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Proteasome Inhibitors for the Treatment of Multiple Myeloma.

Use of proteasome inhibitors (PIs) has been the therapeutic backbone of myeloma treatment over the past decade. Many PIs are being developed and evaluated in the preclinical and clinical setting. The first-in-class PI, bortezomib, was approved by the US food and drug administration in 2003. Carfilzomib is a next-generation PI, which selectively and irreversibly inhibits proteasome enzymatic activities in a dose-dependent manner. Ixazomib was the first oral PI to be developed and has a robust efficacy and favorable safety profile in patients with multiple myeloma. These PIs, together with other

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… Recently, Efentakis et al. demonstrated that cardiotoxicity by carfilzomib is associated with the autophagy pathway and upregulation of protein phosphatase (PP)-2A phosphatase activity but not the inhibition of the proteasome function [ 60 ]. … Molecular mechanism of carfilzomib-induced cardiotoxicity in mice and the emerging cardioprotective role of metformin Blood 2019 133 710 723 10.1182/blood-2018-06-858415 30482794 61. Dimopoulos M.A. Moreau P. Palumbo A. Joshua D. Pour L. Hájek R. Facon T. Ludwig H. Oriol A. Goldschmidt H. …

Cancer in Pregnancy: Therapeutic Decisions at the Intersection of Two Lives.

Background: Cancer during pregnancy is a rare but increasingly encountered condition due to delayed childbearing and improved survival of women with cancer. The coexistence of malignancy and pregnancy poses complex diagnostic and therapeutic challenges, requiring careful balance between maternal prognosis and fetal safety. Objective: This review aims to summarize current evidence on the diagnosis and multidisciplinary management of cancer during pregnancy, focusing on the safe use of oncologic therapies, obstetric decision-making, and maternal and fetal outcomes. Methods: A narrative review wa

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… Potential late complications, including neurodevelopmental alterations, cardiotoxicity, ototoxicity, endocrine disorders, and secondary malignancies, have been described, although without conclusive evidence of a direct causal association with intrauterine chemotherapy exposure [ 4 , 9 ]. … With respect to specific pharmacologic exposures, evidence suggests an increased risk of hearing loss in children exposed to cisplatin, justifying targeted auditory surveillance strategies, whereas available data on cardiotoxicity following prenatal exposure to anthracyclines are generally reassuring …

Углубленный анализ безопасности клеточной терапии CAR-T для твердых опухолей.

В последние годы стремительный прогресс в онкологии, иммунологии и молекулярной биологии привел к резкому усовершенствованию иммунотерапии рака, особенно клеточной терапии CAR-T. Этот новаторский подход включает в себя проектирование Т клеток пациента, чтобы выразить рецепторы, которые специально нацелены на антигены опухоли, расширяя их способность выявлять и устранять раковые клетки. Однако эффективность терапии CAR-T для твердых опухолей зачастую затрудняется из-за сложной микроопухолей (TME). Комплекс TME включает плотную строму, препятствующую инфильтрации Т клеток, аномальные структуры к

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… Detailed are the pulmonary toxicities in the lungs, including cough, dyspnea, pulmonary edema, and ARDS; hepatotoxicity in the liver, evidenced by elevated liver enzymes; nephrotoxicity in the kidneys, marked by AKI; cardiotoxicity in the heart, manifesting as arrhythmias and heart failure; pancreatic … CAR T cell therapy-related cardiovascular outcomes and management: systemic disease or direct cardiotoxicity? JACC CardioOncol. (2020) 2:97–109. doi: 10.1016/j.jaccao.2020.02.011 83. Tchou J, Zhao Y, Levine BL, Zhang PJ, Davis MM, Melenhorst JJ, et al. …

Crosslink between atrial fibrillation and cancer: a therapeutic conundrum.

Atrial fibrillation (AF) is more common in patients with malignancies than in general population. The pathophysiological processes include the pro-inflammatory condition and the exaggerated inflammatory reaction to chemotherapy, radiotherapy, and surgery interventions. Thus, it is pivotal to decrease morbidity and mortality in this group by providing appropriate care and prevention. In this subset, the risk of thromboembolic and bleeding events is high and the common risk score such as CHA2DS2-VASc and HAS-BLED employed in non-oncologic patients have limited evidence in cancer patients. A pauc

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… Additionally, in consecutive treatment protocol, RT and CT worked together synergistically for cardiotoxicity. … Cancer treatment and atrial fibrillation: use of pharmacovigilance databases to detect cardiotoxicity. Eur Heart J Cardiovasc Pharmacother. 2021;7(4):321–3. 10.1093/ehjcvp/pvaa059. (PMID: 32633808). 10.1093/ehjcvp/pvaa059 38. Strickberger SA, Ip J, Saksena S, Curry K, Bahnson TD, Ziegler PD. …

Carfilzomib with immunomodulatory drugs for the treatment of newly diagnosed multiple myeloma.

Carfilzomib, a selective proteasome inhibitor (PI), is approved for the treatment of patients with relapsed or refractory multiple myeloma (MM). Combination regimens incorporating a PI and immunomodulatory drug (IMiD) have been associated with deep responses and extended survival in patients with newly diagnosed MM (NDMM). Carfilzomib-based combinations with immunomodulators are being extensively studied in the frontline setting. The objective of this review was to describe efficacy and safety data for carfilzomib-based, PI/immunomodulatory combinations in NDMM. Information sources were articl

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… Clinical experience with carfilzomib has aided development of strategies for managing and mitigating cardiovascular events [ 56 , 57 ]; clinical guidelines have been developed in collaboration with cardiologists to minimize cardiotoxicity with carfilzomib treatment [ 59 ]. … Predictive biomarkers and practical considerations in the management of carfilzomib-associated cardiotoxicity. Leuk Lymphoma. 2018;59:1981–5. doi: 10.1080/10428194.2017.1403020. 60. Mailankody S, Korde N, Lesokhin AM, Lendvai N, Hassoun H, Stetler-Stevenson M, et al. …

Current Trends and Challenges in the Clinical Translation of Nanoparticulate Nanomedicines: Pathways for Translational Development and Commercialization.

The use of nanotechnology in medicine has the potential to have a major impact on human health for the prevention, diagnosis, and treatment of diseases. One particular aspect of the nanomedicine field which has received a great deal of attention is the design and development of nanoparticulate nanomedicines (NNMs) for drug delivery (i.e., drug-containing nanoparticles). NNMs are intended to deliver drugs via various mechanisms: solubilization, passive targeting, active targeting, and triggered release. The NNM approach aims to increase therapeutic efficacy, decrease the therapeutically effecti

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… Furthermore, the use of pegylated liposomal doxorubicin avoids high plasma peak levels of free drug (Lyass et al., 2000 ) and significantly reduces the risk of cardiotoxicity by preventing doxorubicin release through the heart vasculature (Rahman et al., 2007 ). … Anthracycline-induced cardiotoxicity and the cardiac-sparing effect of liposomal formulation . Int. J. Nanomedicine 2 , 567 – 583 . 18203425 PMC2676818 Riehemann K. Schneider S. W. Luger T. A. Godin B. Ferrari M. Fuchs H. ( 2009 ). Nanomedicine–challenge and perspectives . Angew. Chem. Int. Ed. …

Escaping Antiangiogenic Therapy: Strategies Employed by Cancer Cells.

Tumor angiogenesis is widely recognized as one of the "hallmarks of cancer". Consequently, during the last decades the development and testing of commercial angiogenic inhibitors has been a central focus for both basic and clinical cancer research. While antiangiogenic drugs are now incorporated into standard clinical practice, as with all cancer therapies, tumors can eventually become resistant by employing a variety of strategies to receive nutrients and oxygen in the event of therapeutic assault. Herein, we concentrate and review in detail three of the principal mechanisms of antiangiogenic

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… In this context, optimized or even targeted drug delivery with reduced doses (lowering toxicity) using nano-encapsulated drugs may offer a viable choice; in fact, a recent study used IM-loaded nanoparticles and demonstrated lower cardiotoxicity in rats and improved anticancer activity in breast cancer … Delivery as nanoparticles reduces imatinib mesylate-induced cardiotoxicity and improves anticancer activity Int. J. Nanomed. 2015 10 3163 3170 10.2147/IJN.S75962 PMC4425327 25995626 136. Aguirre-Ghiso J.A. Models, mechanisms and clinical evidence for cancer dormancy Nat. Rev. …

Воздействие сердечного амилоида на пациентов с множественной миеломой: систематический обзор и метаанализ.

КОЛИЧЕСТВО: Иммуноглобулиновая световая цепочка (AL) амилоидоз является широко признанным осложнением множественной миеломы (ММ) с важными прогнозными последствиями. Однако воздействие сердечного амилоидоза на выживание пациентов с ММ исследовалось редко. ЦЕЛЬ: Мы намеревались проводить систематический обзор и метаанализ для количественной оценки прогноза пациентов с синдромом MM с амилоидозом и без него. Мы искали базы данных PubMed, Scopus и Kochrane для проведения исследований по сопоставлению выживаемости пациентов MM с сопутствующим амилоидозом и без него. Первостепенный результат был свя

:: Терапия антиB клеток антихимерной антигенной рецепции Т для лечения амилоидоза и конъюнктурного возврата/отвлечения нескольких миеломы: предварительная эффективность и безопасность.

В то время как иммунотерапии, такие, как терапия CAR T и би-специальные антитела, революционизировали лечение множественной миэломы (ММ), пациенты с амилоидозом были исключены из испытаний с этими агентами из-за проблем, связанных с основной автономией, сердечной травмой и почечной дисфункцией, что может привести к смертельной токсичности этих препаратов. В этом сообщении мы описали результаты two Пациенты с амилоидозом и одновременно с этим MM с основной сердечной и/или почечной дисфункцией, которые прошли антиBCMA CAR T клеточную терапию с синдромом id-cel или цилта-cel, получили профилактик

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… The patient was treated with bortezomib, cyclophosphamide, and dexamethasone and after three cycles achieved a complete hematologic response, but then developed congestive heart failure exacerbation thought to be related to cardiotoxicity from bortezomib. …

Quality of life in adult patients treated with peripheral blood progenitor cell transplantation: the effect of selected psychosocial, demographics and health aspects on quality of life: a retrospective analysis.

AIM: this retrospective study analyses the effect of selected psychosocial, demographics and health aspects on quality of life (QoL) in adult patients treated with peripheral blood progenitor cell transplantation (PBPCT). PATIENTS AND METHODS: The total number of respondents treated with PBPCT between the years 2001-2003 was 95. The return rate of QoL questionnaires was 72.1 % (71 respondents). There were 100 % ratable QoL questionnaire. The average age of all respondents was 55.5 years old. The Czech version of an international generic European Quality of Life Questionnaire - Version EQ-5D w

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… Beside those symptoms, the patient is loaded with results of toxi- city caused by high dose chemotherapy (mucositis, gastro- enteritis, dermatitis, alveolitis, signs of cardiotoxicity and neurotixicity). …

A review on machine learning approaches and trends in drug discovery.

Drug discovery aims at finding new compounds with specific chemical properties for the treatment of diseases. In the last years, the approach used in this search presents an important component in computer science with the skyrocketing of machine learning techniques due to its democratization. With the objectives set by the Precision Medicine initiative and the new challenges generated, it is necessary to establish robust, standard and reproducible computational methodologies to achieve the objectives set. Currently, predictive models based on Machine Learning have gained great importance in t

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… In their work [67] they provide a web-based tool for predicting cardiotoxicity of potassium channel-related chemicals hERG [75] , which can be used in the high-performance virtual detection stage for drug candidates. … In the same way, it is possible to start an experimental phase in the laboratory to generate a set (2130 compounds) of possible new drugs of interest in cardiotoxicity and calculate with DRAGON 3456 descriptors of each of them and include the analysis in a feature selection scheme to end up with an AUC …

The Proliferative and Apoptotic Landscape of Basal-like Breast Cancer.

Basal-like breast cancer (BLBC) is an aggressive molecular subtype that represents up to 15% of breast cancers. It occurs in younger patients, and typically shows rapid development of locoregional and distant metastasis, resulting in a relatively high mortality rate. Its defining features are that it is positive for basal cytokeratins and, epidermal growth factor receptor and/or c-Kit. Problematically, it is typically negative for the estrogen receptor and human epidermal growth factor receptor 2 (HER2), which means that it is unsuitable for either hormone therapy or targeted HER2 therapy. As

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… While these treatments are highly effective in BLBC, the use of chemotherapies are associated with extensive cytotoxicity to non-malignant, proliferating cells, presenting as alopecia, nausea, cardiotoxicity [ 84 , 90 ], and neurotoxicity [ 91 ]. Table 1 Cell cycle directed therapies for BLBC. … Anthracyclines: Molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol. Rev. 2004;56:185–229. doi: 10.1124/pr.56.2.6. 91. Bharadwaj R., Yu H. The spindle checkpoint, aneuploidy, and cancer. …

Case report: A successful second autologous hematopoietic stem cell transplantation in refractory systemic sclerosis, with positive effect on skin involvement, pulmonary function and microcirculation.

BACKGROUND: Systemic sclerosis (SSc) is a complex autoimmune disease characterized by inflammation, vasculopathy and fibrosis of the skin and internal organs. Treatment with autologous hematopoietic cell transplantation (HCT) for progressive SSc has improved overall and event-free survival rates significantly, but unfortunately disease progression after HCT is seen in a subset of patients. Data on the efficacy and safety of second HCT is scarce. CASE: We present a patient with diffuse cutaneous SSc and associated interstitial lung disease (ILD) who successfully underwent a second HCT for prog

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… In general, a second HCT comes with more complications and increased risk of secondary malignancies and cardiotoxicity due to more exposure to alkylating agents. …

The role of vitamin E in the prevention of zoledronic acid-induced nephrotoxicity in rats: a light and electron microscopy study.

IntroductionBisphosphonates are widely used in metastatic cancer such as prostate and breast cancer, and their nephrotoxic effects have been established previously. In this study we aimed to evaluate both the nephrotoxic effects of zoledronic acid (ZA) and the protective effects of vitamin E (Vit-E) on this process under light and electron microscopy.Material and methodsA total of 30 male Sprague-Dawley rats were divided into 3 groups. The first group constituted the control group. The second group was given i.v. ZA of 3 mg/kg once every 3 weeks for 12 weeks from the tail vein. The third group

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… The influence of steroid receptor status on the cardiotoxicity risk in HER2-positive breast cancer patients receiving trastuzumab. Arch Med Sci. 2015;11:371–7. doi: 10.5114/aoms.2015.50969. 18. Xu XL, Gou WL, Wang AY, et al. …

Периоперативные соображения для пациентов с множественной миеломой.

Множественная миелома — неизлечимый рак, характеризующийся распространением клональных плазменных клеток, в основном в костном мозге, но вызывающий широкомасштабные системные осложнения. Кроме того, этот рак обычно встречается у пожилых пациентов, которые часто являются слабыми и страдают от многочисленных коморбидов. Общемировая распространенность множественной миеломы неуклонно возрастает, а терапевтические достижения способствуют повышению уровня выживания. Существует несколько осложнений миеломы, о которых анестезиолог должен знать в связи с самим заболеванием, конкретными и подкрепляющими

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… peripheral neuropathy, somnolence, Stevens-Johnson syndrome, reactivation of latent viral infections Lenalidomide Teratogenicity, myelosuppression, venous thromboembolism, rash, increased risk of secondary malignancy, peripheral neuropathy, somnolence Cyclophosphamide Haemorrhagic cystitis, SIADH, cardiotoxicity …

Randomized phase II study of weekly carfilzomib 70 mg/m2 and dexamethasone with or without cyclophosphamide in relapsed and/or refractory multiple myeloma patients.

In this randomized phase II study (GEM-KyCyDex, clinicaltrials gov. Identifier: NCT03336073), the combination of weekly carfilzomib 70 mg/m2, cyclophosphamide and dexamethasone (KCd) was compared to carfilzomib and dexamethasone (Kd) in relapsed/refractory multiple myeloma (RRMM) after 1-3 prior lines (PL). One hundred and ninety-seven patients were included and randomized 1:1 to receive KCd (97 patients) or Kd (100 patients) in 28-day cycles until progressive disease or unacceptable toxicity occurred. Patient median age was 70 years, and the median number of PL was one (range, 1-3). More than

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… No differences were observed in the occurrence of cardiotoxicity as a cause of discontinuation (8 patients in KCd and 3 in Kd). Sixty percent of patients who presented this unacceptable toxicity were over 70 years of age. However, the timing of the occurrence of toxicity differed between the arms. …

Bortezomib-induced painful neuropathy in patients with multiple myeloma.

Neurotoxicity towards the peripheral nervous system which appears clinically in the form of painful neuropathy is an essential dose-limiting factor during the treatment of multiple myeloma. In this review article different forms of this painful neuropathy are presented together with currently available diagnostic tools which are usually applied to confirm the diagnosis. Also, the most often used neurological scales estimating neurological deficit are presented. Special attention is paid to the management of the reversibility of bortezomib-induced neuropathic pain.

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… Because of cardiotoxicity and the negative impact on cognitive functions they should not be recommended to older patients. They are contraindicated in glaucoma (increase in intraocular hypertension). They exert anticholinergic side effects and also trigger psychotic episodes. …

What is the Reason That the Pharmacological Future of Chemotherapeutics in the Treatment of Lung Cancer Could Be Most Closely Related to Nanostructures? Platinum Drugs in Therapy of Non-Small and Small Cell Lung Cancer and Their Unexpected, Possible Interactions. The Review.

Over the course of several decades, anticancer treatment with chemotherapy drugs for lung cancer has not changed significantly. Unfortunately, this treatment prolongs the patient's life only by a few months, causing many side effects in the human body. It has also been proven that drugs such as Cisplatin, Carboplatin, Oxaliplatin and others can react with other substances containing an aromatic ring in which the nitrogen atom has a free electron group in its structure. Thus, such structures may have a competitive effect on the nucleobases of DNA. Therefore, scientists are looking not only for

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… are correlated with an increased cumulative dose administered. 170 Nevertheless, an entire loss of motor function is extremely rare, and symptoms disappear after a few days and, in rare situations, last for a maximum of 4 years. 154 Neuropathies are the main cause of limiting Oxaliplatin usage. 154 Cardiotoxic … The main side effects reported were neutropenia and gastrointestinal toxicity, but unlike Cisplatin, hepatotoxicity, neuropathy, cardiotoxicity, ototoxicity, and hair loss were not reported. …

Abstracts from the World Congress of Cardiology/Brazilian Congress of Cardiology 2022

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… However, cardiotoxicity is a common side effect of the drug. The pathophysiology of cardiotoxicity is not clearly understood. … Conclusions: Dox-induced cardiotoxicity is associated with diastolic dysfunction, cardiac fibrosis, increased MMP-2 activity, and oxidative stress. NETs are involved in the pathophysiology of dox-induced cardiotoxicity. …

Triple MAPK inhibition salvaged a relapsed post-BCMA CAR-T cell therapy multiple myeloma patient with a BRAF V600E subclonal mutation.

BACKGROUND: Multiple Myeloma (MM) is a progressive plasma cell neoplasm characterized by heterogeneous clonal expansion. Despite promising response rates achieved with anti-BCMA CAR-T cell therapy, patients may still relapse and there are currently no clear therapeutic options in post-CAR-T settings. In this report, we present a case of a post-BCMA CAR-T relapsed/refractory (RR) MM patient with skin extramedullary disease (EMD) in which a novel MAPK inhibition combinatorial strategy was implemented based on next-generation sequencing and in vitro experiments. CASE PRESENTATION: A 61-year-old