Abstract
Non-alcoholic fatty liver disease (NAFLD) is now the most common liver disease affecting high proportion of the population worldwide. NAFLD encompasses a large spectrum of conditions ranging ...from fatty liver to non-alcoholic steatohepatitis (NASH), which can progress to cirrhosis and cancer. NAFLD is considered as a multifactorial disease in relation to the pathogenic mechanisms. Oxidative stress has been implicated in the pathogenesis of NAFLD and NASH and the involvement of reactive oxygen species (ROS) has been suggested. Many studies show the association between the levels of lipid oxidation products and disease state. However, often neither oxidative stress nor ROS has been characterized, despite oxidative stress is mediated by multiple active species by different mechanisms and the same lipid oxidation products are produced by different active species. Further, the effects of various antioxidants have been assessed in human and animal studies, but the effects of drugs are determined by the type of active species, suggesting the importance of characterizing the active species involved. This review article is focused on the role of free radicals and free radical-mediated lipid peroxidation in the pathogenesis of NAFLD and NASH, taking characteristic features of free radical-mediated oxidation into consideration. The detailed analysis of lipid oxidation products shows the involvement of free radicals in the pathogenesis of NAFLD and NASH. Potential beneficial effects of antioxidants such as vitamin E are discussed.
Prognosis of advanced gastrointestinal stromal tumors (GIST) refractory to tyrosine kinase inhibitors (TKIs) is poor. This randomized, placebo-controlled, phase III trial evaluated the efficacy and ...safety of pimitespib, a novel heat shock protein 90 inhibitor, in advanced GIST refractory to standard TKIs.
Patients with histologically confirmed GIST refractory to imatinib, sunitinib, and regorafenib were randomized 2 : 1 to oral pimitespib 160 mg/day or placebo for 5 consecutive days per week in 21-day cycles. Following disease progression by blinded central radiological review (BCRR), cross-over to open-label pimitespib was permitted. The primary endpoint was progression-free survival (PFS) by BCRR in the full analysis set. Secondary endpoints included overall survival (OS) adjusted using the rank-preserving structural failure time (RPSFT) method to reduce the expected confounding impact of cross-over.
From 31 October 2018 to 30 April 2020, 86 patients were randomized to pimitespib (n = 58) or placebo (n = 28). Median PFS was 2.8 months 95% confidence interval (CI) 1.6-2.9 months with pimitespib versus 1.4 months (0.9-1.8 months) with placebo hazard ratio (HR) 0.51 (95% CI 0.30-0.87); one-sided P = 0.006. Pimitespib showed an improvement in cross-over-adjusted OS compared with placebo HR 0.42 (0.21-0.85), one-sided P = 0.007. Seventeen (60.7%) patients receiving placebo crossed-over to pimitespib; median PFS after cross-over was 2.7 months (95% CI 0.7-4.1 months). The most common (≥30%) treatment-related adverse events (AEs) with pimitespib were diarrhea (74.1%) and decreased appetite (31.0%); the most common (≥10%) grade ≥3 treatment-related AE was diarrhea (13.8%). Treatment-related AEs leading to pimitespib discontinuation occurred in three (5.2%) patients.
Pimitespib significantly improved PFS and cross-over-adjusted OS compared with placebo and had an acceptable safety profile in patients with advanced GIST refractory to standard TKIs.
•Pimitespib improved PFS compared with placebo in patients with previously treated advanced GIST.•OS was improved with pimitespib compared with placebo using the RPSFT model.•Exploratory pharmacogenomic analysis showed a benefit of pimitespib irrespective of KIT mutation status.•The safety profile of pimitespib was acceptable, and quality of life was not deteriorated by pimitespib compared with placebo.
Thoracic epidural analgesia (TEA) and intravenous patient-controlled analgesia (IV-PCA) are widely used to mitigate immediate postoperative pain; however, their effects on long-term disability-free ...survival are poorly documented. This study aimed to compare the effects of postoperative TEA and IV-PCA on disability-free survival in patients who underwent thoracic or abdominal surgery.
This post hoc analysis of a prospective observational study included 845 inpatients aged ≥55 years that underwent elective thoracic and abdominal surgery between 1 April 2016 and 28 December 2018 in a tertiary care hospital. Inverse probability of treatment weighted (IPTW) using stabilized inverse propensity scores was adopted to minimize bias. The primary outcome in this study was disability-free survival, defined as survival with a 12-item World Health Organization Disability Assessment Schedule 2.0 score of <16%, assessed at 3 months and 1 year after surgery.
The final analysis included 601 patients who received TEA and 244 who received IV-PCA. After IPTW, the weighted incidence of disability-free survival at 3 months and 1 year was 60.5% and 61.4% in the TEA group and 78.3% and 66.2% in the IV-PCA group, respectively. The adjusted OR for disability-free survival at 3 months and 1 year was 0.84 (95% confidence interval CI: 0.50-1.39) and 1.21 (95% CI: 0.72-2.05), respectively, for the TEA group.
No significant differences were observed in the disability-free survival at 3 months and 1 year after elective thoracic and abdominal surgery in patients aged ≥55 years who received TEA or IV-PCA.
This study is the first in our setting to document the long-term effects of patient-controlled analgesia. In a post hoc analysis of our prospective cohort study, we show that although differences in chronic postsurgical pain exist at 3 months post-surgery, disability-free survival rates at 1 year do not differ irrespective of the choice of patient-controlled analgesia. The findings of this study highlight the need for shared decision-making between clinicians and patients.
A Japan Society of Clinical Oncology (JSCO)-hosted expert meeting was held in Japan on 27 October 2019, which comprised experts from the JSCO, the Japanese Society of Medical Oncology (JSMO), the ...European Society for Medical Oncology (ESMO), the American Society of Clinical Oncology (ASCO), and the Taiwan Oncology Society (TOS). The purpose of the meeting was to focus on what we have learnt from both microsatellite instability (MSI)/deficient mismatch repair (dMMR) biomarkers in predicting the efficacy of anti-programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) immunotherapy, and the neurotrophic tyrosine receptor kinase (NTRK) gene fusions in predicting the efficacy of inhibitors of the tropomyosin receptor kinase (TRK) proteins across a range of solid tumour types. The recent regulatory approvals of the anti-PD-1 antibody pembrolizumab and the TRK inhibitors larotrectinib and entrectinib, based on specific tumour biomarkers rather than specific tumour type, have heralded a paradigm shift in cancer treatment approaches. The purpose of the meeting was to develop international expert consensus recommendations on the use of such tumour-agnostic treatments in patients with solid tumours. The aim was to generate a reference document for clinical practice, for pharmaceutical companies in the design of clinical trials, for ethics committees in the approval of clinical trial protocols and for regulatory authorities in relation to drug approvals, with a particular emphasis on diagnostic testing and patient selection.
•The PD-1 antibody pembrolizumab and the TRK inhibitors larotrectinib and entrectinib recently received regulatory approval.•Such tumour-agnostic regulatory approvals, based on tumour biomarker status, represent a paradigm shift in cancer therapy.•These recommendations provide guidance on which patients should be selected and tested for tumour MSI and NTRK gene fusions.
Sarcomas are a heterogeneous group of malignancies with mesenchymal lineage differentiation. The discovery of neurotrophic tyrosine receptor kinase (NTRK) gene fusions as tissue-agnostic oncogenic ...drivers has led to new personalized therapies for a subset of patients with sarcoma in the form of tropomyosin receptor kinase (TRK) inhibitors. NTRK gene rearrangements and fusion transcripts can be detected with different molecular pathology techniques, while TRK protein expression can be demonstrated with immunohistochemistry. The rarity and diagnostic complexity of NTRK gene fusions raise a number of questions and challenges for clinicians. To address these challenges, the World Sarcoma Network convened two meetings of expert adult oncologists and pathologists and subsequently developed this article to provide practical guidance on the management of patients with sarcoma harboring NTRK gene fusions. We propose a diagnostic strategy that considers disease stage and histologic and molecular subtypes to facilitate routine testing for TRK expression and subsequent testing for NTRK gene fusions.
•NTRK gene fusions are oncogenic drivers in a variety of tumor types including adult and pediatric sarcomas.•TRK inhibitors provide effective treatment options for patients with sarcomas harboring NTRK gene fusions.•Integrating NTRK testing into the management of patients with sarcoma is challenging due to the rarity of this biomarker.•Massive parallel RNA sequencing provides the optimal NTRK fusion test and immunohistochemistry is a valuable screening tool.•We propose a diagnostic strategy that considers histologic and molecular subtypes to facilitate routine NTRK fusion testing.
Background
Cancer chemotherapy is associated with a variety of side effects/adverse events. It is very important that patients adhere to the planned chemotherapy regimen, which necessitates a minimum ...of side effects and that these side effects be kept under control. We have investigated patients’ concerns and symptoms during chemotherapy with the aim to seek solutions that will improve patients’ quality of life during chemotherapy.
Methods
Forty-nine patients with malignant diseases on parenteral antineoplastic agents were sequentially enrolled in this study. These patients completed a questionnaire consisting of 42 items related to non-physical concerns and 52 items of physical symptoms related to chemotherapy. Each patient was also asked to select the three items among these 94 items which affected him/her the most.
Results
The median age of the cancer patients was 62 years and the male-to-female ratio was 18:31. Among the non-physical concerns, the most frequently chosen concern was ‘affects my family or partner,’ followed by anxiety related to treatment. Regarding the physical symptoms, the most frequent complaints were fatigue, alopecia and constipation, while the most troublesome symptoms were nausea, poor taste and paresthesia. Overall, the most frequently expressed concerns were ‘affects my family or partner’ and anxiety related to treatment. Male patients suffered most from fever, fatigue and nausea, and female patients complained more of poor taste and gastrointestinal problems.
Conclusion
Patient perceptions of adverse events associated with cancer chemotherapy apparently have changed from physical symptoms to non-physical concerns. In our patient cohort ‘affects my family or partner’ was the most important concern. One important point to note is that female patients often complained of poor taste because this meant they were unable to cook well.
Background
Rikkunshito, a standardized Japanese herbal medicine, is thought to accelerate gastric emptying and relieve dyspepsia, although no large‐scale, randomized, placebo‐controlled trials of ...rikkunshito have been conducted. This study aimed to determine the efficacy and safety of rikkunshito for treating functional dyspepsia (FD).
Methods
FD patients received 2.5 g rikkunshito or placebo three times a day for 8 weeks in this multicenter, randomized, placebo‐controlled, parallel‐group trial. The primary end point was the proportion of responders at 8 weeks after starting test drug, determined by global patient assessment (GPA). The improvement in four major dyspepsia symptoms severity scale was also evaluated. In addition, plasma ghrelin levels were investigated before and after treatment.
Key Results
Two hundred forty‐seven patients were randomly assigned. In the eighth week, the rikkunshito group had more GPA responders (33.6%) than the placebo (23.8%), although this did not reach statistical significance (p = 0.09). Epigastric pain was significantly improved (p = 0.04) and postprandial fullness tended to improve (p = 0.06) in the rikkunshito group at week 8. Rikkunshito was relatively more effective among Helicobacter pylori‐infected participants (rikkunshito: 40.0% vs placebo: 20.5%, p = 0.07), and seemed less effective among H. pylori‐uninfected participants (rikkunshito: 29.3% vs placebo: 25.6%, p = 0.72). Among H. pylori‐positive individuals, acyl ghrelin levels were improved just in rikkunshito group. There were no severe adverse events in both groups.
Conclusions & Inferences
Administration of rikkunshito for 8 weeks reduced dyspepsia, particularly symptoms of epigastric pain and postprandial fullness. (UMIN Clinical Trials Registry, Number UMIN000003954).
This study aimed to determine the efficacy and safety of rikkunshito, a standardized Japanese herbal medicine, for treating functional dyspepsia. The proportion of responders (GPA scores) and the proportion of participants with individual symptom relief (5‐point Likert scales) were compared between the rikkunshito and placebo groups by using the Fisher's exact test. Administration of rikkunshito for 8 weeks reduced dyspepsia (Responder rates: rikkunshito, 33.6%; placebo, 23.8%; p = 0.09), particularly symptoms of epigastric pain (rikkunshito, 44.0%; placebo 30.3%; p = 0.04) and postprandial fullness (rikkunshito, 50.4%; placebo 37.7%; p = 0.06). Weekly changes in these parameters in the two study groups were compared using the log‐rank test as shown here.
Summary
Background
Significance of monitoring adalimumab trough levels and anti‐adalimumab antibodies (AAA) for disease outcome in Crohn's disease (CD) patients remained unclear.
Aim
To evaluate the ...association of adalimumab trough levels and AAA at week 26 with clinical remission at week 52, the effect of azathiopurine on AAA and factors influencing trough levels in CD patients in the DIAMOND trial.
Methods
We performed this study using adalimumab trough levels, AAA at week 26 and 6‐thioguanine nucleotide (TGN) in red blood cells at week 12. A multiple regression model and receiver operating analysis was performed to identify factors influencing adalimumab trough levels and AAA, and adalimumab thresholds for predicting disease activity.
Results
There was a significant difference of adalimumab trough level at week 26 between patients with disease remission and without at week 52 (7.7 ± 3.3 μg/mL vs 5.4 ± 4.3 μg/mL: P <.001). Adalimumab trough level of 5.0 μg/mL yielded optimal sensitivity and specificity for remission prediction (80.2% and 55.6%, respectively). AAA development at week 26 significantly affected remission at week 52 (P = .021), which was strongly associated with adalimumab trough levels. Female gender and increasing body weight were independently associated with low adalimumab trough levels, and female gender was associated with AAA development. A cut‐off 6TGN level of >222.5 p mol/8 ×108 RBCs yielded sensitivity (100%) and specificity (60.6%) for AAA negativity.
Conclusion
Adalimumab trough levels and AAA occurrence were significantly associated with clinical remission. Higher 6TGN affected AAA negativity. The combination therapy is beneficial in some relevant aspects for CD patients. (UMIN Registration No. 000005146)
Linked ContentThis article is linked to Domènech et al and Nakase papers. To view
these papers visit https://doi.org/10.1111/apt.14350 and https://doi.org/10.1111/apt.14365.
Abstract Advances in vascular tissue engineering have been tremendous over the past 15 years, yet there remains a need to optimize current constructs to achieve vessels having true growth potential. ...Toward this end, it has been suggested that computational models may help hasten this process by enabling time-efficient parametric studies that can reduce the experimental search space. In this paper, we present a first generation computational model for describing the in vivo development of a tissue engineered vein from an implanted polymeric scaffold. The model was motivated by our recent data on the evolution of mechanical properties and microstructural composition over 24 weeks in a mouse inferior vena cava interposition graft. It is shown that these data can be captured well by including both an early inflammatory-mediated and a subsequent mechano-mediated production of extracellular matrix. There remains a pressing need, however, for more data to inform the development of next generation models, particularly the precise transition from the inflammatory to the mechanobiological dominated production of matrix having functional capability.
siDirect (http://design.RNAi.jp/) is a web-based online software system for computing highly effective small interfering RNA (siRNA) sequences with maximum target-specificity for mammalian RNA ...interference (RNAi). Highly effective siRNA sequences are selected using novel guidelines that were established through an extensive study of the relationship between siRNA sequences and RNAi activity. Our efficient software avoids off-target gene silencing to enumerate potential cross-hybridization candidates that the widely used BLAST search may overlook. The website accepts an arbitrary sequence as input and quickly returns siRNA candidates, providing a wide scope of applications in mammalian RNAi, including systematic functional genomics and therapeutic gene silencing.
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