Clinical and radiological features that predict malignant transformation in cystic lesions of the pancreas: a retrospective case note review [version 2; peer review: 2 approved]

BACKGROUND: Pancreatic cystic lesions (PCL) are being detected with increasing frequency. Current methods of stratifying risk of malignant transformation are imperfect. This study aimed to determine the frequency of pancreatic malignancy in patients with PCL and define clinical and radiological features that predict malignant transformation in patients managed by surgery and/or surveillance. METHODS: A retrospective cohort of adults who were evaluated in a tertiary hepatopancreaticobiliary centre between January 2000 - December 2013 with a confirmed PCL and followed up for at least 5 years. All cystic lesions were discussed at a weekly multidisciplinary meeting. RESULTS: A retrospective cohort of adults who were evaluated in a tertiary hepatopancreaticobiliary centre between January 2000 - December 2013 with a confirmed PCL and followed up for at least 5 years. All cystic lesions were discussed at a weekly multidisciplinary meeting. CONCLUSION: The sensitivity of standard diagnostic tests leading to immediate surgery for high-risk PCL (malignant or mucinous) was 92% but with a specificity of just 5%. Surveillance of PCL without high-risk features within a multidisciplinary meeting was associated with a low incidence of cancer development, supporting the use of worrisome clinical and radiological features in the initial stratification of PCL

Elastic fibres in alcoholic liver disease

The literature on the contribution of elastic fibre deposition to alcohol-related liver disease (ARLD) is limited. We studied: (1) 180 liver biopsies from ARLD patients; (2) 20 ARLD explant livers; (3) 213 liver biopsies with non-ARLD injury. Elastic fibres were assessed in terms of their distribution around hepatocytes [pericellular elastosis (PCE)] and within bridging fibrous septa (septal elastosis) and scored using a semiquantitative system. We also investigated the composition of the elastic fibres (oxytalan, elaunin and mature elastic fibres) in 20 cases. PCE was associated with steatohepatitis in ARLD patients and with ARLD when compared to non-ARLD cases (p < 0.001). Oxytalan fibres were identified in PCE in ARLD biopsies and broken dense perisinusoidal mature elastic fibres in explanted livers. Septal elastosis increased from intermediate to advanced fibrosis stage. Early septal elastosis contained oxytalan fibres, whereas septal elastosis at more advanced stages contained mainly mature elastic fibres. PCE is a typical feature of steatohepatitis in ARLD and includes oxytalan fibres. Septal elastosis is a gradual process with a transition from oxytalan to mature elastic fibres usually present in explanted livers. There may be different dynamics in the assembly and reabsorption of pericellular and septal elastic fibres, and a potential role for stratification of patients with advanced stage ARLD

Endoscopic ultrasound-guided fine-needle aspiration vs fine-needle biopsy for the diagnosis of pancreatic neuroendocrine tumors

Background and study aims Endoscopic ultrasoundguided fine-needle aspiration (EUS-FNA) as a method of obtaining preoperative diagnosis of pancreatic neuroendocrine tumors (PanNETs) has been reported in several series. Fine-needle biopsies (FNB) are increasingly employed to obtain core specimens during EUS. However, the differences in efficacy between these sampling methods in the diagnosis of PanNETs still needs to be defined. Patients and methods Over a 13-year period, all patients who underwent EUS-guided tissue sampling of suspicious pancreatic lesions with clinical, endoscopic and pathologic details were entered into an electronic database. Lesions underwent EUS-FNA or FNB sampling, or a combination of the two. The accuracy and safety of different EUS-guided sampling methods for confirmed PanNETs were investigated. Results A total of 91 patients (M/F: 42/49, median age: 57 years), who underwent 102 EUS procedures had a final diagnosis of PanNET. Both EUS-guided sampling modalities were used in 28 procedures, EUS-FNA alone was used in 61 cases, while EUS-FNB alone in 13 cases. Diagnostic yield of EUS-FNA and EUS-FNB alone, including the inadequate specimens, was 77.5 % (95 %CI: 68.9 – 86.2%) and 85.4 % (95 % CI: 74.6 – 96.2 %), respectively. The combination of both sampling modalities established the diagnosis in 96.4 % of cases (27/28) (95 %CI: 89.6 – 100%), significantly superior to EUS-FNA alone (P = 0.023). Diagnostic sensitivity among the adequate samples for EUS-FNA, EUS-FNB and for the combination of the two methods was 88.4 % (95 %CI: 80.9 – 96.0 %), 94.3% (95 %CI: 86.6 – 100%) and 100% (95% CI: 100 – 100 %). There was one reported complication, a post-FNA bleeding, treated conservatively. Conclusions EUS-FNB improves diagnostic sensitivity and confers additional information to cytological assessment of PanNETs

Evaluation of circulating transcript analysis (NETest) in small intestinal neuroendocrine neoplasms after surgical resection

PURPOSE: Surgical resection is the only effective curative strategy for small intestinal neuroendocrine neoplasms (SINENs). Nevertheless, the evaluation of residual disease and prediction of disease recurrence/progression remains a problematic issue. METHODS: We evaluated 13 SINENs that underwent surgical resection of the primary tumour and/or mesenteric mass. Patients were divided in three groups: (a) Group 1: SINENs that underwent resection with curative intent, (b) Group 2: SINENs treated with resection in the setting of metastatic disease, which remained stable and (c) Group 3: SINENs treated with resection in the setting of metastatic disease, with evidence of any progression at follow-up. NETest and chromogranin A were measured pre-operatively and post-operatively during a 22-month median follow-up period and compared with imaging studies. NETest score <20% was determined as normal, 20-40% low, 41-79% intermediate and ≥80% high score. RESULTS: NETest score was raised in all (100%) SINENs pre-operatively. Surgery with curative intent resulted in NETest score reduction from 78.25 ± 15.32 to 25.25 ± 1.75 (p < 0.05). Low NETest scores post-operatively were evident in all cases without clinical evidence of residual disease (Group 1). However, the low disease activity score suggested the presence of microscopic residual disease. In three cases (75%) with stable disease (Group 2) the NETest score was low consistent with indolent disease. In the progressive disease group (Group 3), a high NETest score was present in three cases (60%) and an intermediate NETest score in the remainder (40%). CONCLUSIONS: Blood NETest scores accurately identified SINENs and were significantly decreased by curative surgery. Monitoring NETest post-operatively may facilitate management by identifying the presence of residual/progressive disease

Etiology and Severity of Liver Disease in HIV-Positive Patients With Suspected NAFLD: Lessons From a Cohort With Available Liver Biopsies

BACKGROUND: Spectrum of liver injury among HIV-positive people is wide; in particular, prevalence of nonalcoholic fatty liver disease (NAFLD) seems to be higher compared with HIV-negative people. METHODS: We retrospectively evaluated all liver biopsies performed at Royal Free Hospital from 2000 to 2017 in HIV monoinfected patients with abnormal transaminases, to assess the underlying cause of liver disease and to characterize the extent of fibrosis. We furthermore evaluated the diagnostic accuracy of FIB4 and FibroScan as noninvasive tools for fibrosis assessment. RESULTS: Ninety-seven patients were included. Most common histological findings were NAFLD (28%), nonspecific changes (26%), and normal histology (13%). Twenty percent of the patients had significant fibrosis and 11% had advanced fibrosis. FIB4, at a cutoff of 1.3, had a specificity of 82% and negative predictive value (NPV) of 95% for exclusion of advanced fibrosis. FibroScan was available in 28% patients and 33% had a liver stiffness ≥7.5 kPa. FibroScan showed a specificity of 77% and NPV of 94% for exclusion of significant fibrosis. Among patients with NAFLD (n = 27), 18% had advanced fibrosis, whereas the majority (56%) did not have any fibrosis. The NPV of FIB4 for advanced fibrosis in these patients was 93%. CONCLUSIONS: Among HIV-positive patients with elevated transaminases, a surprisingly high number of patients had nonsignificant changes or even normal histological findings. The prevalence of NAFLD was lower than reported in other series. Use of noninvasive tools with a high NPV for significant fibrosis can help reduce the number of required biopsies

Expression of somatostatin receptors 2 and 5 in circulating tumour cells from patients with neuroendocrine tumours.

BACKGROUND: Neuroendocrine tumours (NET) overexpress somatostatin receptors (SSTR) that can be targeted for therapy. Somatostatin receptor expression is routinely measured by molecular imaging but the resolution is insufficient to define heterogeneity. We hypothesised that SSTR expression could be measured on circulating tumour cells (CTCs) and used to investigate heterogeneity of expression and track changes during therapy. METHODS: MCF-7 cells were transfected with SSTR2 or 5 and spiked into donor blood for analysis by CellSearch. Optimum anti-SSTR antibody concentration and exposure time were determined, and flow cytometry was used to evaluate assay sensitivity. For clinical evaluation, blood was analysed by CellSearch, and SSTR2/5 immunohistochemistry was performed on matched tissue samples. RESULTS: Flow cytometry confirmed CellSearch was sensitive and that detection of SSTR was unaffected by the presence of somatostatin analogue up to a concentration of 100 ng ml(-l). Thirty-one NET patients were recruited: grade; G1 (29%), G2 (45%), G3 (13%), primary site; midgut (58%), pancreatic (39%). Overall, 87% had SSTR-positive tumours according to somatostatin receptor scintigraphy or 68-Ga-DOTATE PET/CT. Circulating tumour cells were detected in 21 out of 31 patients (68%), of which 33% had evidence of heterogeneous expression of either SSTR2 (n=5) or SSTR5 (n=2). CONCLUSIONS: Somatostatin receptors 2 and 5 are detectable on CTCs from NET patients and may be a useful biomarker for evaluating SSTR-targeted therapies and this is being prospectively evaluated in the Phase IV CALMNET trial (NCT02075606)

Cryptic diversity of limestone karst inhabiting land snails (Cyclophorus spp.) in northern Vietnam, their evolutionary history and the description of four new species

Limestone karsts can form terrestrial habitat islands for calcium-dependent organisms. In Vietnam, many karst habitats are threatened, while their rich biodiversity is still far from being thoroughly explored. Given that conservation of karst biota strongly relies on correct species identification, the presence of undetected cryptic species can pose severe problems. The present study focuses on cryptic diversity among karst-inhabiting land snails of the genus Cyclophorus in northern Vietnam, where specimens with a similar shell morphology have been reported from various regions. In order to examine the diversity and evolutionary history of this “widespread morphotype”, we generated a Bayesian phylogeny based on DNA sequence data. Automatic Barcode Gap Discovery (ABGD) and the Bayesian implementation of the Poisson tree processes model (bPTP) contributed to species delimitation and analyses of shell shape and size aided the morphological characterisation of individual species. We found that the examined specimens of the widespread morphotype did not form a single monophyletic group in the phylogeny but clustered into several different clades. We delimited nine different species that develop the widespread morphotype and described four of them as new. Processes of convergent evolution were probably involved in the origin of the delimited species, while their generally allopatric distribution could result from interspecific competition. Our findings indicate ongoing processes of speciation and a potential case of morphological character displacement. The high degree of morphological overlap found among the species underlines the importance of DNA sequence data for species delimitation and description in the genus Cyclophorus. Given the findings of the present study and the high potential that as yet undiscovered cryptic taxa have also evolved in other groups of karst-inhabiting organisms, we argue for a systematic and efficient detection and description of Vietnam’s karst biodiversity to provide a solid basis for future conservation planning.Copyright: © 2019 von Oheimb et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Collagen proportionate area predicts long-term mortality in patients with alcoholic hepatitis

Background and aims: There are several short-term prognostic scores for alcoholic hepatitis (AH) that combine demographical and biochemical parameters. The extent of liver fibrosis may also be relevant to the prognosis of AH with potential added value. We evaluated collagen proportionate area (CPA) as a predictor of short and long-term mortality in AH. Methods: We retrospectively included patients with biopsy-verified AH. Clinical, laboratory and outcome data were collected. CPA and five AH scores were calculated: Maddrey's DF, MELD, GAHS, ABIC, and the Lille Model. Predictors of short and long-term all-cause mortality were assessed using Cox regression analysis. Results: We included 140 patients with AH. In total, 67 (48%) patients died after a median follow-up of 66 (IQR 102) months, with 17 (12%) dying within the first 90-days. CPA was not a predictor of 90-days mortality and had no additional value to the prognostic AH scores on short-term mortality. However, CPA predicted long-term mortality independently of prognostic AH scores. Importantly, CPA and abstinence from alcohol were independent predictors of long-term mortality in patients alive 90 days after the biopsy. Conclusion: CPA predicts long-term mortality in patients with AH independently of abstinence from alcohol but has no prognostic value on short-term mortality

Solving the Uncapacitated Single Allocation p-Hub Median Problem on GPU

A parallel genetic algorithm (GA) implemented on GPU clusters is proposed to solve the Uncapacitated Single Allocation p-Hub Median problem. The GA uses binary and integer encoding and genetic operators adapted to this problem. Our GA is improved by generated initial solution with hubs located at middle nodes. The obtained experimental results are compared with the best known solutions on all benchmarks on instances up to 1000 nodes. Furthermore, we solve our own randomly generated instances up to 6000 nodes. Our approach outperforms most well-known heuristics in terms of solution quality and time execution and it allows hitherto unsolved problems to be solved

AICAR and compound C negatively modulate HCC-induced primary human hepatic stellate cell activation in vitro

Tumour stroma and microenvironment have been shown to affect hepatocellular carcinoma (HCC) growth, with activated hepatic stellate cells (HSC) as a major contributor in this process. Recent evidence suggests that the energy sensor adenosine monophosphate-activated kinase (AMPK) may mediate a series of essential processes during carcinogenesis and HCC progression. Here, we investigated the effect of different HCC cell lines with known TP53 or CTNBB1 mutations on primary human HSC activation, proliferation and AMPK activation. We show that conditioned media obtained from multiple HCC cell lines differently modulate human hHSC proliferation and hHSC AMPK activity in a paracrine manner. Pharmacological treatment of hHSC with AICAR and Compound C inhibited the HCC-induced proliferation/activation of hHSC through AMPK-dependent and AMPK-independent mechanisms, which was further confirmed using mouse embryonic fibroblasts (MEFs) deficient of both catalytic AMPKα isoforms (AMPKα1/α2-/-) and wild type (wt) MEF. Both compounds induced S-phase cell-cycle arrest and, in addition, AICAR inhibited the mTORC1 pathway by inhibiting phosphorylation of 4E-BP1 and S6 in hHSC and wt MEF. Datamining of the Cancer Genome Atlas (TCGA) and the Liver Cancer (LICA-FR) showed that AMPKα1 (PRKAA1) and AMPKα2 (PRKAA2) expression differed depending on the mutation (TP53 or CTNNB1), tumour grading and G1-G6 classification, reflecting the heterogeneity in human HCC. Overall, we provide evidence that AMPK modulating pharmacological agents negatively modulate HCC-induced hHSC activation and may therefore provide a novel approach to target the mutual, tumour-promoting interactions between hHSC and HCC