Platelets in In-stent Restenosis: From Fundamental Role to Possible Prognostic Application

Background Introduction of new generations of stents has decreased the percentage of patients experiencing in-stent restenosis (ISR) following the implantation of stent. However, a large number of patients are still afflicted with this phenomenon, which necessitates further study of ISR pathophysiology.Methods Relevant English literature was searched up to 2018 and retrieved form the PubMed database and Google Scholar search engine. The following keywords were used: “In-stent restenosis”, “Platelet”, “Chemokine”, “Inflammation”, “Vascular smooth muscle cell” and “Neointima”.Results Previous studies have shown that ISR is a pathophysiologic response to damage of the artery wall after its elongation and separation of the atherosclerotic plaque. Development of neointimal hyperplasia (NIH) following this pathophysiologic response is a function of inflammation caused by platelets, monocytes, macrophages, and lymphocytes, as well as rapid migration and proliferation of generally quiescent cells in the median layer of the artery wall.Conclusion After damage to the artery wall, platelets play an essential role in the incidence of NIH by contributing to inflammation and migration of vascular smooth muscle cells and extracellular matrix remodeling, especially via secretion of different chemokines; therefore, developing therapeutic strategies for platelet inhibition in a controlled manner could be the basis of preventive treatments in the near future. In this study, for the first time, we hypothesize that evaluation of platelet activity profile in patients before and after stent implantation may determine the prognosis and likelihood of ISR.     

<i>In vivo</i> Effects of Aqueous Extract of <i>Gongronema latifolium</i> Benth on the Tumor Necrosis Factor-α, Transforming Growth Factor-β, and Hepatic Enzymes

Nonsteroidal anti-inflammatory drugs have a number of side effects. However, some medicinal herbs have anti-inflammatory properties with few side effects. This study aimed to determine the effect of the aqueous extract of Gongronema latifolium (AEGL) leaves on the level of tumor necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) in rabbits. Enzyme-linked immunosorbent assay (ELISA) was performed to determine the effect of the AEGL on the activities of pro-inflammatory cytokine (TNFα), and regulatory cytokine (TGF-β) in rabbits. Also, a colorimetric method was performed to evaluate the levels of AST and ALT. Overall, the weight of the animals increased until the 21st day and then slightly decreased in the last week of treatment. AEGL showed significant (p < 0.05) inhibitory activity against pro-inflammatory and regulatory cytokines. The greatest inhibitory activities against TNF-α (21 days) and TGF-β (14 days) were obtained at a dose of 400 mg/kg of AEGL. No hepatotoxicity was observed within a 28-day period. This study showed that AEGL can be used as a safe herbal anti-inflammatory and immunomodulatory treatment. Further clinical trials are needed to approve this potential.     

Pain and physical activity changes during the COVID-19 state of emergency among Japanese adults aged 40 years or older: A cross-sectional study

Understanding the relationship between pain and physical activity (PA) levels is beneficial for maintaining good health status. However, the impact of pain on changes in PA during the coronavirus disease 2019 (COVID-19) pandemic is unknown. The purpose of this study was to examine whether PA levels pre-, during, and post-COVID-19 state of emergency differ between Japanese adults who had pain after the COVID-19 state of emergency and those who did not.Data were collected from a cross-sectional online survey conducted between October 19 and 28, 2020. The analytic sample consisted of 1967 Japanese adults aged ≥40 years who completed the online survey. Participants completed questionnaires on the presence of pain and duration of PA, defined as the total PA time per week based on activity frequency and time. Participants were asked to report their PA at 3 time points: October 2019 (before the COVID-19 pandemic), April 2020 (during the COVID-19 state of emergency), and October 2020 (after the COVID-19 state of emergency).Among participants aged ≥60 years who reported pain in October 2020, the total PA time was significantly lower than participants who did not report having pain. Furthermore, the total PA time in April 2020 was significantly lower than that in October 2019; however, no significant difference in total PA time was observed between April and October 2020. Among participants aged 40 to 59 years, no significant differences were observed in total PA times at the 3 time points between those with and without pain. In addition, the total PA time in October 2020 significantly increased compared to that in April 2020, although it significantly decreased in April 2020 compared to October 2019.This study suggests that older adults with pain have lower PA levels after the COVID-19 state of emergency.     

Feasibility of Endoscopic Screening for Upper Gastrointestinal Malignancy in a Comprehensive Health Checkup

Objective In an effort to reduce mortality from gastric cancer, endoscopic screening was introduced in 2016 as a nationwide screening program in Japan. Recent developments in high-definition endoscopic imaging and diagnostic strategies have enabled the simultaneous detection of other upper gastrointestinal (U-GI) malignancies. Therefore, we conducted a study to evaluate the feasibility of endoscopic screening for U-GI malignancy in a comprehensive health checkup. Methods We retrospectively reviewed the data of 13,120 participants who had received a comprehensive health checkup in a single institution between April 2012 and March 2018. Participants were divided into two groups [gastrointestinal endoscopy (GIE) group (n=9,142) and gastrointestinal X-ray (X-ray) group (n=3,978)] and compared with regards to the screening results, adverse events, and detection rate of U-GI malignancies (gastric cancer or other) using a propensity-score matched analysis. Results The gastric cancer detection rate was significantly higher in the GIE group [34/9,142 (0.48%)] than in the X-ray group [3/3,978 (0.08%)] (p=0.003). Other U-GI malignancies were found only in the GIE group and comprised two hypopharyngeal cancers, five esophageal cancers, two duodenal cancers, and one duodenal gastrointestinal stromal tumor. Adverse events occurred in 6/9,142 (0.07%) participants in the GIE group and 18/3,978 (0.45%) participants in the X-ray group (p<0.0001). A propensity-score matched analysis yielded 1,551 matched pairs, and the detection rate of gastric cancer and other U-GI malignancies remained significantly higher in the GIE group than in the X-ray group. Conclusion This study indicated that not only gastric cancer but also other U-GI malignancies can be detected by endoscopic screening.     

Short-term efficacy of potassium-competitive acid blocker following gastric endoscopic submucosal dissection: a propensity score analysis

Background: Endoscopic submucosal dissection (ESD) is a promising method for the resection of superficial gastric neoplasms. Vonoprazan is a novel potassium-competitive acid blocker (P-CAB) that is currently considered as a potential alternative to proton pump inhibitors (PPIs) for the treatment of acid-related diseases. However, the utility of vonoprazan in ESD-related ulcers is unclear. Therefore, we compared the short-term efficacies of vonoprazan and the PPI lansoprazole in ESD-related ulcer healing during the first two weeks following intervention.

Methods: This study included 115 superficial gastric neoplasms that were treated by ESD at Hiraka General Hospital between April 2015 and January 2017. Patients treated with P-CAB (20?mg vonoprazan, n?=?62) or PPI (30?mg lansoprazole, n?=?53) were compared using propensity-score matching analysis. Primary outcome was rate of ulcer reduction at two weeks after ESD. Secondary outcomes were coverage ratio of ulcer base by granulation tissue and incidence of postoperative bleeding.

Results: The rate of ulcer reduction was significantly higher (median [range], 80.6% [67.6%–94.5%] vs. 62.7% [33.4%–85.2%]; p?P?Conclusions: P-CAB achieved rapid artificial ulcer healing with promotion of granulation tissue formation. However, conventional PPI with initial intravenous infusion might be sufficient for prevention of postoperative bleeding following gastric ESD.     

Nivolumab-induced Vogt-Koyanagi-Harada-like Syndrome and Adrenocortical Insufficiency with Long-term Survival in a Patient with Non-small-cell Lung Cancer

A 58-year-old man was diagnosed with lung adenocarcinoma with a tumor proportion score of 10%. After six cycles of second-line chemotherapy with nivolumab, he achieved a complete response (CR) but developed uveitis and sensorineural hearing disorder, which were consistent with Vogt-Koyanagi-Harada (VKH)-like syndrome. Simultaneously, pituitary adrenocortical insufficiency was identified. Nivolumab discontinuation and systemic corticosteroid administration resolved these immune-related adverse events (irAEs). The patient has maintained a CR without any chemotherapy for approximately two years. We herein report a patient with a long-term progression-free survival despite chemotherapy discontinuation due to irAEs, including VKH-like syndrome, which were appropriately managed.     

Impact of the Economic Status of the Patient’s Country of Residence on the Outcome of Oncology Clinical Trials

BackgroundProlongation of overall survival (OS) is commonly evaluated as a primary endpoint in confirmative oncology clinical trials; however, it is potentially affected by subsequent treatments carried out in practice. To design and implement multi-regional clinical trials properly, we compared survival outcomes between Organisation for Economic Co-operation and Development (OECD) and non-OECD countries.Materials and MethodsIndividual patient data from industry-sponsored multi-regional phase III oncology trials were obtained from the Project Data Sphere. Patients of each arm were divided into several subgroups based on race and country where patients were enrolled. We defined the member countries of the OECD. Cox regression analysis was conducted to estimate the hazard ratio (HR) for progression-free survival (PFS) and OS between the different subgroups in each trial, followed by a meta-analysis to estimate the summary HR and its confidence interval with a random-effect model.ResultsEleven arms from 10 clinical trials were eligible for the analysis. No statistically significant difference was observed in PFS and OS between Caucasian and Asian. A prolongation of OS was observed in patients enrolled in the OECD group compared with non-OECD group, while no statistically significant difference was observed in PFS.ConclusionThe economic status and healthcare environment of countries where patients reside have an impact on the outcome of OS. Clinical trial sponsors are recommended to consider carefully how to properly design oncology clinical trials including the selection of countries and data management of subsequent treatments.     

Efficacy of topical dimethyl sulfoxide (DMSO) 50% solution vs tretinoin 0.5% cream in treatment of patients with primary macular amyloidosis: A split‐side single‐blinded randomized clinical trial

Primary localized cutaneous amyloidosis (PLCA) is a recalcitrant sporadic dermatological condition and most treatments have failed so far. We studied the efficacy of topical dimethyl sulfoxide (DMSO) 50% solution in comparison with tretinoin 0.5% cream in treatment of macular amyloidosis. In this split‐side within‐person single‐blinded randomized clinical trial, 18 patients with bilateral macular amyloidosis received topical DMSO 50% solution and tretinoin 0.5% cream either on their right or the left side. The colorimetry, pruritus scoring, and photography were done. A significant pigmentation decline per each follow‐up was observed in DMSO group compared to the tretinoin group (tretinoin: ?1.31 vs DMSO: ?7.34; difference in slopes: ?6.03 [95% confidence interval: ?12.06 to ?0.01], P_Interaction = .049). An insignificant diminution trend in pigmentation was observed for both treatments (P_tretinoin = .672, P_DMSO = .092). Also, both treatments relived itchiness, but DMSO completely dispatched itchiness from the first follow‐up (P = .003 for tretinoin and <.0001 for DMSO). In conclusion, our results showed DMSO and tretinoin cream have the positive effect on the both pigmentation and itchiness in PLCA. DMSO may be more beneficial than tretinoin, since DMSO was significantly better in reducing itchiness. More investigations are warranted to provide sufficient evidence.     

Palladium-catalyzed dehydrogenative C–H cyclization for isoindolinone synthesis

In this paper Pd-catalyzed intramolecular dehydrogenative C(sp³)–H amidation for the synthesis of isoindolinones is described. This method features the use of a Pd/C catalyst and the addition of a stoichiometric amount of oxidant is not necessary. A mechanistic study suggested the possible formation of H₂ gas during the reaction.

Pd-catalyzed intramolecular dehydrogenative C(sp³)–H amidation for the synthesis of isoindolinones was developed. Use of Pd/C as a catalyst enables the desired cyclization to proceed smoothly without adding any stoichiometric oxidants.

The isoindolinone scaffold occurs frequently in numerous biologically active compounds ranging from designed medicinal agents to natural products, thus constituting an extremely important class of heterocycles.^1,2 Although a number of synthetic methods exist for the preparation of isoindolinones,³ the development of more general, versatile, and efficient procedures to construct the isoindolinone framework is still an ongoing, intensive research area.Among a variety of synthetic strategies for isoindolinones, methods that make use of transition metal-catalyzed C–H functionalization represent a remarkable approach.⁴ In this research area, catalytic oxidative annulation of N-substituted benzamides and appropriate coupling partners (e.g. alkenes, alkynes, isocyanides, diazo compounds) has been extensively studied, most of which employ transition metals such as rhodium,^4d,g,h,n,o ruthenium,^4l cobalt,^4a,i,j,k and palladium.^4b,m These precedents often require the use of stoichiometric oxidants or prefunctionalized coupling partners to make the process catalytic.On the other hand, an approach that involves intramolecular C–H cyclization of benzamide derivatives exploiting a transition metal catalyst could provide another efficient, facile, and direct access to isoindolinones, although less attention has been paid to such a process (Scheme 1). Kondo et al. previously reported C(sp³)–H aminative cyclization of 2-methyl-N-arylbenzamides in the presence of a copper catalyst along with a stoichiometric amount of di-tert-butyl peroxide as an oxidant, which resulted in the formation of 3-unsubstituted isoindolinones (Scheme 1a).^4c Bedford''s group also developed a copper-based catalytic system composed of 20 mol% of Cu(OTf)₂ and 2 equiv. of PhI(OAc)₂ that successfully effected the intramolecular benzylic C–H sulfamidation of 2-benzyl-N-tosylbenzamides for the synthesis of isoindolinones (Scheme 1b).^4f In both cases, the choice of an oxidant should be crucial for the successful construction of the isoindolinone ring.Open in a separate windowScheme 1C–H cyclization strategies for isoindolinone synthesis.Herein, we describe a catalytic system that enables cyclization of 2-benzyl-N-mesylbenzamides leading to isoindolinone derivatives, in which benzylic C(sp³)–H functionalization in the presence of a palladium catalyst smoothly occurs. It is particularly noteworthy to mention that any stoichiometric oxidants are not necessary for our isoindolinone synthesis. The key to success is the use of Pd/C as a catalyst. In this dehydrogenative process, an only detectable by-product was H₂, which should also be an appealing feature of the process.Based on our fruitful results of the heterocycles synthesis via transition metal-catalyzed C–H cyclization,⁵ our investigation began by examining the conversion of N-tosyl-protected benzamide 1a to the corresponding isoindolinone 2a. During the screening studies utilizing a range of transition metal catalysts as well as various oxidants, it was found that 2a did produce even in the absence of an oxidant when Pd/C was used as a catalyst. Indeed, the use of 10 mol% of Pd/C along with 20 mol% of KOAc enabled the desired cyclization process, providing 2a in 42% yield (6Effect of protecting group^a,b