G levels displayed positive correlation with LMFS (p = 0.006; R = 0.409). High HLA-G expression in tumours was associated with poor cancer specific overall survival in stage II to III (p = 0.01), and with shorter LMFS in stage II patients (p = 0.004). Our findings reveal that sHLA-G levels are associated with distinct progression patterns in consecutive disease stages, indicating a potential value as surrogate marker in the differential prognosis of CRC., (© 2017 UICC.)

Background: Epigenetic mechanisms provide an interface between environmental factors and the genome and are known to play a role in complex diseases such as obesity. These mechanisms, including DNA methylation, influence the regulation of development, differentiation and the establishment of cellular identity. Here we employ two approaches to identify differential methylation between two white adipose tissue depots in obese individuals before and after gastric bypass and significant weight loss. We analyse genome-wide DNA methylation data using (a) traditional paired t tests to identify significantly differentially methylated loci (Bonferroni-adjusted P  ≤ 1 × 10 -7 ) and (b) novel combinatorial algorithms to identify loci that differentiate between tissue types., Results: Significant differential methylation was observed for 3239 and 7722 CpG sites, including 784 and 1129 extended regions, between adipose tissue types before and after significant weight loss, respectively. The vast majority of these extended differentially methylated regions (702) were consistent across both time points and enriched for genes with a role in transcriptional regulation and/or development (e.g. homeobox genes). Other differentially methylated loci were only observed at one time point and thus potentially highlight genes important to adipose tissue dysfunction observed in obesity. Strong correlations ( r  > 0.75, P  ≤ 0.001) were observed between changes in DNA methylation (subcutaneous adipose vs omentum) and changes in clinical trait, in particular for CpG sites within PITX2 and fasting glucose and four CpG sites within ISL2 and HDL. A single CpG site (cg00838040, ATP2C2 ) gave strong tissue separation, with validation in independent subcutaneous ( n  = 681) and omental ( n  = 33) adipose samples., Conclusions: This is the first study to report a genome-wide DNA methylome comparison of subcutaneous abdominal and omental adipose before and after weight loss. The combinatorial approach we utilised is a powerful tool for the identification of methylation loci that strongly differentiate between these tissues. This study provides a solid basis for future research focused on the development of adipose tissue and its potential dysfunction in obesity, as well as the role DNA methylation plays in these processes.

Type 2 diabetes mellitus (T2DM) results from a combination of progressive insulin resistance and loss of pancreatic beta cell function and/or mass. Insulin signalling occurs through the insulin receptor, (INSR) which is alternatively spliced into two isoforms: INSRA (-exon 11) and INSRB (+exon 11). Because the INSR isoforms have different functional characteristics, their relative expression ratio has been implicated in the pathogenesis of insulin resistance and T2DM. We studied levels of INSR isoform mRNA in liver samples taken from 46 individuals with or without T2DM at Roux-en-Y (RYGB) surgery, and on average 17 (± 5.6) months later in 16 of the same individuals (8 diabetic and non-diabetic patients). INSRA or INSRB was also overexpressed in HepG2 cells to ascertain their effect on AKT phosphorylation and PCK1 expression as markers of insulin-mediated metabolic signalling. We found the INSRB:A isoform ratio was reduced in individuals with T2DM in comparison to those with normal glucose tolerance and normalised with remission of diabetes. The INSRB:A ratio increased due to a reduction in the alternatively spliced INSRA isoform following remission of diabetes. Overexpressing INSRA isoform in HepG2 hepatoma cells reduced inhibition of PCK1 transcription and did not increase AKT phosphorylation in response to insulin load compared to the effect of overexpressing the B isoform. Data presented here revitalizes the role of the INSR isoforms in the pathogenesis of T2DM, and suggests that an abrogated INSRB:A ratio that favours the INSRA isoform may negatively impact insulin-mediated metabolic signalling.

Background: Environmental factors can influence obesity by epigenetic mechanisms. Adipose tissue plays a key role in obesity-related metabolic dysfunction, and gastric bypass provides a model to investigate obesity and weight loss in humans., Results: Here, we investigate DNA methylation in adipose tissue from obese women before and after gastric bypass and significant weight loss. In total, 485,577 CpG sites were profiled in matched, before and after weight loss, subcutaneous and omental adipose tissue. A paired analysis revealed significant differential methylation in omental and subcutaneous adipose tissue. A greater proportion of CpGs are hypermethylated before weight loss and increased methylation is observed in the 3' untranslated region and gene bodies relative to promoter regions. Differential methylation is found within genes associated with obesity, epigenetic regulation and development, such as CETP, FOXP2, HDAC4, DNMT3B, KCNQ1 and HOX clusters. We identify robust correlations between changes in methylation and clinical trait, including associations between fasting glucose and HDAC4, SLC37A3 and DENND1C in subcutaneous adipose. Genes investigated with differential promoter methylation all show significantly different levels of mRNA before and after gastric bypass., Conclusions: This is the first study reporting global DNA methylation profiling of adipose tissue before and after gastric bypass and associated weight loss. It provides a strong basis for future work and offers additional evidence for the role of DNA methylation of adipose tissue in obesity.

Background: Type 2 diabetes mellitus (T2DM) is a progressive disease resulting from increasing insulin resistance and reduced pancreatic β-cell insulin secretion. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) inhibits insulin signalling and may contribute to the pathogenesis of T2DM. Others have found elevated ENPP1 levels in muscle, fat, and skin tissues from insulin resistant individuals, but similar data on liver ENPP1 is lacking. The purpose of this study was to compare expression and protein concentrations of ENPP1 in liver between patients with and without T2DM., Methods: Roux-en-Y gastric bypass surgery (RYGB) results in remission of insulin resistance and T2DM thus presenting an opportunity to examine some critical aspects of these conditions. We measured liver ENPP1 gene and protein expression in individuals with or without T2DM at RYGB and on average 17 (±5.6) months later., Results: We found liver ENPP1 protein abundance was lower in individuals with T2DM than in those with normal glucose tolerance, and increased after RYGB surgery in those individuals who had remission of T2DM. ENPP1 positively correlated with insulin sensitivity at the liver (as measured by HOMA-IR), which is contrary to what others have reported in other insulin target tissues., Conclusions: Liver ENPP1 expression in T2DM is the reverse of that expected based on expression in other tissues and is likely due to the unique role the liver has in insulin clearance. The work presented here adds another dimension to the role of ENPP1, and supports the hypothesis that ENPP1 may act as a natural modulator of insulin signalling in the liver.

Type 2 diabetes affects millions of people worldwide, and measuring the kinetics of insulin receptor-insulin interactions is critical to improving our understanding of this disease. In this paper, we describe, for the first time, a rapid, real-time, multiplex surface plasmon resonance (SPR) assay for studying the interaction between insulin and the insulin receptor ectodomain, isoform A (eIR-A). We used a scaffold approach in which anti-insulin receptor monoclonal antibody 83-7 (Abcam, Cambridge, UK) was first immobilized on the SPR sensorchip by amine coupling, followed by eIR-A capture. The multiplex SPR system (ProteOn XPR36™, Bio-Rad Laboratories, Hercules, CA) enabled measurement of replicate interactions with a single, parallel set of analyte injections, whereas repeated regeneration of the scaffold between measurements caused variable loss of antibody activity. Interactions between recombinant human insulin followed a two-site binding pattern, consistent with the literature, with a high-affinity site (dissociation constant K(D1)  = 38.1 ± 0.9 nM) and a low-affinity site (K(D2)  = 166.3 ± 7.3 nM). The predominantly monomeric insulin analogue Lispro had corresponding dissociation constants K(D1)  = 73.2 ± 1.8 nM and K(D2)  = 148.9 ± 6.1 nM, but the fit to kinetic data was improved when we included a conformational change factor in which the high-affinity site was converted to the low-affinity site. The new SPR assay enables insulin-eIR-A interactions to be followed in real time and could potentially be extended to study the effects of humoral factors on the interaction, without the need for insulin labeling., (Copyright © 2013 John Wiley & Sons, Ltd.)

Aminoacylase 1 (ACY1) is a cytosolic enzyme responsible for amino acid deacylation during intracellular protein degradation. ACY1 has been implicated in a number of human tumor types. However, the exact role of ACY1 in tumor development remains elusive because it was found to be lost in small cell lung cancer and renal cell carcinoma but overexpressed in colorectal cancer (CRC). The present study aims to further clarify the relationship of ACY1 with CRC progression. Immunohistochemical staining was performed in tissue microarrays composed of 120 cases of CRC using a monoclonal anti-ACY1 antibody. Immunoreactivity was analyzed in association with patients' clinicopathologic parameters and survival time. The role of ACY1 in cell proliferation and apoptosis was assessed by silencing its expression in HCT116 cells using a small interfering RNA. Strong expression of ACY1 was found to be significantly associated with more advanced TNM stage, lymph node metastasis, positive vascular invasion, and shorter cancer-specific survival. ACY1 knockdown significantly inhibited cell proliferation and induced apoptosis. We concluded that ACY1 expression in CRC varies with stage and appears to play a role in cell proliferation and apoptosis. Further evaluation of ACY1 as a clinically useful prognostic marker and a potential drug target for CRC would seem worthwhile., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The emergence of laser capture microdissection (LCM) and two-dimensional difference gel electrophoresis (2D-DIGE) has been shown to greatly improve the accuracy and sensitivity of global protein expression analysis. However, their combined use in profiling tumour proteome has rarely been reported. In this study, we applied these techniques to profile the protein expression changes of the late stage colorectal cancer (CRC) and its liver metastases. The study revealed that both the primary and secondary tumours showed a distinct protein expression profile compared to normal tissues, but were indistinguishable from each other. Differential analysis between the primary tumour and patient-matched normal colon mucosa identified a total of 71 proteins to be altered in CRC. Over 40% of these proteins have been previously reported as CRC-related proteins, validating the accuracy of the current analysis. We have also identified many previously unknown changes including overexpression of ACY1, HSC70, HnRNP I, HnRNP A3, SET, ANP32A and TUFM in CRC, which have been further verified by western blotting and immunohistochemistry. This study demonstrated that LCM in combination with 2D-DIGE is a powerful tool to analyse the proteome of tumour tissues and may lead to the identification of potential novel protein markers and therapeutic targets for cancer., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The explanation for the rapid improvement in insulin resistance after Roux-en Y gastric bypass (RYGB) may involve mechanisms additional to caloric restriction and improvements in peripheral glucose disposal. 8 severely obese patients underwent a 6-day very low calorie diet (VLCD) (456 kcal/day) followed 1-3 weeks later by RYGB. Insulin resistance was measured by short intravenous insulin tolerance test (IVITT) and by homeostasis model assessment (HOMA) before and again 6 days after the VLCD and after RYGB. In a group of 24 matched patients, HOMA assessments were made before and six days after RYGB. HOMA-IR fell significantly from 6.84.9 to 4.32.9 (p < 0.05) following VLCD, but this was less than the subsequent fall following RYGB (6.8 ± 4.9 to 1.50.4, p < 0.01). Control patients who underwent RYGB alone, reduced their HOMA-IR to 1.50.9 following the operation which was not significantly different from the VLCD then RYGB group. Following VLCD, IVITT showed no significant change. However, 6 days after RYGB, IVITT showed worsened insulin induced glucose uptake (p < 0.05). Patients undergoing VLCD over six days had a reduction in HOMA-IR which was half that of patients undergoing RYGB. Patients who underwent both VLCD and RYGB had a total reduction in HOMA similar to those who underwent the RYGB alone. In contrast, IVITT showed a worsening in insulin induced glucose disposal following RYGB, which suggests worsening peripheral insulin resistance. This study supports the hypothesis that mechanisms other than caloric restriction are involved in the acute improvement in HOMA-IR following RYGB.

Background: Severely obese type 2 diabetics who undergo Roux-en Y gastric bypass surgery have significant improvements in glycaemic control. Little work has been undertaken to establish the independent predictors of such resolution or to develop a predictive model. The aim of this study was to develop a mathematical model and establish independent predictors for the resolution of diabetes., Methods: A consecutive sample of 130 severely obese type 2 diabetics who underwent gastric bypass surgery for weight loss from November 1997 to May 2007 with prospective pre-operative documentation of biochemical and clinical measurements was followed up over 12 months. Logistic discrimination analysis was undertaken to identify those variables with independent predictive value and to develop a predictive model for resolution of type 2 diabetes. Consecutive samples of 130 patients with body mass index (BMI) ≥ 35 with type 2 diabetes were selected. One hundred and twenty-seven patients completed the study with a sufficient data set. Patients were deemed unresolved if (1) diabetic medication was still required after surgery; (2) if fasting plasma glucose (FPG) remained >7 mmol/L; or (3) HbA1c remained >7%., Results: Resolution of diabetes was seen in 84%, while diabetes remained but was improved in 16% of patients. Resolution was rapid and sustained with 74% of those on medication before surgery being able to discontinue this by the time of discharge 6 days following surgery. Five pre-operative variables were found to have independent predictive value for resolution of diabetes, including BMI, HbA1c, FPG, hypertension and requirement for insulin. Two models have been proposed for prediction of diabetes resolution, each with 86% correct classification in this cohort of patients., Conclusions: Type 2 diabetes resolves in a very high percentage of patients undergoing gastric bypass surgery for severe obesity. The key predictive variables include pre-operative BMI, HbA1c, FPG, the presence of hypertension and diabetic status.

Background: In 2008, Troy et al. hypothesised that under fasting conditions, intestinal gluconeogenesis generates glucose levels in the portal vein which trigger the portal sensor to change insulin resistance and that this mechanism contributes to the effects of Roux-en-Y gastric bypass (RYGB) surgery on type 2 diabetes mellitus (T2DM). In a recent paper, Kashyap et al. (Int J Obes 34(3):426-471, 2010) cited this hypothesis as a potential explanation for the early changes in insulin sensitivity and beta cell function seen after RYGB. We proposed a study to examine this possibility., Methods: We simultaneously sampled fasting portal venous blood and central venous blood in 28 patients (eight diabetics and 20 non-diabetics) before and again six days after RYGB surgery in morbidly obese patients, for measurement of glucose levels., Results: We found no significant difference in the glucose levels from the two sites either before or after RYGB in diabetic patients and a small, but significant difference in the post-operative glucose levels from non-diabetic patients (4.2 vs 4.0 mM, p < 0.0001)., Conclusions: Direct simultaneous measurement of fasting glucose in portal and central venous blood before and 6 days after RYGB provides no evidence to support the hypothesis that intestinal gluconeogenesis contributes to the resolution of T2DM seen after RYGB.

Background. Nonresectable neuroendocrine tumour (NET) liver metastases respond poorly to most widely available and used therapies. Selective Internal Radiation Therapy (SIRT) is becoming recognized as a new modality for selectively treating non-resectable liver tumours. This paper presents an experience of 14 patients with non-resectable NET liver metastases treated with SIRT. Methods. Between September 1997 and October 2009 14 patients with extensive NET liver metastases were treated with 2.0 to 3.0 GBq of (90)Yttrium microspheres. Repeat SIRT was undertaken in three patients after 16, 27, and 48 months, respectively. Responses were assessed clinically, biochemically, and with serial CT scans. Survival was measured from initial SIRT. Results. Some response was seen in all 14 patients. Carcinoid syndrome improved or resolved in 10/10 instances. 24-hour urinary 5-HIAA or serum chromogranin A levels fell dramatically in 5/7 patients following SIRT. Serial CT scans revealed partial response or stable disease in all 14 patients. Repeat treatment in three patients experiencing progression was associated with a further response. Median survival after SIRT is 25 months with 6 patients being alive (and 3 patients still asymptomatic), at 19, 22, 23, 23, 58, and 60 months. Conclusions. SIRT is an effective and well-tolerated treatment for non-resectable NET liver metastases capable of both alleviating the carcinoid syndrome and achieving significant tumour regression. Repeat treatment is an option and liver resection after downstaging may also become possible.

Background: The placement of a ring circumferentially around the gastric pouch of a vertical gastric bypass has the advantage of permanently fixing the size of the gastric outlet and slowing the passage of food into the jejunum. Opinion remains divided about the use of rings, and the optimal size., Methods: Since 1990, we have consistently placed a ring at the time of gastric bypass surgery and have an experience with three ring sizes (circumference); 5.5 cm, 6.0 cm and 6.5 cm. Patient data has been recorded prospectively in a computerized database. We have reviewed the outcomes of all patients with at least 12 months follow-up with respect to quality of eating, the need for subsequent ring removal and weight loss., Results: Quality of eating was better in those with the larger rings. Ring removal was undertaken in 7 (14%) of those with a 5.5-cm ring, in 11 (5.1%) with a 6.0 cm ring and in 3 (2%) with a 6.5-cm ring (P<0.05). Ring removal led to a median recorded weight gain of 6.8 kg (-4.13 kg to 32.2 kg). When only those 415 patients in whom the ring was still in situ and there was no known staple-line disruption were considered (5.5 cm - 50, 6 cm - 215, 6.5 cm -150), there was no difference in the weight loss achieved and maintained out to 5 years, although there was a trend for this to be better in those with the larger rings., Conclusion: We conclude that the inclusion of a ring placed around the gastric pouch of a vertical gastric bypass is beneficial for maintenance of weight loss, and a ring size of 6.5-cm circumference should be recommended.

Background: Many patients with colorectal liver metastases die from liver-only disease. Selective internal radiation therapy (SIRT) is an evolving method suitable for treating patients with non-resectable metastatic liver disease., Methods: One hundred patients with advanced colorectal liver metastases were treated with SIRT. A single dose of between 2.0 and 3.0 GBq of (90)Y microspheres was given into the hepatic artery either by a surgically implanted portacath or a percutaneous femoral catheter. When a port was used (n = 87), SIRT was followed by hepatic arterial chemotherapy with 5-fluorouracil., Results: Treatment-related morbidity occurred in 11 patients. Responses to SIRT were assessed by serial computed tomography scans and carcinoembryonic antigen (CEA) measurement. Median CEA level 3 months after SIRT (expressed as percentage of initial CEA) was 18%. Only 5 of 80 patients (6.25%) scanned at 3 months showed disease progression. Survival was significantly more in those who experienced a good tumour marker response and in those who were slow to develop extrahepatic disease. Survival was independently influenced by the use of ongoing hepatic arterial chemotherapy, the extent of liver involvement and the lymph node status of the original primary tumour., Conclusion: Selective internal radiation therapy is a very effective and well-tolerated regional treatment for colorectal liver metastases, which should be considered for those with liver-only metastatic disease.

Background: SIRT is an emerging treatment for liver tumours which relies on the selective uptake by tumour of 90Y microspheres following hepatic arterial injection. Response rates of around 90% are reported. Hepatic arterial injection of MAA gives an indication of the expected distribution of 90Y microspheres within the liver. This study sought to determine if the MAA scan could be predictive of subsequent tumour response., Methods: 58 patients with colorectal hepatic metastases received SIRT. All had pre-treatment MAA planar images and CT scans which were retrospectively reviewed. Tumours were qualitatively considered "cold", "equivocal" or "hot" based on MAA uptake and the ratio of uptake in tumour and normal liver tissue was calculated (TNR). Following SIRT (which included the administration of hepatic arterial Angiotensin 2) tumour response was assessed by CEA changes one to two months after treatment and by serial CT., Results: Uptake was classified as "hot" in 37 patients (Group 1) and "equivocal" or "cold" in 21 (Group 2). CEA levels fell dramatically in over 90% of patients. The falls were not significantly different between the groups. There was no correlation between TNR and tumour response based on CEA changes (r2 = 0.004). CT responses after 3 months were not different in the 2 Groups., Conclusion: The pattern of MAA uptake by colorectal liver tumours after arterial injection is not a predictor of tumour response after treatment by SIRT. The results suggest the doses of 90Y microspheres used may be greater than is necessary.

Background: Gastric bypass has repeatedly been shown to improve and even cure type 2 diabetes by substantially improving insulin resistance. The mechanism by which it achieves this is not currently known, but some have hypothesized that there may be important humoral effects brought about by the bypass of the stomach, duodenum or proximal jejunum. A better understanding of the time course of the changes in insulin resistance after surgery might assist our understanding of potential mechanisms., Methods: Intravenous glucose tolerance tests (IVGTT) were performed in 26 severely obese patients on the morning of gastric bypass surgery and again 6 days later. In addition insulin resistance was assessed in 71 patients undergoing gastric bypass surgery by the homeostasis model assessment (HOMA) method before surgery, and again at 6 days, 3, 6, 9, and 12 months. Patients were divided into 3 groups for analysis: diabetics, impaired glucose tolerance and normal glucose tolerance., Results: All 3 groups of patients were noted to have insulin resistance prior to surgery. This was greatest in the diabetic patients, as indicated by HOMA. There was marked loss of/improvement in insulin resistance within 6 days of gastric bypass by both IVGTT and HOMA methods in all groups, which was maintained over the 12-month period. The study included 31 diabetic patients, of whom only 3 required medication following hospital discharge., Conclusion: The changes in insulin resistance seen after gastric bypass, which are responsible for the resolution or improvement of type 2 diabetes occur within 6 days of the surgery, before any appreciable weight loss has occurred. This finding has implications for our understanding of the mechanism of insulin resistance in severely obese patients and is consistent with a humoral mechanism emanating from the GI tract.

Background: While a great deal has been published regarding the short- and medium-term outcomes of gastric bypass surgery, much less information is available regarding long-term follow-up. Such information would be valuable in changing attitudes towards this surgery., Methods: 342 severely obese patients underwent gastric bypass between June 1990 and April 2003 by a single surgeon. Careful preoperative documentation and follow-up have been maintained on a computerized database. Where necessary, recent followup information has been gained by mailed questionnaire and blood tests., Results: Follow-up data from within the last 12 months is available for 88% of patients. Follow-up time ranges from 0-14 years, with a median of 48.6 months. Of those lost to follow-up, only 24 (7%) have <12 months follow-up. The series includes 261 females and 81 males. Preoperative BMI ranged from 28-99 (median 44). Before surgery, hypertension was present in 138, type 2 diabetes in 62, and dyslipidemia in 265. There was no 30-day peri-operative mortality. Three life-threatening complications occurred. BMI and % excess weight loss after 1, 2, 5 and 10 years were 28.7 and 89%, 28.3 and 87%, 31.2 and 70% and 31 and 75%, respectively. At most recent follow-up, 62% of those with hypertension before surgery were cured and 25% had improved. 85% of those with type 2 diabetes were cured and 10% had improved. No patients with impaired glucose tolerance had progressed to diabetes. 34% of those with dyslipidemia were cured and 38% had improved., Conclusion: The excellent outcomes, in terms of weight loss and improvement in co-morbidities, seen in both the short- and medium-term after gastric bypass, are well maintained into the longer-term.

Background: Selective internal radiation therapy (SIRT) is a new and developing modality for treating non-resectable liver tumours. Evidence is emerging that it is very efficacious in patients with hepatocellular cancer and colorectal liver metastases., Discussion: SIRT generally involves a single delivery of (90)yttrium micro-spheres into the hepatic artery. Preferential uptake is achieved into liver tumours, because of their predominant hepatic arterial blood supply. Average tumour doses of radiation in excess of 200 Gy are achieved. The treatment is generally well tolerated and has been documented by a number of groups internationally to achieve response rates of around 90% in patients with extensive colorectal cancer (CRC) liver metastases. Since the product obtained FDA approval in the USA in 2002, it is being more widely employed and investigated. Unlike other ablative therapies being applied to non-resectable liver tumours, SIRT is indicated even in patients with an extensive burden of liver tumour. Indications, dosing schedules and expected outcomes will become better defined as more groups take up the treatment.

Background: Several species of Helicobacter colonise the biliary tract of animals and cause hepatobiliary diseases. Helicobacter species have also been identified in the gallbladder of a high proportion of Chilean patients with gallbladder cancer., Aim: To determine the presence of Helicobacter species, particularly Helicobacter pylori and Helicobacter bilis, in the gallbladder of patients with non-malignant gallbladder diseases and control patients., Patients and Methods: DNA was extracted from gallbladder samples from 122 consecutive patients undergoing cholecystectomy. The presence of Helicobacter genus-specific or Helicobacter pylori and Helicobacter bilis species-specific DNA was determined by polymerase chain reaction and sequence analysis. The presence of Helicobacter pylori-specific immunoglobulin G in the serum (n=84) and bile (n=104) samples was determined by enzyme linked immunosorbent assay., Results: Helicobacter DNA was detected in 61 (50.0%) gallbladder samples: 29 of 60 (48.3%) patients with symptomatic gallstone, six of 10 (60.0%) patients with asymptomatic gallstones, 11 of 15 (73.3%) patients with other biliary diseases, and 15 of 37 (40.5%) control patients, respectively. Among them, 39 samples were positive for Helicobacter pylori but none were positive for Helicobacter bilis. Sequence analysis of Helicobacter genus-positive samples showed that 56 samples were Helicobacter pylori and five were Helicobacter species 'Liver 3' strain. Overall, there was no significant difference in the detection rate of Helicobacter DNA or the levels of serum and bile Helicobacter pylori-specific immunoglobulin G in the various biliary disease groups compared with control patients. Neither was there any significant difference in the blood biochemistry and liver function tests between patients with positive and negative Helicobacter DNA detection., Conclusion: Helicobacter species' DNA are commonly present in the gallbladder of patients with gallstone diseases and in controls, implying that Helicobacter infection alone may not play a significant role in the formation of gallstones. However, our results do not exclude the possibility of Helicobacter infection as a cofactor in the development of gallstones.

Purpose: Liver surgeons usually recommend against biopsy of colorectal liver metastases because of the risk of local dissemination. To date, only case reports describing this problem have been published. This study is an attempt to quantify the risk of biopsy-related dissemination., Methods: A multicenter, retrospective review was undertaken of cases of colorectal liver metastases presenting for surgery that had undergone a preoperative biopsy., Results: Two hundred thirty-one cases of colorectal liver metastases presenting for surgery were identified. Forty-three cases had undergone a preoperative biopsy (18.6 percent). Seven patients had evidence of dissemination related to the biopsy, giving a risk of dissemination of 16 percent (95 percent confidence interval, 7-30 percent). The risk of dissemination was not related to the type of biopsy. Within the follow-up period (median, 21 months), 3 of the 7 cases with evidence of dissemination and 11 of the 35 without dissemination were alive without disease. Twenty-five percent of the 36 cases without dissemination were resected, whereas 6 of the 7 cases with dissemination were resected., Conclusions: There is a significant risk of local dissemination with biopsy of colorectal liver metastases. In this series this was independent of the type of biopsy. There was no demonstrated effect on resectability or survival, but numbers were small, and the median follow-up was short.

Background: The association between insulin resistance (IR) and obesity and its causal relationship with type 2 diabetes is well recognized. The possibility of an association, causal or otherwise, with other obesity-related co-morbidities warrants consideration., Methods: IR was calculated pre-operatively in 80 patients undergoing gastric bypass surgery for severe obesity, using the homeostasis model assessment (HOMA) method, and again in 70 patients on at least one occasion post-operatively within 12 months. Correlations with weight parameters and pre-existing co-morbidities including diabetes, hypertension, dyslipidemia and hepatic steatosis were made., Results: 78/80 patients had IR pre-operatively which did not correlate with pre-operative weight or BMI. As expected, there were positive correlations between pre-operative IR and abnormal glucose tolerance and diabetes. A positive correlation was also found between IR and hepatic steatosis, but no correlation was noted between IR and hypertension or fasting levels of cholesterol, triglycerides or Chol/HDL cholesterol ratios. Improvement in IR was uniformly seen after gastric bypass, sooner than would be accounted for by weight loss alone. The degree of pre-operative IR was not a predictor of weight loss after gastric bypass in these patients., Conclusions: While IR is an almost universal accompaniment of severe obesity, it does not correlate with the degree of obesity in this group of patients. A number of important co-morbidities show a clear association with IR, and improvement in these after gastric bypass may well be related to striking and rapid changes in IR.

Increasing attention has been given to treatments for colorectal liver metastases ever since hepatic resection was established as being worthwhile. Given the high proportion of patients who die of colorectal cancer with liver-only disease, it seems appropriate to be developing and investigating methods of local liver tumor ablation. Selective internal radiation therapy (SIRT) is a relatively new, not widely used, modality suitable for use even in patients with extensive liver involvement. Fifty patients with advanced, nonresectable, colorectal liver metastases were treated with SIRT between February 1997 and June 1999. Estimated liver involvement was less than 25% in 30 patients, 25% to 50% in 13, and greater than 50% in seven. A single dose of between 2.0 and 3.0 GBq of 90yttrium microspheres was injected into the hepatic artery via a subcutaneous port and followed at 4-week intervals by regional chemotherapy with 5-fluorouracil. SIRT was well tolerated with no treatment-related mortality, although some treatment-related morbidity did occur including a 12% incidence of duodenal ulceration. Responses to SIRT were assessed by serial carcinoembryonic antigen (CEA) measurements and CT scans. Median CEA values 1 and 2 months after SIRT (expressed as percentage of initial CEA) were 19 and 13, respectively. Patients were assigned to one of two groups based on whether or not extrahepatic disease (EHD) developed within 6 months of SIRT. Median survival from SIRT for group 1 (EHD) (n = 26) was 6.9 months (range 1.3 to 18.8 months) and estimated survival +/- standard error at 6, 12, and 18 months was 57.7 +/- 3.8%, 23.1 +/- 4.8%, and 0%, respectively. For group 2 (no EHD) (n = 24), median survival was 17.5 months (range 1.0 to 30.3 months) with estimated survival at 6, 12, 18, 24, and 30 months of 79.2 +/- 2.9%, 66.7 +/- 3.6%, 55.9 +/- 3.3%, 25.2 +/- 4.4%, and 16.8 +/- 5.0%, respectively. This difference is statistically significant by log-rank test (P < 0.010). SIRT is a highly effective and well-tolerated regional treatment for extensive colorectal liver metastases. Tumor marker data suggest that substantial destruction of liver tumors can be achieved in more than 90% of patients by a single treatment. Survival times, particularly for those who do not develop extrahepatic metastases for some time, appear to be extended. SIRT warrants further use and investigation in patients with advanced colorectal liver metastases.

Purpose: To determine the changes in serum levels of proinflammatory cytokines within 48 h after selective internal radiation treatment (SIRT) in patients with advanced liver cancers., Methods and Materials: Twenty-eight patients with advanced liver cancers who underwent SIRT were recruited into the study. Serum levels of interleukin (IL)-1beta, IL-6, IL-8, IL-10, IL-12, tumor necrosis factor-alpha, and interferon-gamma were determined prior to and 3, 6, 12, 24, and 48 h after SIRT. Their changes were correlated to adverse reactions following treatment as assessed by constitutional symptom scores, and routine blood and liver function tests at 24 and 48 h post-SIRT and falls in serum carcinoembryonic antigen (CEA) level 1 month post-SIRT., Results: Serum IL-6 levels were significantly increased at 24 (p < or = 0.05) and 48 h (p < or = 0.01) post-SIRT. In contrast, there was no significant change in the serum levels of other cytokines studied. The increase in serum IL-6 at 24 h post-SIRT was significantly correlated with the changes in serum alanine transferase (p < or = 0.05) and C-reactive protein (p < or = 0.001) levels and total leukocyte counts (p < or = 0.001) at both 24 and 48 h post-SIRT. Changes in serum IL-6 level were also significantly correlated to the rise of serum aspartate transaminase levels at 48 h post-SIRT (p < or = 0.001), but not with the scores of constitutional symptoms or the changes of serum CEA at 1 month post-SIRT., Conclusion: Absence of significant changes in most of proinflammatory cytokines studied confirmed that SIRT is a reasonably safe and well-tolerated treatment with minimal side-effect from the point of view of cytokine-related inflammation. The correlation of serum IL-6 changes with several liver enzymes and C-reactive protein but not with clinical symptom scores or serum CEA levels suggests that the rise in IL-6 levels in the first 48 h following SIRT most likely reflect normal liver cell damage rather than tumor cell damage.

Background/aims: SIRT (selective internal radiation therapy) is a new modality for the treatment of nonresectable liver tumors which has been reported to achieve high response rates. We report our initial experience in patients with extensive colorectal liver metastases., Methodology: Thirty-eight (38) patients were treated with SIRT between February 1997 and November 1998. Liver involvement was < 25% in 19 patients, 25-50% in 9 and > 50% in 10. Patients received 90Yttrium microspheres into the hepatic artery via an arterial port and subsequent 4-weekly cycles of hepatic artery chemotherapy with 5-fluorouracil., Results: SIRT was well tolerated and no treatment-related mortality was observed. Responses to SIRT as indicated by falling tumor markers and serial 3-monthly computed tomography scans were seen in over 90% of patients. Estimated survival at 6, 12 and 18 months was 70%, 46% and 46%, respectively, and was principally determined by the development of extrahepatic metastases., Conclusions: SIRT is well tolerated in patients with extensive colorectal liver metastases and achieves encouraging liver tumor responses, which are well maintained by hepatic artery chemotherapy. The modality warrants wider use and investigation.

Background/aims: An ability to induce a specific immune response to cancer would provide an important new dimension in its management. We report our initial work investigating the safety and efficacy of a dendritic cell vaccine in patients with colorectal cancer., Methodology: Fifteen (15) patients with advanced colorectal cancer had vaccines prepared from autologous dendritic cells pulsed with tumor RNA and keyhole limpet hemocyanin. Vaccines were administered intravenously and patients were observed in hospital for 2 days. Thereafter, consultations were at monthly intervals at which time booster doses were given to a total of 4. Patients were monitored with weekly blood tests, including carcinoembryonic antigen, and 3-monthly computed tomography scans., Results: Flow cytometry confirmed dendritic cell phenotype and in vitro function was confirmed by mixed lymphocyte reaction. No major adverse effects were observed. Eleven of 13 patients tested developed a positive keyhole limpet hemocyanin skin test and in 7 the carcinoembryonic antigen fell suggesting some in vivo anticancer effect. To date no dramatic clinical responses have been observed but follow-up is very short., Conclusions: The therapy was well tolerated. Dendritic cells were verified by phenotype and in vitro function. The positive keyhole limpet hemocyanin skin test confirms in vivo function by effective vaccination to keyhole limpet hemocyanin. Demonstration of any anticancer efficacy will require further follow-up.

Background: Clinical observation reveals a close association between morbid obesity and a variety of serious medical conditions. This report describes the changes observed in some of these co-morbid conditions, following weight loss achieved by silastic ring gastric bypass (SRGBP)., Methods: Between 1990 and 1998, 157 severely obese patients aged 15-62 years underwent SRGBP. Initial and follow-up data was recorded prospectively on a computerized database, with minor subsequent additions being achieved by phone call or questionnaire. Particular attention was given to associated co-morbidities and improvement in these that occurred during follow-up. Median pre-operative BMI was 45 (33-97). Patients were followed for a median 2.5 years. At 2 years post-SRGBP, median BMI was 28 (20-52). Weight loss was statistically significant (p<0.0001)., Results: Before surgery 42 patients were being treated for hypertension and 34 for asthma. Withdrawal of all medication for these conditions was achieved sometime after surgery in 18 and 17 patients respectively. NIDDM was present in 19 patients before surgery and subsequently resolved completely in 18. Eleven of the 12 patients with recognized obstructive sleep apnea before surgery had resolution of this after surgery. Dyslipidemia was present in the majority of patients before surgery and resolved or improved following surgery in almost all instances., Conclusions: The findings indicate that reliable and substantial weight loss can be accomplished by gastric bypass surgery with accompanying major reductions in associated co-morbidities. Such benefits suggest that greater attention should be given to this form of treatment for those with severe obesity.

Background: Regional approaches to the management of hepatic tumours are appropriate in some clinical situations and include hepatic arterial chemotherapy (HAC) and selective internal radiation therapy (SIRT). Both require access to the hepatic artery, which is conveniently achieved with a subcutaneously placed port. Placement and use of these ports may be associated with a variety of technical problems which can impact adversely on the outcome of the treatment. The present paper outlines the problems related to port usage for regional hepatic therapies, with emphasis on the technical aspects of insertion and interpretation and management of subsequent problems., Methods: Hepatic artery port placement was attempted in 129 patients for use with either SIRT and/or HAC. Ports were used or flushed at monthly intervals., Results: Successful port insertion was achieved in 127 patients, of whom 87 received HAC alone, seven received SIRT alone, 28 patients received both and in five patients the port was never used. Methylene blue injection was used to identify anomalous arterial anatomy, which was found in 26 of 95 patients (27%), and significant extrahepatic 'access', which was seen in 25 patients (26%) after initial placement. Forty-six instances of technical problems preventing continued use of the port occurred in 43 patients after a median of 4 (0-36) cycles of chemotherapy, including hepatic artery thrombosis (n = 26), catheter blockage (n = 4), duodenal fistula (n = 3), gastrointestinal (GI) bleeding (n = 3), side-effects (n = 3), access problems (n = 3), extravasation (n = 3) and infection (n = 1)., Conclusion: Methods used to identify, manage and in some instances prevent the occurrence of these problems are discussed.

Human tumours including those of the gastrointestinal tract express a number of specific antigens that can be recognized by T cells, thus providing potential targets for cancer immunotherapy. Dendritic cells (DC) are rare leucocytes that are uniquely potent in their ability to capture, process and present antigens to T cells, and so selectively migrate through tissues to reach lymph nodes and spleen where initiation of immune responses takes place. Studies in murine tumour models have shown clearly that DC are capable of presenting tumour antigens to initiate tumour-specific cytotoxic T cell responses, and DC vaccination can induce anti-tumour activity against both primary tumours and pre-established tumour metastases. These findings together with the ability to culture sufficient numbers of DC from human bone marrow or blood progenitors have prompted the current major interest in their potential use in human tumour vaccination. Vaccine production involves harvesting autologous DC from cultured peripheral blood mononuclear cells in the presence of a cocktail of cytokines, ex vivo exposure of the DC to tumour antigens and return of pulsed DC to the patient to induce tumour immunity. Reports from Phase I/II clinical trials indicate that DC vaccines are safe with little or no side effect, and are capable of initiating antigen-specific T cell responses. Furthermore, defined tumour antigens are not necessarily required, which may make the process more applicable to human cancers, including many gastrointestinal cancers that lack well-characterized tumour-specific antigens. Additional trials of DC vaccination for a variety of human cancers including colorectal cancers are under way, and refinement of vaccine protocols and methods for targeting tumour antigens to DC in vivo are also being explored. There is reason to believe that DC-based vaccination could become an adjunct to current treatments for human cancers including colorectal cancer in the foreseeable future.

Aim: To study the presentation for and outcome of cholecystectomy in patients with acalculous gallbladder pain., Methods: Sixty-six consecutive patients with prospective documentation underwent cholecystectomy for putative acalculous gallbladder pain between December 1988 to April 1995. The diagnosis was made on clinical grounds, but in the majority, a CCK oral cholecystogram was performed. Outcomes were assessed by postal questionnaire mailed in October 1995 or by the last recorded follow- up., Results: Fifty-eight females and eight males, with a median age of 37.5 years had experienced abdominal pain, usually with associated nausea, for a median of three years. Preoperative investigations were non-contributory, with the exception of the CCK oral cholecystogram which was regarded as abnormal in all instances. At a median follow-up of 40 months, 48 patients (72.7%) described their symptoms as either totally relieved or much improved by cholecystectomy., Conclusion: Though the pathophysiology remains poorly understood, there is clearly a group of patients who suffer from gallbladder pain in the absence of gallstones and who benefit from cholecystectomy.

Aim: The incidence of hydatid disease in New Zealand has steadily declined since the introduction of control measures in the early 1960s. However, patients continue to present for management of newly recognised, disseminated or recurrent disease. It is desirable that doctors in New Zealand have some knowledge of current patterns of presentation and management of the disease., Methods: Twenty-five patients with hydatid disease have been seen and managed over a ten-year period by one hepato-biliary surgeon. Their presentation and management is outlined and discussed. Surgery, after pre-treatment with albendazole, was undertaken in 15 patients where eradication seemed possible and desirable and in three others presenting with complications (infection, rupture, fistulation). Albendazole treatment alone was used in six patients (five with uncomplicated recurrent or disseminated disease) and one patient has simply been observed., Results: There were no deaths in 18 patients who underwent surgery and no recurrent disease has been found. Major morbidity was confined to those having surgery for complications. All six patients who received albenzadole alone had a good clinical and radiological response, though they required follow-up., Conclusions: It is suggested that surgery (with albendazole pre-treatment) should be reserved for those with either curable disease or complications and that all others should be managed, in the first instance, by albendazole alone. Providing treatment is instituted before complications develop it should be associated with minimal morbidity.

This paper presents an experience of thirty consecutive patients with hepatic colorectal metastases who were treated with hepatic cryotherapy and subsequent hepatic arterial infusion (HAI) chemotherapy using 5 FU. Patients with colorectal metastases confined to the liver but not suitable for resection, and with liver involvement of less than 50% were offered the treatment. Prospective documentation of all patients was undertaken with data being recorded on a computerised database. Patients had a median of 6 (2-15) lesions with sizes ranging from 1-12 cm. There was no 30 day mortality. Postoperative complications developed in 8 patients but were followed by full recovery in all instances. Side effects from chemotherapy occurred in 23% of cycles. Twenty seven patients have died. Median survival from the time of cryotherapy was 18.2 months (7-34), or 23 months (9-44) from diagnosis of liver lesions. Hepatic cryotherapy with subsequent arterial chemotherapy is safe and well tolerated. The results suggest survival of patients with colorectal hepatic metastases can be improved by the use of this modality of treatment.

Background: The silastic ring (vertical) gastric bypass (SRGB) was introduced by Fobi in 1989, in an effort to combine the advantages of the Roux-en-Y gastric bypass with those of the VBG, while avoiding disadvantages of each. We remain unsure of the ideal ring size., Methods: Sixty-four patients having SRGB between June 1990 and September 1994 had a 5.5 cm ring placed and 24 patients operated between October 1994 and September 1995 had a 6.0 cm ring placed. Weight loss and quality of eating data is compared 12 months after surgery., Results: Median preoperative per cent excess weight was 113 (range 76-209) in the 5.5 cm group and 106 (range 79-196) in the 6.0 cm group. Weight loss was equivalent at 12 months, with median percent excess weight of 33 (range 8-109) and 27 (range 6-81) in the two groups respectively. Quality of eating data appears better in those with the larger ring size. Nine patients with a 5.5 cm ring have subsequently had their ring removed to improve their quality of eating and a further six may require this in the future. One patient with a 6.0 cm ring has had the ring removed and two others may require this be done., Conclusion: An SRGB with a 6.0 cm ring achieves equivalent weight loss to one with a 5.5 cm ring, but with better quality of eating, and less prospect of requiring ring removal. However, there remains a small proportion of patients in whom a 6.0 cm ring is poorly tolerated. For this reason a 6.5 cm ring should be tested.

Background: The silastic ring gastric bypass (SRGB) was introduced by Fobi in 1989, in an effort to combine the advantages of the Roux-en-Y gastric bypass with those of the vertical banded gastroplasty, while avoiding the disadvantages of each., Methods: The results of our first 64 patients who underwent SRGB with a 5.5 cm ring have been reviewed with particular attention to weight loss, short- and medium-term morbidity and patient satisfaction. Most patients have had regular follow-up, and those not seen during the last 6 months were sent a postal questionnaire., Results: The patients included 52 females and 12 males, ranging in age from 23 to 59 years (median age=39 years) at the time of surgery. Median preoperative weight, body mass index (BMI) and % excess weight were 126 kg (range 89-253 kg), 44 kg/m2 (range 36-78 kg/m2) and 113 (range 76-209) respectively. There were no serious postoperative complications and no deaths. Median hospital stay was 7 days (range 5-14 days). Eight patients (13%) are known to have had a staple-line dihiscence. Eighteen patients (28%) have had major difficulties with eating, and in nine (14%) of these the silastic ring has been removed with resolution of the eating problems, but some gain in weight. In the 54 patients with follow-up data at 2 years, median weight was 78 kg (range 55-137 kg), median BMI was 27 kg/m2 (range 20-43 kg/m2) and mean +/- SD % excess weight loss was 69+/-16. After 2 years of follow-up, eight of 54 patients (15%) were unhappy with the results of the procedure., Conclusion: SRGB is an effective, safe and well-tolerated procedure for achieving weight loss in the morbidly obese. The principal drawbacks relate to staple-line problems and eating difficulties related to the silastic ring. A 5.5 cm ring is probably too small to be ideal.

Aim: Malignant ascites may produce a cluster of symptoms including abdominal distension, early satiety, respiratory embarrassment, impaired mobility and lethargy. Successful relief of these symptoms is often difficult to attain. We report on the use of peritoneovenous shunting in a group of patients with troublesome malignant ascites with particular reference to the effectiveness and complications of the procedure., Methods: Twenty one Denver peritoneovenous shunts were placed in 19 patients with malignant ascites. The patients included 16 females and three males and had a median age of 54 years. All had previously been treated with vigorous diuretic therapy and/or repeated paracentesis. Shunt insertion was carried out under general anaesthetic in a manner similar to that described by others., Results: The procedure was well tolerated by most patients. Median hospital stay was 6 days. One patient died 11 days after her surgery from what was thought to be an unrelated cause. Another patient suffered major problems after shunt insertion from exacerbation of pre-existing pleural effusions. All other complications were minor and self limiting. Two shunts failed to function within the first week. Excellent shunt function with resolution of ascite and of associated symptoms was seen in 16 patients. In five late shunt occlusion occurred with resulting reaccummulation of ascites but in four of these shunt function was able to be restored. Median survival in the 18 patients who survived the procedure was 5.5 months and in 14 of these the shunt was functioning at the time of death with good control of ascites., Conclusion: Malignant ascites can result in very troublesome symptoms for patients who may otherwise have some time to live. Peritoneovenous shunting is a well tolerated relatively minor surgical procedure which can achieve excellent control of ascites in the majority of such patients.

Aim: The necessity and desirability of performing percutaneous biopsy of potentially resectable liver tumours is called into question., Methods: Two cases are reported in which percutaneous biopsy of resectable liver tumours was performed unnecessarily and resulted in needle track seeding., Results: In both instances patients who underwent potentially curative liver resection were rendered incurable because of biopsy track recurrence., Conclusion: The common practice of performing percutaneous ultrasound or CT guided biopsy of potentially resectable lesions in the liver is generally neither necessary nor desirable.

Wound infection after cholecystectomy is a not uncommon problem. A retrospective study of 227 cholecystectomies showed the incidence to be 15% when cholecystectomy alone was performed and 30% when a duct exploration was carried out without prophylactic antibiotics. These incidences were reduced to 3.6% and 3.4% respectively when prophylactic antibiotics were used. Though it has been possible to identify a high-risk group of patients, a truly low-risk group is not readily identifiable. It is concluded that prophylactic antibiotics should be given to all patients undergoing cholecystectomy.

To investigate the possible exocrine pancreatic inhibitory actions of amino acids and fat, pancreatic fistula outputs and plasma concentrations of glucagon, somatostatin, and pancreatic polypeptide were measured for response to intravenous (IV) and intraduodenal nutrient administration in six dogs submaximally stimulated with cholecystokinin. Intravenous amino acids caused abrupt and significant 45% to 73% reductions in stimulated pancreatic protein, bicarbonate, and volume outputs. There were no significant associated changes in plasma hormone concentrations and no similar immediate pancreatic inhibition with IV mannitol, thus suggesting a possible direct inhibitory effect of amino acids. Intraduodenal amino acids and IV fat evoked no significant pancreatic output suppression. Intraduodenal fat rapidly caused a significant 40% to 62% reductions in stimulated outputs that were associated with an 81% rise in plasma pancreatic polypeptide concentration, suggesting a gut-mediated inhibition. We conclude that IV amino acids and intraduodenal fat both inhibited stimulated pancreatic secretion but probably by different mechanisms.