Evolution of dynamic, biochemical, and morphological parameters in hypothermic machine perfusion of human livers: A proof-of-concept study.

INTRODUCTION: Hypothermic machine perfusion (HMP) is increasingly investigated as a means to assess liver quality, but data on viability markers is inconsistent and the effects of different perfusion routes and oxygenation on perfusion biomarkers are unclear. METHODS: This is a single-centre, randomised, multi-arm, parallel study using discarded human livers for evaluation of HMP using arterial, oxygen-supplemented venous and non-oxygen-supplemented venous perfusion. The study included 2 stages: in the first stage, 25 livers were randomised into static cold storage (n = 7), hepatic artery HMP (n = 10), and non-oxygen-supplemented portal vein HMP (n = 8). In the second stage, 20 livers were randomised into oxygen-supplemented and non-oxygen-supplemented portal vein HMP (n = 11 and 9, respectively). Changes in dynamic, biochemical, and morphologic parameters during 4-hour preservation were compared between perfusion groups, and between potentially transplantable and non-transplantable livers. RESULTS: During arterial perfusion, resistance was higher and flow was lower than venous perfusion (p = 0.001 and 0.01, respectively); this was associated with higher perfusate markers during arterial perfusion (p>0.05). Supplementary oxygen did not cause a significant alteration in the studied parameters. Morphology was similar between static and dynamic preservation groups. Perfusate markers were 2 fold higher in non-transplantable livers (p>0.05). CONCLUSIONS: Arterial only perfusion might not be adequate for graft perfusion. Hepatocellular injury markers are accessible and easy to perform and could offer insight into graft quality, but large randomised trials are needed to identify reliable quality assessment biomarkers.

Major postoperative complications after pancreatic resection for P-NETS are not associated to earlier recurrence.

BACKGROUND: The oncological impact of surgical complications has been studied in visceral and pancreatic cancer. AIM: To investigate the impact of complications on tumour recurrence after resections for pancreatic neuroendocrine tumours. METHODS: We have retrospectively analysed 105 consecutive resections performed at the Royal Free London Hospital from 1998 to 2014, and studied the long-term outcome of nil-minor (<3) versus major (≥3) Clavien-Dindo complications (CD) on disease-free (DFS) and overall survival (OS). RESULTS: The series accounted for 41 (39%) pancreaticoduodenectomies, two (1.9%) central, 48 (45.7%) distal pancreatectomies, eight (7.6%) enucleations, four (3.8%) total pancreatectomies. Sixteen (15.2%) were extended to adjacent organs, 13 (12.3%) to minor liver resections. Postoperative complications presented in 43 (40.1%) patients; CD grade 1 or 2 in 23 (21.9%), grades ≥3 in 20 (19%). Among 25 (23.8%) pancreatic fistulas, 14 (13.3%) were grades B or C. Thirty-four (32.4%) patients developed exocrine, and 31 (29.5%) endocrine insufficiency. Seven patients died during a median 27 (0-175) months follow up. Thirty-day mortality was 0.9%. OS was 94.1% at 5 years. Thirty tumours recurred within 11.7 (0.8-141.5) months. DFS was 44% at 5 years. At univariate analysis, high-grade complications were not associated with shorter DFS (p = 0.744). At multivariate analysis, no parameter was independent predictor for DFS or OS. The comparison of nil-minor versus major complications showed no DFS difference (p = 0.253). CONCLUSION: From our series, major complications after P-NETs resection are not associated to different disease recurrence; hence do not require different follow up or adjuvant regimens.

Nine scoring models for short-term mortality in alcoholic hepatitis: cross-validation in a biopsy-proven cohort.

BACKGROUND: Several prognostic models have emerged in alcoholic hepatitis (AH), but lack of external validation precludes their universal use. AIM: To validate the Maddrey Discriminant Function (DF); Glasgow Alcoholic Hepatitis Score (GAHS); Mayo End-stage Liver Disease (MELD); Age, Bilirubin, INR, Creatinine (ABIC); MELD-Na, UK End-stage Liver Disease (UKELD), and three scores of corticosteroid response at 1 week: an Early Change in Bilirubin Levels (ECBL), a 25% fall in bilirubin, and the Lille score. METHODS: Seventy-one consecutive patients with biopsy-proven AH, admitted between November 2007-September 2011, were evaluated. The clinical and biochemical parameters were analysed to assess prognostic models with respect to 30- and 90-day mortality. RESULTS: There were no significant differences in the areas under the receiver operating characteristics curve (AUROCs) relative to 30-day/90-day mortality: MELD 0.79/0.84, DF 0.71/0.74, GAHS 0.75/0.78, ABIC 0.71/0.78, MELD-Na 0.68/0.76, UKELD 0.56/0.68. One-week rescoring yielded a trend towards improved predictive accuracies (30-day/90-day AUROCs: 0.69­0.84/0.77­0.86). In patients with admission DF ≥ 32 (n = 31), response to corticosteroids according to ECBL, 25% fall in bilirubin and the Lille model yielded AUROCs of 0.73/0.73, 0.78/0.72 and 0.81/0.82 for a 30-day/90-day outcome respectively. All models showed excellent negative predictive values (NPVs; range: 86­100%), while the positive ones were low (range: 17­50%). CONCLUSIONS: MELD, DF, GAHS, ABIC and scores of corticosteroid response proved to be valid in an independent cohort of biopsy-proven alcoholic hepatitis. MELD modifications incorporating sodium did not confer any prognostic advantage over classical MELD. Based on excellent NPVs, the models are best to identify patients at low risk of death.

A comparison of Ki-67 and mitotic count as prognostic markers for metastatic pancreatic and midgut neuroendocrine neoplasms.

BACKGROUND: The aim of this study was to compare mitotic count (MC) and Ki-67 proliferation index as prognostic markers in pancreatic and midgut neuroendocrine neoplasms (NENs). METHODS: Two hundred eighty-five patients with metastatic NENs were recruited. Concordance between histological grade according to either Ki-67 or MC as defined by the European Neuroendocrine Tumour Society guidelines was assessed and the prognostic significance of Ki-67 or MC were evaluated. RESULTS: There was a discrepancy of 44 and 38% in grade assignment when using Ki-67 or MC in pancreatic and midgut NENs, respectively. In multivariate analysis, grade using Ki-67, but not MC, was a significant prognostic factor in determining overall survival (hazard ratios: midgut G2 2.34, G3 15.1, pancreas G2 2.08, G3 11.3). The prognostic value of Ki-67 was improved using a modified classification (hazard ratios: midgut G2 3.02, for G3 22.1, pancreas G2 5.97, G3 33.8). CONCLUSION: There is a lack of concordance between Ki-67 and MC in assigning tumour grade. Grade according to Ki-67 was a better prognostic marker than MC for metastatic pancreatic and midgut NENs. We suggest that Ki-67 alone should be used for grading pancreatic and midgut NENs and that the current threshold for classifying G1/G2 tumours should be revised from 2 to 5%.

Extraluminal colonic arteriovenous haemangioma: an unusual cause of chronic lower gastrointestinal bleeding.

Lower gastrointestinal bleeding is a common general surgical presentation in acute and chronic settings. Vascular anomalies account for 2% of such cases and can therefore be missed. We discuss a rare vascular anomaly in one of our patients where the diagnosis was not established for a ten-year period. We describe the subsequent management and a brief review of the literature of this uncommon condition.

TNM staging of neoplasms of the endocrine pancreas: results from a large international cohort study.

BACKGROUND: Both the European Neuroendocrine Tumor Society (ENETS) and the International Union for Cancer Control/American Joint Cancer Committee/World Health Organization (UICC/AJCC/WHO) have proposed TNM staging systems for pancreatic neuroendocrine neoplasms. This study aims to identify the most accurate and useful TNM system for pancreatic neuroendocrine neoplasms. METHODS: The study included 1072 patients who had undergone previous surgery for their cancer and for which at least 2 years of follow-up from 1990 to 2007 was available. Data on 28 variables were collected, and the performance of the two TNM staging systems was compared by Cox regression analysis and multivariable analyses. All statistical tests were two-sided. RESULTS: Differences in distribution of sex and age were observed for the ENETS TNM staging system. At Cox regression analysis, only the ENETS TNM staging system perfectly allocated patients into four statistically significantly different and equally populated risk groups (with stage I as the reference; stage II hazard ratio [HR] of death = 16.23, 95% confidence interval [CI] = 2.14 to 123, P = .007; stage III HR of death = 51.81, 95% CI = 7.11 to 377, P < .001; and stage IV HR of death = 160, 95% CI = 22.30 to 1143, P < .001). However, the UICC/AJCC/WHO 2010 TNM staging system compressed the disease into three differently populated classes, with most patients in stage I, and with the patients being equally distributed into stages II-III (statistically similar) and IV (with stage I as the reference; stage II HR of death = 9.57, 95% CI = 4.62 to 19.88, P < .001; stage III HR of death = 9.32, 95% CI = 3.69 to 23.53, P = .94; and stage IV HR of death = 30.84, 95% CI = 15.62 to 60.87, P < .001). Multivariable modeling indicated curative surgery, TNM staging, and grading were effective predictors of death, and grading was the second most effective independent predictor of survival in the absence of staging information. Though both TNM staging systems were independent predictors of survival, the UICC/AJCC/WHO 2010 TNM stages showed very large 95% confidence intervals for each stage, indicating an inaccurate predictive ability. CONCLUSION: Our data suggest the ENETS TNM staging system is superior to the UICC/AJCC/WHO 2010 TNM staging system and supports its use in clinical practice.

Digital image analysis of liver collagen predicts clinical outcome of recurrent hepatitis C virus 1 year after liver transplantation.

Clinical outcomes of recurrent hepatitis C virus after liver transplantation are difficult to predict. We evaluated collagen proportionate area (CPA), a quantitative histological index, at 1 year with respect to the first episode of clinical decompensation. Patients with biopsies at 1 year after liver transplantation were evaluated by Ishak stage/grade, and biopsy samples stained with Sirius red for digital image analysis were evaluated for CPA. Cox regression was used to evaluate variables associated with first appearance of clinical decompensation. Receiver operating characteristic (ROC) curves were also used. A total of 135 patients with median follow-up of 76 months were evaluated. At 1 year, median CPA was 4.6% (0.2%-36%) and Ishak stage was 0-2 in 101 patients, 3-4 in 23 patients, and 5-6 in 11 patients. Decompensation occurred in 26 (19.3%) at a median of 61 months (15-138). Univariately, CPA, tacrolimus monotherapy, and Ishak stage/grade at 1 year were associated with decompensation; upon multivariate analysis, only CPA was associated with decompensation (P = 0.010; Exp(B) = 1.169; 95%CI, 1.037-1.317). Area under the ROC curve was 0.97 (95%CI, 0.94-0.99). A cutoff value of 6% of CPA had 82% sensitivity and 95% specificity for decompensation. In the 89 patients with hepatic venous pressure gradient (HVPG) measurement, similar results were obtained. When both cutoffs of CPA > 6% and HVPG ≥ 6 mm Hg were used, all patients decompensated. Thus, CPA at 1-year biopsy after liver transplantation was highly predictive of clinical outcome in patients infected with hepatitis C virus who underwent transplantation, better than Ishak stage or HVPG.

Presacral carcinoid tumour. Review of the literature and report of a clinically malignant case.

Carcinoid tumours arising in the presacral region are extremely rare and they are usually benign. We report the case of a 37-year-old black man with a clinically malignant carcinoid tumour (well differentiated endocrine carcinoma) occurring in a sacrococcygeal teratoma and already metastasised to pelvic nodes, liver and bone at the time of the initial diagnosis. Such an aggressive behaviour of the presacral carcinoid tumours has never been described. The derivation of these tumours from hindgut rests with reference to embryological development of the tailgut cysts is discussed.

Mapping soil-transmitted helminths in Southeast Asia and implications for parasite control.

Establishing the current status and distribution of soil-transmitted helminths is essential for developing and implementing parasite control. Although Southeast Asia is known to have a high prevalence of infection, a precise estimate of the total disease burden has not been fully described. Here, we use Geographical Information Systems (GIS) to collate and map recent published surveys on soil-transmitted helminth epidemiology and distribution for this region. Distinct geographical variation was observed, which is suggested to reflect climatic variation, as well as behavioral differences. However, for much of the region few data are available, and therefore it proved necessary to generate predictions of the distribution of soil-transmitted helminths using remotely sensed (RS) satellite sensor environmental variables. A significant finding was the importance of land surface temperature in influencing the distribution of Ascaris lumbricoides and Trichuris trichiura. Spatial analyses using RS satellite sensor data were then used to generate predictive maps of infection risk. This information provided the basis for an estimate of the population at risk of infection and the numbers requiring treatment. These applications of GIS and remote sensing provide a good basis for developing control of soil-transmitted helminths in the region.

De-worming school children and hygiene intervention.

Helminths or worm infestations refer to worms that live as parasites in the human body and are a fundamental cause of disease associated with health and nutrition problems beyond gastrointestinal tract disturbances. Globally, over 3.5 billion people are infected with intestinal worms, of which 1.47 billion are with roundworm, 1.3 billion people with hookworm and 1.05 billion with whipworm. School children aged 5 - 15 years suffer the highest infection rate and worm burden that attributes to poor sanitation and hygiene. About 400 million school-age children are infected with roundworm, whipworm and hookworm worldwide, a large proportion of whom are found in the East Asia region (Cambodia, China, Lao PDR, Thailand and Vietnam). These parasites consume nutrients from children they infect, thus retarding their physical development. They destroy tissues and organs, cause abdominal pain, diarrhoea, intestinal obstruction, anaemia, ulcers and other health problems. All of these consequences of infection can slow cognitive development and thus impair learning. De-worming school children by anthelmintic drug treatment is a curative approach for expelling the heavy worm load. However, drug therapy alone is only a short-term measure of reducing worm infection and re-infection is frequent. Control measures through improved sanitation, hygiene and de-worming are needed to prevent infection and re-infection. UNICEF has supported many governments in this (and other) regions to assist in the provision of water supply and sanitary facilities and intensive hygiene education in many schools through the Water, Environment and Sanitation (WES) programme. The UNICEF supported school sanitation and hygiene education (SSHE) programme, and other programmes, could effectively enhance behaviour change in children to break the routes of worm transmission and other waterborne diseases.