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Doxorubicin and daunorubicin are anticancer drugs of the anthracycline class. These compounds are known to produce toxic effects on the heart. However, much less is known about their long-term effects on the heart. For this reason, a study of heart function was undertaken in 115 children who had received doxorubicin up to 15 years previously as part of the treatment regimen for acute lymphoblastic leukemia. The evaluation of these patients included a questionnaire, electrocardiography, exercise testing, and echocardiographic imaging. Fifty-seven percent of the patients had signs of abnormalities of the heart muscle that were revealed as wall stress or altered muscle contractility. Echocardiography revealed that the thickness of the posterior wall of the left ventricle, when adjusted for body size, was significantly smaller in the doxorubicin-treated patients than in normal control subjects. The most important determining factor of the heart muscle abnormalities was the dose of doxorubicin that had been administered; the majority of the patients who had received only a single dose of doxorubicin had little or no indication of any heart abnormality. Eleven patients had heart failure. However, in no case did heart failure appear only as a late complication long after the chemotherapy. Heart failure occurred within a year of doxorubicin treatment, and in five patients heart failure recurred at intervals ranging from 4 to 10 years after chemotherapy. Two patients required heart transplantation. The results indicate that doxorubicin therapy in childhood does indeed result in impaired heart function. The authors suggest that treatment with the drug may result in the destruction of some heart muscle cells, and that as the child grows this loss is reflected in inadequate muscle mass. (Consumer Summary produced by Reliance Medical Information, Inc.)

Abstract Background MicroRNAs (miRNAs) are nucleic acid regulators of many human mRNAs, and are associated with many tumorigenic processes. miRNA expression levels have been used in profiling studies, but some evidence suggests that expression levels do not fully capture miRNA regulatory activity. In this study we integrate multiple gene expression datasets to determine miRNA activity patterns associated with cancer phenotypes and oncogenic pathways in mesenchymal tumors – a very heterogeneous class of malignancies. Results Using a computational method, we identified differentially activated miRNAs between 77 normal tissue specimens and 135 sarcomas and we validated many of these findings with microarray interrogation of an independent, paraffin-based cohort of 18 tumors. We also showed that miRNA activity is imperfectly correlated with miRNA expression levels. Using next-generation miRNA sequencing we identified potential base sequence alterations which may explain differential activity. We then analyzed miRNA activity changes related to the RAS-pathway and found 21 miRNAs that switch from silenced to activated status in parallel with RAS activation. Importantly, nearly half of these 21 miRNAs were predicted to regulate integral parts of the miRNA processing machinery, and our gene expression analysis revealed significant reductions of these transcripts in RAS-active tumors. These results suggest an association between RAS signaling and miRNA processing in which miRNAs may attenuate their own biogenesis. Conclusions Our study represents the first gene expression-based investigation of miRNA regulatory activity in human sarcomas, and our findings indicate that miRNA activity patterns derived from integrated transcriptomic data are reproducible and biologically informative in cancer. We identified an association between RAS signaling and miRNA processing, and demonstrated sequence alterations as plausible causes for differential miRNA activity. Finally, our study highlights the value of systems level integrative miRNA/mRNA assessment with high-throughput genomic data, and the applicability of paraffin-tissue-derived RNA for validation of novel findings.

Objective: Pleomorphic adenoma is the most common benign salivary gland neoplasm in children. Recurrence and malignant transformation are concerns necessitating proper treatment. The goal of this research was to discuss the presentation, evaluation, and management of pediatric pleomorphic adenoma of the head and neck.Methods: Retrospective chart review of patients under 20 years of age treated for pleomorphic adenoma of the head and neck between 1998 and 2017. Data assessed included demographics, clinical presentation, imaging, treatment, complications, recurrence, and follow-up.Results: Forty-one patients with pleomorphic adenoma were identified. Major salivary gland lesions were most common (n = 32, 78.0%); 78.1% (25 of 32) arising in the parotid and 21.9% (7 of 32) in the submandibular glands. Minor salivary gland lesions were removed from the palate (5 of 9, 55.6%), buccal mucosa (2 of 9, 22.2%), parapharyngeal space (1 of 9, 11.1%), and upper lip (1 of 9, 11.1%). Preoperative imaging was reviewed in 32 patients and consisted of nine ultrasound exams, 15 computerized tomography (CT) exams, and 23 magnetic resonance imaging (MRI) exams. Multimodality imaging was performed in 14 of 32 patients. Surgical excision was performed in all patients. Postoperative complications included transient facial paresis (n = 9), Frey syndrome (n = 1), and bacterial pharyngitis (n = 1). Average length of follow-up was 25.5 months; confirmed recurrence occurred in two patients (4.9%).Conclusion: Evaluation of pleomorphic adenoma in children should include preoperative imaging. The goal of surgery should be complete surgical excision with negative margins. Rate of recurrence is low; however, prolonged monitoring is recommended.Level Of Evidence: 4. Laryngoscope, 129:2603-2609, 2019. [ABSTRACT FROM AUTHOR]

Abstract Background The chromodomain, helicase DNA-binding protein 5 (CHD5) is a potential tumor suppressor gene located on chromosome 1p36, a region recurrently deleted in high risk neuroblastoma (NB). Previous data have shown that CHD5 mRNA is present in normal neural tissues and in low risk NB, nevertheless, the distribution of CHD5 protein has not been explored. The aim of this study was to investigate CHD5 protein expression as an immunohistochemical marker of outcome in NB. With this purpose, CHD5 protein expression was analyzed in normal neural tissues and neuroblastic tumors (NTs). CHD5 gene and protein expression was reexamined after induction chemotherapy in a subset of high risk tumors to identify potential changes reflecting tumor response. Results We provide evidence that CHD5 is a neuron-specific protein, absent in glial cells, with diverse expression amongst neuron types. Within NTs, CHD5 immunoreactivity was found restricted to differentiating neuroblasts and ganglion-like cells, and absent in undifferentiated neuroblasts and stromal Schwann cells. Correlation between protein and mRNA levels was found, suggesting transcriptional regulation of CHD5. An immunohistochemical analysis of 90 primary NTs highlighted a strong association of CHD5 expression with favorable prognostic variables (age at diagnosis Reactivation of CHD5 expression after induction chemotherapy was observed mainly in those high risk tumors with induced tumor cell differentiation features. Remarkably, these NB tumors showed good clinical response and prolonged patient survival. Conclusions The neuron-specific protein CHD5 may represent a marker of outcome in NB that can be tested by conventional immunohistochemistry. Re-establishment of CHD5 expression induced by chemotherapy could be a surrogate marker of treatment response.

Background: There are only 15 reported hepatic epidermoid cysts; they include patients presenting congenitally through adulthood, with varied speculations about pathogenesis. Aside from recently reported pancytokeratin staining, no other descriptions have included immunohistochemistry. Splenic epidermoid cysts were recently characterized as positive for HBME-1, p63, CEA, CK7 (luminal), and CK19. We interrogate 2 hepatic epidermoid cysts with a broad panel of immunohistochemistry, with the aim of elucidating histogenesis. Methods: Archives were searched for "liver," "hepatic," and "cyst." Hepatic cysts lined by squamous epithelium were included. Clinical records, macroscopic findings, and hematoxylin and eosin and immunohistochemically stained slides were reviewed. Results: We identified 2 patients with epidermoid cysts of the liver, first detected on antenatal ultrasound. Both were females and asymptomatic; neither had other congenital abnormalities. Cysts enlarged slowly after birth. Resection was at ages 2 and 6 months, done to avoid potentially more difficult surgery in the future. Cysts were unilocular (4.8 cm) and multilocular (7.0 cm). Both were lined by stratified nonkeratinizing squamous to focally transitional-like epithelium and surrounded by paucicellular fibrous stroma. In the multilocular cyst, hepatocytes and fibrous stroma populated septa. Epithelium was positive for HBME-1, p63, CK19, CEA, Cam5.2, and CK7, negative for EMA, D2-40, WT-1, calretinin, and Ca19-9. Cytogenetic analysis of one showed a normal female karyotype. During the study period, 22 other pediatric liver cysts were diagnosed. Conclusion: Hepatic epidermoid cyst is a distinct entity, rare but nevertheless constituting 8% of pediatric hepatic cysts at our institution. It is characterized by intrauterine onset and growth roughly commensurate with that of the fetus/infant; it is apparently unsyndromic. It may be unilocular or multilocular. It stains for an array of epithelial markers as well as HBME-1. Strong immunohistochemical overlap with splenic epidermoid cyst points to a shared pathogenesis and detracts from hypotheses that hepatic epidermoid cysts derive from hepatic elements. [ABSTRACT FROM AUTHOR]

Fanconi-Bickel syndrome is a rare autosomal recessive disorder due to mutations in the facilitative glucose transporter 2 (GLUT2 or SLC2A2) gene resulting in excessive glycogen storage predominantly in the liver and kidney. Previous case reports of this condition have described liver biopsies with glycogen storage and variable steatosis and/or fibrosis. Unlike in other types of glycogen storage disease, hepatocellular adenomas and carcinomas have not been described to date in this syndrome. A 6-year-old boy with consanguineous parents had short stature, poorly controlled rickets, hepatosplenomegaly, and renal tubular dysfunction clinically consistent with Fanconi-Bickel Syndrome. Sequencing of the SLC2A2 gene showed a homozygous variant of unknown significance [c.474A > C (p.Arg158Ser)] causing a missense mutation in an evolutionarily conserved residue. An incidental single hepatic lesion was discovered on imaging, and subsequent resection showed a 2.6 cm well-differentiated hepatocellular carcinoma with moderate atypia, diffuse immunoreactivity for glypican-3, and nuclear b-catenin, and with focal complete loss of the reticulin framework. The non-neoplastic liver showed marked glycogen accumulation with mild periportal fibrosis, rare bridging fibrosis, and no regenerative or adenomatous nodules. By electron microscopy, tumor cells had pleomorphic nuclei, prominent nucleoli, and scant cytoplasm with numerous mitochondria. Well-developed canaliculi were occasionally seen. The non-neoplastic liver showed glycogenosis with abundant cytoplasmic free (non-membrane bound) glycogen. Hepatocellular carcinoma should be considered as a possible complication of Fanconi-Bickel syndrome. This well differentiated carcinoma did not appear to be associated with hepatic adenomatosis as has been described in some hepatocellular carcinomas associated with other hepatic glycogen storage disorders. The nuclear beta-catenin immunoreactivity indicates a role for the Wnt signaling pathway in the pathogenesis of this tumor. [ABSTRACT FROM AUTHOR]