Gastrin and its interactions in the adenoma-carcinoma sequence in the colon

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Natural killer cell maturation markers in the human liver and expansion of an NKG2C+KIR+ population

Background: selected populations of murine natural killer (NK) cells possess memory features to haptens, cytokines, and viruses. Liver-specific adhesion molecules CXCR6 and CD49a have been identified as surface markers in mice. In people, expansion of long-lived terminally differentiated NKG2C+ populations occur in the blood after viral infection. We aimed to compare intrahepatic and blood NK cell receptor expression to determine the existence of CD49a+ and CXCR6+ NK cells in human liver and define the maturation status of NKG2C+ NK cells at this site.Methods: tissue samples were taken from the liver margin of 39 patients with hepatic metastases and flushed with chelating buffer followed by collagenase or mechanical digestion. Paired peripheral blood samples were taken from 15 patients, the remainder being unpaired. Mononuclear cells were isolated by ficoll separation and cell surface staining performed for CD3, CD56, CD16, CD57, CD117, CD161, CD158a, CD158b, CD49a, CD49b, CXCR6, NKG2C, and NKp46. Statistical analysis to compare intrahepatic and blood NK cell receptor expression included the median, IQR, and Mann-Whitney U testFindings: frequencies of NK cell precursors were similar in the liver and the blood (0·91% [0·62–3·26] vs 0·87 [0·41–1·52]); however, expression of all later markers of maturity were reduced including CD16 (47% [40·4–61·4] vs 88·7 [82·2–93·2], p<0·0001), CD57 (30·7% [25·0–53·9] vs 73·4 [70·4–87·6], p=0·0003), and KIR (11·2% [7·5–14·5] vs 26·7 [17·3–30·8], p<0·0001). Expanded hepatic CD16– NK cells were particularly immature with reduced CD57 and increased CD161 compared with the blood. NKG2C+ NK cells were found in similar frequencies in liver and blood. The hepatic NKG2C+ population was terminally differentiated, as in the circulation, but demonstrated a three-fold increase in KIR expression compared with NKG2C– counterparts, which was not seen in the blood. As in previously published research in mice, CD49a+ and CXCR6+ NK cells were liver resident (6·5% [3·9–14·6] liver vs 2·1 [1·3–4·3] blood, p<0·0001, and 65·3 [48·1–75·2] vs 4·5 [1·43–12·12], p=0·0039, respectively). Both populations were immature, with reduced KIR expression.Interpretation: we have shown that the liver contains an expanded population of immature CD16– NK cells. These cells might traffic from the blood and then differentiate into hepatic-specific CD49a+ and CXCR6+ NK cells. The function of these subsets is unknown but their immaturity hints against memory. Terminally differentiated NKG2C+ cells show KIR expansion in the human liver and probably represent an antigen-experienced population, raising the question of whether the liver is a site of NK cell memory acquisitio

Pure laparoscopic liver resection for large malignant tumors: does size matter?

BackgroundLaparoscopic liver resection (LLR) for large malignant tumors can be technically challenging. Data on this topic are scarce, and many question its feasibility, safety, and oncologic efficiency. This study aimed to assess outcomes of LLR for large (≥5 cm) and giant (≥10 cm) malignant liver tumors.MethodsA prospectively collected database of 422 LLRs was reviewed from August 2003 to August 2013. The data for 52 patients undergoing LLR for large malignant tumors were analyzed. A subgroup analysis of giant tumors also is reported.ResultsDuring the period studied, 52 LLRs were performed (males, 53.8 %; mean age, 64.6 years) for large malignant tumors. Colorectal liver metastasis was the most common indication (42.3 %). The 52 LLRs included 32 major (61.5 %) and 20 minor (38.5 %) LLRs for tumors with a mean diameter of 83 mm. The median operative time was 240 min [interquartile range (IQR), 150–330 min], and the blood loss was 500 ml (IQR, 200–1,373 ml). Eight conversions (15.4 %) were performed. Six patients experienced complications (11.5 %). Among the 44 patients with successful LLRs, two patients (4.5 %) had an R1 resection. The median hospital stay was 5 days (range, 1–21 days), and no mortality occurred during a 90-day period. A subgroup analysis of patients with giant tumors showed greater blood loss (p = 0.002) and a longer operative time (p = 0.052) but no difference in terms of conversions (p = 0.64) or complications (p = 0.32).ConclusionThe findings showed that LLR is feasible and safe for large malignant tumors and can be performed with acceptable morbidity and oncologic efficiency. When used for giant malignant tumors, LLR is associated with greater blood loss and a longer operative time but no increase in complications

An international multicentre randomized controlled trial of G17DT in patients with pancreatic cancer

Objectives: This study aimed to investigate G17DT, an immunogen producing neutralising antibodies against the tumour growth factors amidated and glycine-extended forms of gastrin17, in the treatment of pancreatic cancer. Methods: A randomised, double blind, placebo-controlled, group-sequential multicentre trial of G17DT in patients with advanced pancreatic cancer unsuitable for or unwilling to take chemotherapy. Inclusion criteria were a Karnofsky performance score of 60 or higher and a life expectancy of more than 2 months. Patients received G17DT or placebo emulsion at weeks 0, 1, 3, 24 and 52. The primary end point was survival, and the secondary end points were tolerability, Karnofsky performance. Results: A total of 154 patients were recruited: 79 G17DT and 75 placebo. A final analysis of the intention-to-treat population, using a proportional hazards model, stratifying by disease stage and adjusting for interim analysis, gave a hazard ratio for mortality of 0.75 (95% confidence interval, 0.51-1.10, P=0.138; G17DT/placebo). A conventional analysis without adjustment for disease stage or interim analysis, censoring for chemotherapy and excluding protocol violators, gave median survival periods of 151 days (G17DT) and 82 days (placebo) (log-rank test, P = 0.03). Patients developing anti-G17DT responses (73.8%) survived longer than nonresponders or those on placebo(median survival, 176 vs 63 vs 83; log-rank test, P=0.003). G17DT was well tolerated