Evaluating trifluridine + tipiracil hydrochloride in a fixed combination (TAS-102) for the treatment of colorectal cancer

Introduction: Despite major progress in treating advanced colorectal cancer (CRC), prognosis in this population after progression on standard treatment remains dismal and the development of new drugs represents an unmet need. Historically, fluoropyrimidines have played a major role in the treatment of metastatic CRC. TAS-102, a novel combination of trifluridine and tipiracil hydrochloride, has demonstrated improvement in overall survival in the refractory CRC setting, with a safe toxicity profile. Areas covered: A literature review of published clinical studies was performed. Herein, the authors review the pharmacological and clinical data of TAS-102 when used in metastatic CRC, both as a single agent as well as in novel combinations under investigation. Expert opinion: The addition of TAS-102 to the therapeutic armamentarium of metastatic CRC is an encouraging breakthrough considering the demonstrated survival benefit and favorable tolerability profile. Combinations with other agents are under clinical investigation in different settings in an attempt to widen its use. To optimize treatment in today’s era of molecular oncology, efforts should be focused on understanding primary and secondary resistance mechanisms, along with the identification of potential biomarkers of response

Aflatoxin M1 in Milk and some Dairy Products: Level, Effect of Manufature and Public Health Concerns

Aflatoxins (AFs) are toxic and carcinogenic metabolites produced by a variety of fungi. Aflatoxin M1 (AFM1) is the major carcinogenic type frequently found in milk and dairy products, thus posing a significant impact on human health. The current study was undertaken to examine milk and some dairy products for contamination with AFM1 in local markets, Sharkia Governorate, Egypt, as well as the effect of manufacture. A total of 75 samples (15, each) of raw milk, pasteurized milk, yoghurt, processed cheese and Domiati cheese were randomly collected. AFM1 was detected in 27 (36%) out of the examined samples in which the level of AFM1 exceeded the limits (0 ng/L, kg) allowed by Egyptian regulation but only 6 (8%) samples exceeded the limits (50 ng/L, kg) allowed by European Commission regulation. Levels of AFM1 contamination in the examined milk and dairy products with mean values of 35.68 ± 10.90, 45.83 ± 7.80, 7.57 ± 1.92, 24.53 ± 3.91 and 42 ± 4.93 ng/L, kg in raw milk, pasteurized milk, yoghurt, processed cheese and Domiati cheese, respectively, were detected. The level of AFM1 decreased after yoghurt manufactur, while, cheese manufacture showed concentration of AFM1 in curd than those in cheese milk. During refrigeration storage of yoghurt, the mean AFM1 toxin decreased after one, two, three, seven days, respectively, then nearly similar level from seven days to fourteen days of storage. In conclusion, widespread presence of AFM1 in raw milk and some dairy products were considered to be possible hazards for public health especially children therefore, continuous monitoring of AFM1 level in commonly marketed raw milk and dairy products in Sharkia markets should be regularly done. Manufacture and storage had little effect on AFM1 content in milk and dairy products, therefore, new or modern technologies for detoxification of milk should be further studied

Monitoring of RAS mutant clones in plasma of patients with RAS mutant metastatic colorectal cancer

Circulating tumor DNA; Liquid biopsy; Metastatic colorectal cancerADN tumoral circulante; Biopsia liquida; Cáncer colorrectal metastásicoADN tumoral circulant; Biòpsia líquida; Càncer colorectal metastàticPurpose Some patients with histologically confirmed primary mCRC and mutated RAS reported undetectable RAS mutant clones in plasma after receiving anti-VEGF treatment. The aim was to prospectively assess it with its potential therapeutic implications. Methods RAS mutant genes in solid biopsy (before first-line treatment: FOLFOX/CAPOX + bevacizumab) were compared in liquid biopsy (before second-line treatment: panitumumab + FOLFIRI), using Idylla™ system. Discordant results between solid/liquid biopsies were assessed by the next-generation sequencing (NGS) test (solid/liquid biopsies). Results Twenty-three patients were assessed (seven had RAS mutant discrepancies between solid/liquid biopsies). The NGS test confirmed that 3/23 (13%) patients had undetectable RAS mutant clones in liquid biopsy and 3/23 (13%) presented discrepancies in solid biopsy (Idylla™ system vs. NGS test). Conclusion Thirteen percentage of patients had undetectable RAS mutant clones in liquid biopsy after first-line treatment. However, some discrepancies between solid and liquid biopsies have been observed. These results suggest a need to improve accuracy of RAS analyses, especially in solid biopsies.This work was supported by Amgen S.A. Amgen did not have any role in study design; collection, analysis, and interpretation of data; writing the report; and the decision to submit the report for publication

Efficient mapping of hierarchical trees on coarse-grain reconfigurable architectures

Reconfigurable architectures have become increasingly important in recent years. In this paper we present an approach to the problem of executing 3D graphics interactive applications onto these architectures. The hierarchical trees are usually implemented to reduce the data processed, thereby diminishing the execution time. We have developed a mapping scheme that parallelizes the tree execution onto a SIMD reconfigurable architecture. This mapping scheme considerably reduces the time penalty caused by the possibility of executing different tree nodes in SIMD fashion. We have developed a technique that achieves an efficient hierarchical tree execution taking decisions at execution time. It also promotes the possibility of data coherence in order to reduce the execution time. The experimental results show high performance and efficient resource utilization on tested applications

Influenza A and B viruses in the population of Vojvodina, Serbia

At present, two influenza A viruses, H1N1pdm09 and H3N2, along with influenza B virus co-circulate in the human population, causing endemic and seasonal epidemic acute febrile respiratory infections, sometimes with life-threatening complications. Detection of influenza viruses in nasopharyngeal swab samples was done by real-time RT-PCR. There were 60.2% (53/88) positive samples in 2010/11, 63.4% (52/82) in 2011/12, and 49.9% (184/369) in 2012/13. Among the positive patients, influenza A viruses were predominant during the first two seasons, while influenza B type was more active during 2012/13. Subtyping of influenza A positive samples revealed the presence of A (H1N1)pdm09 in 2010/11, A (H3N2) in 2011/12, while in 2012/13, both subtypes were detected. The highest seroprevalence against influenza A was in the age-group 30-64, and against influenza B in adults aged 30-64 and >65. [Projekat Ministarstva nauke Republike Srbije, br. TR31084

Comparison of Conventional and Ultrasound-assisted Extraction Techniques on Mass Fraction of Phenolic Compounds from Sage (Salvia officinalis L.)

An innovative ultrasound-assisted extraction (UAE) is the rapid non-thermal extraction technique, which in comparison to conventional extraction (CE), offers high reproducibility in a short time with simplified manipulation, reduced solvent consumption and lower energy. Optimization of ultrasonic conditions was conducted for devices with nominal output power of 100 and 400 W, including the influence of geometrical parameters of probes regarding ultrasound-assisted extraction. The results showed that the optimal parameters for extraction of total phenols and rosmarinic acid as a dominant compound in sage extracts were as follows: solvent: 30 % ethanol, extraction duration of 11 minutes, and ultrasonic device output power of 400 W. The antioxidant capacity of the obtained extract correlated with the concentration of total phenols and flavonoids, and among individual phenols the rosmarinic acid contributed the most to the antioxidant capacity. The achieved results and statistical analysis (p ≤ 0.05) have shown how UAE resulted in shorter extraction time, and increased extraction capacity of phenolic compounds by using solvents with a less amount of organic phase

Greater bioavailability of xanthophylls compared to carotenes from orange juice (high-pressure processed, pulsed electric field treated, low-temperature pasteurised, and freshly squeezed) in a crossover study in healthy individuals

This study examined the effect of the intake of orange juice provided freshly squeezed (FS) or processed using low-temperature pasteurisation (LP), high-pressure processing (HPP), or pulsed electric field (PEF) treatment on the serum carotenoid concentrations of 12 healthy individuals, aged 20–32 years, enrolled in a crossover study. Participants were instructed to consume 500 ml of orange juice/day for 14 days. Carotenoid concentrations in the orange juice as well as serum samples retrieved on days 7 and 14 were analysed via HPLC. A significant increase in serum xanthophyll concentrations, but not serum carotenes, was observed, with the highest increase in α- and β-cryptoxanthin. The processing technologies applied appeared to affect serum carotenoid concentrations, with concentrations being similar in the HPP and FS orange juice types. As high variability in serum carotenoid concentrations was observed, the effect of different technologies on serum carotenoid concentration warrants further studies with larger sample sizes.This work was supported by the Consejeria de Educacion, Comunidad Autonoma de Madrid, Spain (grants: CAM 07G/0040/2000 and 07G/0041/2000) and by the Instituto de Salud Carlos III, Spain (grant RCMN C03/08)

Two phase I studies of BI 836880, a vascular endothelial growth factor/angiopoietin-2 inhibitor, administered once every 3 weeks or once weekly in patients with advanced solid tumors

BACKGROUND: BI 836880 is a humanized bispecific nanobody® that inhibits vascular endothelial growth factor and angiopoietin-2. Here, we report results from two phase I, nonrandomized, dose-escalation studies (NCT02674152 and NCT02689505; funded by Boehringer Ingelheim) evaluating BI 836880 in patients with confirmed locally advanced or metastatic solid tumors, refractory to standard therapy, or for which standard therapy was ineffective. PATIENTS AND METHODS: Patients aged ≥18 years, with an Eastern Cooperative Oncology Group performance status of 0-2 and adequate organ function received escalating intravenous doses of BI 836880 once every 3 weeks (Q3W; Study 1336.1) or once weekly (QW; Study 1336.6). Primary objectives were maximum tolerated dose (MTD) and recommended phase II dose of BI 836880, based on dose-limiting toxicities (DLTs) during the first cycle. RESULTS: Patients received one of five dosages of 40-1000 mg Q3W (29 patients) or 40-240 mg QW (24 patients). One DLT occurred with Q3W treatment [Grade (G) 3 pulmonary embolism (1000 mg)]. Five DLTs occurred in four patients treated QW [G2 proteinuria (120 mg); G3 hypertension (180 mg); G3 proteinuria and G3 hypertension (240 mg); and G4 respiratory distress (240 mg)]. All patients experienced adverse events, most commonly hypertension with Q3W treatment (89.7%; G3 41.4%), and asthenia with QW treatment (62.5%). Two patients treated Q3W (both 1000 mg) and three patients treated QW (120 mg, 2 patients; 180 mg, 1 patient) experienced partial response. CONCLUSIONS: The MTD of BI 836880 was 720 mg Q3W and 180 mg QW. BI 836880 was generally manageable and demonstrated preliminary efficacy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.govNCT02674152; https://clinicaltrials.gov/ct2/show/NCT02674152 and NCT02689505; https://clinicaltrials.gov/ct2/show/NCT0268950