bluuebunny/crossref_metadata_2025 huggingface dataset:
Variants in RETN gene are associated with steroid-induced osteonecrosis of the femoral head risk among Han Chinese people
Authors: An Feimeng , Zhang Litian , Gao Hongyan , Wang Jiaqi , Liu Chang , Tian Ye , Ma Chao , Zhao Jian , Wang Kunzheng , Wang Jianzhong
Published: March 2020

Background

Gene polymorphism has an important influence on RETN gene expression level, and the increased level of resistin encoded in RETN will lead to metabolic disorder, especially lipid metabolism. Moreover, steroid-induced osteonecrosis of the femoral head (steroid-induced ONFH) is closely related to lipid metabolism level, so this study is intended to explore the relationship of RETN polymorphisms with susceptibility to steroid-induced ONFH in the Chinese Han population.

Methods

In this case-control study, eight single-nucleotide polymorphisms (SNPs) of RETN were genotyped by the Agena MassARRAY system in 199 steroid-induced ONFH patients and 200 healthy controls. The relationship between RETN polymorphisms and steroid-induced ONFH risk was assessed using genetic models and haplotype analyses. Odds ratio (OR) and 95% confidence intervals (CIs) were obtained by logistic regression adjusted for age.

Results

We found significant differences in the distribution of HDL-C, TG/HDL-C, and LDL-C/HDL-C between the patients and the control group (p < 0.05). In allele model and genotype model analysis, rs34861192, rs3219175, rs3745368, and rs1477341 could reduce the risk of steroid-induced ONFH. Further stratified analysis showed that rs3745367 was related to the clinical stage of patients, and rs1477341 was significantly correlated with an increased TG level and a decreased TC/HDL-C level. The linkage analysis showed that two SNPs (rs34861192 and rs3219175) in RETN even significant linkage disequilibrium.

Conclusions

Our results provide the firstly evidence that RETN gene polymorphisms were associated with a reduced risk of steroid-induced ONFH in Chinese Han population.
The efficacy and safety of selective COX-2 inhibitors for postoperative pain management in patients after total knee/hip arthroplasty: a meta-analysis
Authors: Jiang Mingyang , Deng Huachu , Chen Xuxu , Lin Yunni , Xie Xiaoyong , Bo Zhandong
Published: March 2020

Background

Many selective cyclooxygenase (COX-2) inhibitors are currently used in clinical practice. COX-2 inhibitors have good anti-inflammatory, analgesic, antipyretic effects, and gastrointestinal safety. However, the analgesic effects and adverse reactions of COX-2 after total knee/hip arthroplasty (TKA/THA) are not fully known.

Objective

To evaluate the efficacy and safety of selective COX-2 inhibitors in postoperative pain management in patients receiving TKA/THA.

Methods

Randomized controlled trials (RCTs) were retrieved from medical literature databases. Risk ratios (RR) Std mean difference (SMD) and 95% confidence intervals (CI) were calculated to analyze the primary and safety endpoints.

Results

In total, 18 articles (23 trial comparisons) were retrieved comprising 3104 patients. Among them, 1910 patients (61.5%) were randomized to the experimental group whereas 1194 patients (38.5%) were randomized to the control group. The primary endpoints were the patients’ VAS score at rest or on ambulation (within 3 days). We found that VAS score in patients that received selective COX-2 inhibitor was significantly lower compared to those of the control group.

Conclusion

This meta-analysis shows that selective COX-2 inhibitor therapy is effective, safe, and reliable in relieving postoperative pain of THA/TKA.
Initiation and propagation of α-synuclein aggregation in the nervous system
Authors: Hijaz Baraa A. , Volpicelli-Daley Laura A.
Published: March 2020

The two main pathological hallmarks of Parkinson’s disease are loss of dopamine neurons in the substantia nigra pars compacta and proteinaceous amyloid fibrils composed mostly of α-synuclein, called Lewy pathology. Levodopa to enhance dopaminergic transmission remains one of the most effective treatment for alleviating the motor symptoms of Parkinson’s disease (Olanow, Mov Disord 34:812–815, 2019). In addition, deep brain stimulation (Bronstein et al., Arch Neurol 68:165, 2011) to modulate basal ganglia circuit activity successfully alleviates some motor symptoms. MRI guided focused ultrasound in the subthalamic nucleus is a promising therapeutic strategy as well (Martinez-Fernandez et al., Lancet Neurol 17:54–63, 2018). However, to date, there exists no treatment that stops the progression of this disease. The findings that α-synuclein can be released from neurons and inherited through interconnected neural networks opened the door for discovering novel treatment strategies to prevent the formation and spread of Lewy pathology with the goal of halting PD in its tracks. This hypothesis is based on discoveries that pathologic aggregates of α-synuclein induce the endogenous α-synuclein protein to adopt a similar pathologic conformation, and is thus self-propagating. Phase I clinical trials are currently ongoing to test treatments such as immunotherapy to prevent the neuron to neuron spread of extracellular aggregates. Although tremendous progress has been made in understanding how Lewy pathology forms and spreads throughout the brain, cell intrinsic factors also play a critical role in the formation of pathologic α-synuclein, such as mechanisms that increase endogenous α-synuclein levels, selective expression profiles in distinct neuron subtypes, mutations and altered function of proteins involved in α-synuclein synthesis and degradation, and oxidative stress. Strategies that prevent the formation of pathologic α-synuclein should consider extracellular release and propagation, as well as neuron intrinsic mechanisms.
Heparinized chitosan stabilizes the bioactivity of BMP-2 and potentiates the osteogenic efficacy of demineralized bone matrix
Authors: Kim Soyon , Fan Jiabing , Lee Chung-Sung , Chen Chen , Bubukina Ksenia , Lee Min
Published: March 2020

Background

Demineralized bone matrix (DBM), an allograft bone processed to better expose osteoinductive factors such as bone morphogenetic proteins (BMPs), is increasingly used for clinical bone repair. However, more extensive use of DBM is limited by its unpredictable osteoinductivity and low bone formation capacity. Commercial DBM products often employ polymeric carriers to enhance handling properties but such carriers generally do not possess bioactive functions. Heparin is a highly sulfated polysaccharide and is shown to form a stable complex with growth factors to enhance their bioactivities. In this study, a new heparinized synthetic carrier for DBM is developed based on photocrosslinking of methacrylated glycol chitosan and heparin conjugation.

Results

Heparinized chitosan exerts protective effects on BMP bioactivity against physiological stressors related to bone fracture healing. It also enhances the potency of BMPs by inhibiting the activity of BMP antagonist, noggin. Moreover, heparinized chitosan is effective to deliver bone marrow stromal cells and DBM for enhanced osteogenesis by sequestering and localizing the cell-produced or DBM-released BMPs.

Conclusions

This research suggests an essential approach of developing a new hydrogel carrier to stabilize the bioactivity of BMPs and improve the clinical efficacy of current bone graft therapeutics for accelerated bone repair.
Effects of Transcranial Direct Current Stimulation (tDCS) and Approach Bias Modification (ABM) training on food cravings in people taking antipsychotic medication
Authors: Grycuk Luiza , Gordon Gemma , Gaughran Fiona , Campbell Iain C. , Schmidt Ulrike
Published: March 2020

Background

Antipsychotic drug-induced weight gain puts individuals with schizophrenia at increased cardiometabolic risk. As a potential intervention for this problem, we describe the theoretical background and a protocol for a feasibility randomised controlled trial (RCT) of approach bias modification (ABM) training combined with real versus sham (placebo) transcranial direct current stimulation (tDCS). The primary aim of this trial is to obtain information that will guide decision making and protocol development in relation to a future large-scale RCT of ABM and tDCS in this group of participants. Second, the study will assess the preliminary efficacy of ABM + tDCS in reducing food cravings in people who take antipsychotic medication.

Methods

Thirty adults with a DSM-V diagnosis of schizophrenia or schizoaffective disorder treated with anti-psychotic medication will be randomly allocated to receive five sessions that will combine ABM and real or sham tDCS, in a parallel group design. In this feasibility study, a broad range of outcome variables will be examined. Measures will include food craving, psychopathology (e.g. symptoms of schizophrenia and depression), neuropsychological processes (such as attentional bias and impulsiveness), and the tolerability and acceptability of tDCS. The feasibility of conducting a large-scale RCT of ABM + tDCS and appropriateness of tDCS as a treatment for antipsychotic drug-induced weight gain will be evaluated by assessment of recruitment and retention rates, acceptability of random allocation, blinding success (allocation concealment), completion of treatment sessions and research assessments (baseline, post-treatment and follow-up).

Discussion

The effect sizes generated and other findings from this trial will inform a future large-scale RCT with respect to decisions on primary outcome measures and other aspects of protocol development. In addition, results from this study will provide a preliminary indication of the efficacy of ABM + tDCS treatment for antipsychotic drug-induced weight gain.

Trial registration

ISRCTN Registry,ISRCTN13280178. Registered on 16 October 2018.
How can health economics be used in the design and analysis of adaptive clinical trials? A qualitative analysis
Authors: Flight Laura , Julious Steven , Brennan Alan , Todd Susan , Hind Daniel
Published: March 2020

Introduction

Adaptive designs offer a flexible approach, allowing changes to a trial based on examinations of the data as it progresses. Adaptive clinical trials are becoming a popular choice, as the prudent use of finite research budgets and accurate decision-making are priorities for healthcare providers around the world. The methods of health economics, which aim to maximise the health gained for money spent, could be incorporated into the design and analysis of adaptive clinical trials to make them more efficient. We aimed to understand the perspectives of stakeholders in health technology assessments to inform recommendations for the use of health economics in adaptive clinical trials.

Methods

A qualitative study explored the attitudes of key stakeholders—including researchers, decision-makers and members of the public—towards the use of health economics in the design and analysis of adaptive clinical trials. Data were collected using interviews and focus groups (29 participants). A framework analysis was used to identify themes in the transcripts.

Results

It was considered that answering the clinical research question should be the priority in a clinical trial, notwithstanding the importance of cost-effectiveness for decision-making. Concerns raised by participants included handling the volatile nature of cost data at interim analyses; implementing this approach in global trials; resourcing adaptive trials which are designed and adapted based on health economic outcomes; and training stakeholders in these methods so that they can be implemented and appropriately interpreted.

Conclusion

The use of health economics in the design and analysis of adaptive clinical trials has the potential to increase the efficiency of health technology assessments worldwide. Recommendations are made concerning the development of methods allowing the use of health economics in adaptive clinical trials, and suggestions are given to facilitate their implementation in practice.
Optimisation and field validation of odour-baited traps for surveillance of Aedes aegypti adults in Paramaribo, Suriname
Authors: Visser Tessa M. , de Cock Marieke P. , Hiwat Hélène , Wongsokarijo Merril , Verhulst Niels O. , Koenraadt Constantianus J. M.
Published: March 2020

Background

Emerging arboviral diseases like Zika, dengue and chikungunya that are transmitted by Aedes aegypti mosquitoes, are increasingly threatening human health. Blends of human-like synthetic chemical attractants can be used to attract host-seeking mosquitoes. The aim of this study was to test new combinations of traps and odour baits in the laboratory, followed by testing the best candidates in the field to improve Ae. aegypti monitoring and surveillance.

Methods

First, the BG-Suna trap was evaluated for capturing laboratory-reared Ae. aegypti by testing normal and inverted positions in screen cage tests. Secondly, the attractiveness of the MB5 blend, CO2, and their combination was tested. Thirdly, we tested the attractiveness of different trap types (BG-Suna, BG-Sentinel, MM-X and CDC light trap). Finally, we confirmed laboratory results in the field in Paramaribo, Suriname, using the MB5 and BG-Lure odour blends, CO2 and the BG-Sentinel and BG-Bowl trap using a Latin Square design.

Results

The MB5 blend in combination with CO2 outperformed traps baited only with CO2 or MB5 in screen cage tests (P < 0.0001). The BG-Sentinel trap performed equally well as the inverted BG-Suna and was taken to the field (P = 0.729). In the field, we captured Ae. aegypti, Cx. quinquefasciatus and Cx. nigripalpus. We confirmed the laboratory results and found that the combination of the MB5 blend and CO2 almost doubled Ae. aegypti female captures (P = 0.004) and more than doubled Culex spp. female captures (P = 0.005) compared to using only CO2. Interestingly, the MB5 blend outperformed the commercially available BG-Lure, in the BG-Sentinel (P < 0.001). The BG-Bowl also attracted Ae. aegypti when baited with the MB5 blend in similar numbers as the BG-Sentinel baited with the MB5 (P = 0.362).

Conclusions

Our study demonstrated that the BG-Sentinel trap baited with the MB5 blend and CO2 outperforms the current golden standard (BG-Sentinel trap with BG-Lure) for monitoring Ae. aegypti females and males, in both laboratory and field experiments. The BG-Bowl baited with the MB5 blend is a good candidate for home use. Finally, the results show that CO2 is an indispensable component of the attractive blend.
DNA methylation of noncoding RNAs: new insights into osteogenesis and common bone diseases
Authors: Yu Liyuan , Xia Kai , Cen Xiao , Huang Xinqi , Sun Wentian , Zhao Zhihe , Liu Jun
Published: March 2020

Bone diseases such as osteoarthritis, osteoporosis, and bone tumor present a severe public health problem. Osteogenic differentiation is a complex process associated with the differentiation of different cells, which could regulate transcription factors, cytokines, many signaling pathways, noncoding RNAs (ncRNAs), and epigenetic modulation. DNA methylation is a kind of stable epigenetic alterations in CpG islands without DNA sequence changes and is involved in cancer and other diseases, including bone development and homeostasis. ncRNAs can perform their crucial biological functions at the RNA level, and many findings have demonstrated essential functions of ncRNAs in osteogenic differentiation. In this review, we highlight current researches in DNA methylation of two relevant ncRNAs, including microRNAs and long noncoding RNAs, in the initiation and progression of osteogenesis and bone diseases.
The effects of health expenditure on infant mortality in sub-Saharan Africa: evidence from panel data analysis
Authors: Kiross Girmay Tsegay , Chojenta Catherine , Barker Daniel , Loxton Deborah
Published: March 2020

Introduction

Although health expenditure in sub-Saharan African countries is the lowest compared with other regions in the world, most African countries have improved their budget allocations to health care over the past 15 years. The majority of health care sources in sub-Saharan Africa are private and largely involve out-of-pocket expenditure, which may prevent healthcare access. Access to healthcare is a known predictor of infant mortality. Therefore the objective of this study is to determine the impact of health care expenditure on infant mortality in sub-Saharan Africa.

Methods

The study used panel data from World Bank Development Indictors (WDI) from 2000 to 2015 covering 46 countries in sub-Saharan Africa. The random effects model was selected over the fixed effects model based on the Hausman test to assess the effect of health care expenditure on infant and neonatal mortality.

Results

Both public and external health care spending showed a significant negative association with infant and neonatal mortality. However, private health expenditure was not significantly associated with either infant or neonatal mortality. In this study, private expenditure includes funds from households, corporations and non-profit organizations. Public expenditure include domestic revenue as internal transfers and grants, transfers, subsidies to voluntary health insurance beneficiaries, non-profit institutions serving households or enterprise financing schemes as well as compulsory prepayment and social health insurance contributions. External health expenditure is composed of direct foreign transfers and foreign transfers distributed by government encompassing all financial inflows into the national health system from outside the country.

Conclusion

Health care expenditure remains a crucial component of reducing infant and neonatal mortality in sub-Saharan African countries. In the region, where health infrastructure is largely underdeveloped, increasing health expenditure will contribute to progress towards reducing infant and neonatal mortality during the Sustainable Development Goals (SDGs) era. Therefore, governments in the region need to increase amounts allocated to health care service delivery in order to reduce infant mortality.
Optimal mean airway pressure during high-frequency oscillatory ventilation in an experimental model of acute respiratory distress syndrome: EIT-based method
Authors: Liu Songqiao , Zhao Zhanqi , Tan Li , Wang Lihui , Möller Knut , Frerichs Inéz , Yu Tao , Huang Yingzi , Pan Chun , Yang Yi , Qiu Haibo
Published: March 2020

Background

High-frequency oscillatory ventilation (HFOV) may theoretically provide lung protective ventilation. The negative clinical results may be due to inadequate mean airway pressure (mPaw) settings in HFOV. Our objective was to evaluate the air distribution, ventilatory and hemodynamic effects of individual mPaw titration during HFOV in ARDS animal based on oxygenation and electrical impedance tomography (EIT).

Methods

ARDS was introduced with repeated bronchoalveolar lavage followed by injurious mechanical ventilation in ten healthy male pigs (51.2 ± 1.9 kg). Settings of HFOV were 9 Hz (respiratory frequency), 33% (inspiratory time) and 70 cmH2O (∆pressure). After lung recruitment, the mPaw was reduced in steps of 3 cmH2O every 6 min. Hemodynamics and blood gases were obtained in each step. Regional ventilation distribution was determined with EIT.

Results

PaO2/FiO2 decreased significantly during the mPaw decremental phase (p < 0.001). Lung overdistended regions decreased, while recruitable regions increased as mPaw decreased. The optimal mPaw with respect to PaO2/FiO2 was 21 (18.0–21.0) cmH2O, that is comparable to EIT-based center of ventilation (EIT-CoV) and EIT-collapse/over, 19.5 (15.0–21.0) and 19.5 (18.0–21.8), respectively (p = 0.07). EIT-CoV decreasing along with mPaw decrease revealed redistribution toward non-dependent regions. The individual mPaw titrated by EIT-based indices improved regional ventilation distribution with respect to overdistension and collapse (p = 0.035).

Conclusion

Our data suggested personalized optimal mPaw titration by EIT-based indices improves regional ventilation distribution and lung homogeneity during high-frequency oscillatory ventilation.
Selective and taxon-dependent effects of semi-feral cattle grazing on tree regeneration in an old-growth Mediterranean mountain forest
Authors: Fortuny Xavier , Carcaillet Christopher , Chauchard Sandrine
Published: March 2020

Background

In Mediterranean mountain socio-ecosystems, both grazing by livestock and the dry season may influence tree regeneration. However, the relative contributions of these drivers are poorly known, even though present and future canopy composition might result from past and present variations in climate and herbivore density. This study aims to test how semi-feral cattle presence and season affect tree regeneration.

Methods

The study was conducted using permanent plots inside and outside a cattle exclosure in an old-growth Mediterranean forest. Saplings and seedlings were counted five times per year (winter, early spring, middle spring, summer, fall) and monitored over 7 yrs.

Results

Semi-feral cattle exclusion increased Acer, Fagus, Ilex, Pinus, Prunus and Quercus sapling densities and increased Acer, Fraxinus, Ilex, Quercus and Sorbus seedling densities. Interestingly, the dry season did not exert any noticeable effects on the sapling or seedling densities of any of the studied taxa.

Discussion

Semi-feral cattle presence may limit tree regeneration through taxon-dependent effects, which suggests that the current decrease in grazing livestock across the Mediterranean basin will modify recruitment processes and, likely, future forest composition.

Conclusions

Semi-feral cattle presence acts as a selective driver of tree community composition.
Minimally invasive aortic valve replacement with central cannulation: A cost-benefit analysis in a developing country
Authors: Sanad Mohammed , Beshir Hatem
Published: March 2020

Background

Minimally-invasive approaches to aortic valve replacement (MIAVR) are technically and logistically demanding. However, few centers have started using these approaches with standard equipment because of the limited resources. We sought to report intra- and postoperative clinical outcomes and address health resource utilization after MIAVR.

Results

A total of 102 eligible patients who had aortic valve replacement were enrolled in a prospective, multicenter cohort study conducted from June 2015 to December 2017. Fifty patients underwent aortic valve surgery via upper inverted T-shaped hemi-sternotomy (MS), and 52 patients were operated using full sternotomy (FS) in two centers in a developing country. Central cannulation was performed in all cases. Major adverse cardiac events, pain, and wound complications were compared. A cost analysis was performed, and exposure and feasibility for cannulation were assessed. The mean length of MS skin incision was 5.82 ± 0.67 cm. Cumulative cross-clamp time was insignificant between both groups (91.87 ± 34.41 versus 94.91 ± 33.96 min;p= 0.66). MS exhibited shorter ventilation time (6.18 ± 1.86 versus 10.68 ± 12.78 h;p= 0.029) and intensive care stays (33.27 ± 19.75 versus 49.42 ± 47.1 h;p= 0.037). Major adverse cardiac events (MACEs) were compared, and MS group exhibited fewer transfusions (1.18 ± 0.89 versus 1.7 ± 0.97 units;p= 0.002), fewer pulmonary complications (1 (2%) versus 2 (3.8%);p< 0.001), and less sternotomy wound infection (1 (2%) versus 5 (9.6%);p= 0.048). Total operative mortality of 4.46% was recorded (n= 5). Significant cost reduction was recorded favoring MS; central cannulation saved $907.16 and carried a total cost reduction of $580 (9.3%) when compared with the FS approach (p< 0.0001).

Conclusions

With a lack of logistics in developing countries, MIAVR not only has a cosmetic advantage but carries a significant reduction in blood use, respiratory complications, pain, and cost. MIAVR can be feasible, with a rapid learning curve in developing centers.
Imatinib mesylate in advanced chordoma: A multicenter phase II study
Authors: Stacchiotti S. , Ferrari S. , Ferraresi V. , Grignani G. , Crippa F. , Messina A. , Spreafico C. , Tamborini E. , Gronchi A. , Casali P. G.
Published: March 2020

10003

Background: The antitumor activity of Imatinib in chordoma was preliminarily shown in a compassionate series of 18 pts. This prospective Phase II collaborative study was planned thereafter. Methods: From November 2004 to April 2006, 55 pts with progressing advanced chordoma were enrolled in this Phase II study. Cases were provided by 13 Italian centers and one Swiss. Imatinib was given at the planned dose of 800 mg/day (for a received dose intensity in excess of 600 mg/day), until evidence of progression. Mean age was 59 yrs, (range 24–86); PS 0–3 (=2 in 22%); site of origin was the sacrum in 60%, spine in 25%, skull base in 15%; the disease was metastatic in 43% and localized advanced in 57%. All tumors were positive for PDGFRB/PDGFB. Results: In 44 pts evaluable for antitumor response, 37 (84%) had stable disease as their best RECIST response, which was maintained for more than 6 months in 32, for a clinical benefit rate (CR+PR+SD=6mos) of 73%. In 7 of these SD pts (16%), a degree of objective tumor shrinkage was reported. Centralized radiological review is underway, focusing on non-dimensional, “tissue” response, and results thereof will be presented. In 39 pts who were symptomatic at baseline, subjective improvement of symptoms was claimed by 25 (64%). On ITT analysis, median PFS was 32 wks, with 38% of pts free from progression at one year, and 16% on treatment at 18 months. Most frequent drug-related adverse events were nausea (35%) and vomiting (30%), edema (30%), skin rash (28%), G1–3 anemia (24%), asthenia (17%), G1–3 leucopenia (13%). Conclusions: Preliminary evidence of Imatinib efficacy in chordoma was provided in a single-institution, compassionate setting, and is now confirmed by this multicenter Phase II study. On the basis of these data, an international effort on molecular-targeted therapy with Imatinib in advanced chordoma is warranted.

No significant financial relationships to disclose.
Continuous versus interruption of imatinib (IM) in responding patients with advanced GIST after three years of treatment: A prospective randomized phase III trial of the French Sarcoma Group
Authors: Le Cesne A. , Ray-Coquard I. , Bui B. , Rios M. , Adenis A. , Bertucci F. , Duffaud F. , Bourne Branchu V. , Perol D. , Blay J. Y.
Published: March 2020

10005

Background: IM the first-line targeted therapy for advanced GIST, must not be interrupted after one year (yr) in responding patients (pts) and has to be given continuously until disease progression (PD) or intolerance (Blay, Le Cesne et al, ASCO 2004 and 2005). The impact on progression free survival (PFS) of IM discontinuation in long lasting responding pts is unknown. Methods: This prospective national multicenter BFR14 study was initiated in June 2002. After 3 yrs of IM 400mg/day, pts free from progression were randomly offered to continue (C arm) or interrupt (I arm) IM, with the exception of pts initially randomized in the I arm after 1 yr of IM (32 pts). Pts allocated to the I arm could restart IM (same dose) in case of PD. Primary endpoint was PFS. Pts declining randomization proceed with IM. Results: As of december 2006, 286 pts were included in this trial and up to date, 35 non progressive pts at 3 yrs were randomized, 19 and 16 in the I anc C arm respectively. Pt characteristics were well balanced between the two arms. Nine progressions were reported after a median follow-up of 5.3 months (range 0–14) in this cohort of patients. IM reintroduction in the I arm after a re-progression allowed again a tumor control (OR or SD) in all evaluable pts so far. Conclusions: An increase in the rate of PD was observed in patients randomized after 3 years of IM. The final analysis will be performed after the randomization of 50 pts. Updated results including mutational analysis will be presented at the meeting.

No significant financial relationships to disclose.
Mechanisms of sunitinib malate (SU) resistance in gastrointestinal stromal tumors (GISTs)
Authors: Heinrich M. C. , Corless C. L. , Liegl B. , Fletcher C. D. , Raut C. P. , Donsky R. , Bertagnolli M. M. , Harlow A. , Demetri G. D. , Fletcher J. A.
Published: March 2020

10006

Background: SU, an oral, multitargeted inhibitor of KIT, PDGFRs, VEGFRs, FLT3, and RET receptor tyrosine kinases, is now the standard therapy for treatment of imatinib mesylate (IM)-resistant GIST tumors or IM-intolerant GIST patients. However, it is unclear if the clinical efficacy of SU in this setting is due to inhibition of KIT and/or PDGFRA in tumor cells, inhibition of VEGFRs and PDGFRs in endothelial cells and pericytes, respectively, or a combination of antitumor and antiangiogenic effects. In order to address this question, we studied the molecular mechanisms of SU resistance in vitro and in patient-derived tumors. Methods: We studied the in-vitro effects of IM or SU on cells with KIT exon 11 mutations, either alone or in combination with known IM-resistant secondary mutations. In addition, we analyzed tumor samples obtained from patients undergoing salvage surgery after SU treatment failure. Tumor specimens were genotyped for primary and secondary mutations. Results: SU was approximately 2–5-fold more potent than IM against typical GIST-associated KIT exon 11 mutations. In addition, the presence of secondary mutations involving the ATP/drug binding pocket (V654A or T670I) did not substantially alter SU potency. In contrast, these ATP/drug-binding-pocket mutations conferred high-level resistance to IM. However, SU had no significant inhibitory effect on the kinase activity of secondary IM-resistant mutations involving the KIT activation loop (exon 17, codons 816, 820, 822, and 823). Surgical resection was performed on two GIST patients who had clinical progression on SU. Among nine progressing lesions, substitutions were detected in codons 816, 820, and 822; a novel mutation, L783V, was also identified. In contrast, two non-progressing tumors both contained a V654A secondary mutation. Conclusions: Consistent with in-vitro studies, acquired IM-resistant mutations of the KIT activation loop in GIST are associated with clinical resistance to SU and IM. In addition, novel kinase mutations not previously associated with IM resistance may contribute to clinical SU resistance. These findings suggest that the antiangiogenic effects of SU may be insufficient to inhibit GIST progression when the targeted oncogenic kinase remains active.

[Table: see text]
Evaluation of soluble KIT (sKIT) as a potential surrogate marker for TTP in sunitinib malate (SU)-treated patients (pts) with advanced GIST
Authors: Blackstein M. , Huang X. , Demetri G. D. , Casali P. G. , Garrett C. R. , Schöffski P. , Shah M. H. , Verweij J. , Baum C. M. , DePrimo S. E.
Published: March 2020

10007

Background: SU is an oral, multitargeted tyrosine kinase inhibitor of KIT, PDGFRs, VEGFRs, RET and FLT3, approved multinationally for the treatment of imatinib (IM)-resistant/-intolerant GIST. Preliminary analysis in a SU phase I/II GIST study suggested that a decline in plasma sKIT levels may correlate with measures of clinical benefit. We evaluated the potential of sKIT as a surrogate marker for TTP using samples obtained in a randomized, double-blind, placebo-controlled phase III study of SU in pts with IM-resistant/-intolerant GIST, clinical results of which have been reported previously. Methods: 312 pts were randomized (2:1) to receive SU 50 mg (n=207) or placebo (n=105) daily in 6-wk cycles (4 wks on treatment, 2 wks off), respectively. The primary endpoint was TTP as per RECIST. Levels of sKIT in plasma samples were measured in cycle 1 on days 1, 14 and 28 and in cycles 2 and 3 on days 1 and 28 using a performance-validated ELISA. Prentice Criterion, Cox models and the Proportion of Treatment Effect (PTE) were used to analyze the results (PTE of 1 = ideal surrogate). Results: Numbers of pts with matched pairs of baseline and on-study plasma samples varied from 228 pts at cycle 1, day 14 to 106 pts at the end of cycle 3. After 4 wks of treatment (cycle 1, day 28), plasma sKIT levels began to exhibit a significant decrease (P<0.0001) in response to SU treatment; at the same time, changes in the level of sKIT (decreases vs. increases) also became indicators of TTP (HR=0.53; 95% CI, 0.37–0.75; P=0.0003), with decreases associated with longer TTP. This trend continued throughout the sampling period, with the effect persisting off treatment. Although the impact of SU on plasma sKIT levels continued to be seen after 2 cycles, sKIT changes became a better indicator of TTP than initial treatment group by cycle 2, day 28 (PTE = 0.62; HR=0.51; 95% CI, 0.38–0.69; P<0.0001), and at cycle 3, day 1 (PTE = 0.64; HR=0.42; 95% CI, 0.29–0.60; P<0.0001). Conclusion: These preliminary findings suggest that circulating sKIT may be a surrogate marker for TTP in GIST pts after 2 cycles of SU treatment. Further studies are warranted to confirm these findings and to establish whether sKIT can be used as a general surrogate marker of clinical outcomes in GIST pts with SU or other therapies.

[Table: see text]
Adjuvant chemotherapy (CT) with doxorubicin and ifosfamide in resected soft tissue sarcoma (STS): Interim analysis of a randomised phase III trial
Authors: Woll P. J. , van Glabbeke M. , Hohenberger P. , Le Cesne A. , Gronchi A. , Hoekstra H. J. , Radford J. A. , van Coevorden F. , Blay J. ,   EORTC Soft Tissue & Bone Sarcoma Group
Published: March 2020

10008

Background: The impact of adjuvant CT on survival for resected STS remains uncertain. In a 1997 meta-analysis, doxorubicin-based CT significantly improved local and overall relapse free survival (RFS), but not overall survival. Many of the CT regimens used would now be considered suboptimal. We therefore undertook a multicentre randomised trial of intensive CT in patients with excised high grade STS. Methods: Patients with macroscopically resected, Trojani grade II-III STS at any site, no metastases, performance status (PS) <2 and age = 70 were eligible within 4 weeks of surgery. Patients were randomised to observation or CT with 5 cycles of doxorubicin 75 mg/m2, ifosfamide 5 g/m2q 21 days and lenograstim. Patients in both arms received radiotherapy (RT) if the resection was marginal or the tumor recurrent. Stratifications were for institution, disease site, tumor size, planned RT and isolated limb perfusion therapy. Results: Between 1995 and 2003, 351 patients were recruited. 9.5% were ineligible and 4.8% did not receive the allocated treatment. Patient characteristics were evenly distributed between the two arms: 47% > 50 years; 54% male; 33% PS 1. The commonest pathological subtypes were leiomyo- 15%, lipo- 13%, MFH 11%, synovial sarcoma 11%. 60% were grade III. 66% were extremity tumors. Of 175 patients allocated CT, 163 started and 127 completed 5 cycles. 38% had dose reductions or delays, mostly for hematologic toxicity or infection. 88% of patients received RT. An interim analysis for futility has been performed, because survival in the observation arm was better than expected: estimated 5-yr RFS was 52% in both arms and OS 69% (observation arm) and 64% (CT arm). The hypotheses that adjuvant CT improves RFS and OS (with hazard ratios = 0.621) can both be rejected. Conclusions: This is the largest study of adjuvant CT with ifosfamide and doxorubicin ever undertaken in STS. It fails to show a survival advantage for adjuvant CT. Improved survival over previous studies might be due to better surgery and increased use of adjuvant RT. Further analysis of this study will allow more detailed assessment of the role of adjuvant CT in resected STS and will contribute to an updated meta-analysis.

[Table: see text]
Response assessment using dynamic MR imaging in non-metastatic osteosarcoma
Authors: Reddick W. E. , Hoffer F. A. , Billups C. A. , Jenkins J. J. , Wu J. , Daw N. C.
Published: March 2020

10018

Background: Conventional static imaging methods are of limited utility in assessing osteosarcoma (OS) response to neoadjuvant chemotherapy primarily due to the lack of significant change in tumor size. Methods: We prospectively evaluated the utility of dynamic contrast-enhanced MR imaging (DEMRI) in assessing tumor response as part of a phase II trial of multiagent chemotherapy for treatment of OS from 1999 to 2006. Forty-two subjects (median age, 13.5 years) with non-metastatic OS of the extremity (27 femur, 10 tibia, 3 humerus, 1 fibula, and 1 ulna) underwent one or more DEMRI examinations and had histological assessment of tumor response. DEMRI was performed at baseline (before course 1 of chemotherapy [week 0]), at week 9 (after 3 courses of chemotherapy), and at week 12 (after 4 courses of chemotherapy before definitive surgery). Quantitative DEMRI measures reflecting rate and intensity of enhancement (dynamic vector magnitude [DVM]) and regional contrast transfer between the plasma and extracellular/extravascular spaces (kep) were analyzed in relation to histological response. Nonparametric Wilcoxon signed-rank test was used to compare DEMRI parameters during preoperative chemotherapy with baseline. Logistic regression was used to examine the association between DEMRI parameters and histological response at each time point. Results: Both DEMRI parameters at week 9 and at week 12 of preoperative chemotherapy were significantly decreased from baseline (p<0.001). Patients with lower DVM or lower kep at week 9 or at week 12 ( Table ) were significantly more likely to have good histological response (>90% tumor necrosis). Conclusions: DEMRI is a non-invasive method that can be used to assess tumor response to neoadjuvant chemotherapy in OS. A slower rate of contrast accumulation in the extracellular/extravascular space corresponds to increased tumor necrosis.

[Table: see text]

No significant financial relationships to disclose.
RECIST and Choi criteria for response assessment (RA) in patients with inoperable and metastatic gastrointestinal stromal tumours (GISTs) on imatinib mesylate. Cambridge GIST study group experience
Authors: Bulusu V. R. , Jephcott C. R. , Fawcett S. , Cook N. , Hatcher H. , Moyle P. , Carroll N. , Earl H. , Save V. , Hardwick R.
Published: March 2020

10019

Background: Imatinib Mesylate (IM) induces an overall response rate of 84% in patients (pts) with metastatic GISTs. Standard RA is by RECIST criteria. This may underestimate the true benefit of IM in such pts. Choi et al observed ↓ in size (10%) and or density (D) (15%) correlated well with disease specific survival. We report our experience using both RECIST and Choi criteria for RA in GIST pts on IM. Methods: Between 2003 and 06, 24 pts with metastatic or inoperable GISTs were treated with IM. 50 lesions (Liver 20, Omentum 21, Primary 9) were identified at presentation on contrast CT (Siemens multi slice CT, IV Niopam, GE PACS system). 3 monthly CT was used for RA until tumour progression (PD) or death. Parameters recorded were: 1.Largest dimension 2. Lesion density (Mean Hounsfield units, HFU) 3.New lesions 4.Any new features. RECIST and Choi criteria were both applied for RA. Results: N=50. At 3 months (m) only 16% of the lesions achieved partial response (PR) by RECIST and 24% increased in size by a mean of 22.5% (Range 3–150%). RA as measured by Choi criteria revealed 88% of lesions had either a 10% ↓ in size or a 15% ↓ in D at 3 m. Mean ↓ in D was 29% (95% CI 24.6–33.4). At 18 m 50% of the lesions achieved PR and 20% had PD by RECIST criteria, and with Choi criteria 68% RR was recorded. Calcification, haemorrhage and perforation within the lesions spuriously altered the mean D value in 15% of the lesions which made assessment by Choi criteria difficult. In 5 pts new hepatic cystic lesions (range 2–22) appeared with a mean D of 16 HF. None were detected in extra-hepatic sites. 4 pts showed new calcifications within lesions 3–18 m on IM. Enhancing nodules within lesions were seen in 4 pts predating clinical PD by 6–18 m. Conclusions: Choi criteria were found to be reproducible in our pts. RRs at 3 months using Choi criteria (88%) were far greater than by RECIST criteria (16%). RRs were more similar at 18 m (68% Choi vs 50% RECIST).Using density for RA can become unreliable in the presence of perforation, calcification and haemorrhage. These criteria should be evaluated by a radiologist experienced in assessing the response to IM in GISTs with awareness of their limitations.

No significant financial relationships to disclose.
Subpopulation analyses in a worldwide treatment-use trial of sunitinib (SU) in GIST patients (pts) with resistance or intolerance to prior imatinib (IM) therapy
Authors: Reichardt P. , Kang Y. K. , Ruka W. , Seddon B. , Baum C. M. , Demetri G. D.
Published: March 2020

10022

Background: SU is an oral, multitargeted TKI of KIT, PDGFRs, VEGFRs, RET and FLT3, approved multinationally for the treatment of IM-resistant/-intolerant GIST. The aims of this study are to provide access to SU to GIST pts who were ineligible for SU clinical trials or for whom SU is unavailable prior to regulatory approval in their country, and to collect safety/efficacy data in a large number of GIST pts. Methods: In this ongoing open-label study, pts with advanced GIST and prior IM failure receive SU at a starting dose of 50 mg/d in 6-wk cycles (4 wks on treatment, 2 wks off). Assessments include safety/tolerability measures, response (per local standard of care) and OS. Because of the variability of response evaluations, treatment duration (TD; time from first dose to the earlier of termination date or 2 wks after last dose) was analyzed as a surrogate efficacy measure. Results: As of March 1, 2006, 768 pts enrolled at 96 centers in 33 countries had received =1 dose of SU (ITT population). Of these, 362 had discontinued treatment (lack of efficacy: 25%; AE: 12%). Median TD (ITT population) was 126 d (range: 1–618); 55% of pts had received =3 mos of treatment; 32%, =6 mos and 16%, =9 mos. Median TD was similar for pts irrespective of tumor histological subtype (epithelioid: 125 d, n=85; spindle cell: 127 d, n=414; mixed: 126 d, n=100; other subtypes: 114 d, n=158; P=0.17). Median TD was longer in pts with ECOG PS 0/1 (127 d, n=637) vs 2 (84 d, n=96; P<0.0001) and pts aged <65 (127d, n=486) vs =65 yrs (97d, n=281; P=0.011). Median OS has not been reached. The impact of baseline factors on survival will be presented. The most common AEs of any cause were fatigue (42%), diarrhea (38%) and nausea (32%), which were usually grade 1/2. The most common grade =3 AEs of any cause were abdominal pain (4%), vomiting (3%) and dehydration (2%). 3% of pts have demonstrated hypothyroidism. Hematologic AEs (total, grade 3/4) included anemia (56%, 5%), thrombocytopenia (35%, 5%) and neutropenia (22%, 10%). Conclusions: In this ongoing study of a large, relatively heterogeneous population of IM-resistant/-intolerant GIST pts, SU demonstrated acceptable tolerability and clinical efficacy that is highly consistent with prior studies.

No significant financial relationships to disclose.
A phase I study of nilotinib alone and in combination with imatinib (IM) in patients (pts) with imatinib-resistant gastrointestinal stromal tumors (GIST) - Study update
Authors: Von Mehren M. , Reichardt P. , Casali P. G. , Blay J. , Debiec-Rychter M. , Dumez H. , Cheung W. , Feifel B. , Veronese M. , Demetri G. D.
Published: March 2020

10023

Background: Nilotinib is a novel tyrosine kinase inhibitor (TKI) targeting KIT, PDGFR, and Bcr-Abl and inhibiting the proliferation of both IM-sensitive and -resistant cells in vitro. We report the results of a phase I study in GIST pts resistant to IM and other TKIs. Methods: Pts with progressive disease received nilotinib alone (400 mg p.o. bid) or escalating doses of nilotinib (200 mg qd, 400 mg qd, or 400 mg bid) in combination with IM (400 mg p.o. bid), or nilotinib 400 mg bid plus IM 400 mg qd. Pharmacokinetic (PK) analyses were performed. Tumor assessments (RECIST) were done every 8 weeks. Baseline samples of 18 GISTs were analyzed for KIT and PDGFR mutations. Results: 53 pts received nilotinib, alone (n=18) or in combination with IM (n=35), for a median of 134 days (range 8 to 430 days). Thirty-nine pts (74%) had failed second-line therapies including sunitinib, AMG-706, dasatinib or RAD001. Most frequent adverse events were grade 1 (17% of pts) or 2 (51% of pts) including: skin toxicity, fatigue, myalgia, headache, abdominal pain, nausea, vomiting, diarrhea, constipation, hyperbilirubinemia and edema. Six pts experienced dose limiting hyperbilirubinemia or skin rash. One pt on nilotinib alone achieved partial response (PR) for > 6 months and 36 pts (68%)-13 on nilotinib alone-, had SD ranging from 6 weeks to > 6 months. Median progression-free survival was 134 days overall and 178 days for pts on nilotinib alone. Genotyping revealed mutations in KIT exon 9 (n=4) or 11 (n=11), and KIT WT (n=3). The single PR occurred in KIT exon 11 mutant GIST following previous adjuvant imatinib and intolerance to imatinib 800 mg. KIT was WT in 2 out of 8 pts with SD > 6 months. Conclusions: Nilotinib, alone and in combination with IM has promising clinical activity in pts with GIST resistant to prior TKIs. Tolerability is acceptable for both nilotinib 400 mg bid, alone and in combination with IM 400 mg qd, which are the recommended doses for future studies.

No significant financial relationships to disclose.
Identification of therapeutic targets in angiosarcoma
Authors: Ravi V. , Kim S. , Dim D. , Hicks D. , Aggarwal C. , Hostetter G. , Cheney R. T. , Bittner M. , Trump D. L. , Wong M. K.
Published: March 2020

10030

Background: Human angiosarcoma is an aggressive malignancy with ability to invade locally and metastasize widely. Even with a multimodality approach, the local recurrence rate is 81% and 5 year disease-free survival is 17% for all comers. Durability of the responses to treatment options such as paclitaxel is 4 to 5 months. Our previous work shows that enhanced cell migration and invasion are integral to the chemoresistant angiosarcoma phenotype. However the molecular mechanism of this is unknown. Methods: In order to address this and to identify new therapeutic strategies, we analyzed formalin fixed paraffin embedded (FFPE) archival angiosarcoma specimens from 17 consecutive patients at our institution to identify aberrations at the DNA level that were highly prevalent. DNA was extracted from FFPE angiosarcoma specimens using the proteinase K method. Good quality DNA with an yield more than 5 micrograms was obtained from 10 out of 17 patients and these samples were assayed for DNA dosage differences compared to genomic reference DNA using array comparative genomic hybridization. High density 244K Agilent arrays were used to evaluate these specimens to enhance the precision of the estimates in this rare disease. Results: Statistically significant (p<0.001) aberrations with prevalence greater than 50% were noted in several genes including NOTCH2, MAML1 (notch signaling intermediate), oncomodulin, calnexin, sequestosome1, zinc finger proteins and ADAMTS2. This is particularly important since Notch and its ligand Jagged are developmental genes critical to tumorigenesis and there is emerging evidence of their role in endothelial activation. Conclusions: Aberrations involving the notch signaling pathway occur with a high prevalence in angiosarcomas and may serve as a target for therapeutic intervention.

No significant financial relationships to disclose.