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The survival of pediatric cancer patients has significantly increased thanks to the improvement of oncological treatments. Therefore, it is of utmost importance to manage short- and long-term cardiovascular complications. In pediatric cardio-oncology, there are no recognized guidelines as in adults. Several recommendations and many indications have been derived from the data obtained in the adult cancer population, resulting in greater discrepancies in the clinical management of patients. The aim of this position paper of the Italian Society of Pediatric Cardiology (SICP) is to collect the main evidence regarding the diagnosis, prevention, treatment and follow-up of cardiotoxicity in children, to provide useful indications for clinical practice, and to promote a network between pediatric centers.

The landscape of oncology drug development has witnessed remarkable advancements over the last few decades, significantly improving clinical outcomes and quality of life for patients with cancer. Project Optimus, introduced by the U.S. Food and Drug Administration, stands as a groundbreaking endeavor to reform dose selection of oncology drugs, presenting both opportunities and challenges for the field. To address complex dose optimization challenges, an Oncology Dose Optimization IQ Working Group was created to characterize current practices, provide recommendations for improvement, develop a clinical toolkit, and engage Health Authorities. Historically, dose selection for cytotoxic chemotherapeutics has focused on the maximum tolerated dose, a paradigm that is less relevant for targeted therapies and new treatment modalities. A survey conducted by this group gathered insights from member companies regarding industry practices in oncology dose optimization. Given oncology drug development is a complex effort with multidimensional optimization and high failure rates due to lack of clinically relevant efficacy, this Working Group advocates for a case-by-case approach to inform the timing, specific quantitative targets, and strategies for dose optimization, depending on factors such as disease characteristics, patient population, mechanism of action, including associated resistance mechanisms, and therapeutic index. This white paper highlights the evolving nature of oncology dose optimization, the impact of Project Optimus, and the need for a tailored and evidence-based approach to optimize oncology drug dosing regimens effectively., (© 2024 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Identifying medicinally relevant compounds from natural resources generally involves the tedious work of screening plants for the desired activity before capturing the bioactive molecules from them. In this work, we created a paper-based ligand fishing platform to vastly simplify the discovery process. This paper-based method exploits the enzymatic cascade reaction between α-glucosidase (GAA), glucose oxidase (GOx), and horseradish peroxidase (HRP), to simultaneously screen the plants and capture the GAA inhibitors from them. The designed test strip could capture ligands in tandem with screening the plants, and it features a very simply operation based on direct visual assessment. Multiple acylated flavonol glycosides from the leaves of Quercus variabilis Blume were newly found to possess GAA inhibitory activities, and they may be potential leads for new antidiabetic medications. Our study demonstrates the prospect of the newly discovered GAA ligands as potential bioactive ingredients as well as the utility of the paper-based ligand fishing method., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: This white paper provides guidance regarding the process for establishing and maintaining international collaborations to conduct oncology/neurology-focused chemotherapy-induced peripheral neurotoxicity (CIPN) research., Methods: An international multidisciplinary group of CIPN scientists, clinicians, research administrators, and legal experts have pooled their collective knowledge regarding recommendations for establishing and maintaining international collaboration to foster advancement of CIPN science., Results: Experts provide recommendations in 10 categories: (1) preclinical and (2) clinical research collaboration; (3) collaborators and consortiums; (4) communication; (5) funding; (6) international regulatory standards; (7) staff training; (8) data management, quality control, and data sharing; (9) dissemination across disciplines and countries; and (10) additional recommendations about feasibility, policy, and mentorship., Conclusion: Recommendations to establish and maintain international CIPN research collaboration will promote the inclusion of more diverse research participants, increasing consideration of cultural and genetic factors that are essential to inform innovative precision medicine interventions and propel scientific discovery to benefit cancer survivors worldwide., Relevance to Inform Research Policy: Our suggested guidelines for establishing and maintaining international collaborations to conduct oncology/neurology-focused chemotherapy-induced peripheral neurotoxicity (CIPN) research set forth a challenge to multinational science, clinical, and policy leaders to (1) develop simple, streamlined research designs; (2) address logistical barriers; (3) simplify and standardize regulatory requirements across countries; (4) increase funding to support international collaboration; and (5) foster faculty mentorship., (© 2024. The Author(s).)

The ongoing therapeutic revolution in multiple myeloma care can be traced to the turn of the millennium with the unanticipated discovery in 1999 that the cereblon binding small molecule thalidomide had profound clinical effectiveness and, simultaneously, the emergence of a new class of targeted therapies inhibiting the proteasome, both of which ultimately target ubiquitinated protein degradation. These contemporaneous discoveries forever changed the landscape of multiple myeloma care, substantially extending survival. Foreshadowing this seismic change, Nobel Prize winning work on the proteasome ubiquitin pathway had stimulated the development of highly specific proteasome inhibitor small molecules, particularly PS-341 (later named bortezomib). An abundance of the proteasome in hematologic malignancies had been recognized and thus PS-341 was logically being explored in relevant preclinical models. Concurrent with phase I trials, which were soon to prove the significant clinical relevance of preclinical models, the laboratory of Dr. Kenneth Anderson and colleagues at Dana-Farber, in partnership with Dr. Julian Adams and scientists at ProScript (later Millennium Pharmaceuticals) first demonstrated that the proteasome inhibitor PS-341 inhibited growth, induced apoptosis, and overcame drug resistance in human multiple myeloma cells. This landmark paper in Cancer Research set the stage for a paradigm shift in how multiple myeloma was managed across all stages of the disease, which changed the lives of patients worldwide. See related article by Hideshima and colleagues, Cancer Res 2001;61:3071-6., (©2023 American Association for Cancer Research.)

Interventional radiology (IR) is a valuable resource when caring for pediatric solid tumor patients. As minimally invasive, image-guided procedures become more relied upon to answer challenging diagnostic questions and provide alternative therapeutic options, IR is poised to become a contributing member of the multidisciplinary oncology team. Improved imaging techniques allow for better visualization during biopsy procedures, transarterial locoregional treatments have the potential to deliver targeted cytotoxic therapy while limiting systemic side effects, and percutaneous thermal ablation can be used to treat chemo-resistant tumors of various solid organs. Additionally, interventional radiologists are able to perform routine, supportive procedures for oncology patients that include central venous access placement, lumbar punctures, and enteric feeding tube placements with high levels of technical success and excellent safety profiles., (© 2023 Wiley Periodicals LLC.)

Cellular viability measurements quantify decreased proliferation or increased cytotoxicity caused by drug candidates or potential environmental toxins. Direct viability measures count each cell to provide an accurate readout. This approach can prove analytically challenging and time-consuming when cells are maintained in 3D structures akin to tissues or solid tumors. While less labor-intensive, indirect viability measures can be less accurate due to the heterogeneous structural and chemical microenvironment that arises when cells are maintained in tissue-like architectures and in contact with extracellular matrices. Here we determine the analytical figures of merit of five indirect viability assays in the paper-based cell culture platform we continue to develop in our laboratory: calcein-AM staining, the CellTiter-Glo assay, imaging fluorescent protein expression, propidium iodide staining, and the resazurin assay. We also determined the compatibility of each indirect assay with hypoxic conditions, intra-experimental repeatability, inter-experimental reproducibility, and ability to predict a potency value for a known antineoplastic drug. Our results show that each assay has benefits and drawbacks to consider when choosing the appropriate readout to answer a particular research question. We also highlight that only one indirect readout is unaffected by hypoxia, a commonly overlooked variable in cell culture that likely yields inaccurate viability measures.

Survival in cancer is continuously improving due to evolving oncological treatment. Therefore, cardiovascular short-term and long-term side effects gain crucial importance for overall outcome. Cardiotoxicity not only presents as heart failure, but also as treatment-resistant hypertension, acute coronary ischemia with plaque rupture or vasospasm, thromboembolism, arrhythmia, pulmonary hypertension, diastolic dysfunction, acute myocarditis and others. Recent recommendations have proposed baseline cardiac risk assessment and surveillance strategies. Major challenges are the availability of monitoring and imaging resources, including echocardiography with speckle tracking longitudinal strain (GLS), serum biomarkers such as natriuretic peptides (NT-proBNP) and highly sensitive cardiac troponins. This Austrian consensus encompasses cardiotoxicity occurrence in frequent antiproliferative cancer drugs, radiotherapy, immune checkpoint inhibitors and cardiac follow-up considerations in cancer survivors in the context of the Austrian healthcare setting. It is important to optimize cardiovascular risk factors and pre-existing cardiac diseases without delaying oncological treatment. If left ventricular ejection fraction (LVEF) deteriorates during cancer treatment (from >10% to <50%), or myocardial strain decreases (>15% change in GLS), early initiation of cardioprotective therapies (angiotensin-converting enzyme inhibitors, angiotensin or beta receptor blockers) is recommended, and LVEF should be reassessed before discontinuation. Lower LVEF cut-offs were recently shown to be feasible in breast cancer patients to enable optimal anticancer treatment. Interdisciplinary cardio-oncology cooperation is pivotal for optimal management of cancer patients., (© 2022. The Author(s).)

Chemotherapeutic drugs have been widely used in the treatment of cancer disease for about 70 years. The development of new treatments has not hindered their use, and oncologists still prescribe them routinely, alone or in combination with other antineoplastic agents. However, all chemotherapeutic agents can induce hypersensitivity reactions (HSRs), with different incidences depending on the culprit drug. These reactions are the third leading cause of fatal drug-induced anaphylaxis in the United States. In Europe, deaths related to chemotherapy have also been reported. In particular, most reactions are caused by platinum compounds, taxanes, epipodophyllotoxins and asparaginase. Despite their prevalence and relevance, the ideal pathways for diagnosis, treatment and prevention of these reactions are still unclear, and practice remains considerably heterogeneous with vast differences from center to center. Thus, the European Network on Drug Allergy and Drug Allergy Interest Group of the European Academy of Allergy and Clinical Immunology organized a task force to provide data and recommendations regarding the allergological work-up in this field of drug hypersensitivity reactions. This position paper aims to provide consensus on the investigation of HSRs to chemotherapeutic drugs and give practical recommendations for clinicians that treat these patients, such as oncologists, allergologists and internists. Key sections cover risk factors, pathogenesis, symptoms, the role of skin tests, in vitro tests, indications and contraindications of drug provocation tests and desensitization of neoplastic patients with allergic reactions to chemotherapeutic drugs. Statements, recommendations and unmet needs were discussed and proposed at the end of each section., (© 2021 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Biologicals are crucial targeted therapeutic agents in oncological, immunological, and inflammatory diseases, and their use in clinical practice is broadening. In recent years, the spread of Personalized Precision Medicine has facilitated a proliferation of new treatment options, especially biologicals. Consequently, biologicals are now among the drugs that most frequently cause hypersensitivity reactions (HSRs). Patients can develop HSRs to these agents during the first-lifetime exposure or after repeated exposure, and these HSRs can be potentially life-threatening or limit therapeutic options. Despite the relatively high prevalence, the underlying mechanisms of these HSRs remain obscure, and the optimal management pathways are still a matter of discussion. In this Position Paper, the authors will provide evidence-based recommendations for diagnosing and managing HSRs to biologicals. Additionally, the document defines unmet needs as an opportunity to shape future research., (© 2021 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Cancer therapy-related cardiac dysfunction (CTRCD) is a complication of selected cancer therapy agents associated with decline in left ventricular ejection fraction (LVEF). Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have established benefits in heart failure with reduced ejection fraction, but their efficacy for preventing CTRCD remains controversial. This narrative systematic review assessed the efficacy and safety of ACEI/ARB in the prevention of cancer therapy LVEF decline. We systematically searched PubMed, Embase and Cochrane from January 1980 to June 2022. Studies of interest were randomised controlled trials of patients with normal LVEF and active malignancy receiving cancer therapy, randomised to receive either an ACEI or ARB compared with a control group. The outcome was the change in LVEF from baseline to the end of the follow-up period. Death, clinical heart failure and adverse drug reactions were recorded. A total of 3731 search records were screened and 12 studies were included, comprising a total of 1645 participants. Nine studies assessed the prevention of anthracycline-induced LVEF decline, of which five showed a beneficial effect (1%-14% higher LVEF in treated groups), whereas four studies showed no effect. Three studies assessed the prevention of trastuzumab-induced LVEF decline, of which one showed a beneficial effect (4% higher LVEF) in a subset of participants. There are mixed data regarding the efficacy of ACEI/ARB in preventing the LVEF decline in patients undergoing anthracycline or trastuzumab therapy, with evidence suggesting no clinically meaningful benefit observed in recent studies., (© 2024 Royal Australasian College of Physicians.)

In 2021, the World Health Organization released the fifth edition of the central nervous system (CNS) tumor classification. This classification uses histopathology and molecular pathogenesis to group tumors into more biologically and molecularly defined entities. The prognosis of brain cancer, particularly malignant tumors, has remained poor worldwide, approximately 308,102 new cases of brain and other CNS tumors were diagnosed in the year 2020, with an estimated 251,329 deaths. The cost and time-consuming nature of studies to find new anticancer agents makes it necessary to have well-designed studies. In the present study, the pathways that can be targeted for drug development are discussed in detail. Some of the important cellular origins, signaling, and pathways involved in the efficacy of bioactive molecules against CNS tumorigenesis or progression, as well as prognosis and common approaches for treatment of different types of brain tumors, are reviewed. Moreover, different study tools, including cell lines, in vitro, in vivo, and clinical trial challenges, are discussed. In addition, in this article, natural products as one of the most important sources for finding new chemotherapeutics were reviewed and over 700 reported molecules with efficacy against CNS cancer cells are gathered and classified according to their structure. Based on the clinical trials that have been registered, very few of these natural or semi-synthetic derivatives have been studied in humans. The review can help researchers understand the involved mechanisms and design new goal-oriented studies for drug development against CNS malignancies., (© 2024 Wiley Periodicals LLC.)

Cancer profoundly influences morbidity and fatality rates worldwide. Patients often have dismal prognoses despite recent improvements in cancer therapy regimens. However, potent biomolecules derived from natural sources, including medicinal and dietary plants, contain biological and pharmacological properties to prevent and treat various human malignancies. Capsaicin is a bioactive phytocompound present in red hot chili peppers. Capsaicin has demonstrated many biological effects, including antioxidant, anti-inflammatory, antimicrobial, and anticarcinogenic capabilities. This review highlights the cellular and molecular pathways through which capsaicin exhibits antineoplastic activities. Our work also depicts the synergistic anticancer properties of capsaicin in conjunction with other natural bioactive components and approved anticancer drugs. Capsaicin inhibits proliferation in various cancerous cells, and its antineoplastic actions in numerous in vitro and in vivo carcinoma models impact oncogenesis, tumor-promoting and suppressor genes, and associated signaling pathways. Capsaicin alone or combined with other phytocompounds or approved antineoplastic drugs triggers cell cycle progression arrest, generating reactive oxygen species and disrupting mitochondrial membrane integrity, ultimately stimulating caspases and promoting death. Furthermore, capsaicin alone or in combination can promote apoptosis in carcinoma cells by enhancing the p53 and c-Myc gene expressions. In conclusion, capsaicin alone or in combination can have enormous potential for cancer prevention and intervention, but further high-quality studies are needed to firmly establish the clinical efficacy of this phytocompound., (© 2024 John Wiley & Sons Ltd.)

Recently, various studies have been devoted to the study of transient receptor potential vanilloid member 1 (TRPV1)-related diseases, potential drugs, and related mechanisms. The objective of this investigation was to examine the significant areas and cutting-edge developments in TRPV1 study within recent decades. Articles or reviews were obtained from the Web of Science Core Collection. VOSviewer 1.6.18 and CiteSpace 6.1 R2 software were utilized to examine publication growth, distribution by country/region, institution, journal, authorship, references, and keywords. The software identified keywords with a high citation burstiness to determine emerging topics. From 1990 to 2023, the annual global publications increased by 62,000%, from 1 to 621. Journal of neuroscience published the most manuscripts and Nature produced the highest citations. The USA, Seoul National University and Di marzo V were the most productive and impactful institution, country, and author, respectively. "TRPV1," "Capsaicin receptor," "Activation," and "Pain" are the most important keywords. The burst keywords "TRPV1 channel," "Oxidative stress," "TRPV1 structure," and "Cancer" are supposed to be the research frontiers. The present study offers valuable insights into the understanding of TRPV1 and pain-related conditions. The research on TRPV1 has demonstrated a steady increase in studies related to pain-related diseases in the past few decades. The significance of TRPV1 in cancer pathogenesis and the resolution of its structure will emerge as a new academic trend in this field, providing direction for more widespread and comprehensive studies in the future., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Inactivation of the most important tumour suppressor gene TP53 occurs in most, if not all, human cancers. Loss of functional wild-type p53 is achieved via two main mechanisms: mutation of the gene leading to an absence of tumour suppressor activity and, in some cases, gain-of-oncogenic function; or inhibition of the wild-type p53 protein mediated by overexpression of its negative regulators MDM2 and MDMX. Because of its high potency as a tumour suppressor and the dependence of at least some established tumours on its inactivation, p53 appears to be a highly attractive target for the development of new anticancer drugs. However, p53 is a transcription factor and therefore has long been considered undruggable. Nevertheless, several innovative strategies have been pursued for targeting dysfunctional p53 for cancer treatment. In mutant p53-expressing tumours, the predominant strategy is to restore tumour suppressor function with compounds acting either in a generic manner or otherwise selective for one or a few specific p53 mutations. In addition, approaches to deplete mutant p53 or to target vulnerabilities created by mutant p53 expression are currently under development. In wild-type p53 tumours, the major approach is to protect p53 from the actions of MDM2 and MDMX by targeting these negative regulators with inhibitors. Although the results of at least some clinical trials of MDM2 inhibitors and mutant p53-restoring compounds are promising, none of the agents has yet been approved by the FDA. Alternative strategies, based on a better understanding of p53 biology, the mechanisms of action of compounds and treatment regimens as well as the development of new technologies are gaining interest, such as proteolysis-targeting chimeras for MDM2 degradation. Other approaches are taking advantage of the progress made in immune-based therapies for cancer. In this Review, we present these ongoing clinical trials and emerging approaches to re-evaluate the current state of knowledge of p53-based therapies for cancer., (© 2024. Springer Nature Limited.)

The oncogenic BRAFV600E kinase leads to abnormal activation of the MAPK signaling pathway and thus, uncontrolled cellular proliferation and cancer development. Based on our previous virtual screening studies which issued 2-acetamido-1,3 benzothiazole-6-carboxamide scaffold as active pharmacophore displaying selectivity against the mutated BRAF, eleven new substituted benzothiazole derivatives were designed and synthesized by coupling of 2-acetamidobenzo[d]thiazole-6-carboxylic acid with the appropriate amines in an effort to provide even more efficient inhibitors and tackle drug resistance often developed during cancer treatment. All derived compounds bore the benzothiazole scaffold substituted at position-2 by an acetamido moiety and at position-6 by a carboxamide functionality, the NH moiety of which was further linked through an alkylene linker to a sulfonamido (or amino) aryl (or alkyl) functionality or a phenylene linker to a sulfonamido aromatic (or non-aromatic) terminal pharmacophore in the order -C 6 H 4 -NHSO 2 -R or reversely -C 6 H 4 -SO 2 N(H)-R. These analogs were subsequently biologically evaluated as potential BRAFV600E inhibitors and antiproliferative agents in several colorectal cancer and melanoma cell lines. In all assays applied, one analog, namely 2-acetamido-N-[3-(pyridin-2-ylamino)propyl]benzo[d]thiazole-6-carboxamide (22), provided promising results in view of its use in drug development., (© 2023 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

First-in-human (FIH) dose-escalation trials on oncology should prioritize safety and emphasize efficacy. We reviewed the FIH trials of 67 anti-tumor products approved by the Food and Drug Administration between 2018 and 2023 and found that the "3 + 3" design remains the predominant dose-escalation method (66.2%). The number of patients receiving sub-therapeutic doses is positively correlated with the maximum tolerated dose (MTD) or maximum dose (MD) to starting dose ratio (P = 0.056) and the number of dose levels in trials (P < 0.001). In addition, the proportion of products with a high ratio in antibody drugs is higher than that in small molecules (P < 0.001). The MTD or MD exceeded the label dose by three or more doses in 22.03% of the products. In conclusion, optimizing the starting dose selection method, refining the way of determining doses, and finding alternative indicators to replace toxicity as the endpoints will increase the effectiveness and broaden the beneficiary scope., (© 2024. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

Diabetes and cancer are two prevalent disorders, pose significant public health challenges and contribute substantially to global mortality rates, with solely 10 million reported cancer-related deaths in 2020. This review explores the pathological association between diabetes and diverse cancer progressions, examining molecular mechanisms and potential therapeutic intersections. From altered metabolic landscapes to dysregulated signaling pathways, the intricate links are delineated, offering a comprehensive understanding of diabetes as a modulator of tumorigenesis. Cancer cells develop drug resistance through mechanisms like enhanced drug efflux, genetic mutations, and altered drug metabolism, allowing them to survive despite chemotherapeutic agent. Glucose emerges as a pivotal player in diabetes progression, and serving as a crucial energy source for cancer cells, supporting their biosynthetic needs and adaptation to diverse microenvironments. Glycation, a non-enzymatic process that produces advanced glycation end products (AGEs), has been linked to the etiology of cancer and has been shown in a number of tumor forms, such as leiomyosarcomas, adenocarcinomas, and squamous cell carcinomas. Furthermore, in aggressive and metastatic breast cancer, the receptor for AGEs (RAGE) is increased, which may increase the malignancy of the tumor. Reprogramming glucose metabolism manifests as hallmark cancer features, including accelerated cell proliferation, angiogenesis, metastasis, and evasion of apoptosis. This manuscript encapsulates the dual narrative of diabetes as a driver of cancer progression and the potential of repurposed antidiabetic drugs as formidable countermeasures. The amalgamation of mechanistic understanding and clinical trial outcomes establishes a robust foundation for further translational research and therapeutic advancements in the dynamic intersection of diabetes and cancer., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Optimized dosages provide a secure foundation for the development of well-tolerated and effective oncology drugs. Project Optimus, an initiative within the Oncology Center of Excellence, strives to reform the dosage optimization and dosage selection paradigm in oncology. This initiative stems from the availability of targeted drugs and from the demand for more tolerable dosages from patients, caregivers, and advocates. Reforming dosage optimization for oncology drugs requires a paradigm shift from the one employed for cytotoxic chemotherapy to one that understands and considers the unique attributes of targeted therapy, immunotherapy, and cellular therapy. Limited characterization of dosage during drug development may result in (1) patients not staying on a therapy long-term due to poor tolerability, (2) failure to establish positive benefit-risk in clinical trials for regulatory approval (3) withdrawal of drugs from the market (4) removal of indications of drugs from the market. Timely access to drugs is important for all patients with cancer, so it is vital to iteratively analyze all nonclinical and clinically relevant data at each stage of development and leverage quantitative approaches, innovative trial designs, and regulatory support to arrive at dosages with favorable benefit-risk. This review highlights the key challenges and opportunities to embracing this new paradigm and realizing the full potential of new oncology therapies., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA.)

Chemotherapy is the cornerstone of antineoplastic treatment in patients with malignancies. The cardiotoxic effect of antineoplastic therapy has been known for many decades. Part of chemotherapy-induced cardiotoxicity is the development of heart rhythm disturbances. This short review aims to provide a compact overview for the clinical cardiologist of the dysrhythmic potential created by antineoplastic agents in cancer survivors., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

The US FDA's Project Optimus initiative that emphasizes dose optimization prior to marketing approval represents a pivotal shift in oncology drug development. It has a ripple effect for rethinking what changes may be made to conventional pivotal trial designs to incorporate a dose optimization component. Aligned with this initiative, we propose a novel seamless phase II/III design with dose optimization (SDDO framework). The proposed design starts with dose optimization in a randomized setting, leading to an interim analysis focused on optimal dose selection, trial continuation decisions, and sample size re-estimation (SSR). Based on the decision at interim analysis, patient enrollment continues for both the selected dose arm and control arm, and the significance of treatment effects will be determined at final analysis. The SDDO framework offers increased flexibility and cost-efficiency through sample size adjustment, while stringently controlling the Type I error. This proposed design also facilitates both accelerated approval (AA) and regular approval in a "one-trial" approach. Extensive simulation studies confirm that our design reliably identifies the optimal dosage and makes preferable decisions with a reduced sample size while retaining statistical power., (© 2024 John Wiley & Sons Ltd.)

Nanotechnology is considered a successful approach for cancer diagnosis and treatment. Preferentially, cancer cell recognition and drug targeting via nano-delivery system include the penetration of anticancer agents into the cell membrane to damage the cancer cell by protein modification, DNA oxidation, or mitochondrial dysfunction. The past research on nano-delivery systems and their target has proven the beneficial achievement in a malignant tumor. Modern perceptions using inventive nanomaterials for cancer management have been offered by a multifunctional platform based on various nano-carriers with the probability of imaging and cancer therapy simultaneously. Emerging nano-delivery systems in cancer therapy still lack knowledge of the biological functions behind the interaction between nanoparticles and cancer cells. Since the potential of engineered nanoparticles addresses the various challenges, limiting the success of cancer therapy subsequently, it is a must to review the molecular targeting of a nano-delivery system to enhance the therapeutic efficacy of cancer. This review focuses on using a nano-delivery system, an imaging system, and encapsulated nanoparticles for cancer therapy., (© 2024 International Union of Biochemistry and Molecular Biology.)

Resistance to chemotherapy and targeted therapies constitute a common hallmark of most cancers and represent a dominant factor fostering tumor relapse and metastasis. Fibronectin, an abundant extracellular matrix glycoprotein, has long been proposed to play an important role in the pathobiology of cancer. Recent research has unraveled the role of Fibronectin in the onset of chemoresistance against a variety of antineoplastic drugs including DNA-damaging agents, hormone receptor antagonists, tyrosine kinase inhibitors, microtubule destabilizing agents, etc. The current review summarizes the role played by Fibronectin in mediating drug resistance against diverse anticancer drugs. We have also discussed how the aberrant expression of Fibronectin drives the oncogenic signaling pathways ultimately leading to drug resistance through the inhibition of apoptosis, promotion of cancer cell growth and proliferation., (© 2023 Wiley Periodicals LLC.)

The tumor biology of human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) promotes the development of central nervous system (CNS) metastases, with 25% of patients with HER2-positive BC developing CNS metastases. Furthermore, the incidence of HER2-positive BC brain metastases has increased in the last decades, likely because of the improved survival with targeted therapies and better detection methods. Brain metastases are detrimental to quality of life and survival and represent a challenging clinical problem, particularly in elderly women, who comprise a substantial proportion of patients diagnosed with BC and often have comorbidities or an age-related decline in organ function. Treatment options for patients with BC brain metastases include surgical resection, whole-brain radiation therapy, stereotactic radiosurgery, chemotherapy, and targeted agents. Ideally, local and systemic treatment decisions should be made by a multidisciplinary team, with input from several specialties, based on an individualized prognostic classification. In elderly patients with BC, additional age-associated conditions, such as geriatric syndromes or comorbidities, and the physiologic changes associated with aging, may impact their ability to tolerate cancer therapy and should be considered in the treatment decision-making process. This review describes the treatment options for elderly patients with HER2-positive BC and brain metastases, focusing on the importance of multidisciplinary management, the different points of view from the distinct disciplines, and the role of oncogeriatric and palliative care in this vulnerable patient group., (© 2023. The Author(s), under exclusive licence to Springer Healthcare Ltd., part of Springer Nature.)

Purpose: Chemotherapy induced peripheral neuropathy (CIPN) is a debilitating condition that is a direct consequence of receiving cancer treatment. The molecular aetiology of CIPN is not well understood, and it is theorised that there may be a genetic component. Genetic polymorphisms in Glutathione-S Transferase (GST) genes, including GSTT1, GSTM1 and GSTP1, encode for enzymes known to metabolise drugs used in chemotherapy, and have been theorised to be associated with CIPN. This study aimed to investigate four markers in these genes for an association in a mixed cancer cohort in relation to CIPN (n = 172)., Methods: CIPN was measured using the neuropathy item from the Patient Reported Outcome Common Terminology Criteria for Adverse Event (PRO-CTCAE) assessment. Genotyping for all samples was performed using PCR for the GSTM1 and GSTT1 null variants and restriction fragment length polymorphisms for the GSTP1 and GSTM1 polymorphisms., Results: No associations were found for the GST gene markers in relation to CIPN within our study, or CIPN severity. Longitudinal stratification of the CIPN phenotypes to examine links for neuropathy, identified nominally significant protective associations with the GSTM* null allele (p-value = 0.038, OR = 0.55) and the presence of pain at month 2 of treatment, as well as a risk factor for pain related month 2 of treatment for individuals with the GSTT1*null allele (p-value = 0.030, OR = 1.64). Higher severity of pain in patients with CIPN persisted at each time-point compared to those without CIPN., Conclusion: No significant results for an association between CIPN with polymorphisms in GSTM1, GSTT1 and GSTP1 were identified. However, associations for the GSTM1¬-null and GSTT1-null polymorphisms with pain at month 2 following chemotherapy were identified., (© 2023. The Author(s).)

Paper incorporated with ZnO nanostructures (called ZnO paper) is a flexible substrate material with applications in many areas including UV detectors and gas sensors. In this work, we tested the cytotoxicity of ZnO paper against cancer cells. The ZnO paper was placed in culture media of different cancer cell lines including A549, H1299, and WI38 with and without the targeted anti-lung cancer drugs Iressa and Staurosporine, and cell viability was determined. We found that ZnO nanoparticles were cytotoxic to all the cell lines examined, and cell viability was further reduced by increasing the deposition time of these nanoparticles. In addition, cytotoxicity was enhanced when both the ZnO paper and the anticancer drugs were present in the culture media. Our experimental results indicate that ZnO paper can be used for cytotoxicity test and the development of future novel anticancer drugs. [ABSTRACT FROM AUTHOR]

Purpose: Adherence to oral anticancer treatments (OATs) is a critical issue in metastatic breast cancer (MBC) to enhance survivorship and quality of life. The study is aimed to analyze the main themes and attributes related to OATs in MBC patients. This research is part of a project titled "Enhancing Therapy Adherence Among Metastatic Breast Cancer Patients" designed to produce a predictive model of non-adherence, a decision support system, and guidelines to improve adherence to OATs., Methods: The study consists of an exploratory observational and qualitative analysis using a focus group method. A semi-structured interview guide was developed to handle relevant OAT themes. Wordcloud plots, network analysis, and sentiment analysis were performed., Results: Nineteen female MBC patients participated in the protocol (age mean 55.95, SD = 6.87). Four main themes emerged: (theme 1) individual clinical pathway; (theme 2) barriers to adherence; (theme 3) resources to adherence; (theme 4) patients' perception of new technologies. The Wordcloud and network analysis highlighted the important role of treatment side effects and the relationship with the clinician in the modulation of adherence behavior. This result is consistent with the sentiment analysis underscoring patients experience fear of issues related to clinical values and ineffective communication and discontinuity of the doctor in charge of the patient care., Conclusion: The study highlighted the key role of the individual, relational variables, and side effects as internal and external determinants influencing adherence to MBC. Finally, the opportunity offered by eHealth technology to connect with other patients with similar conditions and share experiences could be a relief for MBC patients., (© 2024. The Author(s).)

Purpose: This study describes chemotherapy-induced nausea and vomiting (CINV) control rates in pediatric and adult patients who did or did not receive guideline-consistent CINV prophylaxis., Methods: We conducted a systematic literature review of studies published in 2000 or later that evaluated CINV control in patients receiving guideline-consistent vs. guideline-inconsistent CINV prophylaxis and reported at least one CINV-related patient outcome. Studies were excluded if the guideline evaluated was not publicly available or not developed by a professional organization. Over-prophylaxis was defined as antiemetic use recommended for a higher level of chemotherapy emetogenicity than a patient was receiving., Results: We identified 7060 citations and retrieved 141 publications for full-text evaluation. Of these, 21 publications (14 prospective and seven retrospective studies) evaluating guidelines developed by six organizations were included. The terms used to describe CINV endpoints and definition of guideline-consistent CINV prophylaxis varied among studies. Included studies either did not address over-prophylaxis in their definition of guideline-consistent CINV prophylaxis (48%; 10/21) or defined it as guideline-inconsistent (38%; 8/21) or guideline-consistent (3/21; 14%). Eleven included studies (52%; 11/21) reported a clinically meaningful improvement in at least one CINV endpoint in patients receiving guideline-consistent CINV prophylaxis. Ten reported a statistically significant improvement., Conclusions: This evidence supports the use of guideline-consistent prophylaxis to optimize CINV control. Institutions caring for patients with cancer should systematically adapt CINV CPGs for local implementation and routinely evaluate CINV outcomes., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

We report herein, the design and synthesis of benzimidazole-oxadiazole derivatives as new inhibitors for vascular endothelial growth factor receptor-2 (VEGFR-2). The designed members were assessed for their in vitro anticancer activity against three cancer cell lines and two normal cell lines; A549, MCF-7, PANC-1, hTERT-HPNE and CCD-19Lu. Compounds 4c and 4d were found to be the most effective compounds against three cancer cell lines. Compounds 4c and 4d were then tested for their in vitro VEGFR-2 inhibitory activity, safety profiles, and selectivity indices using the normal hTERT-HPNE and CCD-19Lu cell lines. It was determined that compound 4c was the most effective and safe member of the produced chemical family. Vascular endothelial growth factor A (VEGFA) immunolocalizations of compounds 4c and 4d were evaluated relative to control by VEGFA immunofluorescence staining. Compounds 4c and 4d inhibited VEGFR-2 enzyme with half-maximal inhibitory concentration values of 0.475 ± 0.021 and 0.618 ± 0.028 µM, respectively. Molecular docking of the target compounds was carried out in the active site of VEGFR-2 (Protein Data Bank: 4ASD)., (© 2024 The Author(s). Drug Development Research published by Wiley Periodicals LLC.)

The liver is one of the most important organs in the human body. It performs many important functions, including being responsible for the metabolism of most drugs, which is often associated with its drug-induced damage. Currently, there are no ideal pharmacological models that would allow the evaluation of the effect of newly tested drugs on the liver in preclinical studies. Moreover, the influence of hepatic metabolism on the effectiveness of the tested drugs is rarely evaluated. Therefore, in this work we present an advanced model of the liver, which reflects most of the morphologically and metabolically important features of the liver in vivo, namely: three-dimensionality, cellular composition, presence of extracellular matrix, distribution of individual cell types in the structure of the liver model, high urea and albumin synthesis efficiency, high cytochrome p450 activity. In addition, the work, based on the example of commonly used anticancer drugs, shows how important it is to take into account hepatic metabolism in the effective assessment of their impact on the target organ, in this case cancer. In our research, we have shown that the most similar to liver in vivo are 3D cellular aggregates composed of three important liver cells, namely hepatocytes (HepG2), hepatic stellate cells (HSCs), and hepatic sinusoidal endothelial cells (HSECs). Moreover, we showed that the cells in 3D aggregate structure need time (cell-cell interactions) to improve proper liver characteristic. The triculture model additionally showed the greatest ability to metabolize selected anticancer drugs., (© 2024 Wiley‐VCH GmbH.)

Background: Chemotherapy is a common treatment for cancer, but it is associated with adverse drug reactions like oral mucositis. This condition destroys basal cells in the oral mucosal layer, causing inflammation and ulceration. This can impact the patient's physical, emotional, and psychological well-being, affecting treatment outcomes and quality of life. This study aims to determine the prevalence, severity, and risk factors of chemotherapy-induced oral mucositis among adult cancer patients., Methods: The study was a cross-sectional study conducted among adult cancer patients receiving chemotherapy at the cancer unit of Mbarara Regional Referral Hospital in southwestern Uganda. Data was collected through patient interviews, oral examinations, and patient chart reviews., Results: Out of 268 patients, 115 (42.9%) experienced oral mucositis. Grade 2 oral mucositis was the most common (44.3%) followed by grade 1 (35.7%) and grade 3 (20.0%). Independent risk factors of chemotherapy-induced oral mucositis were female gender (Adjusted Odds Ratio (AOR) = 2.19, 95% confidence interval [CI]: 1.27-3.78; p-value = 0.005), poor oral hygiene (AOR = 3.70, 95% CI: 1.51-9.10; p-value = 0.04), and receiving chemotherapy containing an alkylating agent (AOR = 3.17, 95% CI: 1.63-6.19; p-value < 0.001)., Conclusion: The study found that two out of five chemotherapy patients developed oral mucositis, with nearly half being grade 2. The risk factors identified in our study were comparable to those reported in previous studies. Therefore, identification and assessment of cancer patients at high risk for chemotherapy-induced oral mucositis should be routinely done for proper and timely management., (© 2023 John Wiley & Sons Australia, Ltd.)

Cervical cancer (CC) is the fourth most common malignancy in female patients. "Human papillomavirus" (HPV) contamination is a leading cause of all forms of cervical cancer, accounting for an expected 570,000 reported incidents in 2018. Two HPV strains (16 and 18) are responsible for 70% of CC and pre-cancerous cervical abnormalities. CC is one of the foremost reasons for the malignancy death rate in India among women ranging from 30 to 69 years of age in India, responsible for 17% of all cancer deaths. Currently approved cervical cancer treatments are associated with adverse reactions that might harm the lives of women affected by this disease. Consequently, probiotics can play a vital role in the treatment of CC. It is reflected from various studies regarding the role of probiotics in the diagnosis, prevention or treatment of cancer. In this review article, we have discussed the rationale of probiotics for treatment of CC, the role of probiotics as effective adjuvants in anti-cancer therapy and the combined effect of the anti-cancer drug along with probiotics to minimize the side effects due to chemotherapy., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: The objective of this systematic review was to determine whether oral and dental hygiene protocols (DHPs) reduce the incidence and severity of oral mucositis (OM) during antineoplastic treatment., Materials and Methods: This PROSPERO-registered systematic review (CRD42021295322) was based on searches of publicly accessible databases, including PubMed, Scopus, Web of Science, LILACS, EBSCOhost, LIVIVO, Embase, and gray literature (Google Scholar, ProQuest, and Energy) until December 2021. Twenty-five articles from these searches and 14 articles retrieved from the references therein were evaluated in this systematic review and meta-analysis. The risk of bias (RoB) was assessed using RoB-2 and ROBINS-I for randomized (RCT) and non-randomized (n-RCT) clinical trials, respectively. A meta-analysis was performed on RCTs and n-RCTs in two subgroups to evaluate oral mouth rinses or DHP. GRADE-pro was used to assess the degree of certainty of the evidence., Results: Of the 3367 articles retrieved, 25 RCTs and 14 n-RCTs involving 2109 and 754 patients, respectively, were included in the analyses. RoB was low for RCTs and moderate-to-very severe for n-RCTs. High heterogeneity and publication RoB were identified. In RCTs, mouth rinses (p = 0.830) and DHP (p = 0.100) did not reduce the incidence of OM. However, mouth rinses strongly reduced the severity of OM (p < 0.001; Cohen's d =  - 1.87, 95% confidence interval [CI] =  - 2.49 to - 1.24). In non-RCTs, mouth rinses (p < 0.001) and DHP (p < 0.001) reduced the relative risk of OM 0.38 (95% CI = 0.24 to 0.59) and 0.64 (95% CI = 0.53 to 0.70) times, respectively. In addition, DHP strongly reduced OM severity (Cohen's d =  - 0.81, 95% CI =  - 1.03 to - 0.59). GRADE-pro showed high certainty of OM severity and incidence in RCTs and non-RCTs, respectively, and low (OM incidence in RCTs) to very low (OM severity in non-RCTs) certainty in other outcomes., Conclusion: DHPs strongly reduce the severity and moderately reduce the incidence of OM. However, further studies with low heterogeneity are needed to validate these findings., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Synthesis of molecular hybrids, obtained by combination of two or more pharmacophoric groups of different bioactive substances in order to produce more efficient drugs, is now a frequently used approach in medicinal chemistry. Following this strategy, we synthetized a library of 3-methylidene-1-tosyl-2,3-dihydro-1,8-naphthyridin-4(1H)-ones, combining a 1,8-naphthyridin-4-one motif with an exo-methylidene bond conjugated with a carbonyl group, pharmacophoric units that are present in many natural, biologically active compounds with anticancer potential. We reasoned that such bifunctional conjugates may have enhanced cytotoxic activity. The title compounds were synthesized in a four step reaction sequence. β-Ketophosphonate, obtained from methyl N-tosylnicotinate and diethyl methylphosphonate, was reacted with various aldehydes giving 3-diethoxyphosphoryl-2,3-dihydro-1,8-naphthyridin-4(1H)-ones as keto-enol tautomers. Later, these compounds were transformed into 3-methylidene-1-tosyl-2,3-dihydro-1,8-naphthyridin-4(1H)-ones applying the Horner-Wadsworth-Emmons methodology. Then, the cytotoxicity of the new compounds was assessed on two cancer cell lines, promyelocytic leukemia HL-60 and breast cancer adenocarcinoma MCF-7, and for comparison, on human umbilical vein endothelial cells HUVEC. The most active and selective analog, 2-ethyl-3-methylidene-1-tosyl-2,3-dihydro-1,8-naphthyridin-4(1H)-one 4 a was chosen for more detailed studies on HL-60 cell line, to determine molecular mechanisms of its anticancer activity. It was shown that 4 a strongly inhibited proliferation and induced apoptosis which could be attributed to its ability to cause DNA damage., (© 2023 Wiley‐VCH GmbH.)

Immuno-oncology (IO) therapies have changed the cancer treatment landscape. Immune checkpoint inhibitors (ICIs) have improved overall survival in 20-40% of patients with malignancies that were previously refractory. Due to the uniqueness in biology, modalities and patient responses, drug development strategies for IO differed from that traditionally used for cytotoxic and target therapies in oncology, and quantitative pharmacology utilizing modeling approach can be applied in all phases of the development process. In this review, we used case studies to showcase how various modeling methodologies were applied from translational science and dose selection through to label change, using examples that included anti-programmed-death-1 (anti-PD-1), anti-programmed-death ligand-1 (anti-PD-L1), anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4), and anti-glucocorticoid-induced tumor necrosis factor receptor-related protein (anti-GITR) antibodies. How these approaches were utilized to support phase I-III dose selection, the design of phase III trials, and regulatory decisions on label change are discussed to illustrate development strategies. Model-based quantitative approaches have positively impacted IO drug development, and a better understanding of the biology and exposure-response relationship may benefit the development and optimization of new IO therapies., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: Early diagnosis of chemotherapy-induced cardiotoxicity plays an important role in preventing heart failure. The main aim of our study was to assess left ventricular (LV) dyssynchrony measured by phase analysis of gated single-photon emission computed tomography (SPECT) as an early sign of cardiotoxicity after breast cancer chemotherapy., Methods: This cross-sectional study was conducted on patients with stage ≤ 3 breast cancer and no history of cardiovascular disease or diabetes. After mastectomy, the patients underwent rest gated SPECT myocardial perfusion imaging (MPI). Sixty patients with normal gated SPECT-MPI were selected and the imaging was performed after chemotherapy with doxorubicin, cyclophosphamide and paclitaxel. LV function and contractility parameters were extracted by QGS software and the results were compared with the t test method. The abnormality of at least one of the three phase analysis indices was considered as left ventricular dyssynchrony (LVD)., Results: The average LV end-systolic volume and ejection fraction (LVEF) before and after chemotherapy were (16.2 ± 8.0 ml and 21.6 ± 11.6 ml) and (73.4 ± 7.9% and 67.5 ± 9.2%) respectively, which showed a significant decrease (P < 0.05). In 2 patients (3.3%), the LVEF decreased to less than 50% after chemotherapy. The average parameters of left ventricular contractility before and after chemotherapy were, respectively, as follows: PHB (24.1 ± 7.5 and 33.8 ± 16.4), PSD (9.4 ± 6.1 and 5.7 ± 1.9) and entropy (28.9 ± 7.1 and 35.6 ± 9.7), which showed a significant increase (P < 0.05). LVD was observed in 14 patients (23.4%) after chemotherapy and prevalence of LVD was significantly higher in patients who had received a cumulative dose of doxorubicin of more than 400 mg/m 2 (P = 0.005). There was no relationship between age and body mass index with the incidence of LVD after chemotherapy (P > 0.05)., Conclusion: Using phase analysis of gated SPECT-MPI, chemotherapy-induced LVD was seen in a significant number of patients with breast cancer, especially with a high cumulative dose of doxorubicin. LVD might indicate chemotherapy-induced cardiotoxicity before LVEF becomes abnormal., (© 2024. The Author(s) under exclusive licence to The Japanese Society of Nuclear Medicine.)

Objectives: MRI-derived extracellular volume (ECV) allows characterization of myocardial changes before the onset of overt pathology, which may be caused by cancer therapy cardiotoxicity. Our purpose was to review studies exploring the role of MRI-derived ECV as an early cardiotoxicity biomarker to guide timely intervention., Materials and Methods: In April 2022, we performed a systematic search on EMBASE and PubMed for articles on MRI-derived ECV as a biomarker of cancer therapy cardiotoxicity. Two blinded researchers screened the retrieved articles, including those reporting ECV values at least 3 months from cardiotoxic treatment. Data extraction was performed for each article, including clinical and technical data, and ECV values. Pooled ECV was calculated using the random effects model and compared among different treatment regimens and among those who did or did not experience overt cardiac dysfunction. Meta-regression analyses were conducted to appraise which clinical or technical variables yielded a significant impact on ECV., Results: Overall, 19 studies were included. Study populations ranged from 9 to 236 patients, for a total of 1123 individuals, with an average age ranging from 12.5 to 74 years. Most studies included patients with breast or esophageal cancer, treated with anthracyclines and chest radiotherapy. Pooled ECV was 28.44% (95% confidence interval, CI, 26.85-30.03%) among subjects who had undergone cardiotoxic cancer therapy, versus 25.23% (95%CI 23.31-27.14%) among those who had not (p = .003)., Conclusion: A higher ECV in patients who underwent cardiotoxic treatment could imply subclinical changes in the myocardium, present even before overt cardiac pathology is detectable., Clinical Relevance Statement: The ability to detect subclinical changes in the myocardium displayed by ECV suggests its use as an early biomarker of cancer therapy-related cardiotoxicity., Key Points: • Cardiotoxicity is a common adverse effect of cancer therapy; therefore, its prompt detection could improve patient outcomes. • Pooled MRI-derived myocardial extracellular volume was higher in patients who underwent cardiotoxic cancer therapy than in those who did not (28.44% versus 25.23%, p = .003). • MRI-derived myocardial extracellular volume represents a potential early biomarker of cancer therapy cardiotoxicity., (© 2023. The Author(s).)

Four piroxicam metal complexes; NiL 2 , PtL 2 , PdL 2 , and AgL were synthesized and characterized by different techniques with enhanced antibacterial and anticancer activity. Regarding in vitro antimicrobial activity, complex NiL 2 displayed potent antibacterial effect against Escherichia coli and Pseudomonas aeruginosa that was 1.9-folds higher than piroxicam (minimum inhibitory concentration [MIC] = 31.85, 65.32 µM), respectively. In case of G+ve bacteria, complex PtL 2 had potent activity on Staphylococcus aureus which was 2.1-folds higher than piroxicam (MIC = 43.12 µM), while activity of complex AgL against Enterococcus faecalis was threefolds higher than piroxicam (MIC = 74.57 µM. Complexes PtL 2 and PdL 2 exhibited higher inhibition of DNA gyrase than piroxicam (IC 50  = 6.21 µM) in the range of 1.9-1.7-folds. The in vitro antiproliferative activity depicted that all investigated complexes showed better cytotoxic effect than piroxicam, specifically Pt and Pd complexes which had lower IC 50 values than piroxicam on human liver cancer cell line HepG2 by 1.8 and 1.7-folds, respectively. While Pd and Ag complexes showed 2 and 1.6-folds better effect on human colon cancer cell line HT-29 compared with piroxicam. Molecular modeling studies including docking on Stranded DNA Duplex (1juu) and DNA gyrase enzyme (1kzn) that gave good insight about interaction of complexes with target molecules, calculation of electrostatic potential map and global reactivity descriptors were performed., (© 2024 Wiley Periodicals LLC.)

Darolutamide is an oral nonsteroidal androgen receptor antagonist used to delay the process of prostate cancer to metastatic disease and to increase the quality of life for people with advanced prostate cancer. Here, a second spectrofluorimetric method was advanced for quantifying Darolutamide in pharmaceutical formulation and spiked human plasma. This method depends on the fluorescence derivatization of Darolutamide with 4-chloro-7-nitrobenzo-2-oxa-1,3-diazole (NBD-Cl) at 75°C in a (pH 9) of borate buffer to produce a fluorescent derivative that can be detected at 520 nm after excitation at 460 nm. The method has been validated using ICH criteria, and it demonstrated linearity in the range 5-200 ng ml -1 . The limit of detection (LOD) and limit of quantitation (LOQ) were 1.15 and 3.84 nm, respectively. The proposed method was applied precisely and accurately for quantifying Darolutamide within the pharmaceutical formulation and spiking human plasma without any interferences. Moreover, the method's sustainability was evaluated and compared with the published method using two greenness assessment tools termed analytical eco-scale and Analytical GREEnness (AGREE). These findings suggest that the method is more sustainable than the published method., (© 2024 John Wiley & Sons Ltd.)

Background: The 2022 ESC Guidelines on Cardio-Oncology recommend baseline cardiovascular risk stratification before starting anticancer drugs, using the new risk assessment tools proposed by the Heart Failure Association (HFA) and the International Cardio-Oncology Society (ICOS).Our study aimed to assess the clinical application of HFA/ICOS risk score in breast cancer patients undergoing chemotherapy and its usefulness in predicting the development of chemotherapy-related cardiac dysfunction (CTRCD)., Methods: A prospective multicentric study enrolled 109 breast cancer patients treated with anthracyclines with or without trastuzumab. A cardiological evaluation, including ECG and echocardiogram at baseline (T0), 3 (T1), 6 (T2), and 12 months (T3) after starting treatment was performed. HFA/ICOS score was assessed in all patients. The population was divided into low, medium, high, and very-high risk.During follow-up, CTRCD and other cardiovascular events have been evaluated., Results: 61 patients were low risk, 37 medium, 9 high, 2 very-high risk criteria. We found a significantly higher incidence of overall cardiotoxicity (CTRCD and other cardiovascular events) in the very-high risk group (100%) compared with the medium (29%) and low risk groups (13%). CTRCD incidence was also significantly higher in the high risk group (55%). CTRCD resulted as being associated with baseline arterial hypertension and baseline HFA/ICOS risk score of high ( p  = 0.006) or very-high ( p  < 0.0001)., Conclusion: Our study confirms the HFA/ICOS score's ability to predict cardiovascular toxicity in breast cancer women and the need for close monitoring especially in high and very-high risk patients., (Copyright © 2024 Italian Federation of Cardiology - I.F.C. All rights reserved.)

This study aimed to investigate the characterization of zinc oxide nanoparticles (ZnONPs) produced from Cucurbita pepo L. (pumpkin seeds) and their selective cytotoxic effectiveness on human colon cancer cells (HCT 116) and African Green Monkey Kidney, Vero cells. The study also investigated the antioxidant activity of ZnONPs. The study also examined ZnONPs' antioxidant properties. This was motivated by the limited research on the comparative cytotoxic effects of ZnO NPs on normal and HCT116 cells. The ZnO NPs were characterized using Fourier-transform infrared spectroscopy (FTIR), Thermogravimetric Analysis (TGA), Transmission Electron Microscope/Selected Area Electron Diffraction (TEM/SAED), and Scanning Electron Microscope-Energy Dispersive X-ray (SEM-EDX) for determination of chemical fingerprinting, heat stability, size, and morphology of the elements, respectively. Based on the results, ZnO NPs from pumpkins were found to be less than 5 μm and agglomerates in nature. Furthermore, the ZnO NPs fingerprinting and SEM-EDX element analysis were similar to previous literature, suggesting the sample was proven as ZnO NPs. The ZnO NPs also stable at a temperature of 380°C indicating that the green material is quite robust at 60-400°C. The cell viability of Vero cells and HCT 116 cell line were measured at two different time points (24 and 48 h) to assess the cytotoxicity effects of ZnO NP on these cells using AlamarBlue assay. Cytotoxic results have shown that ZnO NPs did not inhibit Vero cells but were slightly toxic to cancer cells, with a dose-response curve IC50 = ~409.7 μg/mL. This green synthesis of ZnO NPs was found to be non-toxic to normal cells but has a slight cytotoxicity effect on HCT 116 cells. A theoretical study used molecular docking to investigate nanoparticle interaction with cyclin-dependent kinase 2 (CDK2), exploring its mechanism in inhibiting CDK2's role in cancer. Further study should be carried out to determine suitable concentrations for cytotoxicity studies. Additionally, DPPH has a significant antioxidant capacity, with an IC50 of 142.857 μg/mL. RESEARCH HIGHLIGHTS: Pumpkin seed extracts facilitated a rapid, high-yielding, and environmentally friendly synthesis of ZnO nanoparticles. Spectrophotometric analysis was used to investigate the optical properties, scalability, size, shape, dispersity, and stability of ZnO NPs. The cytotoxicity of ZnO NPs on Vero and HCT 116 cells was assessed, showing no inhibition of Vero cells and cytotoxicity of cancer cells. The DPPH assay was also used to investigate the antioxidant potential of biogenic nanoparticles. A molecular docking study was performed to investigate the interaction of ZnO NPs with CDK2 and to explore the mechanism by which they inhibit CDK2's role in cancer., (© 2023 Wiley Periodicals LLC.)

Background: Drug hypersensitivity reactions (DHRs) to platinum-based drugs are heterogenous and restrict their access, and drug desensitization (DD) has provided a ground-breaking procedure for their re-introduction, although the response is heterogeneous. We aimed to identify the phenotypes, endotypes, and biomarkers of reactions to carboplatin and oxaliplatin and their response to DD., Methods: Seventy-nine patients presenting with DHRs to oxaliplatin (N = 46) and carboplatin (N = 33) were evaluated at the Allergy Departments of two tertiary care hospitals in Spain. Patient symptoms, skin testing, biomarkers, and outcomes of 267 DDs were retrospectively analyzed., Results: Oxaliplatin-reactive patients presented with type I (74%), cytokine release reaction (CRR) (11%), and mixed (Mx) (15%) phenotypes. In contrast, carboplatin reactive patients presented with predominantly type I (85%) and Mx (15%) but no CRRs. Out of 267 DDs, breakthrough reactions (BTRs) to oxaliplatin occurred twice as frequently as carboplatin (32% vs. 15%; p < .05). Phenotype switching from type I to another phenotype was observed in 46% of oxaliplatin DDs compared to 21% of carboplatin DDs. Tryptase was elevated in type I and Mx reactions, and IL-6 in CRR and Mx, indicating different mechanisms and endotypes., Conclusion: Carboplatin and oxaliplatin induced three different types of reactions with defined phenotypes and endotypes amendable to DD. Although most of the initial reactions for both were type I, oxaliplatin presented with unique CRR reactions. During DD, carboplatin reactive patients presented mostly type I BTR, while oxaliplatin-reactive patients frequently switched from type I to CRR, providing a critical difference and the need for personalized DD protocols., (© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

The spiro[3.3]heptane core, with the non-coplanar exit vectors, was shown to be a saturated benzene bioisostere. This scaffold was incorporated into the anticancer drug sonidegib (instead of the meta-benzene), the anticancer drug vorinostat (instead of the phenyl ring), and the anesthetic drug benzocaine (instead of the para-benzene). The patent-free saturated analogs obtained showed a high potency in the corresponding biological assays., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Background/objectives: High-risk Hodgkin lymphoma (HRHL) in children is curable with combined modality therapy. The Association of Pediatric Hematology-Oncology of Central America (AHOPCA) is a consortium of cancer centers from Central America. In 2004, AHOPCA implemented a guideline with a short course of chemotherapy (mStanfordV), strict diagnostics, and radiation guidelines, aimed at reducing abandonment and improving outcomes., Methods: Newly diagnosed children less than 18 years of age with high-risk HL (Ann Arbor stages: IIB, IIIB, IV) from AHOPCA centers were staged with chest radiography and ultrasound or computed tomography. Therapy was a modified Stanford V (mStanfordV), substituting cyclophosphamide for mechlorethamine and involved field radiation., Results: Of 219 patients with HRHL, 181 patients were eligible and evaluable; 146 (81%) were boys, 22% being less than 6 years; 43 were stage IIB, 84 IIIB, and 54 IV. Thirty-one (17%) abandoned therapy, 28 (15%) progressed, 30 (17%) relapsed, and eight (4%) died of toxicity. Radiation guidelines were not followed. Five-year abandonment-sensitive event-free survival and overall survival (AS-EFS, AS-OS ± SE) for the cohort were 46% ± 4% and 56% ± 4%; 5-year AS-OS for stages IIB, IIIB, and IV was 76% ± 7%, 59% ± 7%, and 35% ± 7% (p = .0006)., Conclusion: Despite instituting a short treatment guideline, it did not improve the abandonment rate (17%) and did not achieve the reported outcomes of Stanford V. The cyclophosphamide dose used to replace merchlorethamine was inadequate. Despite strict guidelines, the radiation therapy application was inaccurate. Weekly chemotherapy may have adversely affected abandonment of therapy by increasing the burden of travel time. Based on these results, AHOPCA established a new abandonment strategy and a new guideline., (© 2023 Wiley Periodicals LLC.)

First-in-class (FIC) designation became a hallmark of innovation, however, even at the marketing authorization stage, little is known about the clinical benefits these products deliver. We identified the provenance of the FIC drugs that entered the French market from 2008 to 2018 and matched these medicines to the clinical benefit grading by Haute Autorité de Santé (HAS) and Prescrire. Analyses were performed using descriptive statistics to present our findings by drug origin and therapeutic area and to establish the degree of concordance between HAS and Prescrire. Of the 135 FIC drugs identified, 71.1% (n = 96) originated from the industry, 16.3% (n = 22) from academia, and 12.6% (n = 17) from joint partnerships. Three therapeutic areas accounted for most FIC medications: antineoplastic (25.9%, N = 35), anti-infective (14.1%, N = 19), and metabolic (11.1%, N = 15) agents. HAS and Prescrire agreed on 60.74% of clinical benefit gradings. According to HAS, only 5% of all FIC drugs had substantial added benefit, and only 3%, according to Prescrire. HAS and Prescrire graded 45.9% and 68.2%, respectively, of FIC drugs as no clinical benefit and 48.9% and 28.9%, respectively, as some clinical benefit. FIC-designated drugs are primarily of industry (> 70%) rather than academic origin. We found that 55% of FIC medicines that entered the French market over the 10-year period deliver no additional clinical benefit. Whereas FIC medicines may represent important scientific advancements in drug development, in > 50% of cases, the new mode of action does not translate into additional clinical benefits for patients., (© 2023 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

The study of epigenetic translational modifications had drawn great interest for the last few decades. These processes play a vital role in many diseases and cancer is one of them. Histone acetyltransferase (HAT) and histone deacetylases (HDACs) are key enzymes involved in the acetylation and deacetylation of histones and ultimately in post-translational modifications. Cancer frequently exhibits epigenetic changes, particularly disruption in the expression and activity of HDACs. It includes the capacity to regulate proliferative signalling, circumvent growth inhibitors, escape cell death, enable replicative immortality, promote angiogenesis, stimulate invasion and metastasis, prevent immunological destruction, and genomic instability. The majority of tumours develop and spread as a result of HDAC dysregulation. As a result, HDAC inhibitors (HDACis) were developed, and they today stand as a very promising therapeutic approach. One of the most well-known and efficient therapies for practically all cancer types is chemotherapy. However, the efficiency and safety of treatment are constrained by higher toxicity. The same has been observed with the synthetic HDACi. Natural products, owing to many advantages over synthetic compounds for cancer treatment have always been a choice for therapy. Hence, naturally available molecules are of particular interest for HDAC inhibition and HDAC has drawn the attention of the research fraternity due to their potential to offer a diverse array of chemical structures and bioactive compounds. This diversity opens up new avenues for exploring less toxic HDAC inhibitors to reduce side effects associated with conventional synthetic inhibitors. The review presents comprehensive details on natural product HDACi, their mechanism of action and their biological effects. Moreover, this review provides a brief discussion on the structure activity relationship of selected natural HDAC inhibitors and their analogues which can guide future research to discover selective, more potent HDACi with minimal toxicity., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: Antineoplastic agent-induced systolic dysfunction is a major reason for interruption of anticancer treatment. Although targeted anticancer agents infrequently cause systolic dysfunction, their combinations with chemotherapies remarkably increase the incidence. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provide a potent in vitro model to assess cardiovascular safety. However, quantitatively predicting the reduction of ejection fraction based on hiPSC-CMs is challenging due to the absence of the body's regulatory response to cardiomyocyte injury., Methods: Here, we developed and validated an in vitro-in vivo translational platform to assess the reduction of ejection fraction induced by antineoplastic drugs based on hiPSC-CMs. The translational platform integrates drug exposure, drug-cardiomyocyte interaction, and systemic response. The drug-cardiomyocyte interaction was implemented as a mechanism-based toxicodynamic (TD) model, which was then integrated into a quantitative system pharmacology-physiological-based pharmacokinetics (QSP-PBPK) model to form a complete translational platform. The platform was validated by comparing the model-predicted and clinically observed incidence of doxorubicin and trastuzumab-induced systolic dysfunction., Results: A total of 33,418 virtual patients were incorporated to receive doxorubicin and trastuzumab alone or in combination. For doxorubicin, the QSP-PBPK-TD model successfully captured the overall trend of systolic dysfunction incidences against the cumulative doses. For trastuzumab, the predicted incidence interval was 0.31-2.7% for single-agent treatment and 0.15-10% for trastuzumab-doxorubicin sequential treatment, covering the observations in clinical reports (0.50-1.0% and 1.5-8.3%, respectively)., Conclusions: In conclusion, the in vitro-in vivo translational platform is capable of predicting systolic dysfunction incidence almost merely depend on hiPSC-CMs, which could facilitate optimizing the treatment protocol of antineoplastic agents., (© 2023. The Author(s).)

Tumour-associated macrophages are an essential component of the tumour microenvironment and have a role in the orchestration of angiogenesis, extracellular matrix remodelling, cancer cell proliferation, metastasis and immunosuppression, as well as in resistance to chemotherapeutic agents and checkpoint blockade immunotherapy. Conversely, when appropriately activated, macrophages can mediate phagocytosis of cancer cells and cytotoxic tumour killing, and engage in effective bidirectional interactions with components of the innate and adaptive immune system. Therefore, they have emerged as therapeutic targets in cancer therapy. Macrophage-targeting strategies include inhibitors of cytokines and chemokines involved in the recruitment and polarization of tumour-promoting myeloid cells as well as activators of their antitumorigenic and immunostimulating functions. Early clinical trials suggest that targeting negative regulators (checkpoints) of myeloid cell function indeed has antitumor potential. Finally, given the continuous recruitment of myelomonocytic cells into tumour tissues, macrophages are candidates for cell therapy with the development of chimeric antigen receptor effector cells. Macrophage-centred therapeutic strategies have the potential to complement, and synergize with, currently available tools in the oncology armamentarium., (© 2022. Springer Nature Limited.)

The purification of a protein inhibiting lipid peroxidation led to the discovery of the selenoperoxidase GPx4 forty years ago. Thus, the evidence of the enzymatic activity was reached after identifying the biological effect and unambiguously defined the relationship between the biological function and the enzymatic activity. In the syllogism where GPx4 inhibits lipid peroxidation and its inhibition is lethal, cell death is operated by lipid peroxidation. Based on this rationale, this form of cell death emerged as regulated iron-enforced oxygen toxicity and was named ferroptosis in 2012. In the last decades, we learned that reduction of lipid hydroperoxides is indispensable and, in cooperation with prooxidant systems, controls the critical steady state of lipid peroxidation. This concept defined the GPx4 reaction as both the target for possible anti-cancer therapy and if insufficient, as cause of degenerative diseases. We know the reaction mechanism, but the details of the interaction at the membrane cytosol interface are still poorly defined. We know the gene structure, but the knowledge about expression control is still limited. The same holds true for post-transcriptional modifications. Reverse genetics indicate that GPx4 has a role in inflammation, immunity, and differentiation, but the observations emerging from these studies need a more specifically addressed biochemical evidence. Finally, the role of GPx4 in spermatogenesis disclosed an area unconnected to lipid peroxidation. In its mitochondrial and nuclear form, the peroxidase catalyzes the oxidation of protein thiols in two specific aspects of sperm maturation: stabilization of the mid-piece and chromatin compaction. Thus, although available evidence converges to the notion that GPx4 activity is vital due to the inhibition of lipid peroxidation, it is reasonable to foresee other unknown aspects of the GPx4 reaction to be disclosed. [Display omitted] • GPx4 is the vital selenoperoxidase active on membrane lipid hydroperoxides. • The redox center is flanked by a site for binding the phospholipid polar head. • GPx4 prevents regulated cell death routines operated by peroxidation. • Survival controlled by GPx4 impacts on immunity inflammation and differentiation. • Protein oxidation by distinct GPx4 isoforms is indispensable to sperm maturation. [ABSTRACT FROM AUTHOR]