Prognostic clinical factors in pretreated colorectal cancer patients receiving regorafenib: Implications for clinical management

Background: We assessed the impact on survival of angiogenesis and inflammation-related factors, particularly LDH serum levels, platelet, neutrophil and lymphocyte counts, and neutrophil-to-lymphocyte ratio (NLR), in metastatic colorectal cancer patients receiving regorafenib monotherapy. Methods: LDH serum levels, neutrophil, lymphocyte and platelet counts were collected at the start of regorafenib monotherapy. Cut-offvalues were calculated by ROC curve analysis. Survival analyses were performed by Kaplan-Meier method, and multivariate analysis by Cox method. Results: A total of 208 patients were eligible for analysis. Among factors who were related with worse overall survival and who maintained their role at the multivariate analysis, high platelet count (Exp(b):1.4963, 95% CI:1.0130-2.2103, p = 0.0439) and high neutrophil/lymphocyte ratio (Exp(b):1.6963, 95% CI:1.0757-2.6751, p = 0.0237) were those who more deeply were related to worse overall survival. High lymphocyte count (Exp(b):0.4527, 95% CI:0.2801-0.7316, p = 0.0013) was correlated with improved overall survival. Conclusions: High neutrophil, high platelet, low lymphocyte count and/or high NLR may represent negative prognostic factors in patients receiving regorafenib monotherapy. It is advisable that these factors are taken into account in the design of subsequent trials in colorectal cancer patients receiving this drug

SISO Space Reference FOM - Tools and Testing

The Simulation Interoperability Standards Organization (SISO) Space Reference Federation Object Model (SpaceFOM) version 1.0 is nearing completion. Earlier papers have described the use of the High Level Architecture (HLA) in Space simulation as well as technical aspects of the SpaceFOM. This paper takes a look at different SpaceFOM tools and how they were used during the development and testing of the standard.The first organizations to develop SpaceFOM-compliant federates for SpaceFOM development and testing were NASA's Johnson Space Center (JSC), the University of Calabria (UNICAL), and Pitch Technologies.JSC is one of NASA's lead centers for human space flight. Much of the core distributed simulation technology development, specifically associated with the SpaceFOM, is done by the NASA Exploration Systems Simulations (NExSyS) team. One of NASA's principal simulation development tools is the Trick Simulation Environment. NASA's NExSyS team has been modifying and using Trick and TrickHLA to help develop and test the SpaceFOM.The System Modeling And Simulation Hub Laboratory (SMASH-Lab) at UNICAL has developed the Simulation Exploration Experience (SEE) HLA Starter kit, that has been used by most SEE teams involved in the distributed simulation of a Moon base. It is particularly useful for the development of federates that are compatible with the SpaceFOM. The HLA Starter Kit is a Java based tool that provides a well-structured framework to simplify the formulation, generation, and execution of SpaceFOM-compliant federates.Pitch Technologies, a company specializing in distributed simulation, is utilizing a number of their existing HLA tools to support development and testing of the SpaceFOM. In addition to the existing tools, Pitch has developed a few SpaceFOM specific federates: Space Master for managing the initialization, execution and pacing of any SpaceFOM federation; EarthEnvironment, a simple Root Reference Publisher; and Space Monitor, a graphical tool for monitoring reference frames and physical entities.Early testing of the SpaceFOM was carried out in the SEE university outreach program, initiated in SISO. Students were given a subset of the FOM, that was later extended. Sample federates were developed and frameworks were developed or adapted to the early FOM versions.As drafts of the standard matured, testing was performed using federates from government, industry, and academia. By mixing federates developed by different teams the standard could be tested with respect to functional correctness, robustness and clarity.These frameworks and federates have been useful when testing and verifying the design of the standard. In addition to this, they have since formed a starting point for developing SpaceFOM-compliant federations in several projects, for example for NASA, ESA as well as SEE

Pancreatic tumors imaging: an update

Currently, ultrasound (US), computed tomography (CT) and Magnetic Resonance imaging (MRI) represent the mainstay in the evaluation of pancreatic solid and cystic tumors affecting pancreas in 80-85% and 10-15% of the cases respectively. Integration of US, CT or MR imaging is essential for an accurate assessment of pancreatic parenchyma, ducts and adjacent soft tissues in order to detect and to stage the tumor, to differentiate solid from cystic lesions and to establish an appropriate treatment. The purpose of this review is to provide an overview of pancreatic tumors and the role of imaging in their diagnosis and management. In order to a prompt and accurate diagnosis and appropriate management of pancreatic lesions, it is crucial for radiologists to know the key findings of the most frequent tumors of the pancreas and the current role of imaging modalities. A multimodality approach is often helpful. If multidetector-row CT (MDCT) is the preferred initial imaging modality in patients with clinical suspicion for pancreatic cancer, multiparametric MRI provides essential information for the detection and characterization of a wide variety of pancreatic lesions and can be used as a problem-solving tool at diagnosis and during follow-up

Health-related Quality of Life in the Phase III LUME-Colon 1 Study: Comparison and Interpretation of Results From EORTC QLQ-C30 Analyses

QVRS; Nintedanib; Temps de deterioramentCVRS; Nintedanib; Tiempo para el deterioroHRQoL; Nintedanib; Time to deteriorationIntroduction We used European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) data from the LUME-Colon 1 study to illustrate different methods of statistical analysis for health-related quality of life (HRQoL), and compared the results. Patients and Methods Patients were randomized 1:1 to receive nintedanib 200 mg twice daily plus best supportive care (n = 386) or matched placebo plus best supportive care (n = 382). Five methods (mean treatment difference averaged over time, using a mixed-effects growth curve model; mixed-effects models for repeated measurements (MMRM); time-to-deterioration (TTD); status change; and responder analysis) were used to analyze EORTC QLQ-C30 global health status (GHS)/QoL and scores from functional scales. Results Overall, GHS/QoL and physical functioning deteriorated over time. Mean treatment difference slightly favored nintedanib over placebo for physical functioning (adjusted mean, 2.66; 95% confidence interval [CI], 0.97-4.34) and social functioning (adjusted mean, 2.62; 95% CI, 0.66-4.47). GHS/QoL was numerically better with nintedanib versus placebo (adjusted mean, 1.61; 95% CI, −0.004 to 3.27). MMRM analysis had similar results, with better physical functioning in the nintedanib group at all timepoints. There was no significant delay in GHS/QoL deterioration (10%) and physical functioning (16%) with nintedanib versus placebo (TTD analysis). Status change analysis showed a higher proportion of patients with markedly improved GHS/QoL and physical functioning in the nintedanib versus placebo groups. Responder analysis showed a similar, less pronounced pattern. Conclusion Analyses of EORTC QLQ-C30 data showed that HRQoL was not impaired by treatment with nintedanib versus placebo. Analysis and interpretation of HRQoL endpoints should consider symptom type and severity and course of disease.This work was supported by Boehringer Ingelheim. Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Syneos Health Communications during the preparation of this manuscript

Representation of grossone-based arithmetic in simulink for scientific computing

AbstractNumerical computing is a key part of the traditional computer architecture. Almost all traditional computers implement the IEEE 754-1985 binary floating point standard to represent and work with numbers. The architectural limitations of traditional computers make impossible to work with infinite and infinitesimal quantities numerically. This paper is dedicated to the Infinity Computer, a new kind of a supercomputer that allows one to perform numerical computations with finite, infinite, and infinitesimal numbers. The already available software simulator of the Infinity Computer is used in different research domains for solving important real-world problems, where precision represents a key aspect. However, the software simulator is not suitable for solving problems in control theory and dynamics, where visual programming tools like Simulink are used frequently. In this context, the paper presents an innovative solution that allows one to use the Infinity Computer arithmetic within the Simulink environment. It is shown that the proposed solution is user-friendly, general purpose, and domain independent

Pooled safety analysis from phase III studies of trifluridine/tipiracil in patients with metastatic gastric or gastroesophageal junction cancer and metastatic colorectal cancer

Metastatic colorectal cancer; Renal impairment; SafetyCáncer colorrectal metastásico; Insuficiencia renal; SeguridadCàncer colorectal metastàtic; Insuficiència renal; SeguretatBackground Trifluridine/tipiracil (FTD/TPI) showed clinical benefit, including improved survival and manageable safety in previously treated patients with metastatic colorectal (mCRC) or gastric/gastroesophageal junction (mGC/GEJC) cancer in the phase III RECOURSE and TAGS trials, respectively. A pooled analysis was conducted to further characterize FTD/TPI safety, including management of haematologic toxicities and use in patients with renal or hepatic impairment. Patients and methods Adults with ≥2 prior regimens for advanced mGC/GEJC or mCRC were randomized (2 : 1) to FTD/TPI [35 mg/m2 twice daily days 1-5 and 8-12 (28-day cycle); same dosage in both trials] or placebo plus best supportive care. Adverse events (AEs) were summarized in the safety population (patients who received ≥1 dose) and analysed by renal/hepatic function. Results TAGS and RECOURSE included 335 and 533 FTD/TPI-treated and 168 and 265 placebo-treated patients, respectively. Overall safety of FTD/TPI was similar in TAGS and RECOURSE. Haematologic (neutropenia, anaemia) and gastrointestinal (nausea, diarrhoea) AEs were most commonly observed. Laboratory-assessed grade 3-4 neutropenia occurred in 37% (TAGS)/38% (RECOURSE) of FTD/TPI-treated patients (median onset: 29 days/55 days), and 96% (TAGS)/97% (RECOURSE) of cases resolved regardless of renal/hepatic function. Supportive medications for neutropenia were received by 17% (TAGS) and 9% (RECOURSE); febrile neutropenia was reported in 2% and 4%, respectively. Overall grade ≥3 AEs were more frequent in patients with moderate renal impairment [81% (TAGS); 85% (RECOURSE)] versus normal renal function (74%; 67%); anaemia and neutropenia were more common in patients with renal impairment. FTD/TPI safety (including haematologic AEs) was consistent across patients with normal and mildly impaired hepatic function. Conclusions These results support FTD/TPI as a well-tolerated treatment in patients with mGC/GEJC or mCRC, with a consistent safety profile. Safety was largely similar in patients with normal or mildly impaired renal/hepatic function; however, patients with renal impairment should be monitored for haematologic toxicities.This work was supported by Taiho Oncology, Inc. and Taiho Pharmaceutical (no grant number). This analysis was funded by Taiho Oncology, Inc. Professional medical writing and editorial assistance were provided by Vasupradha Vethantham, Meredith Kalish, and Jennifer L. Robertson at Ashfield MedComms, an Inizio company, funded by Taiho Oncology, Inc

The international open-label early-access study of trifluridine/tipiracil (TAS-102) in patients with pretreated metastatic colorectal cancer (phase IIIb)

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Early changes in plasma DNA levels of mutant KRAS as a sensitive marker of response to chemotherapy in pancreatic cancer

Pancreatic cancer (PDAC) is still lacking of reliable markers to monitor tumor response. CA 19-9 is the only biomarker approved, despite it has several limitations in sensitivity and specificity. Since mutations of KRAS occur in more than 90% of tumors, its detection in circulating free tumor DNA (cftDNA) could represent a biomarker to monitor chemotherapy response. Twenty-seven advanced PDAC patients given first-line 5-fluorouracil, irinotecan and oxaliplatin or gemcitabine and nab-paclitaxel were enrolled. Three ml of plasma were collected: 1) before starting chemotherapy (baseline); 2) at day 15 of treatment; and 3) at each clinical follow-up. cftDNA was extracted and analysed for KRAS mutations (mutKRAS) by digital droplet PCR. Nineteen patients displayed a mutKRAS in baseline plasma samples. There was a statistically significant difference in progression-free survival (PFS) and overall survival (OS) in patients with increase vs. stability/reduction of cftDNA in the sample collected at day 15 (median PFS 2.5 vs 7.5 months, p = 0.03; median OS 6.5 vs 11.5 months, p = 0.009). The results of this study demonstrate that cftDNA mutKRAS changes are associated with tumor response to chemotherapy and support the evidence that mutKRAS in plasma may be used as a new marker for monitoring treatment outcome and disease progression in PDAC