ABSTRACT

Doxorubicin (DOX) is a highly effective chemotherapeutic drug, but its long-term use can cause cardiotoxicity and drug resistance. Accumulating evidence demonstrates that p53 is directly involved in DOX toxicity and resistance. One of the primary causes for DOX resistance is the mutation or inactivation of p53. Moreover, because the non-specific activation of p53 caused by DOX can kill non-cancerous cells, p53 is a popular target for reducing toxicity. However, the reduction in DOX-induced cardiotoxicity (DIC) via p53 suppression is often at odds with the antitumor advantages of p53 reactivation. Therefore, in order to increase the effectiveness of DOX, there is an urgent need to explore p53-targeted anticancer strategies owing to the complex regulatory network and polymorphisms of the p53 gene. In this review, we summarize the role and potential mechanisms of p53 in DIC and resistance. Furthermore, we focus on the advances and challenges in applying dietary nutrients, natural products, and other pharmacological strategies to overcome DOX-induced chemoresistance and cardiotoxicity. Lastly, we present potential therapeutic strategies to address key issues in order to provide new ideas for increasing the clinical use of DOX and improving its anticancer benefits.

PMID:37242146 | DOI:10.3390/nu15102259

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PubMed articles on: Cardio-Oncology

Prognostic Impact of Global Longitudinal Strain and NT-proBNP on Early Development of Cardiotoxicity in Breast Cancer Patients Treated with Anthracycline-Based Chemotherapy

Medicina (Kaunas). 2023 May 15;59(5):953. doi: 10.3390/medicina59050953.

ABSTRACT

Background. The most important anthracycline side effect is cardiotoxicity, resulting in congestive heart failure (HF). Early detection of cardiac dysfunction and appropriate treatment can improve outcomes and reduce the progression of HF. The aim of our study was to evaluate changes in clinical data, echocardiographic parameters, and NT-proBNP, as well as their associations with early anthracycline-induced cardiotoxicity (AIC) in patients treated with anthracycline-based chemotherapy. Methods and Materials. Patients with breast cancer were prospectively assessed with echocardiography, as well as NT-proBNP testing at baseline, (T0), after two cycles (T1) and four cycles (T2) of chemotherapy. AIC was defined as a new decrease in the LVEF of 10 percentage points, to a value below the lower limit of normal. Results.We evaluated 85 patients aged 54.5 ± 9.3 years. After a cumulative dose of 237.9 mg/m2 of doxorubicin, 22 patients (25.9%) met the criteria of AIC after chemotherapy. Patients who subsequently progressed to cardiotoxicity had demonstrated a significantly larger impairment in LV systolic function compared to those who did not develop cardiotoxicity (LVEF: 54.0 ± 1.6% vs. 57.1 ± 1.4% at T1, p< 0.001, and 49.9 ± 2.1% vs. 55.8 ± 1.6% at T2, p< 0.001; GLS: -17.8 ± 0.4% vs. -19.3 ± 0.9% at T1, p< 0.001, and -16.5 ± 11.1% vs. -18.5 ± 0.9% at T2, p< 0.001, respectively). The levels of NT-proBNP increased significantly from 94.8 ± 43.8 ng/L to 154.1 ± 75.6 ng/L, p< 0.001. A relative decrease in GLS ≤ -18.0% (sensitivity: 72.73%; specificity: 92.06%; AUC, 0.94; p< 0.001) and a relative increase in NT-proBNP > 125 ng/L (sensitivity: 90.0%; specificity: 56.9%; AUC, 0.78; p< 0.001) from baseline to T1 predicted subsequent LV cardiotoxicity at T2. Conclusions. Decrease in GLS and elevation in NT-proBNP were significantly associated with AIC, and these could potentially be used to predict subsequent declines in LVEF with anthracycline-based chemotherapy.

PMID:37241185 | DOI:10.3390/medicina59050953

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PubMed articles on: Cardio-Oncology

Echocardiographic Findings in Asymptomatic Mediastinal Lymphoma Survivors Years after Treatment Termination

J Clin Med. 2023 May 12;12(10):3427. doi: 10.3390/jcm12103427.

ABSTRACT

Patients treated due to mediastinal lymphomas are at risk of cardiovascular complications, as they receive chemotherapy, usually containing anthracyclines, often combined with thoracic radiotherapy. The aim of this prospective study was to assess early asymptomatic cardiac dysfunction using resting and dobutamine stress echocardiography (DSE) at least 3 years after the end of mediastinal lymphoma treatment. Two groups of patients were compared: those treated with chemoradiotherapy and those exclusively treated with chemotherapy. Left ventricular contractile reserve (LVCR) during DSE was assessed using changes in LV ejection fraction (LVEF), LV global longitudinal strain (LV GLS), and a novel parameter-Force, which is the ratio of the systolic blood pressure to the LV end-systolic volume. The study included 60 patients examined at a median of 89 months after the end of treatment. Resting echocardiography showed normal LVEF of 58.9 ± 9.6%, borderline LV GLS of -17.7 ± 3%, decreased mean stroke volume (SV) of 51.4 ± 17 mL, and indexed SV of 27.3 ± 8 mL/m2, and the right ventricular free wall longitudinal strain (LS) was impaired in some patients but not in all. There were no significant differences between the groups, with the exception of arterial hypertension, which was more common in the chemotherapy group (32% vs. 62.5%, p= 0.04). In resting echocardiography, only LV posterior wall LS differed significantly and was impaired in patients treated with chemotherapy (-19.1 ± 3.1% vs. -16.5 ± 5.1%, p= 0.04). DSE, performed in 21 patients after a median of 166 months from the end of cancer treatment, detected new contractility disorders in 1 patient (4.8%) and decreased LVCR in the majority of patients when determined using changes in LVEF or LV GLS, and in all patients when assessed with changes in Force. Conclusions: Most asymptomatic mediastinal lymphoma survivors showed preserved ventricular function on resting echocardiography. However, all of them showed impaired LV contractile reserve on DSE, as assessed with a simple parameter-Force. This may indicate subtle LV dysfunction and confirms the need for long-term monitoring of patients with potentially cardiotoxic cancer treatment.

PMID:37240533 | DOI:10.3390/jcm12103427

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PubMed articles on: Cardio-Oncology

Primary Cardiac Schwannoma: A Meta-Analysis of Individual Case Reports

J Clin Med. 2023 May 9;12(10):3356. doi: 10.3390/jcm12103356.

ABSTRACT

Primary cardiac schwannoma (PCS) is a neurogenic tumor that arises from Schwann cells. Malignant schwannoma (MSh) is an aggressive cancer comprising 2% of all sarcomas. Information on the proper management of these tumors is limited. Four databases were searched for case reports/series of PCS. The primary outcome was overall survival (OS). Secondary outcomes included therapeutic strategies and the corresponding outcomes. Among 439 potentially eligible studies, 53 met the inclusion criteria. The patients included had 43.72 ± 17.76 years and 28.3% were males. Over 50% of patients had MSh, with 9.4% also demonstrating metastases. Schwannoma commonly occurs in the atria (66.0%). Left-sided PCS were more common than right-sided ones. Surgery was performed in almost 90% of the cases; chemotherapy and radiotherapy were used in 16.9% and 15.1% of cases, respectively. Compared to benign cases, MSh occurs at a younger age and is commonly located on the left side. OS of the entire cohort at 1 and 3 years were 60.7%, and 54.0%, respectively. Females and males OS were similar up to 2 years follow-up. Surgery was associated with higher OS (p < 0.01). Surgery is the primary treatment option for both benign and malignant cases and was the only factor associated with a relative improvement in survival.

PMID:37240461 | DOI:10.3390/jcm12103356

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PubMed articles on: Cardio-Oncology

Inflammasome Activity in the Skeletal Muscle and Heart of Rodent Models for Duchenne Muscular Dystrophy

Int J Mol Sci. 2023 May 9;24(10):8497. doi: 10.3390/ijms24108497.

ABSTRACT

Duchenne muscular dystrophy (DMD) is characterized by wasting of muscles that leads to difficulty moving and premature death, mainly from heart failure. Glucocorticoids are applied in the management of the disease, supporting the hypothesis that inflammation may be driver as well as target. However, the inflammatory mechanisms during progression of cardiac and skeletal muscle dysfunction are still not well characterized. Our objective was to characterize the inflammasomes in myocardial and skeletal muscle in rodent models of DMD. Gastrocnemius and heart samples were collected from mdxmice and DMDmdx rats (3 and 9-10 months). Inflammasome sensors and effectors were assessed by immunoblotting. Histology was used to assess leukocyte infiltration and fibrosis. In gastrocnemius, a tendency towards elevation of gasdermin D irrespective of the age of the animal was observed. The adaptor protein was elevated in the mdxmouse skeletal muscle and heart. Increased cleavage of the cytokines was observed in the skeletal muscle of the DMDmdx rats. Sensor or cytokine expression was not changed in the tissue samples of the mdxmice. In conclusion, inflammatory responses are distinct between the skeletal muscle and heart in relevant models of DMD. Inflammation tends to decrease over time, supporting the clinical observations that the efficacy of anti-inflammatory therapies might be more prominent in the early stage.

PMID:37239853 | DOI:10.3390/ijms24108497

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PubMed articles on: Cardio-Oncology

Characterization of functioning in breast cancer survivors: an interpretive descriptive analysis study based on the International Classification of Functioning, Disability, and Health (ICF) and the Item-Perspective Classification Framework

Disabil Rehabil. 2023 May 26:1-19. doi: 10.1080/09638288.2023.2212915. Online ahead of print.

ABSTRACT

PURPOSE: Breast cancer survivors may experience a variety of disabilities that could potentially compromise their independent functioning. This study aimed to examine their perspectives and experts on their functioning and interpret concepts with the International Classification of Functioning, Disability, and Health (ICF) and the Item-Perspective Classification Framework (IPF).

METHODS: Interpretive descriptive methods were used with in-depth interviewing with 16 breast cancer survivors and 22 experts using a semi-structured interview guide. The interviews were recorded, transcribed, and qualitatively analyzed using thematic analysis. The extracted data were linked to the ICF Core Set for Breast cancer and were interpreted by the IPF.

RESULTS: Four main themes emerged to define the functioning of breast cancer survivors: body functioning, physical functioning, social functioning, and mental functioning. Three other factors were also categorized as modifiers of functioning personal, emotional, and environmental. The 592 extracted meaningful concepts were linked to 38 (47%) categories from the ICF: 16 Body Functions, 14 Activities and Participation, and 8 Environmental Factors. The IPF classified all the extracted concepts, and most rational appraisals fell in the biological (B) domain. The concepts that required emotional appraisal were classified in Psychology (P).

CONCLUSION: Psychological and emotional factors were pivotal in defining functioning in patients with BC.

PMID:37237439 | DOI:10.1080/09638288.2023.2212915

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PubMed articles on: Cardio-Oncology

Association between RCT methodology and disease indication with mineralocorticoid-related toxicity for patients receiving abiraterone acetate for advanced prostate cancer: A meta-analysis of RCTs

Clin Genitourin Cancer. 2023 Apr 23:S1558-7673(23)00093-9. doi: 10.1016/j.clgc.2023.04.007. Online ahead of print.

ABSTRACT

INTRODUCTION: While abiraterone acetate (AA) has demonstrated survival benefit in advanced prostate cancer (APC), meaningful cardiotoxicity is observed. It is unclear whether the magnitude differs based on disease indication and concurrent steroid administration.

METHODS: We performed a systematic review and meta-analysis of phase II/III RCTs of AA in APC published as of August 11, 2020. Primary outcomes examined were all- and high-grade (grade ≥ 3) hypokalemia and fluid retention, and secondary outcomes included hypertension and cardiac events. We performed random effects meta-analysis comparing intervention (AA + steroid) and control (placebo ± steroid), stratified by treatment indication and whether patients received steroids.

RESULTS: Among 2,739 abstracts, we included 6 relevant studies encompassing 5901 patients. Hypokalemia and fluid retention were observed more frequently among patients receiving AA (odds ratio [OR] 3.10 [95% CI 1.69-5.67] and 1.41 [95% CI 1.19-1.66]). This was modified by whether patients in the control received steroids: trials where control patients did not demonstrated a larger association between AA and hypokalemia (OR 6.88 [95% CI 1.48-2.36] versus OR 1.86 [95% CI 4.97-9.54], P < .0001) and hypertension (OR 2.53 [95% CI 1.91-3.36] vs. OR 1.55 [95% CI 1.17-2.04], P = .1) than those where steroids were administered. We observed heterogeneity due to indication: there were greater effects on hypokalemia (P < 0001), hypertension (P = .03), and cardiac disorders (P = .01) among patients treated for mHSPC than mCRPC.

CONCLUSIONS: The magnitude of cardiotoxicity with AA differs based on trial design and disease indication. These data are valuable in treatment decisions and highlight utilization of appropriate data for counseling.

PMID:37236862 | DOI:10.1016/j.clgc.2023.04.007

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PubMed articles on: Cardio-Oncology

Trastuzumab-Mediated Cardiotoxicity and Its Preventive Intervention by Zingerone through Antioxidant and Inflammatory Pathway in Rats

J Pers Med. 2023 Apr 27;13(5):750. doi: 10.3390/jpm13050750.

ABSTRACT

Trastuzumab (TZB) is a new medicine, used to treat cancers of the breast and stomach. However, the cardiotoxic potential of this drug edges out its clinical advantages. The present study was designed to find out the effect of zingerone against trastuzumab-mediated cardiotoxicity in rats. In this study, five groups of rats with eight animals in each group were used. Group 1 was treated with normal saline, as a normal control (NC); Group 2 was treated with TZB (6 mg/kg/week-for five weeks) intraperitoneally as a toxic control. Groups 3 and 4 were pre-treated with zingerone (50 and 100 mg/kg, as per their body weight orally) along with five doses of TZB for five weeks, and Group 5 was treated with zingerone (100 mg/kg, body weight orally) as a control. TZB treatment showed cardiotoxicity as evidenced by increased levels of aspartate aminotransferase (AST), creatine kinase-myocardial band (CK-MB), lactate dehydrogenase (LDH), and lipid peroxidation (LPO) and decreased level of glutathione (GSH), and antioxidant enzymes such as glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-s- transferase (GST), catalase (CAT), and superoxide dismutase (SOD) activities. Zingerone pre-treatment significantly decreased the levels of AST, CK-MB, LDH, and LPO and increased GSH and antioxidant enzymes content toward their normal level. In the TZB-alone administered group, inflammatory cytokines (IL-2 and TNF-α) levels were also elevated. Pre-treatment with zingerone restored the level of IL-2 and TNF-α toward normal level. The current findings undoubtedly demonstrated zingerone's cardioprotective nature against TZB-mediated cardiotoxicity in rats with the evidence of histopathological recall.

PMID:37240920 | DOI:10.3390/jpm13050750

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PubMed articles on: Cardio-Oncology

Cardiotoxicity of targeted therapies in children with haematological malignancies and solid tumors

Anticancer Agents Med Chem. 2023 May 25. doi: 10.2174/1871520623666230525162147. Online ahead of print.

ABSTRACT

Cardiotoxicity represents an important acute or chronic adverse event of treatment modalities for childhood cancer. In the last two decades the emergence of novel cancer therapies has aimed to increase unaided or mostly in combination with conventional chemotherapy for the survival rates of pediatric cancer especially for those patients with relapsed and/or refractory disease. The use of emerging targeted therapies in combination with conventional chemotherapy is related to cardiovascular adverse events mostly reported in adults. The aim of our short review was to investigate the cardiotoxic side effects of targeted chemotherapeutic agents as monoclonal antibodies and small molecules in pediatric cancer patients.

PMID:37231721 | DOI:10.2174/1871520623666230525162147

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PubMed articles on: Cardio-Oncology

Preoptimisation in patients with acute obstructive colon cancer (PREOCC) - a prospective registration study protocol

BMC Gastroenterol. 2023 May 25;23(1):186. doi: 10.1186/s12876-023-02799-z.

ABSTRACT

BACKGROUND: Postoperative mortality and morbidity rates are high in patients with obstructing colon cancer (OCC). Different treatment options have been evaluated over the years, mainly for left sided OCC. Optimising the preoperative health condition in elective colorectal cancer (CRC) treatment shows promising results. The aim of this study is to determine whether preoptimisation is feasible in patients with OCC, with a special interest/focus on right-sided OCC, and if, ultimately, optimisation reduces mortality and morbidity (stoma rates, major and minor complications) rates in OCC.

METHODS: This is a prospective registration study including all patients presenting with OCC in our hospital. Patients with OCC, treated with curative intent, will be screened for eligibility to receive preoptimisation before surgery. The preoptimisation protocol includes; decompression of the small bowel with a NG-tube for right sided obstruction and SEMS or decompressing ileostomy or colostomy, proximal to the site of obstruction, for left sided colonic obstructions. For the additional work-up, additional nutrition by means of parenteral feeding (for patients who are dependent on a NG tube) or oral/enteral nutrition (in case the obstruction is relieved) is provided. Physiotherapy with attention to both cardio and muscle training prior surgical resection is provided. The primary endpoint is complication-free survival (CFS) at the 90 day period after hospitalisation. Secondary outcomes include pre- and postoperative complications, patient- and tumour characteristics, surgical procedures, total in hospital stay, creation of decompressing and/or permanent ileo- or colostomy and long-term (oncological) outcomes.

DISCUSSION: Preoptimisation is expected to improve the preoperative health condition of patients and thereby reduce postoperative complications.

TRIAL REGISTRATION: Trial Registry: NL8266 date of registration: 06-jan-2020.

STUDY STATUS: Open for inclusion.

PMID:37231376 | PMC:PMC10214621 | DOI:10.1186/s12876-023-02799-z

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PubMed articles on: Cardio-Oncology

A Brain, A Heart, and the Courage: Balancing Benefit and Toxicity of Immunotherapy in Melanoma

Am Soc Clin Oncol Educ Book. 2023 May;43:e390594. doi: 10.1200/EDBK_390594.

ABSTRACT

The overall survival of advanced melanoma has improved dramatically. Immunotherapies, specifically checkpoint inhibitors, have played a large role in this improvement. These agents have also shown benefit in the adjuvant setting, are approved for treatment of resected stage II, III, and IV melanoma, and play an evolving role in the neoadjuvant setting. Although generally well tolerated, immune-related adverse events occur and can be severe. Here we focus on some severe and potentially long term toxicities, including cardiovascular and neurologic toxicities. Our understanding of the acute and long-term toxicities of immune checkpoint inhibitors continues to evolve. Oncologists must continue to balance cancer risk and treatment-related toxicities.

PMID:37229626 | DOI:10.1200/EDBK_390594

28 May 2023

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PubMed articles on: Cancer & VTE/PE

Hypercoagulability State Combined with Post-Treatment Hypofibrinolysis in Invasive Breast Cancer: A Seven-Year Follow-Up Evaluating Disease-Free and Overall Survival

Life (Basel). 2023 Apr 28;13(5):1106. doi: 10.3390/life13051106.