Case report: Histological findings of peri-appendicitis in three children with SARS-CoV-2 – related multisystem inflammatory syndrome: A mark for systemic inflammation?

Background: Multisystem inflammatory syndrome in children (MIS-C) is a rare but serious condition that can potentially develop after SARS-CoV-2 infection in children. Gastrointestinal manifestation in MIS-C can mimic acute abdomen, potentially leading to unnecessary surgical treatment. Immune-mediated mechanisms seem to be a determining factor in its pathogenesis, and histological studies can help to shed light on this aspect. We describe three cases of children diagnosed with MIS-C that underwent appendectomy. Methods: We retrospectively collected the clinical features and histological findings of three previously healthy children who underwent appendectomy for clinical suspicion of acute appendicitis but were later diagnosed with MIS-C. Findings: The three children presentedwith prominent abdominalmanifestations andfever leading tothe suspicion of acute abdomen.Histological findings showed transmural and perivascular inflammation. Notably, CD68+ macrophages were predominant in the child with milder abdominal symptoms without cardiac injury, while CD3+ lymphocytes in the patient presented with more severe abdominal pain and cardiovascular involvement at admission. Interpretation: Gastrointestinal symptoms of children with MIS-C improve after proper immunomodulatory therapy, conversely showing inadequate response to surgical appendectomy. Histological findings revealed different inflammatory cell infiltration that primarily involved perivisceral fat and vessels, and subsequently mucosal tissue, in contrast to other forms of acute appendicitis. Our findings suggest that this kind of peri-appendicitis in MIS-C could represent a focal sign of systemic inflammation, with different histological patterns compared to other forms of acute appendicitis

The Role of Nutrition in Primary and Secondary Prevention of Cardiovascular Damage in Childhood Cancer Survivors

Innovative therapeutic strategies in childhood cancer led to a significant reduction in cancer-related mortality. Cancer survivors are a growing fragile population, at risk of long-term side effects of cancer treatments, thus requiring customized clinical attention. Antineoplastic drugs have a wide toxicity profile that can limit their clinical usage and spoil patients’ life, even years after the end of treatment. The cardiovascular system is a well-known target of antineoplastic treatments, including anthracyclines, chest radiotherapy and new molecules, such as tyrosine kinase inhibitors. We investigated nutritional changes in children with cancer from the diagnosis to the end of treatment and dietary habits in cancer survivors. At diagnosis, children with cancer may present variable degrees of malnutrition, potentially affecting drug tolerability and prognosis. During cancer treatment, the usage of corticosteroids can lead to rapid weight gain, exposing children to overweight and obesity. Moreover, dietary habits and lifestyle often dramatically change in cancer survivors, who acquire sedentary behavior and weak adherence to dietary guidelines. Furthermore, we speculated on the role of nutrition in the primary prevention of cardiac damage, investigating the potential cardioprotective role of diet-derived compounds with antioxidative properties. Finally, we summarized practical advice to improve the dietary habits of cancer survivors and their families

The Role of Nutrition in Primary and Secondary Prevention of Cardiovascular Damage in Childhood Cancer Survivors

Innovative therapeutic strategies in childhood cancer led to a significant reduction in cancer-related mortality. Cancer survivors are a growing fragile population, at risk of long-term side effects of cancer treatments, thus requiring customized clinical attention. Antineoplastic drugs have a wide toxicity profile that can limit their clinical usage and spoil patients’ life, even years after the end of treatment. The cardiovascular system is a well-known target of antineoplastic treatments, including anthracyclines, chest radiotherapy and new molecules, such as tyrosine kinase inhibitors. We investigated nutritional changes in children with cancer from the diagnosis to the end of treatment and dietary habits in cancer survivors. At diagnosis, children with cancer may present variable degrees of malnutrition, potentially affecting drug tolerability and prognosis. During cancer treatment, the usage of corticosteroids can lead to rapid weight gain, exposing children to overweight and obesity. Moreover, dietary habits and lifestyle often dramatically change in cancer survivors, who acquire sedentary behavior and weak adherence to dietary guidelines. Furthermore, we speculated on the role of nutrition in the primary prevention of cardiac damage, investigating the potential cardioprotective role of diet-derived compounds with antioxidative properties. Finally, we summarized practical advice to improve the dietary habits of cancer survivors and their families

Meccanismi molecolari della cardiotossicità indotta da antracicline e radioterapia

Il sistema cardiovascolare, con le sue peculiari caratteristiche di scarsa capacità rigenerativa ed enorme sensibilità allo stress ossidativo, è tra i principali bersagli delle tossicità indotte dalla chemioterapia e dalla radioterapia. Tra i chemioterapici, le Antracicline rappresentano un inequivocabile modello di cardiotossicità, essendone ben caratterizzati i fattori di rischio, l’epidemiologia e i principali meccanismi patogenetici. La cardiotossicità indotta da Antracicline è in gran parte dei casi ascrivibile ad una cardiopatia dilatativa a prevalente disfunzione sistolica, identificata tramite ecocardiografia come una riduzione di 10 punti della frazione di eiezione (LVEF) rispetto al valore basale o comunque < 50%. La patogenesi del danno cardiaco indotto da antracicline coinvolge meccanismi patogenetici diversi da quelli responsabili dell’attività antineoplastica. Tra questi, lo stress ossidativo, la disfunzione mitocondriale, l’alterazione del pool dei fosfati ad alta energia, la deregolazione del calcio intracellulare e l’alterazione dei pathways trascrizionali coinvolti nel normale funzionamento cardiaco sono tra i più importanti meccanismi coinvolti. La conseguente riduzione dell’efficienza metabolica ed energetica della cellula comporta una riduzione della funzionalità dei sarcomeri e un aumento dell’indice apoptotico cardiomiocitario; tali alterazioni determinano una disfunzione miocardica che progredisce verso l’insufficienza cardiaca conclamata. Trattamenti radioterapici del torace e del mediastino, analogamente alle antracicline, sono in grado di causare danni a livello cardiaco, che, mediamente, si manifestano ad anni dall’irradiamento. Essendo coinvolti il miocardio, i vasi coronarici e il pericardio, le manifestazioni di tale cardiotossicità sono molteplici: la più importante è, senza dubbio, la fibrosi del miocardio che conduce a cardiomiopatia e scompensa cardiaco. Alla base della comparsa di cardiotossicità indotta da radiazioni vi sono diversi meccanismi fisiopatologici: infiammazione e attivazione di numerose citochine, tra cui interleuchine, fattori di crescita tissutali e molecole di adesione; aumento della produzione di radicali liberi a livello tissutale; comparsa di danno microvascolare, con conseguente ipossia tissutale. Tali meccanismi culminano con l’attivazione di fibroblasti e miofibroblasti e quindi con l’aumento di matrice collagenica e fibrosi; questi processi sono tipici del danno a carico di miocardio e pericardio. A livello coronarico, invece, si assiste ad aumento della formazione di placche ateromasiche che coinvolgono, contrariamente ai normali processi ateromasici, principalmente vasi di piccolo e medio calibro

The novel butyrate derivative phenylalanine-butyramide protects from doxorubicin-induced cardiotoxicity

Butyric acid (BUT), a short chain fatty acid produced daily by the gut microbiota, has proven beneficial in models of cardiovascular diseases. With advancements in cancer survival, an increasing number of patients are at risk of anticancer drug cardiotoxicity. Here we assess whether the novel BUT derivative phenylalanine-butyramide (FBA) protects from doxorubicin (DOXO) cardiotoxicity, by decreasing oxidative stress and improving mitochondrial function

The novel butyrate derivative phenylalanine-butyramide protects from doxorubicin-induced cardiotoxicity.

Butyric acid (BUT), a short chain fatty acid produced daily by the gut microbiota, has proven beneficial in models of cardiovascular diseases. With advancements in cancer survival, an increasing number of patients are at risk of anticancer drug cardiotoxicity. Here we assess whether the novel BUT derivative phenylalanine-butyramide (FBA) protects from doxorubicin (DOXO) cardiotoxicity, by decreasing oxidative stress and improving mitochondrial function. In C57BL6 mice, DOXO produced left ventricular dilatation assessed by echocardiography. FBA prevented left ventricular dilatation, fibrosis and cardiomyocyte apoptosis when co-administered with DOXO. DOXO increased atrial natriuretic peptide, brain natriuretic peptide, connective tissue growth factor, and matrix metalloproteinase-2 mRNAs, which were not elevated on co-treatment with FBA. DOXO, but not FBA + DOXO mice, also showed higher nitrotyrosine levels, and increased inducible nitric oxide synthase expression. Accordingly, DOXO hearts showed lower levels of intracellular catalase vs. sham, while pre-treatment with FBA prevented this decrease. We then assessed for reactive oxygen species (ROS) emission: DOXO induced increased activity of mitochondrial superoxide dismutase and higher production of H O , which were blunted by FBA pre-treatment. FBA also ameliorated mitochondrial state 3 and state 4 respiration rates that were compromised by DOXO. Furthermore, in DOXO animals, the mitochondrial degree of coupling was significantly increased vs. sham, while FBA was able to prevent such increase, contributing to limit ROS production, Finally, FBA reduced DOXO damage in human cellular models, and increased the tumour-killing action of DOXO. Phenylalanine-butyramide protects against experimental doxorubicin cardiotoxicity. Such protection is accompanied by reduction in oxidative stress and amelioration of mitochondrial function