Project description:Urothelial carcinoma (UC) is a common cancer associated with a poor prognosis in patients with advanced disease. Platinum-based chemotherapy has remained the cornerstone of systemic anticancer treatment for many years, and recent developments in the treatment landscape have improved outcomes. In this review, we provide an overview of systemic treatment for UC, including clinical data supporting the current standard of care at each point in the treatment pathway and author interpretations from a UK perspective. Neoadjuvant cisplatin-based chemotherapy is recommended for eligible patients with muscle-invasive bladder cancer and is preferable to adjuvant treatment. For first-line treatment of advanced UC, platinum-eligible patients should receive cisplatin- or carboplatin-based chemotherapy, followed by avelumab maintenance in those without disease progression. Among patients unable to receive platinum-based chemotherapy, immune checkpoint inhibitor (ICI) treatment is an option for those with programmed death ligand 1 (PD-L1)-positive tumours. Second-line or later treatment options depend on prior treatment, and enfortumab vedotin is preferred after prior ICI and chemotherapy, although availability varies between countries. Additional options include rechallenge with platinum-based chemotherapy, an ICI, or non-platinum-based chemotherapy. Areas of uncertainty include the optimal number of first-line chemotherapy cycles for advanced UC and the value of PD-L1 testing for UC.
Project description:Long-term cardiovascular complications of cancer therapy are becoming ever more prevalent due to increased numbers of cancer survivors. Cancer therapy-induced cardiotoxicity (CTIC) is an incompletely understood consequence of various chemotherapies, targeted anti-cancer agents and radiation therapy. It is typically detected clinically by a reduction in cardiac left ventricular ejection fraction, assessed by echocardiography. However, once cardiac functional decline is apparent, this indicates irreversible cardiac damage, highlighting a need for the development of diagnostics which can detect CTIC prior to the onset of functional decline. There is increasing evidence to suggest that pathological alterations to cardiac metabolism play a crucial role in the development of CTIC. This review discusses the metabolic alterations and mechanisms which occur in the development of CTIC, with a focus on doxorubicin, trastuzumab, imatinib, ponatinib, sunitinib and radiotherapy. Potential methods to diagnose and predict CTIC prior to functional cardiac decline in the clinic are evaluated, with a view to both biomarker and imaging-based approaches. Finally, the therapeutic potential of therapies which manipulate cardiac metabolism in the context of adjuvant cardioprotection against CTIC is examined. Together, an integrated view of the role of metabolism in pathogenesis, diagnosis and treatment is presented.
Project description:The advancement in therapy has provided a dramatic improvement in the rate of recovery among cancer patients. However, this improved survival is also associated with enhanced risks for cardiovascular manifestations, including hypertension, arrhythmias, and heart failure. The cardiotoxicity induced by chemotherapy is a life-threatening consequence that restricts the use of several chemotherapy drugs in clinical practice. This article addresses the prevalence of cardiotoxicity mediated by commonly used chemotherapeutic and immunotherapeutic agents. The role of susceptible genes and radiation therapy in the occurrence of cardiotoxicity is also reviewed. This review also emphasizes the protective role of antioxidants and future perspectives in anticancer drug-induced cardiotoxicities.
Project description:Novel anticancer medicines, including targeted therapies and immune checkpoint inhibitors, have greatly improved the management of cancers. However, both conventional and new anticancer treatments induce cardiac adverse effects, which remain a critical issue in clinic. Cardiotoxicity induced by anti-cancer treatments compromise vasospastic and thromboembolic ischemia, dysrhythmia, hypertension, myocarditis, and cardiac dysfunction that can result in heart failure. Importantly, none of the strategies to prevent cardiotoxicity from anticancer therapies is completely safe and satisfactory. Certain clinically used cardioprotective drugs can even contribute to cancer induction. Since G protein coupled receptors (GPCRs) are target of forty percent of clinically used drugs, here we discuss the newly identified cardioprotective agents that bind GPCRs of adrenalin, adenosine, melatonin, ghrelin, galanin, apelin, prokineticin and cannabidiol. We hope to provoke further drug development studies considering these GPCRs as potential targets to be translated to treatment of human heart failure induced by anticancer drugs.
Project description:Anticancer chemotherapies have been shown to produce severe side effects, with cardiotoxicity from anthracycline being the most notable. Identifying risk factors for anticancer therapy-induced cardiotoxicity in cancer patients as well as understanding its underlying mechanism is essential to improving clinical outcomes of chemotherapy treatment regimens. Moreover, cardioprotective agents against anticancer therapy-induced cardiotoxicity are scarce. Human induced pluripotent stem cell technology offers an attractive platform for validation of potential single nucleotide polymorphism with increased risk for cardiotoxicity. Successful validation of risk factors and mechanism of cardiotoxicity would aid the development of such platform for novel drug discovery and facilitate the practice of personalized medicine.
Project description:Chemotherapy-induced cardiac toxicity is an undesirable yet very common effect that increases the risk of death and reduce the quality of life of individuals undergoing chemotherapy. However, no feasible methods and techniques are available to monitor and detect the degree of cardiotoxicity at an early stage. Therefore, in this project, we aim to develop a fluorescent nanoprobe to image the toxicity within the cardiac tissue induced by an anticancer drug. We have observed that vascular cell adhesion molecule 1 (VCAM1) protein alone with collagen was overly expressed within the heart, when an animal was treated with doxorubicin (DOX), because of inflammation in the epithelial cells. We hypothesize that developing a VCAM1-targeted peptide-based (VHPKQHRGGSKGC) fluorescent nanoprobe can detect and visualize the affected heart. In this regard, we prepared a poly(lactic-co-glycolic acid) (PLGA) nanoparticle linked with VCAM1 peptide and rhodamine B (PLGA-VCAM1-RhB). Selective binding and higher accumulation of the PLGA-VCAM1-RhB nanoprobes were detected in DOX-treated human cardiomyocyte cells (HCMs) compared to the untreated cells. For in vivo studies, DOX (5 mg/kg) was injected via the tail vein once in two weeks for 6 weeks (3 injection total). PLGA-VCAM1-RhB and PLGA-RhB were injected via the tail vein after 1 week of the last dose of DOX, and images were taken 4 h after administration. A higher fluorescent signal of PLGA-RhB-VCAM-1 (48.62% ± 12.79%) was observed in DOX-treated animals compared to the untreated control PLGA-RhB (10.61% ± 4.90) within the heart, indicating the specificity and targeting ability of PLGA-VCAM1-RhB to the inflamed tissues. The quantified fluorescence intensity of the homogenized cardiac tissue of PLGA-RhB-VCAM1 showed 156% higher intensity than the healthy control group. We conclude that PLGA-VCAM1-RhB has the potential to bind inflamed cardiac cells, thereby detecting DOX-induced cardiotoxicity and damaged heart at an early stage.
Project description:Doxorubicin (DOX, an anthracycline) is a widely used chemotherapy agent against various forms of cancer; however, it is also known to induce dose-dependent cardiotoxicity leading to adverse complications. Investigating the underlying molecular mechanisms and strategies to limit DOX-induced cardiotoxicity might have potential clinical implications. Our previous study has shown that expression of microRNA-377 (miR-377) increases in cardiomyocytes (CMs) after cardiac ischemia-reperfusion injury in mice, but its specific role in DOX-induced cardiotoxicity has not been elucidated. In the present study, we investigated the effect of anti-miR-377 on DOX-induced cardiac cell death, remodeling, and dysfunction. We evaluated the role of miR-377 in CM apoptosis, its target analysis by RNA sequencing, and we tested the effect of AAV9-anti-miR-377 on DOX-induced cardiotoxicity and mortality. DOX administration in mice increases miR-377 expression in the myocardium. miR-377 inhibition in cardiomyocyte cell line protects against DOX-induced cell death and oxidative stress. Furthermore, RNA sequencing and Gene Ontology (GO) analysis revealed alterations in a number of cell death/survival genes. Intriguingly, we observed accelerated mortality and enhanced myocardial remodeling in the mice pretreated with AAV9-anti-miR-377 followed by DOX administration as compared to the AAV9-scrambled-control-pretreated mice. Taken together, our data suggest that in vitro miR-377 inhibition protects against DOX-induced cardiomyocyte cell death. On the contrary, in vivo administration of AAV9-anti-miR-377 increases mortality in DOX-treated mice.
Project description:Adriamycin, a widely used anthracycline antibiotic in multiple chemotherapy regimens, has been challenged by the cardiotoxicity leading to fatal congestive heart failure in the worst condition. The present study demonstrated that Dihydromyricetin, a natural product extracted from ampelopsis grossedentat, exerted cardioprotective effect against the injury in Adriamycin-administrated ICR mice. Dihydromyricetin decreased ALT, LDH and CKMB levels in mice serum, causing a significant reduction in the toxic death triggered by Adriamycin. The protective effects were also indicated by the alleviation of abnormal electrocardiographic changes, the abrogation of proliferation arrest and apoptotic cell death in primary myocardial cells. Further study revealed that Dihydromyricetin-rescued loss of anti-apoptosis protein ARC provoked by Adriamycin was involved in the cardioprotection. Intriguingly, the anticancer activity of Adriamycin was not compromised upon the combination with Dihydromyricetin, as demonstrated by the enhanced anticancer effect achieved by Adriamycin plus Dihydromyricetin in human leukemia U937 cells and xenograft models, in a p53-dependent manner. These results collectively promised the potential value of Dihydromyricetin as a rational cardioprotective agent of Adriamycin, by protecting myocardial cells from apoptosis, while potentiating anticancer activities of Adriamycin, thus further increasing the therapeutic window of the latter one.
Project description:Cardiotoxicity is a frequent and often lethal complication of doxorubicin (DOX)-based chemotherapy. Here, we report that hydropersulfides (RSSH) are the most effective reactive sulfur species in conferring protection against DOX-induced toxicity in H9c2 cardiac cells. Mechanistically, RSSH supplementation alleviates the DOX-evoked surge in reactive oxygen species (ROS), activating nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent pathways, thus boosting endogenous antioxidant defenses. Simultaneously, RSSH turns on peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a master regulator of mitochondrial function, while decreasing caspase-3 activity to inhibit apoptosis. Of note, we find that RSSH potentiate anticancer DOX effects in three different cancer cell lines, with evidence that suggests this occurs via induction of reductive stress. Indeed, cancer cells already exhibit much higher basal hydrogen sulfide (H2S), sulfane sulfur, and reducing equivalents compared to cardiac cells. Thus, RSSH may represent a new promising avenue to fend off DOX-induced cardiotoxicity while boosting its anticancer effects.
Project description:BackgroundStructured reporting and standardized criteria are increasingly recognized as means of improving both radiological and clinical practice by allowing for better content and clarity. Our aim was to examine oncologists' opinions and expectations concerning the radiologist's report to identify general needs in daily practice and ways to improve interdisciplinary communication.MethodsA 19-question survey was sent to 230 oncologists from three different countries (France, Romania, Switzerland) identified on the online web pages of different hospitals and private clinics. The survey was sent by electronic mail with an online survey program (Google Forms®). All recipients were informed of the purpose of the study. The data were collected by the online survey program and analysed through filtering the results and cross-tabulation.ResultsA total of 52 responses were received (response rate of 22.6%). The majority of the respondents (46/52, 88%) preferred the structured report, which follows a predefined template. Most of the respondents (40/52, 77%) used RECIST 1.1 or iRECIST in tumour assessment. Nearly half of the oncologists (21/52, 40%) measured 1-3 cases per week. On a 10-point Likert scale, 34/52 (65%) oncologists rated their overall level of satisfaction with radiologists' service between 7 and 10. In contrast, 12/52 (19%) oncologists rated the radiologists' service between 1 and 4. Moreover, 42/52 (80%) oncologists acknowledged that reports created by a radiologist with a subspecialty in oncologic imaging were superior to those created by a general radiologist.ConclusionStructured reports in oncologic patients and the use of RECIST criteria are preferred by oncologists in their daily clinical practice, which signals the need for radiologists also to implement such reports to facilitate communication. Furthermore, most of the oncologists we interviewed recognized the added value provided by radiologists specializing in oncologic imaging. Because this subspecialty is present in only a few countries, generally in large clinics, further training might become a challenge; nevertheless, intensive efforts should be made to enhance expertise in cancer imaging.