ABSTRACT
Although anthraquinone derivatives possess significant antitumor activity, most of them also displayed those side effects like cardiotoxicity, mainly owing to their inhibition of topoisomerase II of DNA repair mechanisms. Our raised design strategy by switching therapeutic target from topoisomerase II to histone deacetylase (HDAC) has been applied to the design of anthraquinone derivatives in current study. Consequently, a series of novel HDAC inhibitors with a tricylic diketone of anthraquinone as a cap group have been synthesized. After screening and evaluation, compounds 4b, 4d, 7b and 7d have displayed the comparable inhibition in enzymatic activity and cell proliferation than that of Vorinostat (SAHA). Notably, compound 4b showed certain selectivity of antiproliferative effects on cancer cell lines over non-cancer cell lines.
PMID:32611998 | DOI:10.1248/cpb.c20-00206
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the management of surgery or invasive procedures in patients taking anti-vitamin K oral anticoagulants Body Weight (kg)Enoxaparin dose every 12 hours (IU)<50200050-69400070-89600090-110800011010000 The treatment with Enoxaparin will be initiated soon after randomization (maximum allowed starting time 12h after randomization). The treatment will be administered every 12 hours in the intervention group and every 24 hours in the control group. Treatments will be administered in the two arms until hospital discharge or the primary outcomes detailed below occur.
MAIN OUTCOMES: Primary Efficacy Endpoint: Clinical worsening, defined as the occurrence of at least one of the following events, whichever comes first: 1.Death2.Acute Myocardial Infarction [AMI]3.Objectively confirmed, symptomatic arterial or venous thromboembolism [TE]4.Need of either: a.Continuous Positive Airway Pressure (Cpap) or Non-Invasive Ventilation (NIV) orb.IMV in patients who at randomisation were in standard oxygen therapy by delivery interfaces5.Need for IMV, in patients who at randomisation were in Cpap or NIV Time to the occurrence of each of these events will be recorded. Clinical worsening will be analysed as a binary outcome as well as a time-to-event one. Secondary Efficacy Endpoints: Any of the following events occurring within the hospital stay 1.Death2.Acute Myocardial Infarction [AMI]3.Objectively confirmed, symptomatic arterial or venous thromboembolism [TE]4.Need of either: a.Continuous Positive Airway Pressure (Cpap) or Non-Invasive Ventilation (NIV) orb.IMV in patients who at randomisation were in standard oxygen therapy by delivery interfaces5.Need for IMV in patients who at randomisation were in Cpap or NIV6.Improvement of laboratory parameters of disease severity, including: o D-dimer levelo Plasma fibrinogen levelso Mean Platelet Volumeo Lymphocyte/Neutrophil ratioo IL-6 plasma levels MORTALITY AT 30 DAYS: Information about patients' status will be sought in those who are discharged before 30 days on Day 30 from randomisation. Time to the occurrence of each of these events will be recorded. Each of these events will be analysed as a binary outcome and as a time-to-event one. Primary safety endpoint: Major bleeding, defined as an acute clinically overt bleeding associated with one or more of the following: Decrease in haemoglobin of 2 g/dl or more;Transfusion of 2 or more units of packed red blood cells;Bleeding that occurs in at least one of the following critical sites [intracranial, intraspinal, intraocular (within the corpus of the eye; thus, a conjunctival bleed is not an intraocular bleed), pericardial, intra-articular, intramuscular with compartment syndrome, or retroperitoneal];Bleeding that is fatal (defined as a bleeding event that was the primary cause of death or contributed directly to death);Bleeding that necessitates surgical intervention Time to the occurrence of each of these events will be recorded. Each of these events will be analysed as a binary outcome and as a time-to-event one. Secondary safety endpoint: Clinically Relevant non-major bleeding, defined as an acute clinically overt bleeding that does not meet the criteria for major and consists of: 1.Any bleeding compromising hemodynamic2.Spontaneous hematoma larger than 25 cm2, or 100 cm2 if there was a traumatic cause3.Intramuscular hematoma documented by ultrasonography4.Epistaxis or gingival bleeding requiring tamponade or other medical intervention5.Bleeding from venipuncture for >5 minutes6.Haematuria that was macroscopic and was spontaneous or lasted for more than 24 hours after invasive procedures7.Haemoptysis, hematemesis or spontaneous rectal bleeding requiring endoscopy or other medical intervention8.Any other bleeding requiring temporary cessation of a study drug. Time to the occurrence of each of these events will be recorded. Each of these events will be analysed as a binary outcome and as a time-to-event one.
RANDOMISATION: Randomisation (wit[...]
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PubMed articles on: Cancer & VTE/PE
Clinical effect of bronchial arterial infusion chemotherapy and CalliSpheres drug-eluting beads in patients with stage II-IV lung cancer: A prospective cohort study
Shang B, et al. Thorac Cancer 2020.
ABSTRACT
BACKGROUND: CalliSpheres are drug-eluting beads used for tumor artery embolization, with clinical benefits in a number of cancer types. The aim of the study was to examine the clinical benefits and complications of patients with stage II-IV lung cancer treated with CalliSpheres drug-eluting beads for embolization versus conventional vascular interventional treatment.
METHODS: This was a prospective cohort study conducted from August 2018 to May 2019. The patients were grouped according to traditional bronchial arterial infusion chemotherapy (infusion group) or bronchial arterial chemoembolization with CalliSpheres drug-eluting beads loaded with adriamycin (CallisSphere group). Short-term effects, serum tumor markers, and adverse reactions during follow-up were compared between the two groups.
RESULTS: There were 60 participants enrolled into the study with 30 in each group including 54 men and six women, 42-78 years of age. In the CalliSphere group, compared with the infusion group, the disease control rate was 93.3% versus 73.3% (P = 0.080) and the objective remission rate (ORR) was 86.7% versus 60.0% (P = 0.039); the three- and six-month progression-free survival (PFS) and six-month overall survival (OS) were better in the CalliSphere group (three-month PFS: 96.7% vs. 73.3%, P = 0.026; six-month PFS: 87.5% vs. 57.1%, P = 0.045; six-month OS: 87.5% vs. 52.7%, P = 0.024); after treatment, the tumor markers in the CalliSphere group were lower (CEA: P < 0.001; CYFRA21-1: P = 0.014). There were no differences in adverse reactions between the two groups.
CONCLUSIONS: The clinical effect of bronchial arterial chemoembolization with drug-eluting beads on lung cancer is probably significant and could improve the short-term response, PFS, and OS in patients with stage IIIV lung cancer, without increasing severe adverse reactions.
KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: The clinical effect of bronchial arterial chemoembolization with drug-eluting beads on lung cancer is probably significant and could improve the short-term response, PFS, and OS in patients with stage II-IV lung cancer, without increasing severe adverse reactions.
WHAT THIS STUDY ADDS: The ORR, PFS, OS was better in the CalliSphere group than that of infusion group; CEA and CYFRA21-1 were significant lower in CalliSphere group.
PMID:32603550 | DOI:10.1111/1759-7714.13522
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PubMed articles on: Cardio-Oncology
Sacubitril/valsartan in the treatment of cancer therapy-related cardiac dysfunction
Wang Y, et al. Int J Cardiol 2020.
NO ABSTRACT
PMID:32610154 | DOI:10.1016/j.ijcard.2020.06.041
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h a 1:1 randomisation ratio) will be centrally performed by using a secure, web-based system, which will be developed by the Methodological and Statistical Unit at the Azienda Ospedaliero-Universitaria of Modena. Randomisation stratified by 4 factors: 1) Gender (M/F); 2) Age (<75<302) with random variable block sizes will be generated by STATA software. The web-based system will guarantee the allocation concealment. Blinding (masking) The study is conceived as open-label: patients and all health-care personnel involved in the study will be aware of the assigned group.
NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The target sample size is based on the hypothesis that LMWH administered at high doses versus low doses will significantly reduce the risk of clinical worsening. The overall sample size in this study is expected to be 300 with 150 in the Low-Dose LMWH control group and 150 in the High-Dose LMWH intervention group, recruited over 10-11 months. Assuming an alpha of 5% (two tailed) and a percentage of patients who experience clinical worsening in the control group being between 25% and 30%, the study will have 80% power to detect at least 50% relative reduction in the risk of death between low and high doses of heparin.
TRIAL STATUS: Protocol version 1.2 of 11/05/2020. Recruitment start (expected): 08/06/2020 Recruitment finish (expected): 30/04/2021 Trial registration EudraCT 2020-001972-13, registered on April 17th, 2020 Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.
PMID:32586394 | PMC:PMC7316577 | DOI:10.1186/s13063-020-04475-z
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PubMed articles on: Cancer & VTE/PE
Predictors of Post-Thrombotic Syndrome in Pediatric Thrombosis: A Systematic Review and Meta-Analysis of the Literature
Engel ER, et al. J Thromb Haemost 2020.
ABSTRACT
BACKGROUND: Post-thrombotic syndrome (PTS) is a significant complication of pediatric deep venous thrombosis (DVT). There is a gap in the understanding of the risk factors associated with the development of pediatric PTS preventing the early identification of those patients at greatest risk, and the development of risk-stratified interventions.
OBJECTIVES: To conduct a systematic review and meta-analysis of the literature on prognostic factors for PTS development in pediatric patients.
METHODS: A systematic search of MEDLINE, EMBASE, and the Cochrane Library from 1960 to December 2018 was performed. Eligible studies reported at least one prognostic factor for PTS development in patients <21
RESULTS AND CONCLUSIONS: Twelve studies (n= 1,160 patients) met criteria for inclusion. Ninety-three percent of patients with an extremity DVT(n=1076) were assessed for PTS. PTS developed in 40% (n=434) of these patients. Central venous catheter-associated DVT (odds ratio [OR] 1.8, 95% CI 1.08-2.98), complete veno-occlusion (OR 1.89, 95% CI 1.04-3.46), and incomplete DVT resolution (OR 2.07, 95% CI 1.4-3.07) were identified as candidate prognostic factors for pediatric PTS. These findings should be interpreted in the context of the heterogeneity of the included studies and the limitations of current pediatric PTS assessment tools. Further, the predictive value of these prognostic factors will need to be validated in future collaborative prospective multicenter studies that maximize the homogeneity of pediatric DVT patients.
PMID:32614496 | DOI:10.1111/jth.14984
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PubMed articles on: Cardio-Oncology
Cardiovascular Toxicities of Bruton's Tyrosine Kinase Inhibitors
Pineda-Gayoso R, et al. Curr Treat Options Oncol 2020 - Review.
ABSTRACT
There has been a significant shift in the management of B cell malignancies over the past decade. Initial strategies involving the use of systemic chemotherapies have been gradually replaced by more targeted therapies to improve survival and overall tolerability. Bruton's tyrosine kinase inhibitors are breakthrough drugs that have been approved to treat many B cell malignancies. Despite their demonstrated benefits, unintended events still occur including various cardiotoxicities. In this review, we discuss the rationale behind developing these agents, their common cardiovascular toxicities, and associated management challenges.
PMID:32607825 | DOI:10.1007/s11864-020-00764-6
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PubMed articles on: Cancer & VTE/PE
Reducing the risk of venous thromboembolism following superficial endovenous treatment: A UK and Republic of Ireland consensus study
Dattani N, et al. Phlebology 2020.
ABSTRACT
OBJECTIVES: Venous thromboembolism is a potentially fatal complication of superficial endovenous treatment. Proper risk assessment and thromboprophylaxis could mitigate this hazard; however, there are currently no evidence-based or consensus guidelines. This study surveyed UK and Republic of Ireland vascular consultants to determine areas of consensus.
METHODS: A 32-item survey was sent to vascular consultants via the Vascular and Endovascular Research Network (phase 1). These results generated 10 consensus statements which were redistributed (phase 2). 'Good' and 'very good' consensus were defined as endorsement/rejection of statements by >67% and >85% of respondents, respectively.
RESULTS: Forty-two consultants completed phase 1. This generated seven statements regarding risk factors mandating peri-procedural pharmacoprophylaxis and three statements regarding specific pharmacoprophylaxis regimes. Forty-seven consultants completed phase 2. Regarding venous thromboembolism risk factors mandating pharmacoprophylaxis, 'good' and 'very good' consensus was achieved for 5/7 and 2/7 statements, respectively. Regarding specific regimens, 'very good' consensus was achieved for 3/3 statements.
CONCLUSIONS: The main findings from this study were that there was 'good' or 'very good' consensus that patients with any of the seven surveyed risk factors should be given pharmacoprophylaxis with low-molecular-weight heparin. High-risk patients should receive one to two weeks of pharmacoprophylaxis rather than a single dose.
PMID:32611228 | DOI:10.1177/0268355520936420
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PubMed articles on: Cardio-Oncology
Involvement of ROS/NLRP3 Inflammasome Signaling Pathway in Doxorubicin-Induced Cardiotoxicity
Wei S, et al. Cardiovasc Toxicol 2020.
ABSTRACT
Doxorubicin (Dox) is widely used in cancer therapy, but the clinical application is limited by its cardiotoxicity. The underlying mechanism of Dox-induced cardiotoxicity remains unclear. Present study aimed to evaluate the role of NLRP3 inflammasome in Dox-induced cardiotoxicity. The NLRP3 inflammasome was activated in the myocardium of Dox-treating (5 mg/kg, once every other day, cumulative dosage to 15 mg/kg and sacrificed after 2 days of last Dox injection) C57BL/6 mice as shown by the up-regulation of NLRP3 and Caspase-1 p20. Dox (1 μM for 48 h) induced the apoptosis of H9c2 cells and primary cardiomyocytes concomitantly with up-regulation of NLRP3, ASC and Caspase-1 p20 expressions, as well as the increased IL-1β secretion, suggesting the activation of NLRP3 inflammasome. These effects of Dox on H9c2 cells and primary cardiomyocytes can be reversed by MCC950, a specific inhibitor of NLRP3. In view of the key role of ROS on the Dox-induced cardiotoxicity, the relationship between ROS and NLRP3 was further investigated. The ROS level was increased in myocardium, H9c2 cells and primary cardiomyocytes after treating with Dox. Decreasing ROS level by NAC can inhibit the NLRP3 inflammasome activation, secretion of IL-1β and apoptosis in Dox-treating H9c2 cells and primary cardiomyocytes. Collectively, this study reveals a crucial role of ROS/NLRP3-associated inflammasome activation in Dox-induced cardiotoxicity, and NLRP3 inflammasome may represent a new therapeutic target for Dox-induced cardiotoxicity.
PMID:32607760 | DOI:10.1007/s12012-020-09576-4
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PubMed articles on: Cancer & VTE/PE
Resection of recurrent hepatocellular carcinoma with thrombi in the inferior vena cava, right atrium, and phrenic vein: a report of three cases
Tomita K, et al. World J Surg Oncol 2020.
ABSTRACT
BACKGROUND: Prognosis for patients with advanced hepatocellular carcinoma with a tumor thrombus in the inferior vena cava or right atrium is extremely poor due to cancer progression, pulmonary embolism, and congestion of the circulatory system caused by right heart failure. Surgical resection of the tumor thrombi may potentially yield better results than non-surgical treatments through prevention of sudden death. However, the benefits of surgical resection in patients with hepatocellular carcinoma and a tumor thrombus extending to the inferior vena cava, right atrium, and potentially in the phrenic vein are unclear. Here, we report three such cases.
CASE PRESENTATION: Of the total 136 patients who underwent hepatectomies for hepatocellular carcinoma in our institution, three patients with prior hepatectomies and recurrent hepatocellular carcinoma had tumor thrombi in the inferior vena cava, right atrium, and phrenic vein. Surgical resections were performed, as there was a possibility of sudden death, despite the risk of leaving residual tumor. For all patients, we performed resection of the tumor thrombi in the inferior vena cava and right atrium and combined diaphragm resection. Surgical resection was performed using the total hepatic vascular exclusion technique in all cases. Additional passive veno-venous bypass was also performed in two cases, in which complete tumor resections could not be achieved. The microscopic surgical margins of the combined resected diaphragms were positive in all cases. Progression-free survival was 20.2, 3.8, and 9.5 months for case 1, 2, and 3, respectively. The respective overall postoperative survival was 98.0, 38.9, and 30.9 months. The patients died due to liver cirrhosis, acute heart failure, and hepatocellular carcinoma, respectively. Sudden death did not occur for any of the patients.
CONCLUSION: Surgical resections may extend prognosis for patients with recurrent hepatocellular carcinoma with tumor thrombi in the inferior vena cava, right atrium, and phrenic vein, although the indications should be considered carefully.
PMID:32571339 | PMC:PMC7310451 | DOI:10.1186/s12957-020-01914-8
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PubMed articles on: Cardio-Oncology
The microRNA-34a-Induced Senescence-Associated Secretory Phenotype (SASP) Favors Vascular Smooth Muscle Cells Calcification
Zuccolo E, et al. Int J Mol Sci 2020.
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