Clinical significance of Src expression and activity in human neoplasia.

Src, a 60 kDa non-receptor tyrosine kinase, is the product of normal c-src of the human genome and member of the Src protein tyrosine kinases family (SFK). As described by Martin and Rous, a genetic recombination between c-src and the RSV oncogene of Rous sarcoma virus results in a modified Src protein, with increased intrinsic activity and transforming potential in animal and human tissues. Several in vitro and in vivo studies supported this theory providing insight in the signalling pathways involved. Accumulating evidence from studies on clinical samples supported the role of Src in the process of carcinogenesis and disease progression in several human malignancies. Some studies have further reinforced the significance of the kinase in malignacy by correlating its expression and/or activity with important clinicopathological parameters, such as tumour stage, histopathological grade, proliferative capacity and most importantly patient's survival. This review is a comprehensive report of the published evidence on the expression and clinical significance of Src in human malignancy, which constitutes the background of the current studies and clinical trials on the use of Src inhibitors as novel potent antineoplastic strategy

Relationship between antidiabetic treatment with QT dispersion during acute coronary syndromes in type 2 diabetes: Comparison between patients receiving sulfonylureas and insulin

Patients with acute coronary syndromes (ACS) show prolongation of QT interval duration and its dispersion (QTd). Prolongation of QTd has been associated with inhomogeneity of ventricular recovery times and high arrhythmyogenic potential. Previous studies have shown that preservation of the ischaemic preconditioning is associated with shorter QTd. Sulfonylureas may inhibit cardiac ischaemic preconditioning. The effect, however, of the previous treatment with sulfonylureas on QTd in patients with ACS has not been studied so far. This cross-sectional study examined the effect of the previous antidiabetic treatment on QTd in patients with type 2 diabetes during ACS. A total of 150 patients with ACS (myocardial infarction: n = 120; unstable angina: n = 30) admitted to the coronary care unit of our hospital were studied. Three groups of patients were examined: patients without diabetes (n = 60); patients with type 2 diabetes treated with sulfonylureas alone or in combination with metformin (n = 50); and patients treated with insulin alone or in combination with metformin (n = 40). Standard 12-lead ECG recordings at admission to the coronary care unit were obtained. QT interval duration and QTd were measured using ECG analysis software. At admission, QTd was not different between diabetic and nondiabetic patients (72.1 +/- 21.7 vs. 78.4 +/- 21.3 msec, p = 0.13, respectively). Similarly, the values of the above interval were also not different between patients with type 2 diabetes treated with sulfonylureas and insulin (73.8 +/- 23.9 vs. 70.1 +/- 18.5 msec, p = 0.55, respectively). It is concluded that the previous treatment with either sulfonylureas or insulin does not affect QTd in patients with type 2 diabetes and ACS

Evaluation of FAK and src expression in human benign and malignant thyroid lesions

Focal Adhesion Kinase (FAK) and Src have been reported to regulate tumor growth, invasion, metastasis and angiogenesis. The present study aimed to evaluate by immunohistochemistry the clinical significance of FAK and Src expression in 108 patients with benign and malignant thyroid lesions. Total FAK expression provided a distinct discrimination between malignant and benign (p=0.00001), as well as between papillary carcinoma and hyperplastic nodules thyroid lesions (p=0.00005), being also associated with follicular cells' proliferative capacity (p=0.0003). In malignant thyroid lesions, total FAK expression was associated with tumor size (p=0.0455), and presence of capsular (p=0.0102) and lymphatic (p=0.0173) invasion. Total Src expression was borderline increased in cases of papillary carcinoma compared to hyperplastic nodules (p=0.0993), being also correlated with tumor size (p=0.0169). FAK and Src expression was ascribed to a significant extent to the phosphorylated forms of the enzymes, which provided a better discrimination between malignant and benign thyroid lesions. The current data revealed that FAK and to a lesser extent Src expression could be considered of clinical utility in thyroid neoplasia with potential use as therapeutic targets. © 2010 Arányi Lajos Foundation

Impact of donor mismatches at individual HLA-A, -B, -C, -DR, and -DQ loci on the development of HLA-specific antibodies in patients listed for repeat renal transplantation.

We have analyzed the relationship between donor mismatches at each HLA locus and development of HLA locus-specific antibodies in patients listed for repeat transplantation. HLA antibody screening was undertaken using single-antigen beads in 131 kidney transplant recipients returning to the transplant waiting list following first graft failure. The number of HLA mismatches and the calculated reaction frequency of antibody reactivity against 10,000 consecutive deceased organ donors were determined for each HLA locus. Two-thirds of patients awaiting repeat transplantation were sensitized (calculated reaction frequency over 15%) and half were highly sensitized (calculated reaction frequency of 85% and greater). Antibody levels peaked after re-listing for repeat transplantation, were independent of graft nephrectomy and were associated with length of time on the waiting list (odds ratio 8.4) and with maintenance on dual immunosuppression (odds ratio 0.2). Sensitization was independently associated with increasing number of donor HLA mismatches (odds ratio 1.4). All mismatched HLA loci contributed to the development of HLA locus-specific antibodies (HLA-A: odds ratio 3.2, HLA-B: odds ratio 3.4, HLA-C: odds ratio 2.5, HLA-DRB1: odds ratio 3.5, HLA-DRB3/4/5: odds ratio 3.9, and HLA-DQ: odds ratio 3.0 (all significant)). Thus, the risk of allosensitization following failure of a first renal transplant increases incrementally with the number of mismatches at all HLA loci assessed. Maintenance of re-listed patients on dual immunosuppression was associated with a reduced risk of sensitization

Impact of Frailty on Short-Term Outcomes After Laparoscopic and Open Hepatectomy

BACKGROUND: Although laparoscopic hepatectomy (LH) is associated with improved short-term outcomes compared to open hepatectomy (OH), it is unknown whether frail patients also benefit from LH. The aim of this study was to evaluate the impact of frailty on post-operative outcomes after LH and OH. PATIENTS AND METHODS: Consecutive patients who underwent LH and OH between January 2011 and December 2018 were identified from a prospective database. Frailty was assessed using the modified Frailty Index (mFI), with patients scoring mFI ≥ 1 deemed to be frail. RESULTS: Of 1826 patients, 34.7% (N = 634) were frail and 18.6% (N = 340) were elderly (≥ 75 years). Frail patients had significantly higher 90-day mortality (6.6% vs. 2.9%, p < 0.001) and post-operative complications (36.3% vs. 26.1%, p < 0.001) than those who were not frail, effects that were independent of patient age on multivariate analysis. For those undergoing minor resections, the benefits of LH vs. OH were similar for frail and non-frail patients. Length of hospital stay was 53% longer in OH (vs. LH) in frail patients, compared to 58% longer in the subgroup of non-frail patients. CONCLUSIONS: Frailty is independently associated with inferior post-operative outcomes in patients undergoing hepatectomy. However, the benefits of laparoscopic (compared to open) hepatectomy are similar for frail and non-frail patients. Frailty should not be a contraindication to laparoscopic minor hepatectomy in carefully selected patients

Significance of predicted future liver remnant volume on liver failure risk after major hepatectomy: a case matched comparative study

IntroductionFuture liver remnant volume (FLRV), a risk factor for liver failure (PHLF) after major hepatectomy (MH), is not routinely measured. This study aimed to evaluate the association between FLRV and PHLF.Patients and methodsAll patients undergoing MH (4 + segments) between 2011 and 2018 were identified from a prospectively maintained single-centre database. Perioperative data were collected for patients with PHLF, who were matched (1:2) with non-PHLF controls. FLRV and FLRV% (i.e., % of total liver volume) were calculated retrospectively from preoperative CT scans using Synapse-3D software, and compared between the PHLF and matched control groups.ResultsOf 711 patients undergoing MH, PHLF occurred in 27 (3.8%), of whom 24 had preoperative CT scans available. These patients were matched to 48 non-PHLF controls, 98% of whom were classified as being at high risk of PHLF on preoperative risk scoring. FLRV% was significantly lower in the PHLF group, compared to matched controls (median: 28.7 vs. 35.2%, p = 0.010), with FLRV% &lt; 30% in 58% and 29% of patients, respectively. Assessment of the ability of FLRV% to differentiate between PHLF and matched controls returned an area under the ROC curve of 0.69, and an optimal cut-off value of FLRV% &lt; 31.5%, which yielded 79% sensitivity and 67% specificity.ConclusionsFLRV% is significantly predictive of PHLF after MH, with over half of patients with PHLF having FLRV% &lt; 30%. In light of this, we propose that all patients should undergo risk stratification prior to MH, with the high risk patients additionally being assessed with CT volumetry