The Redox Imbalance and the Reduction of Contractile Protein Content in Rat Hearts Administered with L-Thyroxine and Doxorubicin

Oxidative stress and disorders in calcium balance play a crucial role in the doxorubicin-induced cardiotoxicity. Moreover, many cardiotoxic targets of doxorubicin are regulated by iodothyronine hormones. The aim of the study was to evaluate effects of tetraiodothyronine (0.2, 2 mg/L) on oxidative stress in the cardiac muscle as well as contractility and cardiomyocyte damage markers in rats receiving doxorubicin (1.5 mg/kg) once a week for ten weeks. Doxorubicin was administered alone (DOX) or together with a lower (0.2T4 + DOX) and higher dose of tetraiodothyronine (2T4 + DOX). Two groups received only tetraiodothyronine (0.2T4, 2T4). Coadministration of tetraiodothyronine and doxorubicin increased the level of lipid peroxidation products and reduced RyR2 level when compared to untreated control and group exposed exclusively to doxorubicin. Insignificant differences in SERCA2 and occasional histological changes were observed. In conclusion, an increase of tetraiodothyronine level may be an additional risk factor of redox imbalance and RyR2 reduction in anthracycline cardiotoxicity

Tirapazamine-Doxorubicin Interaction Referring to Heart Oxidative Stress and Ca2+ Balance Protein Levels

Doxorubicin (DOX) causes long-term cardiomyopathy that is dependent on oxidative stress and contractility disorders. Tirapazamine (TP), an experimental adjuvant drug, passes the same red-ox transformation as DOX. The aim of the study was to evaluate an effect of tirapazamine on oxidative stress, contractile protein level, and cardiomyocyte necrosis in rats administered doxorubicin. Rats were intraperitoneally injected six times once a week with tirapazamine in two doses, 5 (5TP) and 10 mg/kg (10TP), while doxorubicin was administered in dose 1.8 mg/kg (DOX). Subsequent two groups received both drugs simultaneously (5TP+DOX and 10TP+DOX). Tirapazamine reduced heart lipid peroxidation and normalised RyR2 protein level altered by doxorubicin. There were no significant changes in GSH/GSSG ratio, total glutathione, cTnI, AST, and SERCA2 level between DOX and TP+DOX groups. Cardiomyocyte necrosis was observed in groups 10TP and 10TP+DOX

Systemic treatment of Krukenberg tumors

Of all ovarian tumors with distinct biological features, 10-25% are secondary ovarian tumors. Among the most common cancers that cause ovarian metastasis are breast cancer, colorectal cancer, endometrium, as well as gastric and lateral cancer. Krukenberg tumors remain asymptomatic until the tumor reaches a certain size, as in the case of primary ovarian cancer. Symptoms are non-specific: abdominal pain (42%), postmenopausal bleeding (18%), weight loss (6%) and an increasing abdominal girth (15%). Diagnostic procedures should include physical examination, basic blood and biochemistry tests, radiographic imaging and endoscopy. There are currently no uniform guidelines to be followed in order to treat this cancer. However, the survival rate of selected subgroups of patients may be enhanced by means of cytoreductive surgery (performable among patients with good general health condition), where the metastases are limited only to the ovaries, where the primary tumor is derived from the colorectal cancer, and where there is the absence or minimal residual disease. It is still controversial to use adjuvant chemotherapy following the metastasectomy of Krukenberg tumors. Although this type of treatment seems to provide a survival benefit, there are currently no randomized prospective trials available so as to confirm or deny. Future research should, therefore, be focused on the potentially synergistic effect of surgery and perioperative administration of cytotoxic therapies targeted at high response rates. Studies on new molecularly targeted drugs can also be beneficial

Oncoplastic breast surgery techniques - a new look at surgical treatment of breast cancer

Breast cancer is the most common cancer among Polish women [1], thus, the problem of surgical treatment of breasts, especially with regard to conserving and/or reconstruction surgery, is extensively discussed. Currently, in Poland, efforts are made to increase the number of oncologic and reconstructive breast centers which offer specialized treatment of this cancer, the so-called ‘Breast Units’ [1]. This paper analyzes methods of reconstructions, discusses the techniques used in particular types of surgeries and additionally informs the reader of the oncological aspects of the procedures. Based on literature, statistical data of breast reconstructions from Poland and the world are presented. Moreover, complications and psychological aspects of mammary gland surgery are dealt with, and the aesthetic effects of breast reconstructions are discussed. To support of our findings, we also present selected clinical cases from the oncological and reconstructive point of view

Dietary Copper Deficiency Leads to Changes in Gene Expression Indicating an Increased Demand for NADH in the Prefrontal Cortex of the Rat’s Brain

Copper is an essential element to brain cells as it is a cofactor and a structural component of various enzymes involved in energy metabolism pathways. Accumulating evidence points to the pivotal role of copper deficiency in neurodegeneration resulting from impaired copper homeostasis. Despite the indisputable role of copper in mitochondrial respiration, its homeostasis regulation in the brain tissue remains unclear. The assessment of changes in the expression of genes encoding key pathways of energy metabolism can greatly benefit further studies exploring copper’s role in neurodegeneration. Using a rat model, we investigate whether the replacement of the inorganic form of copper with metallic nanoparticles containing copper or complete deprivation of copper from the diet have an impact on the expression of genes involved in energy metabolism in the prefrontal cortex of the rats’ brain. Herein, we indicate that removing inorganic copper from the normal standard diet or the replacement with copper nanoparticles can lead to programmed energy metabolism changes. It can be recognized that some of these changes indicate an increased demand for NADH in the prefrontal cortex of the rat’s brain, probably as a result of adaptation effect

Phase 2 study of retifanlimab (INCMGA00012) in patients (pts) with selected solid tumors (POD1UM-203).

International audience2571 Background: Checkpoint inhibitors (CPIs) are an effective treatment (tx) for many tumor types. Retifanlimab, an investigational humanized anti–PD-1 monoclonal antibody, has shown safety, pharmacology, and clinical activity consistent with the class. POD1UM-203 (NCT03679767) assessed efficacy and safety of retifanlimab in pts with selected solid tumors where CPI monotherapy is highly active. Methods: Eligible pts (≥18 y) had tx-naïve metastatic non-small cell lung cancer (NSCLC) with high PD-L1 expression (tumor proportion score ≥50%), cisplatin ineligible locally-advanced/metastatic urothelial cancer (UC) with PD-L1 expression (combined positive score ≥10%), unresectable/metastatic melanoma, or tx-naïve locally advanced/metastatic clear-cell renal cell carcinoma (RCC). Measurable disease (RECIST v1.1) was required. ECOG PS >1 and prior PD-1/PD-L1 directed tx were exclusions. Retifanlimab was administered as an IV infusion at 500 mg every 4 wks over 30 min. Primary endpoint was investigator-assessed objective response rate (ORR). Secondary endpoints were duration of response (DOR), disease control rate (DCR), progression-free survival, overall survival, safety, and pharmacokinetics. Results: A total of 121 pts (35 melanoma, 23 NSCLC, 29 UC, 34 RCC) received ≥1 dose of retifanlimab and were included in the analyses. Median duration of tx was 169 d (range, 1–442). The efficacy cut-off for the primary analysis occurred once all pts had been followed for at least 6 mo from the time of initial tx. Confirmed RECIST v1.1 responses were observed in all tumor types (Table) and were consistent with published ORR for other CPIs; median DOR was not reached for any tumor cohort and tx was ongoing at the time of data cutoff for 17, 11, 9, and 15 pts with melanoma, NSCLC, UC, and RCC, respectively. The most common tx-emergent AEs (TEAEs, >10% incidence) were asthenia (17.4%), arthralgia (14.9%), decreased appetite (14.0%), pruritus (12.4%), rash (10.7%), and urinary tract infection (10.7%); majority of TEAEs were low grade (≤ grade 2) and none led to tx discontinuation. Immune-related AEs occurred in 23 pts (19.0%), most common (>1% incidence) were hypothyroidism (7.4%), rash (4.1%), hyperthyroidism (2.5%), and pruritus (1.7%). Immune-related AEs led to dose delay in 5 pts (4.1%), but none led to tx discontinuation and/or dose interruption. Conclusions: Retifanlimab demonstrated antitumor activity and was generally well-tolerated in pts with melanoma, NSCLC, UC, or RCC comparable with approved CPIs for these tumor types. These results support ongoing further development of retifanlimab. Clinical trial information: NCT03679767. [Table: see text

The Lack of Synergy between Carvedilol and the Preventive Effect of Dexrazoxane in the Model of Chronic Anthracycline-Induced Cardiomyopathy

The anticancer efficacy of doxorubicin (DOX) is dose-limited because of cardiomyopathy, the most significant adverse effect. Initially, cardiotoxicity develops clinically silently, but it eventually appears as dilated cardiomyopathy with a very poor prognosis. Dexrazoxane (DEX) is the only FDA-approved drug to prevent the development of anthracycline cardiomyopathy, but its efficacy is insufficient. Carvedilol (CVD) is another product being tested in clinical trials for the same indication. This study’s objective was to evaluate anthracycline cardiotoxicity in rats treated with CVD in combination with DEX. The studies were conducted using male Wistar rats receiving DOX (1.6 mg/kg b.w. i.p., cumulative dose: 16 mg/kg b.w.), DOX and DEX (25 mg/kg b.w. i.p.), DOX and CVD (1 mg/kg b.w. i.p.), or a combination (DOX + DEX + CVD) for 10 weeks. Afterward, in the 11th and 21st weeks of the study, echocardiography (ECHO) was performed, and the tissues were collected. The addition of CVD to DEX as a cardioprotective factor against DOX had no favorable advantages in terms of functional (ECHO), morphological (microscopic evaluation), and biochemical alterations (cardiac troponin I and brain natriuretic peptide levels), as well as systemic toxicity (mortality and presence of ascites). Moreover, alterations caused by DOX were abolished at the tissue level by DEX; however, when CVD was added, the persistence of DOX-induced unfavorable alterations was observed. The addition of CVD normalized the aberrant expression of the vast majority of indicated genes in the DOX + DEX group. Overall, the results indicate that there is no justification to use a simultaneous treatment of DEX and CVD in DOX-induced cardiotoxicity

The differential effects of green tea on dose-dependent doxorubicin toxicity

Background: Doxorubicin (DOX) is an anticancer drug displaying cardiac and hepatic adverse effects mostly dependent on oxidative stress. Green tea (GT) has been reported to play a protective role in diseases resulting from oxidative stress. Objective: The objective of this study was to evaluate if GT protects against DOX-induced oxidative stress, heart and liver morphological changes, and metabolic disorders. Methods: Male Wistar rats received intraperitoneal injection of DOX (1.0 or 2.0 mg/kg b.w.) for 7 weeks or concomitantly GT extract soluble in drinking water. Results: There were multidirectional effects of GT on blood metabolic parameters changed by DOX. Among all tested biochemical parameters, statistically significant protection of GT against DOX-induced changes was revealed in case of blood fatty acid–binding protein, brain natriuretic peptide, and superoxide dismutase. Conclusion: DOX caused oxidative stress in both organs. It was inhibited by GT in the heart but remained unchanged in the liver. DOX-induced general toxicity and histopathological changes in the heart and in the liver were mitigated by GT at a higher dose of DOX and augmented in rats treated with a lower dose of the drug

Assessment of the Impact of Carvedilol Administered Together with Dexrazoxan and Doxorubicin on Liver Structure and Function, Iron Metabolism, and Myocardial Redox System in Rats

Late cardiotoxicity is a formidable challenge in anthracycline-based anticancer treatments. Previous research hypothesized that co-administration of carvedilol (CVD) and dexrazoxane (DEX) might provide superior protection against doxorubicin (DOX)-induced cardiotoxicity compared to DEX alone. However, the anticipated benefits were not substantiated by the findings. This study focuses on investigating the impact of CVD on myocardial redox system parameters in rats treated with DOX + DEX, examining its influence on overall toxicity and iron metabolism. Additionally, considering the previously observed DOX-induced ascites, a seldom-discussed condition, the study explores the potential involvement of the liver in ascites development. Compounds were administered weekly for ten weeks, with a specific emphasis on comparing parameter changes between DOX + DEX + CVD and DOX + DEX groups. Evaluation included alterations in body weight, feed and water consumption, and analysis of NADPH2, NADP+, NADPH2/NADP+, lipid peroxidation, oxidized DNA, and mRNA for superoxide dismutase 2 and catalase expressions in cardiac muscle. The iron management panel included markers for iron, transferrin, and ferritin. Liver abnormalities were assessed through histological examinations, aspartate transaminase, alanine transaminase, and serum albumin level measurements. During weeks 11 and 21, reduced NADPH2 levels were observed in almost all examined groups. Co-administration of DEX and CVD negatively affected transferrin levels in DOX-treated rats but did not influence body weight changes. Ascites predominantly resulted from cardiac muscle dysfunction rather than liver-related effects. The study’s findings, exploring the impact of DEX and CVD on DOX-induced cardiotoxicity, indicate a lack of scientific justification for advocating the combined use of these drugs at histological, biochemical, and molecular levels