Phase 1b/2 study of orally administered pexidartinib in combination with radiation therapy and temozolomide in patients with newly diagnosed glioblastoma.

Background: Glioblastoma (GBM) has a median survival of <2 years. Pexidartinib (PLX3397) is a small-molecule inhibitor of CSF1R, KIT, and oncogenic FTL3, which are implicated in GBM treatment resistance. Results from glioma models indicate that combining radiation therapy (RT) and pexidartinib reduces radiation resistance.

Volumetric absorptive microsampling meets electromembrane extraction for the first time: Case example of doxorubicin and its metabolite in whole blood samples.

Background: Microsampling of biological fluids followed by innovative sample pre-treatment reflects trends in bioanalytical chemistry. Volumetric absorptive microsampling (VAMS) enables exact whole blood volume collection and reduces the impact of hematocrit on the assay. In animal studies, it complies with the 3R principles (refine, reduce, replace).

Characterization of a new model of chemotherapy-induced heart failure with reduced ejection fraction and nephrotic syndrome in Ren-2 transgenic rats.

All anthracyclines, including doxorubicin (DOXO), the most common and still indispensable drug, exhibit cardiotoxicity with inherent risk of irreversible cardiomyopathy leading to heart failure with reduced ejection fraction (HFrEF). Current pharmacological strategies are clearly less effective for this type of HFrEF, hence an urgent need for new therapeutic approaches. The prerequisite for success is thorough understanding of pathophysiology of this HFrEF form, which requires an appropriate animal model of the disease.

Exploring the effects of topoisomerase II inhibitor XK469 on anthracycline cardiotoxicity and DNA damage.

Anthracyclines, such as doxorubicin (adriamycin), daunorubicin, or epirubicin, rank among the most effective agents in classical anticancer chemotherapy. However, cardiotoxicity remains the main limitation of their clinical use. Topoisomerase IIβ has recently been identified as a plausible target of anthracyclines in cardiomyocytes.

Cardiac miRNA expression during the development of chronic anthracycline-induced cardiomyopathy using an experimental rabbit model.

Anthracycline cardiotoxicity is a well-known complication of cancer treatment, and miRNAs have emerged as a key driver in the pathogenesis of cardiovascular diseases. This study aimed to investigate the expression of miRNAs in the myocardium in early and late stages of chronic anthracycline induced cardiotoxicity to determine whether this expression is associated with the severity of cardiac damage. Cardiotoxicity was induced in rabbits via daunorubicin administration (daunorubicin, 3 mg/kg/week; for five and 10 weeks), while the control group received saline solution.

Effect of LED photobiomodulation on dental implant osseointegration: An in vivo study.

Background: Photobiomodulation (PBM) may be prescribed after dental surgery to accelerate tissue healing and improve implant stability. The objective of this study is to evaluate the efficiency of LED-PBM on the dental implant osseointegration.

Methods: A total of 48 implants (Kontact) were inserted in 8 Yucatan minipigs (6 implants per minipig) divided into 2 groups (test and control).

Effect of bone density on the survival of 407 sandblasted and acid-etched dental implants: A retrospective multicenter study.

Background: This study evaluated the success and survival rate of sandblasted and acid-etched dental implants according to the patient's bone quality.

Methods: A multicenter retrospective study was conducted in five clinical centers between 2016 and March 2019. A total of 407 implants (KONTACT S, Biotech Dental, France) placed in 229 patients (61.

Targeted treatment of severe vascular malformations harboring PIK3CA and TEK mutations with alpelisib is highly effective with limited toxicity.

This was a prospective cohort study of eighteen patients with large and debilitating vascular malformations with one or more major systemic complications. In all patients, we discovered activating alterations in either TEK or PIK3CA. Based on these findings, targeted treatment using the PI3K inhibitor alpelisib was started with regular check-ups, therapy duration varied from 6 to 31 months.

Experimental analysis and numerical fatigue life prediction of 3D-Printed osteosynthesis plates.

The trend towards patient-specific medical orthopedic prostheses has led to an increased use of 3D-printed surgical implants made of Ti6Al4V. However, uncertainties arise due to varying printing parameters, particularly with regards to the fatigue limit. This necessitates time-consuming and costly experimental validation before they can be safely used on patients.

Development of a Rat Model of Intra-Amniotic Inflammation Ultrasound-Guided Administration of a Triggering Agent in the Gestational Sac to Enable Analysis of Individual Amniotic Fluid Samples.

To develop a rat model of intra-amniotic inflammation, characterized by the concentration of interleukin-6 in the amniotic fluid, induced by an ultrasound-guided transabdominal administration of lipopolysaccharide into individual gestational sacs. An ultrasound-guided transabdominal intra-amniotic administration of lipopolysaccharide or phosphate-buffered saline (PBS) as control was performed in rats on embryonic day 18. Only accessible gestational sacs with precise recording of their positions were injected.

CSF1 receptor inhibition of tenosynovial giant cell tumor using novel disease-specific MRI measures of tumor burden.

Monitoring treatment of tenosynovial giant cell tumor (TGCT) is complicated by the irregular shape and asymmetrical growth of the tumor. We compared responses to pexidartinib by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 with those by tumor volume score (TVS) and modified RECIST (m-RECIST).

Primary prevention of chronic anthracycline cardiotoxicity with ACE inhibitor is temporarily effective in rabbits, but benefits wane in post-treatment follow-up.

Angiotensin-converting enzyme inhibitors (ACEis) have been used to treat anthracycline (ANT)-induced cardiac dysfunction, and they appear beneficial for secondary prevention in high-risk patients. However, it remains unclear whether they truly prevent ANT-induced cardiac damage and provide long-lasting cardioprotection. The present study aimed to examine the cardioprotective effects of perindopril on chronic ANT cardiotoxicity in a rabbit model previously validated with the cardioprotective agent dexrazoxane (DEX) with focus on post-treatment follow-up (FU).

Results from Phase I Extension Study Assessing Pexidartinib Treatment in Six Cohorts with Solid Tumors including TGCT, and Abnormal CSF1 Transcripts in TGCT.

Purpose: To assess the response to pexidartinib treatment in six cohorts of adult patients with advanced, incurable solid tumors associated with colony-stimulating factor 1 receptor (CSF1R) and/or KIT proto-oncogene receptor tyrosine kinase activity.

Patients And Methods: From this two-part phase I, multicenter study, pexidartinib, a small-molecule tyrosine kinase inhibitor that targets CSF1R, KIT, and FMS-like tyrosine kinase 3 (FLT3), was evaluated in six adult patient cohorts (part 2, extension) with advanced solid tumors associated with dysregulated CSF1R. Adverse events, pharmacokinetics, and tumor responses were assessed for all patients; patients with tenosynovial giant cell tumor (TGCT) were also evaluated for tumor volume score (TVS) and patient-reported outcomes (PRO).

Myofibroblastic tumor of the esophagus - a case report of long-term follow-up and literature review.

Background: Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal neoplasm with intermediate malignant potential. Although most often seen in the lungs, it can occur at multiple anatomical locations, including the gastrointestinal tract. An esophageal lesion is extremely rare, however.

Clinically Translatable Prevention of Anthracycline Cardiotoxicity by Dexrazoxane Is Mediated by Topoisomerase II Beta and Not Metal Chelation.

Background: Anthracycline-induced heart failure has been traditionally attributed to direct iron-catalyzed oxidative damage. Dexrazoxane (DEX)-the only drug approved for its prevention-has been believed to protect the heart via its iron-chelating metabolite ADR-925. However, direct evidence is lacking, and recently proposed TOP2B (topoisomerase II beta) hypothesis challenged the original concept.

Prodrug of ICRF-193 provides promising protective effects against chronic anthracycline cardiotoxicity in a rabbit model in vivo.

The anthracycline (ANT) anticancer drugs such as doxorubicin or daunorubicin (DAU) can cause serious myocardial injury and chronic cardiac dysfunction in cancer survivors. A bisdioxopiperazine agent dexrazoxane (DEX) has been developed as a cardioprotective drug to prevent these adverse events, but it is uncertain whether it is the best representative of the class. The present study used a rabbit model of chronic ANT cardiotoxicity to examine another bisdioxopiperazine compound called GK-667 (meso-(butane-2,3-diylbis(2,6-dioxopiperazine-4,1-diyl))bis(methylene)-bis(2-aminoacetate) hydrochloride), a water-soluble prodrug of ICRF-193 (meso-4,4'-(butan-2,3-diyl)bis(piperazine-2,6-dione)), as a potential cardioprotectant.

Structure-Activity Relationship Study of Dexrazoxane Analogues Reveals ICRF-193 as the Most Potent Bisdioxopiperazine against Anthracycline Toxicity to Cardiomyocytes Due to Its Strong Topoisomerase IIβ Interactions.

Cardioprotective activity of dexrazoxane (ICRF-187), the only clinically approved drug against anthracycline-induced cardiotoxicity, has traditionally been attributed to its iron-chelating metabolite. However, recent experimental evidence suggested that the inhibition and/or depletion of topoisomerase IIβ (TOP2B) by dexrazoxane could be cardioprotective. Hence, we evaluated a series of dexrazoxane analogues and found that their cardioprotective activity strongly correlated with their interaction with TOP2B in cardiomyocytes, but was independent of their iron chelation ability.

Development of water-soluble prodrugs of the bisdioxopiperazine topoisomerase IIβ inhibitor ICRF-193 as potential cardioprotective agents against anthracycline cardiotoxicity.

The bisdioxopiperazine topoisomerase IIβ inhibitor ICRF-193 has been previously identified as a more potent analog of dexrazoxane (ICRF-187), a drug used in clinical practice against anthracycline cardiotoxicity. However, the poor aqueous solubility of ICRF-193 has precluded its further in vivo development as a cardioprotective agent. To overcome this issue, water-soluble prodrugs of ICRF-193 were prepared, their abilities to release ICRF-193 were investigated using a novel UHPLC-MS/MS assay, and their cytoprotective effects against anthracycline cardiotoxicity were tested in vitro in neonatal ventricular cardiomyocytes (NVCMs).

Spindle Cell Hemangioma and Atypically Localized Juxtaglomerular Cell Tumor in a Patient with Hereditary BRIP1 Mutation: A Case Report.

Spindle cell hemangioma is a benign vascular tumor typically occurring in the dermis or subcutis of distal extremities as red-brown lesions that can grow in both size and number over time. They can be very painful and potentially disabling. A family history of cancer or previous history may be relevant and must be taken into consideration.

Role of serum biomarkers in cancer patients receiving cardiotoxic cancer therapies: a position statement from the Cardio-Oncology Study Group of the Heart Failure Association and the Cardio-Oncology Council of the European Society of Cardiology.

Serum biomarkers are an important tool in the baseline risk assessment and diagnosis of cardiovascular disease in cancer patients receiving cardiotoxic cancer treatments. Increases in cardiac biomarkers including cardiac troponin and natriuretic peptides can be used to guide initiation of cardioprotective treatments for cancer patients during treatment and to monitor the response to cardioprotective treatments, and they also offer prognostic value. This position statement examines the role of cardiac biomarkers in the management of cancer patients.

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited.

Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19.

Design, Setting, And Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin.

Anticancer pentamethinium salt is a potent photosensitizer inducing mitochondrial disintegration and apoptosis upon red light illumination.

Despite progress in the development and application of novel therapeutic agents, cancer remains a major cause of death worldwide. Therefore, there is a need for new approaches to increase therapeutic options and efficiency. The metabolism of cancer cells differs from that of non-malignant cells and their mitochondria show altered activities that can be utilized as a target for drug development.

Investigation of Structure-Activity Relationships of Dexrazoxane Analogs Reveals Topoisomerase II Interaction as a Prerequisite for Effective Protection against Anthracycline Cardiotoxicity.

Bisdioxopiperazine agent dexrazoxane (ICRF-187) has been the only effective and approved drug for prevention of chronic anthracycline cardiotoxicity. However, the structure-activity relationships (SARs) of its cardioprotective effects remain obscure owing to limited investigation of its derivatives/analogs and uncertainties about its mechanism of action. To fill these knowledge gaps, we tested the hypothesis that dexrazoxane derivatives exert cardioprotection via metal chelation and/or modulation of topoisomerase II (Top2B) activity in chronic anthracycline cardiotoxicity.

A Cyclic Pentamethinium Salt Induces Cancer Cell Cytotoxicity through Mitochondrial Disintegration and Metabolic Collapse.

Cancer cells preferentially utilize glycolysis for ATP production even in aerobic conditions (the Warburg effect) and adapt mitochondrial processes to their specific needs. Recent studies indicate that altered mitochondrial activities in cancer represent an actionable target for therapy. We previously showed that salt 1-, a quinoxaline unit (with cytotoxic activity) incorporated into a meso-substituted pentamethinium salt (with mitochondrial selectivity and fluorescence properties), displayed potent cytotoxic effects in vitro and in vivo, without significant toxic effects to normal tissues.

and investigation of cardiotoxicity associated with anticancer proteasome inhibitors and their combination with anthracycline.

Although proteasome inhibitors (PIs) are modern targeted anticancer drugs, they have been associated with a certain risk of cardiotoxicity and heart failure (HF). Recently, PIs have been combined with anthracyclines (ANTs) to further boost their anticancer efficacy. However, this raised concerns regarding cardiac safety, which were further supported by several studies on immature cardiomyocytes.