bluuebunny/crossref_metadata_2025 huggingface dataset:
Macrocyclic MR contrast agents: evaluation of multiple-organ gadolinium retention in healthy rats
Authors: Bussi Simona , Coppo Alessandra , Celeste Roberto , Fanizzi Antonello , Fringuello Mingo Alberto , Ferraris Andrea , Botteron Catherine , Kirchin Miles A. , Tedoldi Fabio , Maisano Federico
Published: February 2020

Objectives

The purpose of this study was to compare Gd levels in rat tissues after cumulative exposure to four commercially available macrocyclic gadolinium-based contrast agents (GBCAs).

Methods

Sixty-five male Sprague-Dawley rats were randomized to four exposure groups (n = 15 per group) and one control group (n = 5). Animals in each exposure group received 20 GBCA administrations (four per week of ProHance®, Dotarem®, Clariscan™, or Gadovist® for 5 consecutive weeks) at a dose of 0.6 mmol/kg bodyweight. After 28-days’ recovery, animals were sacrificed and tissues harvested for Gd determination by inductively coupled plasma-mass spectroscopy (ICP-MS). Histologic assessment of the kidney tissue was performed for all animals.

Results

Significantly (p ≤ 0.005; all evaluations) lower Gd levels were noted with ProHance® than with Dotarem®, Clariscan™, or Gadovist® in all soft tissue organs: 0.144 ± 0.015 nmol/g vs. 0.342 ± 0.045, 0.377 ± 0.042, and 0.292 ± 0.047 nmol/g, respectively, for cerebrum; 0.151 ± 0.039 nmol/g vs. 0.315 ± 0.04, 0.345 ± 0.053, and 0.316 ± 0.040 nmol/g, respectively, for cerebellum; 0.361 ± 0.106 nmol/g vs. 0.685 ± 0.330, 0.823 ± 0.495, and 1.224 ± 0.664 nmol/g, respectively, for liver; 38.6 ± 25.0 nmol/g vs. 172 ± 134, 212 ± 121, and 294 ± 127 nmol/g, respectively, for kidney; and 0.400 ± 0.112 nmol/g vs. 0.660 ± 0.202, 0.688 ± 0.215, and 0.999 ± 0.442 nmol/g, respectively, for skin. No GBCA-induced macroscopic or microscopic findings were noted in the kidneys.

Conclusions

Less Gd is retained in the brain and body tissues of rats 28 days after the last exposure to ProHance® compared to other macrocyclic GBCAs, likely due to unique physico-chemical features that facilitate more rapid and efficient clearance.
Redefining the structure of structured reporting in radiology
Authors: Nobel J. Martijn , Kok Ellen M. , Robben Simon G. F.
Published: February 2020

Structured reporting is advocated as a means of improving reporting in radiology to the ultimate benefit of both radiological and clinical practice. Several large initiatives are currently evaluating its potential. However, with numerous characterizations of the term in circulation, “structured reporting” has become ambiguous and is often confused with “standardization,” which may hamper proper evaluation and implementation in clinical practice. This paper provides an overview of interpretations of structured reporting and proposes a clear definition that differentiates structured reporting from standardization. Only a clear uniform definition facilitates evidence-based implementation, enables evaluation of its separate components, and supports (meta-)analyses of literature reports.
Protective properties of heme oxygenase-1 expressed in umbilical cord mesenchymal stem cells help restore the ovarian function of premature ovarian failure mice through activating the JNK/Bcl-2 signal pathway-regulated autophagy and upregulating the circulating of CD8+CD28− T cells
Authors: Yin Na , Wu Chenting , Qiu Jianping , Zhang Yueming , Bo Le , Xu Ying , Shi Mengdie , Zhu Songyue , Yang Guangzhao , Mao Caiping
Published: February 2020

Background

Umbilical cord-derived mesenchymal stem cell (UCMSCs) transplantation has been widely studied in premature ovarian failure (POF). However, the underlying mechanism remains elusive. This study aims to investigate the protective properties and mechanisms of heme oxygenase-1 (HO-1) expressed in UCMSCs in restoring the ovarian function of POF mice.

Methods

In in vitro and in vivo experiments, mice were treated with the presence or absence of the HO-1/shHO-1-transfected UCMSCs, and the administration of SP600125 or anisomycin, the inhibitor or activator of JNK. The viability and apoptosis of granulosa cells (GCs) at different time points of co-cultivation were assessed in vitro. In in vivo experiments, mouse ovarian function was assessed by detecting the serum levels of hormone and observing the ovarian morphological changes. Multiple molecular indices of JNK/Bcl-2 signal pathway were performed. And the autophagy changes in GCs were assessed by detecting the associated cytokines and observing the intracellular autophagosome accumulation. Additionally, the spleen levels of CD8+CD28− T cells and serum levels of interleukin 10 (IL-10) were tested to evaluate the immune mechanisms involved.

Results

UCMSCs transfected with shHO-1 or treated with SP600125 inhibited GCs’ viability and promoted its apoptosis in a time-dependent manner in vitro. In in vivo experiments, mice in both groups showed little therapeutic efficiency which presented as the increased extent of ovarian fibrosis with decreased number of functional follicles, and disordered hormone production. Additionally, the JNK/Bcl-2-associated cytokines were obviously declined. The inhibited autophagy-related cytokines, the chromatin condensation and abound vacuolar autophagosome in GCs, and weakened fluorescence intensity by MDC were observed. The downregulated levels of CD8+CD28− T cells and serum levels of IL-10 were also detected. The damages above can be alleviated with HO-1-MSCs treatment or anisomycin administration.

Conclusions

HO-1 expressed in UCMSCs is critical in restoring the ovarian function in POF mice with UCMSC transplantation, which is mediated by the activation of JNK/Bcl-2 signal pathway-regulated autophagy and upregulating the circulating of CD8+CD28− T cells.
Working towards a better understanding of type 2 diabetes care organization with First Nations communities: a qualitative assessment
Authors: Wozniak Lisa A. , Johnson Jeffrey A. , Eurich Dean T.
Published: February 2020

Background

Diabetes care is suboptimal in First Nations populations. Innovative and culturally-relevant approaches are needed to promote proactive organization of diabetes care for diabetes patients on-reserve in Canada. The Reorganizing the Approach to Diabetes care through the Application of Registries (RADAR) model is one strategy to improve care: an integrated disease registry and electronic health record for community healthcare workers with centralized care coordination. The aim of this study was to qualitatively assess the organization of type 2 diabetes care in participating communities in Alberta, Canada, at baseline prior to implementing RADAR.

Methods

Using qualitative description, we purposefully sampled healthcare workers involved in diabetes care at each health center. We used the 5Rs framework (i.e., Recognize, Register, Resource, Relay, Recall) to inform the baseline assessment and conducted group interviews in 6 communities with 16 healthcare workers. Detailed notes were taken and validated by participants. Data was managed using ATLAS.ti 8 and analyzed using content analysis.

Results

We found strong commitment and effort by local healthcare workers to support people living with type 2 diabetes in their communities. However, healthcare workers were limited in their ability to identify (i.e., recognize), track (i.e., register and relay) and manage (i.e., resource and recall) people with type 2 diabetes as proposed by the 5Rs framework. The organization of diabetes care was often reactive and dependent on patients’ abilities to navigate the health system. Interestingly, participants talked about the 5Rs in relationship to one another, not in a linear or isolated manner.

Conclusions

Overall, the organization of diabetes care in participating communities did not align with the recommended approach of the 5Rs framework. In addition, we propose “reimagining” the 5Rs to reflect the interdependence and mediation of components situated within human and financial resources. This will better equip healthcare workers to assess, plan and execute organized and proactive diabetes care. However, the onus on people living with type 2 diabetes to engage with healthcare services remains a concern.

Trial registration

ISRCTN.com,ISRCTN14359671.
Complementary horse-assisted therapy for substance use disorders: a randomized controlled trial
Authors: Gatti Francesca , Walderhaug Espen , Kern-Godal Ann , Lysell Jeanette , Arnevik Espen Ajo
Published: February 2020

Background

Treatment completion is the greatest challenge for the treatment of substance use disorders (SUDs). A previous investigation showed that complementary horse-assisted therapy (cHAT) was associated with higher retention in treatment and completion than standard treatment alone. This randomized controlled trial further explored the benefits of cHAT for patients with SUDs.

Methods

Fifty patients in residential SUD treatment at the Department of Addiction Treatment, Oslo University Hospital, were randomly allocated to either cHAT (cHAT group) or treatment as usual alone (TAU-only group). The primary end-point was treatment completion. Secondary end-points were dropout, transfer to another treatment, and time in treatment.

Results

The multinomial logistic regression analysis found no statistically significant association between intervention (cHAT) and treatment outcome (completion, dropout, transferred) among the 37 participants who were ultimately recruited to the study. Some unforeseen challenges were encountered in the study: a high number of subjects transferred to another treatment, variable attendance at cHAT sessions, and long temporary exits. Nevertheless, 44% of participants in the cHAT group completed their treatment, compared with 32% in the TAU-only group; this observation encourages further investigation in a larger sample.

Conclusions

Though no association was identified between cHAT and treatment retention or completion, our study may have been underpowered. Further work in a larger clinical population is needed; observational studies with repeated measures may also be useful for investigating whether cHAT increases retention in treatment or rates of completion, two important factors for successful SUD treatment.

Trial registration The trial was registered and approved on 14 October 2011 by the Regional Committee for Medical and Health Research Ethics with registration number 2011/1642 and registered at ClinicalTrials.gov on 21 February 2013 with registration number NCT01795755
Urbanicity, hypothalamic-pituitary-adrenal axis functioning, and behavioral and emotional problems in children: a path analysis
Authors: Evans B. E. , van der Ende J. , Greaves-Lord K. , Huizink A. C. , Beijers R. , de Weerth C.
Published: February 2020

Background

Urbanization is steadily increasing worldwide. Previous research indicated a higher incidence of mental health problems in more urban areas, however, very little is known regarding potential mechanisms underlying this association. We examined whether urbanicity was associated with mental health problems in children directly, and indirectly via hypothalamic-pituitary-adrenal (HPA)-axis functioning.

Methods

Utilizing data from two independent samples of children we examined the effects of current urbanicity (n = 306, ages seven to 12 years) and early childhood urbanicity (n = 141, followed from birth through age 7 years). Children’s mothers reported on their mental health problems and their family’s socioeconomic status. Salivary cortisol samples were collected during a psychosocial stress procedure to assess HPA axis reactivity to stress, and at home to assess basal HPA axis functioning. Neighborhood-level urbanicity and socioeconomic conditions were extracted from Statistics Netherlands. Path models were estimated using a bootstrapping procedure to detect indirect effects.

Results

We found no evidence for a direct effect of urbanicity on mental health problems, nor were there indirect effects of urbanicity through HPA axis functioning. Furthermore, we did not find evidence for an effect of urbanicity on HPA axis functioning or effects of HPA axis functioning on mental health problems.

Conclusions

Possibly, the effects of urbanicity on HPA axis functioning and mental health do not manifest until adolescence. An alternative explanation is a buffering effect of high family socioeconomic status as the majority of children were from families with an average or high socioeconomic status. Further studies remain necessary to conclude that urbanicity does not affect children’s mental health via HPA axis functioning.
Cyclosporine-a attenuates retinal inflammation by inhibiting HMGB-1 formation in rats with type 2 diabetes mellitus
Authors: Wang Peng , Chen Fei , Zhang Xuedong
Published: February 2020

Background

Cyclosporine-A has been regarded as an immunoregulatory and anti-inflammatory drug for the treatment of various immune inflammatory diseases. However, the effect of Cyclosporine-A on the retina of type 2 diabetic rats and the underlying mechanism remains to be elucidated. The objective of the present study was to investigate the effect and mechanism of Cyclosporine-A on diabetic retinopathy.

Methods

Male Sprague-Dawley rats were established to type 2 diabetic model. After 6 weeks, diabetic rats and normal controls were intravitreally injected with. Cs-A (42 ng/2 μL) to the left eye, and 2 μL DMSO to the right eye for the control.. Another group of normal wild-type rats was subjected to intravitreal injections into. The left eyes with 5 μL PBS or HMGB-1 (5 ng/5 μL) or HMGB-1(5 ng/5 μL) plus. Cs-A (42 ng/2 μL), respectively. Retinal morphological changes were observed with. Hematoxylin–eosin staining. Expressions of HMGB-1, IL-1β and TNF-α were. Detected by immunohistochemistry, ELISA or Western blot or RT-PCR.

Results

Retinal expression levels of IL-1β and TNF-α were upregulated in type 2. diabetic rats and in normal rats with intravitreal injection of HMGB-1, which were. Attenuated by intravitreal Cs-A. Moreover, Cs-A decreased HMGB-1 expression in. diabetic retina and relieved the retinopathy in type 2 diabetic rats.

Conclusions

Intravitreal administration of Cs-A showed a protective effect on retina. of diabetic rats, possibly by downregulating retinal expressions of IL-1β and TNF-α. via the suppression of HMGB-1.
Locus coeruleus pathology in progressive supranuclear palsy, and its relation to disease severity
Authors: Kaalund Sanne Simone , Passamonti Luca , Allinson Kieren S. J. , Murley Alexander G. , Robbins Trevor W. , Spillantini Maria Grazia , Rowe James B.
Published: February 2020

The locus coeruleus is the major source of noradrenaline to the brain and contributes to a wide range of physiological and cognitive functions including arousal, attention, autonomic control, and adaptive behaviour. Neurodegeneration and pathological aggregation of tau protein in the locus coeruleus are early features of progressive supranuclear palsy (PSP). This pathology is proposed to contribute to the clinical expression of disease, including the PSP Richardson’s syndrome. We test the hypothesis that tau pathology and neuronal loss are associated with clinical heterogeneity and severity in PSP.

We used immunohistochemistry in post mortem tissues from 31 patients with a clinical diagnosis of PSP (22 with Richardson’s syndrome) and 6 control cases. We quantified the presence of hyperphosphorylated tau, the number of pigmented cells indicative of noradrenergic neurons, and the percentage of pigmented neurons with tau-positive inclusions. Ante mortem assessment of clinical severity using the PSP rating scale was available within 1.8 (±0.9) years for 23 patients.

We found an average 49% reduction of pigmented neurons in PSP patients relative to controls. The loss of pigmented neurons correlated with disease severity, even after adjusting for disease duration and the interval between clinical assessment and death. The degree of neuronal loss was negatively associated with tau-positive inclusions, with an average of 44% of pigmented neurons displaying tau-inclusions.

Degeneration and tau pathology in the locus coeruleus are related to clinical heterogeneity of PSP. The noradrenergic deficit in the locus coeruleus is a candidate target for pharmacological treatment. Recent developments in ultra-high field magnetic resonance imaging to quantify in vivo structural integrity of the locus coeruleus may provide biomarkers for noradrenergic experimental medicines studies in PSP.
Tau-tubulin kinase 1 and amyloid-β peptide induce phosphorylation of collapsin response mediator protein-2 and enhance neurite degeneration in Alzheimer disease mouse models
Authors: Ikezu Seiko , Ingraham Dixie Kaitlin L. , Koro Lacin , Watanabe Takashi , Kaibuchi Kozo , Ikezu Tsuneya
Published: February 2020

The accumulation of phosphorylated tau protein (pTau) in the entorhinal cortex (EC) is the earliest tau pathology in Alzheimer’s disease (AD). Tau tubulin kinase-1 (TTBK1) is a neuron-specific tau kinase and expressed in the EC and hippocampal regions in both human and mouse brains. Here we report that collapsin response mediator protein-2 (CRMP2), a critical mediator of growth cone collapse, is a new downstream target of TTBK1 and is accumulated in the EC region of early stage AD brains. TTBK1 transgenic mice show severe axonal degeneration in the perforant path, which is exacerbated by crossing with Tg2576 mice expressing Swedish familial AD mutant of amyloid precursor protein (APP). TTBK1 mice show accumulation of phosphorylated CRMP2 (pCRMP2), in the EC at 10 months of age, whereas age-matched APP/TTBK1 bigenic mice show pCRMP2 accumulation in both the EC and hippocampal regions. Amyloid-β peptide (Aβ) and TTBK1 suppress the kinetics of microtubule polymerization and TTBK1 reduces the neurite length of primary cultured neurons in Rho kinase-dependent manner in vitro. Silencing of TTBK1 or expression of dominant-negative Rho kinase demonstrates that Aβ induces CRMP2 phosphorylation at threonine 514 in a TTBK1-dependent manner, and TTBK1 enhances Aβ-induced CRMP2 phosphorylation in Rho kinase-dependent manner in vitro. Furthermore, TTBK1 expression induces pCRMP2 complex formation with pTau in vitro, which is enhanced upon Aβ stimulation in vitro. Finally, pCRMP2 forms a complex with pTau in the EC tissue of TTBK1 mice in vivo, which is exacerbated in both the EC and hippocampal tissues in APP/TTBK1 mice. These results suggest that TTBK1 and Aβ induce phosphorylation of CRMP2, which may be causative for the neurite degeneration and somal accumulation of pTau in the EC neurons, indicating critical involvement of TTBK1 and pCRMP2 in the early AD pathology.
A novel to perform a thermoelastic analysis using digital image correlation and the boundary element method
Authors: Oberg Matheus B. A. M. , de Oliveira Daniel F. , Goulart Jhon N. V. , Anflor Carla T. M.
Published: February 2020

This work aims for a novel thermoelastic analysis methodology based on experimental steady-state temperature data and numerical displacement evaluation. The temperature data was acquired using thermal imaging and used as the input for a boundary element method (BEM) routine to evaluate its consequent thermoelastic displacement. The thermoelastic contribution to the resultant displacement arises in the BEM formulation as a domain integral, which compromises the main benefits of the BEM. To avoid the necessity of domain discretization, the radial integration method (RIM) was applied to convert the thermoelastic domain integral into an equivalent boundary integral. Due to its mathematical development, the resultant formulation from RIM requires the temperature difference to be input as a function. The efficacy of the proposed methodology was verified based on experimental displacement fields obtained via digital image correlation (DIC) analysis. For this purpose, a CNC (computer numerical control) marker was developed to print the speckle pattern instead of preparing the specimen by using manual spray paint or using commercially available pre-painted adhesives. The good agreement observed in the comparison between the numerical and experimental displacements indicates the viability of the proposed methodology.
Development and proof-of-concept of a multicenter, patient-centered cancer registry for breast cancer patients with metastatic disease—the “Breast cancer care for patients with metastatic disease” (BRE-4-MED) registry
Authors: Stangl Stephanie , Haas Kirsten , Eichner Felizitas A. , Grau Anna , Selig Udo , Ludwig Timo , Fehm Tanja , Stüber Tanja , Rashid Asarnusch , Kerscher Alexander , Bargou Ralf , Hermann Silke , Arndt Volker , Meyer Martin , Wildner Manfred , Faller Hermann , Schrauder Michael G. , Weigel Michael , Schlembach Ulrich , Heuschmann Peter U. , Wöckel Achim
Published: February 2020

Background

Patients with metastatic breast cancer (MBC) are treated with a palliative approach with focus on controlling for disease symptoms and maintaining high quality of life. Information on individual needs of patients and their relatives as well as on treatment patterns in clinical routine care for this specific patient group are lacking or are not routinely documented in established Cancer Registries. Thus, we developed a registry concept specifically adapted for these incurable patients comprising primary and secondary data as well as mobile-health (m-health) data.

Methods

The concept for patient-centered “Breast cancer care for patients with metastatic disease” (BRE-4-MED) registry was developed and piloted exemplarily in the region of Main-Franconia, a mainly rural region in Germany comprising about 1.3 M inhabitants. The registry concept includes data on diagnosis, therapy, progression, patient-reported outcome measures (PROMs), and needs of family members from several sources of information including routine data from established Cancer Registries in different federal states, treating physicians in hospital as well as in outpatient settings, patients with metastatic breast cancer and their family members. Linkage with routine cancer registry data was performed to collect secondary data on diagnosis, therapy, and progression. Paper and online-based questionnaires were used to assess PROMs. A dedicated mobile application software (APP) was developed to monitor needs, progression, and therapy change of individual patients. Patient’s acceptance and feasibility of data collection in clinical routine was assessed within a proof-of-concept study.

Results

The concept for the BRE-4-MED registry was developed and piloted between September 2017 and May 2018. In total n = 31 patients were included in the pilot study, n = 22 patients were followed up after 1 month. Record linkage with the Cancer Registries of Bavaria and Baden-Württemberg demonstrated to be feasible. The voluntary APP/online questionnaire was used by n = 7 participants. The feasibility of the registry concept in clinical routine was positively evaluated by the participating hospitals.

Conclusion

The concept of the BRE-4-MED registry provides evidence that combinatorial evaluation of PROMs, needs of family members, and raising clinical parameters from primary and secondary data sources as well as m-health applications are feasible and accepted in an incurable cancer collective.
A study of the chemical effect of marble and granite slurry on green mortar compressive strength
Authors: Amin Shereen K. , Allam Mostafa E. , Garas Gihan L. , Ezz Hisham
Published: February 2020

Background

The marble and granite industries in Egypt produce a vast amount of by-product slurry waste that could be used in green mortar production suitable for construction purposes. This research highlights the effect of the chemical constituents of marble and granite waste powders on the compressive strength of the green concrete produced. A chemical analysis of the constituents of granite and marble wastes was compared with those of the cement to study the effect of these components on the hydration reaction inside the mixture. The experiment was based on replacing the same proportions of sand and cement in the green concrete mixes with each of granite and marble waste powders after dissolving it in the water content.

Results

The study revealed that by replacing 5% of cement in (NC5) mix, 10% of sand in (NF10) mix, as well as 5% of cement and 10% of sand in (NC5 + NF10) mix, by granite waste powder, the compressive strength values increased by 33%, 39%, and 41%, respectively. This was due to the presence of more than 26% fine free silica particles in granite which undergo pozzolanic reaction with calcium hydroxide present in mortar pores producing calcium silicate hydrate (CSH) crystals resulting in high strength to the cement mortar. For the same mixes containing marble powder, the compressive strength showed less values by − 14%, 10%, and 0% for NC5, NF10, and NC5 + NF10 mixes, respectively, when compared to the control mix values.

Conclusion

Although the waste particles worked as filler, it was observed that its presence in the mixture improved the particle packing and increased the cohesion of the composites.
Liquefaction structures induced by the M5.7 earthquake on May 28, 2018 in Songyuan, Jilin Province, NE China and research implication
Authors: Shao Zhu-Fu , Zhong Jian-Hua , Howell John , Hao Bing , Luan Xi-Wu , Liu Ze-Xuan , Ran Wei-Min , Zhang Yun-Feng , Yuan Hong-Qi , Liu Jing-Jing , Ni Liang-Tian , Song Guan-Xian , Liu Jin-Lin , Zhang Wen-Xin , Zhao Bing
Published: February 2020

An earthquake of magnitude M5.7 occurred in Yamutu village, Songyuan City, Jilin Province, NE China (45°16′12″N/124°42′35″E) on May 28, 2018, with a focal depth of 13 km. The epicenter is located at the intersection of the Fuyu/Songyuan-Zhaodong Fault, Second Songhua River Fault and Fuyu North Fault which lies northwest of Tancheng-Lujiang Fault (Tan-Lu Fault). The earthquake-induced widespread liquefaction structures and ground surface fissures within 3 km from the epicenter, caused serious disasters to the local surroundings. The visible liquefied structures include sand volcanoes, liquefied sand mounds, sand dikes and sand sills. Sand volcanoes can be divided into sand volcano with a crater, sand volcano without a crater and water volcano (no sand). Other soft-sediment deformation structures (SSDS) induced by the earthquake include deformation lamination, load and flame structures, deformation folds, dish structures, convolute bedding and water-escape structures. The formation process of the sand volcanoes comprises three stages: (1) building up excess pore-fluid pressure in the liquefied layer, (2) cracking of the low-permeable overlying layer, and (3) mixture of sand-water venting out of the ground surface. During the upward movement, the liquefied sand is injected into the low-permeable layer to form sand veins, sand sills and various types of deformation structures. Vertical distribution of seismic liquefaction structure can be divided into four zones: the thoroughly liquefied zone, the lower liquefied zone with SSDS, the upper liquefied zone with SSDS, and the ground surface liquefied zone. The liquefaction occurred at a burial depth of 2–5 m, and the thickness of liquefied sand is 2 m. NE-SW (35°–215°) trending compressive stress is possibly the seismogenic trigger of the Songyuan M5.7 earthquake that caused the fault (Fuyu/Songyuan-Zhaodong Fault) to reactivate. The study of the Songyuan seismic liquefaction structures gives insight into the prediction of modern earthquakes and disaster-prone areas. Meanwhile it provides abundant basic material for studying earthquake-induced SSDS in both ancient and modern sediments. The research is obviously of great significance to reveal that the northern Tan-Lu Fault has entered a stage of active seismic activity since the twenty-first century.
Comparison of expansion-based explicit time-integration schemes for acoustic wave propagation
Authors: Spa Carlos , Rojas Otilio , de la Puente Josep
Published: February 2020

We have developed a von Neumann stability and dispersion analysis of two time-integration techniques in the framework of Fourier pseudospectral (PS) discretizations of the second-order wave equation. The first technique is a rapid expansion method (REM) that uses Chebyshev matrix polynomials to approximate the continuous solution operator of the discrete wave equation. The second technique is a Lax-Wendroff method (LWM) that replaces time derivatives in the Taylor expansion of the solution wavefield with their equivalent spatial PS differentiations. In both time-integration schemes, each expansion term [Formula: see text] results in an extra application of the spatial differentiation operator; thus, both methods are similar in terms of their implementation and the freedom to arbitrarily increase accuracy by using more expansion terms. Nevertheless, their limiting Courant-Friedrichs-Lewy stability number [Formula: see text] and dispersion inaccuracies behave differently as [Formula: see text] varies. We establish the [Formula: see text] bounds for both methods in cases of practical use, [Formula: see text], and we confirm the results by numerical simulations. For both schemes, we explore the dispersion dependence on modeling parameters [Formula: see text] and [Formula: see text] on the wavenumber domain, through a new error metric. This norm weights errors by the source spectrum to adequately measure the accuracy differences. Then, we compare the theoretical computational costs of LWM and REM simulations to attain the same accuracy target by using the efficiency metric [Formula: see text]. In particular, we find optimal [Formula: see text] pairs that ensure a certain accuracy at a minimal computational cost. We also extend our dispersion analysis to heterogeneous media and find the LWM accuracy to be significantly better for representative [Formula: see text] values. Moreover, we perform 2D wave simulations on the SEG/EAGE Salt Model, in which larger REM inaccuracies are clearly observed on waveform comparisons in the range [Formula: see text].
Institutional experience with total neoadjuvant therapy for low-lying rectal tumors.
Authors: Sanders Jason , Goldbeck Lauren D. , Muller Donald A. , Dutta Sunil W. , Kunk Paul Raymond , Hedrick Traci , Hoang Sook , Reilley Matthew , Friel Charles , Le Tri Minh , Janowski Einsley-Marie
Published: February 2020

123

Background: Surgery has traditionally been the primary treatment for rectal cancer with consideration of neoadjuvant and adjuvant therapies based on stage. Recent studies have shown that Total Neoadjuvant Therapy (TNT) may provide excellent outcomes, with a possibility of non-operative management in patients with rectal cancer. This study is an initial report of our institution’s watchful waiting strategy. Methods: Patients with Stage II-III, low rectal adenocarcinomas treated from 2015-2018 with TNT were retrospectively reviewed. Patients were surgical candidates with no planned surgery. All patients received definitive radiation (median dose 54 Gy, range 50-56 Gy, at 1.8-2 Gy/fx) with concurrent Xeloda, with additional chemotherapy delivered either prior to or following chemoradiation. Kaplan-Meier (KM) method was utilized to estimate the 2 year permanent ostomy and surgery free survivals. Univariate and multivariate analysis using binary logistic regression were performed to assess the odds ratio (OR) of the need for surgery, with 95% confidence interval (CI). Results: 28 patients were treated with TNT with a median age of 59 years (range 32-79 yrs) and median follow up of 24 months (range 6-51 mon). Reasons for TNT included: clinical trial (50%, n = 14), patient desire to avoid surgery (43%, n = 12), and history of LDR prostate brachytherapy (7%, n = 2). The majority of patients had Stage III disease (68%, n = 19). Median tumor distance from the anal verge was 3 cm (range 0-7 cm). 75% (n = 21) of patients were initially managed without surgery, with 5 patients requiring LAR and 2 requiring APR for residual disease. 4 patients initially treated without surgery experienced local recurrence (LR) requiring APR, with a median time to LR of 20 months (range 12-27 mon). The KM estimated 2 year permanent ostomy and surgery free survivals were 69% and 56% respectively. Distant metastases occurred in two patients at 2 and 7 months post RT. An incomplete response on post-treatment MRI predicted eventual receipt of surgery (p = 0.012, OR = 19.8, 95% CI 1.9-202, compared to complete responders). Conclusions: These results support the growing evidence that TNT may provide a non-surgical option for select patients with low lying rectal cancer.
Clinical utility of comprehensive circulating tumor DNA (ctDNA) testing compared to standard-of-care (SoC) tissue testing in first-line (1L) metastatic colorectal cancer (mCRC) patients (pts).
Authors: Benavides Manuel , Alcaide Julia , Alvarez Martina , Torres Esperanza , Sevilla Isabel , Gil Calle Silvia , Reyna Carmen , Alés Inmaculada , Durán Gema , Wolman Roberto , Cazorla Mireya , Jimenez Gallego Pedro , López Irene , Cantero Alexandra , Godoy Ana , Lanman Richard B. , Faull Iris , Odegaard Justin , Kim Il Jin , Alba Emilio
Published: February 2020

15

Background: Accurate genotyping is mandatory for the management of mCRC pts. Tissue-based testing is still the SoC; however, is not available for all pts. and may be exhausted by serial testing, resulting in incomplete genotyping. We aimed to establish the validity of comprehensive non-invasive ctDNA testing in 1L mCRC pts for whom SoC tissue genotyping was available. Methods: 1L mCRC pts were tested with a comprehensive ctDNA test (Guardant360), a RAS ctDNA test (OncoBeam), and SoC tissue testing at the time of diagnosis. The primary endpoint was NCCN guideline biomarker discovery rate ( KRAS, NRAS, and BRAF mutations, ERBB2 amplification, and microsatellite instability). Results: In 91 evaluable pts, the biomarker discovery rate was 54.9% (50/91) for SoC tissue testing, 59.3% (54/91) for comprehensive ctDNA testing ( p= 0.0318 for non-inferiority vs. SoC), and 42.9% (39/91) for RAS ctDNA testing (inferiority not rejected vs. SoC). Both comprehensive and RAS ctDNA testing showed high positive agreement (85%, 44/52, and 86%, 31/36) and negative agreement (96%, 268/279, and 93%, 93/100) relative to SoC tissue testing at the gene level. Expanding genotyping beyond KRAS codon 12/13 mutations increased biomarker discovery rate by 56% for tissue testing (50/91 vs. 32/91, McNemar’s p< 0.0001) and by 64% for comprehensive ctDNA (54/91 vs. 33/91, McNemar’s p< 0.0001). Turnaround time was significantly shorter for comprehensive ctDNA testing vs. SoC tissue testing (mean 11.7 days vs. 23.0 days, paired T-test p= 0.0002). On retrospective analysis, 92% of biomarker-positive pts would have been identified at 2 weeks using the comprehensive ctDNA test for initial genotyping with reflex to tissue for biomarker-negative pts, whereas initial use of SoC tissue testing would have identified only 85% of positive pts at 4 weeks (Fisher’s exact p< 0.0001). Conclusions: As previously reported for lung cancer, comprehensive ctDNA testing in 1L mCRC identifies at least as many biomarker-positive pts as SoC tissue genotyping with high concordance to tissue and in half the turnaround time.
Effect of adding bevacizumab to chemotherapy on pathologic response to preoperative systemic therapy of potentially resectable colorectal cancer liver metastases (CLM): A systematic review and meta-analysis.
Authors: Jácome Alexandre A. , Oliveira Fernanda A. , Silva Flora De Moraes Lino , Lima João Paulo da Silveira Nogueira
Published: February 2020

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Background: Perioperative CT and resection of CLM are potentially curative therapies in the management of metastatic colorectal cancer (mCRC). Retrospective studies suggest that preoperative bevacizumab increases pathologic response, which is a surrogate endpoint for overall survival (OS). We conducted the first systematic review and meta-analysis addressing the effect of bevacizumab on pathologic response to preoperative therapy of CLM. Methods: We systematically searched PubMed, Cochrane Library, Embase and LILACS from January/2004 to August/2019 for studies that have compared the pathologic response to CT plus bevacizumab versus CT alone as preoperative therapy of potentially resectable CLM. The primary endpoint was pathologic complete response (pCR). Secondary endpoint was major response (MaR) (0-50% residual cancer cells or tumor regression grade (TRG) 1-3 in liver specimen). The likelihood of preoperative therapy being associated with pCR or MaR has been expressed by odds ratio (OR) and 95% confidence intervals (CI) using a random-effects model. Results: Of the 1,319 studies yielded by the search, 9 studies were retained, totaling 1,202 patients (516 CT plus bevacizumab versus 686 CT alone). The addition of bevacizumab to CT increased the pCR rate, but it did not reach statistical significance (OR: 1.24, 95% CI 0.81 – 1.92, p = 0.32). However, MaR was significantly superior in the bevacizumab group (OR: 2.20, 95% CI 1.47 – 3.29, p < 0.001). A higher percentage of patients have been submitted to oxaliplatin-based regimens in bevacizumab group compared to CT alone group (84% versus 68%, p < 0.001), while irinotecan-based regimens have been more common in the CT alone group (11% versus 28%, p < 0.001). Conclusions: The addition of bevacizumab to preoperative CT was associated with higher rates of pathologic response in liver resection of CLM. Anti-angiogenics might potentially improve the recurrence-free survival and OS in the management of potentially resectable CLM and should be evaluated as preoperative therapy in randomized clinical trials.
Use and impact of perioperative chemotherapy in patients with resectable colorectal cancer metastases.
Authors: Body Amy , Lee Margaret , Wong Hui-Li , Pope Alun , Jalali Azim , Shapiro Jeremy David , Kosmider Suzanne , Tie Jeanne , Barnett Frances Sarah , Richardson Gary Edward , Yip Desmond , Lim Stephanie Hui-Su , McKendrick Joseph James , Gibbs Peter , Wong Rachel
Published: February 2020

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Background: There is conflicting evidence regarding benefit of perioperative chemotherapy (p-chemo) for metastatic colorectal cancer (mCRC) patients (pts) undergoing resection of metastases (mets). Aims: To describe use of and outcomes from p-chemo in mCRC pts who underwent resection of isolated liver or lung mets. Methods: Pts were identified from the TRACC (Treatment of Recurrent and Advanced Colorectal Cancer) database, a multi-centre registry of mCRC pts. P-chemo was defined as chemotherapy within 12 weeks of surgery. Multivariate (MV) analysis using a Cox proportional hazards model was undertaken. Results: 371 pts were identified. Median age was 64 (27 – 90), 169 (45%) had de novo stage IV disease, 96% were ECOG 0-1. 284 (77%) had liver-only and 87 (23%) lung-only mets. 242 (65%) pts received p-chemo (58 pre-op alone, 134 post-op alone, 50 both). 62 (19%) pts also received a biologic agent (47/62 pre-op). Median age was 68 and 61 years in no p-chemo and p-chemo groups, respectively (p<0.0001). 53% of no p-chemo pts and 23% of p-chemo pts had had prior adjuvant chemotherapy (p<0.001). On MV analysis, p-chemo was a significant predictor of survival (HR 0.52, 95% CI 0.32-0.88, p=0.014). The other significant predictor of improved survival was ECOG PS of 0 (HR 0.58, p=0.019). Predictors of worse survival were rectal primary (HR 1.98 p=0.009), male gender (HR 1.69 p=0.03) and de-novo metastatic disease (HR 2.63, p=0.006). Prior adjuvant chemo, age, liver vs lung mets, use of perioperative biologics, BRAF and RAS status had no significant impact. In an exploratory analysis, the group considered “resectable” upfront (n=281) was analysed separately, perioperative chemotherapy was not a significant predictor of survival in this subgroup (HR 0.69, p=0.26). Conclusions: In routine care there is a variable approach to the use of p-chemo in pts with potentially resectable liver or lung mets. P-chemo is associated with improved survival in this analysis, although this was not confirmed in the separate analysis of the “resectable” subgroup. Due to the retrospective nature of the study confounding by unmeasurable factors is possible. This study supports ongoing consideration of P-chemo in pts with resectable mets.
IKKα as a potential novel target for treatment of colorectal cancer.
Authors: Quinn Jean A. , Patel Meera , Pennel Kathryn AF , Flanagan Dustin , Horgan Paul G. , McMillan Donald C. , MacKay Simon , Sansom Owen , Edwards Joanne
Published: February 2020

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Background: Colorectal cancer (CRC) is a heterogeneous disease leading to different survival outcomes for patients with the same stage of disease. The non-canonical NF-κB pathway has been shown to have a key role in tumorigenesis, and the aim of this study was to investigate the role of IKKα, the main catalytic component of this pathway in CRC. Methods: A tissue microarray was retrospectively constructed from a patient cohort (1033) with stage I-III CRC who underwent surgery. IHC was utilised to examine cytoplasmic and punctate IKKα expression and determine any association with clincopathological features and cancer specific survival (CSS). To assess IKKα inhibition, organoids were prepared from wild type (WT) mouse colon, mouse models of CRC (Apc and Apc.KRAS.pT53.TGFbR2 (AKPT)) and patient derived human organoids. These were treated with an IKKα inhibitor, SU1433 and organoid size and cell viability assessed. Results: High cytoplasmic expression of IKKα was associated with increasing T stage (p = 0.012), poor tumour differentiation (p = 0.010), tumour necrosis (p = 0.013) and low proliferation status (p = 0.013) but was not associated with CSS. High punctate IKKα expression associated with tumour differentiation (p = 0.001), necrosis (p = 0.004), proliferation (p = 0.044) and MMR competence (p < 0.001) and was also significantly associated with reduced CSS (HR1.20 95%CI 1.02-1.42, p < 0.001). SU1433 did not significantly impact on WT (C57/B16) organoid viability up to a concentration of 1 uM, however organoid size and cell viability was significantly reduced in a dose dependent manner in organoids from both Apc and AKPT mouse models. A similar reduction was observed in patient derived human organoids. Conclusions: Punctate IKKα expression was associated with poor cancer specific survival in CRC patients, and inhibition with SU1433, impacted on CRC mouse and patient derived human organoid size and cell viability. These results suggest that, following further investigation and confirmation, IKKα may be employed as a novel therapeutic target in CRC.
NeoRAS: Incidence of RAS reversion from RAS mutated to RAS wild type.
Authors: Henry Jason , Willis Jason , Parseghian Christine Megerdichian , Raghav Kanwal Pratap Singh , Johnson Benny , Dasari Arvind , Stone David , Jeyakumar Nikeshan , Coker Oluwadara , Raymond Victoria M. , Lanman Richard B. , Overman Michael J. , Kopetz Scott
Published: February 2020

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Background: RAS mutations are found in ~50% of patients (pts) with metastatic colorectal cancer (mCRC) and associated with resistance to anti-EGFR. Circulating tumor DNA (ctDNA) enables detection of resistant RASMUT arising from RASWT. Recently there has been interest in defining the converse: RASMUT tumors that revert to RASWT, with early results suggesting rates of ~7%. Clinical trials in this population are in development, though the incidence has not been validated with robust methodologies. Methods: 1) We identified 74 mCRC pts with baseline RASMUT and longitudinal ctDNA or tissue data enrolled in ATTACC (NCT01196130), a prospective genomic matching protocol utilizing paired tissue/ctDNA samples at baseline. We evaluated serial samples for RAS loss. 2) Using an external cohort of pts with mCRC and serial ctDNA with a targeted NGS assay sequencing all KRAS/ NRAS exons (Guardant360, Guardant Health), we screened pts for baseline RASMUT with no evidence of prior anti-EGFR exposure and evaluated for RAS loss. Results: 74 pts met criteria of RASMUT CRC with serial samples in ATTACC. Of these, 51 retained RASMUT. 22 pts had very low or absent levels of other clonal alterations such as APC or TP53 and are therefore unable to reliably detect RAS loss. One patient had true RAS loss with NRAS G13R, APC and TP53 mutations at baseline and persistent high-level APC and TP53 mutations without a detectable NRAS mutation, for an overall rate of RAS loss of 2% (1/52). In the second cohort we identified 162 pts, 34 of which had insufficient ctDNA to assess RAS loss on the serial sample as defined by loss of clonal alterations like APC and TP53. Of the remaining 128 patients, 11 had RAS loss (8.5%, with 1 NRAS, 10 KRAS). We next compared the relative mutant allele frequency (rMAF) between RAS retainers and RAS loss. The median baseline rMAF for pts who lost RAS was 0.74, compared to 0.86 in pts retaining RAS (p = 0.045). Conclusions: RAS reversion in mCRC from RASMUT to RASWT is uncommon and occurs at a rate between 2-8% in our two cohorts. RAS reversion is associated with a lower rMAF at baseline, suggesting subclonality. Liquid biopsies must be interpreted carefully, such that a determination of RAS mutation status is most informative in the presence of truncal APC and/or TP53 mutations.
Genetic variants in R-Spondin/RNF43 complex and gene expression levels to predict efficacy of cetuximab (cet) in patients (pts) with metastatic colorectal cancer (mCRC): Data from the FIRE-3 phase III trial.
Authors: Battaglin Francesca , Xiao Yi , Millstein Joshua , Seeber Andreas , Arai Hiroyuki , Wang Jingyuan , Puccini Alberto , Tokunaga Ryuma , Naseem Madiha , Soni Shivani , Berger Martin D. , Barzi Afsaneh , Zhang Wu , Stintzing Sebastian , Heinemann Volker , Lenz Heinz-Josef
Published: February 2020

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Background: Wnt signaling deregulation is a primary driver of colorectal carcinogenesis. RNF43 is a key suppressor of Wnt activation while R-Spodin inhibits RNF43 activity. RNF43 mutations are associated with the serrated neoplasia pathway, BRAF mutation and MSI. We hypothesized that genetic variants in the R-Spodin/RNF43 complex and corresponding genes expression levels may predict cetuximab efficacy in mCRC pts. Methods: Genomic DNA from blood samples of pts enrolled in the randomized FIRE-3 trial was genotyped through the OncoArray, a custom array manufactured by Illumina. The impact on outcome of 17 functional SNPs within RNF43/ ZNRF3, LGR4/5 and RSPO1/2/3 was analyzed in 129 pts treated with first-line FOLFIRI/cet and 107 pts treated with FOLFIRI/bevacizumab (bev). Gene expression levels were measured from tumor tissue samples from 102 pts in the cet arm by HTG EdgeSeq Oncology Biomarker Panel. False discovery rate (FDR) for gene expression analysis was computed using the Benjamini-Hochberg approach (significant Q < 0.1). Results: In the cet cohort, pts with the C/C genotype of ZNRF3 rs132531 had significantly shorter overall survival compared to any T allele carriers (mOS: 20.3 vs 52 mo) in both univariable (HR 3.61, 95% CI 1.65-7.88, P < .001) and multivariable analysis (adjusted P = .01). Conversely, RSPO1 rs4652964 any G allele carriers showed increased tumor response (TR) rates compared to the A/A genotype (83 vs 66 %, P = .04). These associations were not observed in bev arm. Lower gene expression levels of RNF43 were associated with shorter PFS in pts with right-sided tumors receiving FOLFIRI/cet ( P = .006, Q < 0.1). RSPO1 expression levels were also associated with TR in the same subgroup (70 vs 10% in high vs low; P = .001, Q < .05). RNF43 expression was associated with TR in pts with left-sided tumors (82% in high vs 58% in low, P = .014, Q = 0.1). Conclusions: Our results provide the first evidence that germline polymorphisms and tumor gene expression levels of RNF43/ ZNRF3 and RSPO1 may have a predictive value in mCRC pts receiving first-line cetuximab-based treatment and contribute to modulate anti-EGFRs activity.