Prognostic value of the neutrophil/lymphocyte ratio in enteropancreatic neuroendocrine tumors.

Accessible prognostic tools are needed to individualize treatment of neuroendocrine tumors (NETs). Data suggest neutrophil/lymphocyte ratios (NLRs) have prognostic value in some solid tumors, including NETs. In the randomized double-blind CLARINET study (NCT00353496; EudraCT 2005-004904-35), the somatostatin analog lanreotide autogel/depot increased progression-free survival (PFS) compared with placebo in patients with inoperable or metastatic intestinal and pancreatic NETs (grades 1-2, Ki-67 < 10%). The exploratory post-hoc analyses presented here evaluated the prognostic value of NLR in the CLARINET study cohort, in the context of and independently from treatment. Kaplan-Meier PFS plots were generated for patients with available NLR data, in subgroups based on NLR values, and 24-month survival rates were calculated. P values and hazard ratios for prognostic effects were generated using Cox models. 31216222 Baseline characteristics were balanced between lanreotide autogel/depot 120 mg (n = 100) and placebo (n = 101) arms. Irrespective of treatment, raw 24-month PFS rates were comparable across subgroups based on NLR tertiles [37.3% (low), 38.8% (middle), 38.8% (high); n = 67 per group] and NLR cutoff of 4 [38.1% (NLR ≤ 4; n = 176), 40.0% (NLR > 4; n = 25)]. Furthermore, NLRs were not prognostic in Cox models, irrespective of subgroups used. The therapeutic effect of lanreotide autogel/depot 120 mg was independent of NLRs (P > 0.1). These exploratory post-hoc analyses in patients with advanced intestinal and pancreatic NETs contrast with previous data suggesting NLR has prognostic potential in NETs. This may reflect the inclusion of patients with lower-grade tumors or use of higher NLR cutoff values in the current analysis.

Efficacy and Safety of Sunitinib in Patients with Well-Differentiated Pancreatic Neuroendocrine Tumours.

BACKGROUND: In a phase III study, sunitinib led to a significant increase in progression-free survival (PFS) versus placebo in patients with pancreatic neuroendocrine tumours (panNETs). This study was a post-marketing commitment to support the phase III data. METHODS: In this ongoing, open-label, phase IV trial (NCT01525550), patients with progressive, advanced unresectable/metastatic, well-differentiated panNETs received continuous sunitinib 37.5 mg once daily. Eligibility criteria were similar to those of the phase III study. The primary endpoint was investigator-assessed PFS per Response Evaluation Criteria in Solid Tumours v1.0 (RECIST). Other endpoints included PFS per Choi criteria, overall survival (OS), objective response rate (ORR), and adverse events (AEs). RESULTS: Sixty-one treatment-naive and 45 previously treated patients received sunitinib. By March 19, 2016, 82 (77%) patients had discontinued treatment, mainly due to disease progression. Median treatment duration was 11.7 months. Investigator-assessed median PFS per RECIST (95% confidence interval [CI]) was 13.2 months (10.9-16.7): 13.2 (7.4-16.8) and 13.0 (9.2-20.4) in treatment-naive and previously treated patients, respectively. ORR (95% CI) per RECIST was 24.5% (16.7-33.8) in the total population: 21.3% (11.9-33.7) in treatment-naive and 28.9% (16.4-44.3) in previously treated patients. Median OS, although not yet mature, was 37.8 months (95% CI, 33.0-not estimable). The most common treatment-related AEs were neutropenia (53.8%), diarrhoea (46.2%), and leukopenia (43.4%). CONCLUSIONS: This phase IV trial confirms sunitinib as an efficacious and safe treatment option in patients with advanced/metastatic, well-differentiated, unresectable panNETs, and supports the phase III study outcomes. AEs were consistent with the known safety profile of sunitinib.

Contribution of Red Wine Consumption to Human Health Protection.

Wine consumption has been popular worldwide for many centuries. Based on in vitro and in vivo studies, a certain amount of everyday wine consumption may prevent various chronic diseases. This is due, in part, to the presence and amount of important antioxidants in red wine, and, therefore, research has focused on them. Wine polyphenols, especially resveratrol, anthocyanins, and catechins, are the most effective wine antioxidants. Resveratrol is active in the prevention of cardiovascular diseases by neutralizing free oxygen radicals and reactive nitrogenous radicals; it penetrates the blood-brain barrier and, thus, protects the brain and nerve cells. It also reduces platelet aggregation and so counteracts the formation of blood clots or thrombi. The main aim of this review is to summarize the current findings about the positive influence of wine consumption on human organ function, chronic diseases, and the reduction of damage to the cardiovascular system.

Lanreotide in metastatic enteropancreatic neuroendocrine tumors.

BACKGROUND: Somatostatin analogues are commonly used to treat symptoms associated with hormone hypersecretion in neuroendocrine tumors; however, data on their antitumor effects are limited. METHODS: We conducted a randomized, double-blind, placebo-controlled, multinational study of the somatostatin analogue lanreotide in patients with advanced, well-differentiated or moderately differentiated, nonfunctioning, somatostatin receptor-positive neuroendocrine tumors of grade 1 or 2 (a tumor proliferation index [on staining for the Ki-67 antigen] of <10%) and documented disease-progression status. The tumors originated in the pancreas, midgut, or hindgut or were of unknown origin. Patients were randomly assigned to receive an extended-release aqueous-gel formulation of lanreotide (Autogel [known in the United States as Depot], Ipsen) at a dose of 120 mg (101 patients) or placebo (103 patients) once every 28 days for 96 weeks. The primary end point was progression-free survival, defined as the time to disease progression (according to the Response Evaluation Criteria in Solid Tumors, version 1.0) or death. Secondary end points included overall survival, quality of life (assessed with the European Organization for Research and Treatment of Cancer questionnaires QLQ-C30 and QLQ-GI.NET21), and safety. RESULTS: Most patients (96%) had no tumor progression in the 3 to 6 months before randomization, and 33% had hepatic tumor volumes greater than 25%. Lanreotide, as compared with placebo, was associated with significantly prolonged progression-free survival (median not reached vs. median of 18.0 months, P<0.001 by the stratified log-rank test; hazard ratio for progression or death, 0.47; 95% confidence interval [CI], 0.30 to 0.73). The estimated rates of progression-free survival at 24 months were 65.1% (95% CI, 54.0 to 74.1) in the lanreotide group and 33.0% (95% CI, 23.0 to 43.3) in the placebo group. The therapeutic effect in predefined subgroups was generally consistent with that in the overall population, with the exception of small subgroups in which confidence intervals were wide. There were no significant between-group differences in quality of life or overall survival. The most common treatment-related adverse event was diarrhea (in 26% of the patients in the lanreotide group and 9% of those in the placebo group). CONCLUSIONS: Lanreotide was associated with significantly prolonged progression-free survival among patients with metastatic enteropancreatic neuroendocrine tumors of grade 1 or 2 (Ki-67 <10%). (Funded by Ipsen; CLARINET ClinicalTrials.gov number, NCT00353496; EudraCT 2005-004904-35.).

Enriching the drinking water of rats with extracts of Salvia officinalis and Thymus vulgaris increases their resistance to oxidative stress.

Nature is an attractive source of therapeutic compounds. In comparison to the artificial drugs, natural compounds cause less adverse side effects and are suitable for current molecularly oriented approaches to drug development and their mutual combining. Medicinal plants represent one of the most available remedy against various diseases. Proper examples are Salvia officinalis L. and Thymus vulgaris L. which are known aromatic medicinal plants. They are very popular and frequently used in many countries. The molecular mechanism of their biological activity has not yet been fully understood. The aim of this study was to ascertain if liver cells of experimental animals drinking extracts of sage or thyme will manifest increased resistance against oxidative stress. Adult Sprague-Dawley rats were divided into seven groups. They drank sage or thyme extracts for 2 weeks. At the end of the drinking period, blood samples were collected for determination of liver biochemical parameters and hepatocytes were isolated to analyze (i) oxidatively generated DNA damage (conventional and modified comet assay), (ii) activities of antioxidant enzymes [superoxide dismutase (SOD), glutathione peroxidase (GPx)] and (iii) content of glutathione. Intake of sage and thyme had no effect either on the basal level of DNA damage or on the activity of SOD in rat hepatocytes and did not change the biochemical parameters of blood plasma. Simultaneously, the activity of GPx was significantly increased and the level of DNA damage induced by oxidants was decreased. Moreover, sage extract was able to start up the antioxidant protection expressed by increased content of glutathione. Our results indicate that the consumption of S.officinalis and T.vulgaris extracts positively affects resistency of rat liver cells against oxidative stress and may have hepatoprotective potential.

Induction of the mitochondrial permeability transition (MPT) by micromolar iron: liberation of calcium is more important than NAD(P)H oxidation.

The mitochondrial permeability transition (MPT) plays an important role in cell death. The MPT is triggered by calcium and promoted by oxidative stress, which is often catalyzed by iron. We investigated the induction of the MPT by physiological concentrations of iron. Isolated rat liver mitochondria were initially stabilized with EDTA and bovine serum albumin and energized by succinate or malate/pyruvate. The MPT was induced by 20µM calcium or ferrous chloride. We measured mitochondrial swelling, the inner membrane potential, NAD(P)H oxidation, iron and calcium in the recording medium. Iron effectively triggered the MPT; this effect differed from non-specific oxidative damage and required some residual EDTA in the recording medium. Evidence in the literature suggested two mechanisms of action for the iron: NAD(P)H oxidation due to loading of the mitochondrial antioxidant defense systems and uptake of iron to the mitochondrial matrix via a calcium uniporter. Both of these events occurred in our experiments but were only marginally involved in the MPT induced by iron. The primary mechanism observed in our experiments was the displacement of adventitious/endogenous calcium from the residual EDTA by iron. Although artificially created, this interplay between iron and calcium can well reflect conditions in vivo and could be considered as an important mechanism of iron toxicity in the cells.

The European Neuroendocrine Tumour Society registry, a tool to assess the prognosis of neuroendocrine neoplasms.

BACKGROUND: Neuroendocrine neoplasms (NENs) are rare tumours with variable clinical behaviour. Their natural history is ideally best approached in large, multicentre and multinational registries with long-term patients' follow-up. The European Neuroendocrine Tumour Society registry aims to obtain information regarding NEN outcomes and prognostic factors in a European frame. PATIENTS AND METHODS: We collected data from 7 national NEN registries (Belgium, Czech Republic, Germany, Greece, Poland, Spain, Switzerland), representing 10,102 patients. Anonymised/pseudonymised data were collected in a secured server. Descriptive statistical methods were applied, as well as Kaplan-Meier survival curves and multivariable analyses for prognostic factors of overall survival (OS). RESULTS: median age of the study population was 60 years (range: 18-102), 48% were female. Common primary tumour sites were pancreas (27%) and small intestine (21%). Stage 4 disease was found in 47% of patients, while 26/10/16% had stage 1/2/3 disease, respectively. Grading (n = 6952) was G1/2/3 in 48/37/15% of the patients, respectively. Surgery was the main treatment, provided to 71% of patients, followed by somatostatin analogues (32%), chemotherapy (20%), Peptide receptor Radionuclide Therapy (PRRT) (9%) and targeted therapies (8%). OS at 5 years was 74%, influenced by grade, stage and tissue of origin in multivariate analysis. A Ki67 cut-off value set at 55% within the G3 group allowed to separate 2 groups with a meaningful different OS. CONCLUSION: We report the first analysis of the European Neuroendocrine Tumour Society registry, comprising 10,102 patients with NEN from 7 European countries. This large cohort study describes prognostic factors for the survival of NENs throughout Europe, including primary tumour site, grade, stage and treatment.

Lanreotide autogel/depot in advanced enteropancreatic neuroendocrine tumours: final results of the CLARINET open-label extension study.

PURPOSE: In the phase III CLARINET study (NCT00353496), lanreotide autogel/depot (lanreotide) significantly improved progression-free survival (PFS) vs placebo in patients with non-functioning intestinal or pancreatic neuroendocrine tumours (NETs). The aim of CLARINET open-label extension (OLE) (NCT00842348) was to evaluate long-term safety and efficacy of lanreotide in these patients. METHODS: Patients from the CLARINET study were eligible for the OLE if they had stable disease (irrespective of treatment group) or progressive disease (PD) (placebo-treated patients only). All patients in the OLE received lanreotide 120 mg every 28 days. Computed tomography or magnetic resonance imaging scans were conducted every 6 months and assessed locally for PD (the final scan was also assessed centrally). RESULTS: Overall, 89 patients took part in the OLE (lanreotide, n = 42; placebo, n = 47). Median (range) exposure to lanreotide in patients who received lanreotide in the core study and OLE (LAN-LAN group) was 59.0 (26.0-102.3) months. In this group, the overall incidences of adverse events (AEs) and treatment-related AEs were lower in the OLE than in the core study. Median [95% CI] PFS in the LAN-LAN group was 38.5 [30.9; 59.4] months. In placebo-treated patients with PD at the end of the core study, time to death or subsequent PD during the OLE was 19 [10.1; 26.7] months. CONCLUSIONS: This study provides new evidence on the long-term safety profile and sustained anti-tumour effects of lanreotide autogel/depot in indolent and progressive metastatic intestinal or pancreatic NETs.

Expression of molecules of the Wnt pathway and of E-cadherin in the etiopathogenesis of human thymomas.

The molecular pathogenesis of thymoma remains largely unknown. It has been recently demonstrated, that activation of Wnt signaling pathway leads to increased incidence of thymoma in murine models. The present study investigated the activation of molecules of the Wnt signaling pathway in human thymoma. A total of 112 thymoma cases with complete clinical and follow-up data and 8 controls were included in the present study. Patients with thymoma and controls were examined immunohistochemically for ß-catenin and E-cadherin. The mRNA expression levels of CTNNB1, CCND1, MYC, AXIN2 and CDH1 were analyzed by reverse transcription-quantitative PCR. Immunohistochemically, ß-catenin and E-cadherin were overexpressed in neoplastic cells of all thymomas. In type A, B1 and non-invasive type B2 thymoma, both molecules were located in the cytoplasm, in contrast to invasive type B2 and B3 thymoma, where membranous immunopositivities were observed. mRNA expression levels of genes involved in the Wnt pathway and of E-cadherin were significantly increased in both type A and B thymoma compared with controls; increasing gradually from type B1 to B3, and with higher stage of disease. In recurrent type B thymoma, the mRNA expression of the molecules was significantly higher. Despite the activation of Wnt pathway in indolent type A thymoma, the negative feedback of the pathway was preserved by overexpression of inhibitory molecule axin2, which was not overexpressed in type B thymoma. In summary, the Wnt pathway was activated in human thymoma and may contribute to oncogenesis. Detection of molecules of the Wnt pathway may be of diagnostic and prognostic value.

Vitamin D for prevention of sternotomy healing complications: REINFORCE-D trial.

BACKGROUND: Most cardiac surgery patients undergo median sternotomy during open heart surgery. Sternotomy healing is an arduous, very complex, and multifactorial process dependent on many independent factors affecting the sternum and the surrounding soft tissues. Complication rates for median sternotomy range from 0.5 to 5%; however, mortality rates from complications are very variable at 7-80%. Low calcidiol concentration below 80 nmol/L results in calcium absorptive impairment and carries a risk of bone loss, which is considered as a risk factor in the sternotomy healing process. The primary objective of this clinical trial is to compare the incidence of all postoperative sternotomy healing complications in two parallel patient groups administered cholecalciferol or placebo. The secondary objectives are focused on general patient recovery process: sternal bone healing grade at the end of the trial, length of hospitalization, number of days spent in the ICU, number of days spent on mechanical lung ventilation, and number of hospital readmissions for sternotomy complications. METHODS: This clinical trial is conducted as monocentric, randomized, double-blind, placebo-controlled, with planned enrollment of 600 patients over 4 years, approximately 300 in the placebo arm and 300 in the treatment arm. Males and females from 18 to 95 years of age who fulfill the indication criteria for undergoing cardiac surgery with median sternotomy can be included in this clinical trial, if they meet the eligibility criteria. DISCUSSION: REINFORCE-D is the first monocentric trial dividing patients into groups based on serum calcidiol levels, and with dosing based on serum calcidiol levels. This trial may help to open up a wider range of postoperative healing issues. TRIAL REGISTRATION: EU Clinical Trials Register, EUDRA CT No: 2016-002606-39 . Registered on September 8, 2016.

Anti-tumour effects of lanreotide for pancreatic and intestinal neuroendocrine tumours: the CLARINET open-label extension study.

In the CLARINET study, lanreotide Autogel (depot in USA) significantly prolonged progression-free survival (PFS) in patients with metastatic pancreatic/intestinal neuroendocrine tumours (NETs). We report long-term safety and additional efficacy data from the open-label extension (OLE). Patients with metastatic grade 1/2 (Ki-67 ≤ 10%) non-functioning NET and documented baseline tumour-progression status received lanreotide Autogel 120 mg (n = 101) or placebo (n = 103) for 96 weeks or until death/progressive disease (PD) in CLARINET study. Patients with stable disease (SD) at core study end (lanreotide/placebo) or PD (placebo only) continued or switched to lanreotide in the OLE. In total, 88 patients (previously: lanreotide, n = 41; placebo, n = 47) participated: 38% had pancreatic, 39% midgut and 23% other/unknown primary tumours. Patients continuing lanreotide reported fewer adverse events (AEs) (all and treatment-related) during OLE than core study. Placebo-to-lanreotide switch patients reported similar AE rates in OLE and core studies, except more diarrhoea was considered treatment-related in OLE (overall diarrhoea unchanged). Median lanreotide PFS (core study randomisation to PD in core/OLE; n=101) was 32.8 months (95% CI: 30.9, 68.0). A sensitivity analysis, addressing potential selection bias by assuming that patients with SD on lanreotide in the core study and not entering the OLE (n=13) had PD 24 weeks after last core assessment, found median PFS remaining consistent: 30.8 months (95% CI: 30.0, 31.3). Median time to further PD after placebo-to-lanreotide switch (n=32) was 14.0 months (10.1; not reached). This OLE study suggests long-term treatment with lanreotide Autogel 120 mg maintained favourable safety/tolerability. CLARINET OLE data also provide new evidence of lanreotide anti-tumour benefits in indolent and progressive pancreatic/intestinal NETs.

Ultraviolet A radiation potentiates the cytotoxic and genotoxic effects of 7 H-dibenzo[c,g]carbazole and its methyl derivatives.

7H-Dibenzo[c,g]carbazole (DBC) is a heterocyclic aromatic hydrocarbon that is carcinogenic in many species and tissues. DBC is a common environmental pollutant, and is therefore constantly exposed to sunlight. However, there are limited data exploring the toxicity of DBC photoexcitation products. Here, we investigated the impact of ultraviolet (UV) A radiation on the biological activity of DBC and its methyl derivatives, 5,9-dibenzo[c,g]carbazole and N-methyl dibenzo[c,g]carbazole, on human skin HaCaT keratinocytes. Co-exposure of HaCaT cells to UVA and DBC derivatives resulted in a sharp dose-dependent decrease in cell survival and apparent changes in cell morphology. Under the same treatment conditions, significant increases in DNA strand breaks, intracellular reactive oxygen species, and oxidative damage to DNA were observed in HaCaT cells. Consistent with these results, an apparent inhibition in superoxide dismutase, but not glutathione peroxidase activity, was detected in cells treated with DBC and its derivatives under UVA irradiation. The photoactivation-induced toxicity of individual DBC derivatives correlated with the electron excitation energies approximately expressed as the energy difference between the highest occupied and the lowest vacant molecular orbital. Our data provide the first evidence that UVA can enhance the toxicity of DBC and its derivatives. Photoactivation-induced conversion of harmless chemical compounds to toxic photoproducts associated with reactive oxygen species generation may substantially amplify the adverse health effects of UVA radiation and contribute to increased incidence of skin cancer.

The role of FDG-PET/CT in the detection of recurrent colorectal cancer.

PURPOSE: The conventional diagnostic techniques used to assess recurrence of colorectal cancer (CRCR) often yield unspecific findings. Integrated FDG-PET/CT seems to offer promise for the differential diagnosis of benign and malignant lesions. The aim of this study was to compare the value of FDG-PET and PET/CT in the detection of CRCR subsequent to colonic resection or rectal amputation. METHODS: The population for this retrospective study comprised 84 patients with suspected CRCR. The sensitivity, specificity and accuracy of PET and PET/CT were calculated for (a) intra-abdominal extrahepatic recurrences, (b) extra-abdominal and/or hepatic recurrences and (c) all recurrences, and tumour marker levels were analysed. RESULTS: The sensitivity, specificity and overall accuracy of PET in detecting intra-abdominal extrahepatic CRCR were 82%, 88% and 86%, respectively, compared with 88%, 94% and 92%, respectively, for PET/CT. The corresponding figures for detection of extra-abdominal and/or hepatic CRCR were 74%, 88% and 85% for PET and 95%, 100% and 99% for PET/CT. Considering the entire population, the sensitivity, specificity and overall accuracy of PET were 80%, 69% and 75%, respectively, compared with 89%, 92% and 90%, respectively, for PET/CT. FDG-PET/CT examination correctly detected 40 out of a total of 45 patients with CRCR. Two of five patients with falsely negative FDG-PET/CT findings had local microscopic recurrences and one had miliary liver metastases. Of 39 patients without CRCR, three showed false positive FDG-PET/CT results. Two of these cases were due to increased accumulation in inflammatory foci in the bowel wall, while one was due to haemorrhaging into the adrenal gland. CONCLUSION: FDG-PET/CT appears to be a very promising method for distinguishing a viable tumour from fibrous changes, thereby avoiding unnecessary laparotomy.