Ferroptosis, Inflammation, and Microbiome Alterations in the Intestine in the Göttingen Minipig Model of Hematopoietic-Acute Radiation Syndrome.

Hematopoietic acute radiation syndrome (H-ARS) involves injury to multiple organ systems following total body irradiation (TBI). Our laboratory demonstrated that captopril, an angiotensin-converting enzyme inhibitor, mitigates H-ARS in Göttingen minipigs, with improved survival and hematopoietic recovery, as well as the suppression of acute inflammation. However, the effects of captopril on the gastrointestinal (GI) system after TBI are not well known. We used a Göttingen minipig H-ARS model to investigate captopril's effects on the GI following TBI (60Co 1.79 or 1.80 Gy, 0.42-0.48 Gy/min), with endpoints at 6 or 35 days. The vehicle or captopril (0.96 mg/kg) was administered orally twice daily for 12 days, starting 4 h post-irradiation. Ilea were harvested for histological, protein, and RNA analyses. TBI increased congestion and mucosa erosion and hemorrhage, which were modulated by captopril. GPX-4 and SLC7A11 were downregulated post-irradiation, consistent with ferroptosis at 6 and 35 days post-irradiation in all groups. Interestingly, p21/waf1 increased at 6 days in vehicle-treated but not captopril-treated animals. An RT-qPCR analysis showed that radiation increased the gene expression of inflammatory cytokines IL1B, TNFA, CCL2, IL18, and CXCL8, and the inflammasome component NLRP3. Captopril suppressed radiation-induced IL1B and TNFA. Rectal microbiome analysis showed that 1 day of captopril treatment with radiation decreased overall diversity, with increased Proteobacteria phyla and Escherichia genera. By 6 days, captopril increased the relative abundance of Enterococcus, previously associated with improved H-ARS survival in mice. Our data suggest that captopril mitigates senescence, some inflammation, and microbiome alterations, but not ferroptosis markers in the intestine following TBI.

Cardiac and Pericardial Neoplasms in Children: Radiologic-Pathologic Correlation.

Primary cardiac and pericardial neoplasms are rare in the pediatric population and can include both benign and malignant lesions. Rhabdomyomas, teratomas, fibromas, and hemangiomas are the most common benign tumors. The most common primary cardiac malignancies are soft-tissue sarcomas, including undifferentiated sarcomas, rhabdomyosarcomas, and fibrosarcomas. However, metastatic lesions are more common than primary cardiac neoplasms. Children with primary cardiac and pericardial tumors may present with nonspecific cardiovascular symptoms, and their clinical presentation may mimic that of more common nonneoplastic cardiac disease. The diagnosis of cardiac tumors has recently been facilitated using noninvasive cardiac imaging. Echocardiography is generally the first-line modality for evaluation. Cardiac MRI and CT are used for tissue characterization and evaluation of tumor size, extension, and physiologic effect. The varied imaging appearances of primary cardiac neoplasms can be explained by their underlying abnormality. Treatment of these lesions varies from conservative management, with spontaneous regression of some lesions such as rhabdomyomas, to surgical resection, particularly in patients with associated heart failure. With adequate imaging techniques and knowledge of the pathologic basis of the neoplasm, it is often possible to differentiate benign from malignant tumors, which can greatly affect adequate and timely treatment. ©RSNA, 2023 Quiz questions for this article are available through the Online Learning Center.

Pathology Competencies in Medical Education and Educational Cases: Update 2023.

Pathology is a core component of medical school curricula because understanding the pathogenesis of the disease is foundational both for diagnostic efficiency and optimal use of ancillary resources in patient care. The Pathology Competencies for Medical Education (PCME) were developed as a national resource of expectations of pathology knowledge for medical students. The PCME are composed of three competencies: disease mechanisms and processes, organ system pathology, and diagnostic pathology and therapeutic pathology. The learning goals and learning objectives of the PCME that were first published in 2017 have been carefully revised and updated. Significant additions were made to fill gaps of the original PCME objectives, and some learning objectives have been retired or moved to more appropriate locations within the competencies. As curricula and the practice of medicine change, the PCME will continue to be revised and updated periodically. They have and will continue to serve as the organizing principle for the growing number of educational cases published by Academic Pathology. Nomenclature in the original and revised PCME will allow for continued linking of previous and new educational cases to the revised learning objectives. PCME and the educational cases can be adapted into any type of curricula. Having a widely accepted resource of learning objectives in pathology will help students and medical educators focus on essential components of pathology for the future practice of medicine.

Educational Case: Urinary Stones.

The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, seehttp://journals.sagepub.com/doi/10.1177/2374289517715040. 1.

Educational Case: Thymoma.

The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040. 1.

Mediastinal Masses in Children: Radiologic-Pathologic Correlation.

Most pediatric masses in the chest are located in the mediastinum. These masses are often initially detected incidentally on chest radiographs in asymptomatic children, although some patients may present with respiratory symptoms. At chest radiography, the mediastinum has been anatomically divided into anterior, middle, and posterior compartments. However, with the International Thymic Malignancy Interest Group classification scheme, which is based on cross-sectional imaging findings, the mediastinum is divided into prevascular, visceral, and paravertebral compartments. In the prevascular compartment, tumors of thymic origin, lymphomas, germ cell tumors, and vascular tumors are encountered. In the visceral compartment, lymphadenopathy and masses related to the foregut are seen. In the paravertebral compartment, neurogenic tumors are most common. Using the anatomic location in combination with knowledge of the imaging and pathologic features of pediatric mediastinal masses aids in accurate diagnosis of these masses to guide treatment and management decisions. An invited commentary by Lee and Winant is available online. ©RSNA, 2021.

Educational Case: Acute Cystitis.

The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040.1.

Educational Case: Autosomal Dominant Polycystic Kidney Disease.

The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040.1.

Clinically Unsuspected Injection Drug Abuse in Hospitalized Teens Diagnosed on Pathology.

Intravenous injection of medications intended for oral use can lead to pulmonary hypertension and death. Pathologic findings in the lung include embolization of foreign material, with the specific identification of excipients accomplished through special stains. Risk factors for this type of drug abuse include indwelling venous access and chronic medical problems. These risk factors, especially in adolescent and young adult patients, should prompt intravenous drug use as a possibility of lung disease/lesions. We describe 2 patients from a pediatric hospital with pulmonary pathology indicative of intravenous drug use, identified in autopsy and surgical pathology cases. Drug abuse was not clinically suspected in either patient until the time of pathologic exam, emphasizing a need for the pathologist to be able to recognize the associated histologic changes.

Educational Case: Peripheral Nerve Sheath Tumors.

The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040.

Primary Lung Tumors in Children: Radiologic-Pathologic Correlation From the Radiologic Pathology Archives.

Primary lung tumors in children are rare, with a narrow range of diagnostic considerations. However, the overlapping imaging appearances of these tumors necessitate attention to key discriminating imaging and pathologic features. In the neonate and infant, the important considerations include pleuropulmonary blastoma (PPB), infantile fibrosarcoma, and fetal lung interstitial tumor. Among these tumors, imaging findings such as air-filled cysts in type 1 PPB and homogeneously low attenuation of fetal lung interstitial tumors are relatively specific. Key pathologic and genetic discriminators among this group of tumors include the DICER1 germline mutation found in PPB and the t(12,15)(p13;q25) translocation and ETV6-NTRK3 fusion gene seen in infantile fibrosarcoma. Primary lung tumors in older children include inflammatory myofibroblastic tumors (IMTs), carcinoid salivary gland-type tumors of the lung, recurrent respiratory papillomatosis, and other rare entities. IMT, a spindle-cell proliferation with inflammatory elements, is the most common lung tumor in children. Anaplastic lymphoma kinase, a receptor-type protein tyrosine kinase, is present in 50% of these tumors, and this finding may support an imaging diagnosis of IMT. Carcinoid tumors account for a substantial portion of childhood lung tumors, and their characteristic avid enhancement on images corresponds to the compressed fibrovascular stroma histologically. Furthermore, novel imaging agents used with somatostatin receptor analogs have an emerging role in the evaluation of carcinoid tumors. Although less common than mucoepidermoid carcinoma, adenoid cystic carcinoma tends to recur given the perineural spread seen histologically. Integrating radiologic and pathologic knowledge is critical to accurate diagnosis, treatment planning, and surveillance of primary lung tumors in children.

Rapidly growing subcutaneous mass in an infant.

Fibrous hamartoma of infancy (FHI) is a benign mesenchymal tumor of young children. It has a broad clinical differential diagnosis and is often clinically confused for vascular and malignant soft tissue neoplasms. Recognition of the unique histologic features of FHI, a triphasic population of mature adipose tissue, mature fibrous tissue, and immature mesenchymal tissue, will ensure the correct diagnosis. In this report we present a case of this rare entity, including the associated clinical, radiologic, and histologic findings.

Educational Case: Wilms Tumor.

The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040.

Segmental storiform collagenomas: Expanding the spectrum of PTEN hamartoma tumor syndrome in children.

A 4-year-old girl with autism spectrum disorder and congenital heart disease presented to dermatology clinic for evaluation of skin growths present since infancy. Physical examination was significant for macrocephaly and agminated skin-colored to pink papulonodules in a segmental distribution on the right lower back and buttocks, biopsy of which showed storiform collagenomas (sclerotic fibromas). Genetic testing revealed a pathogenic missense mutation in the PTEN gene, and a diagnosis of PTEN hamartoma tumor syndrome was made. The segmental nature of her storiform collagenomas is unique, to our knowledge, and may be explained by a postzygotic second-hit PTEN mutation, contributing to the growing spectrum of clinical findings associated with PTEN hamartoma tumor syndrome.

Histologic and Molecular Profile of Pediatric Insulinomas: Evidence of a Paternal Parent-of-Origin Effect.

CONTEXT: Acquired insulinomas are rare causes of hyperinsulinemic hypoglycemia in children and are much less common than focal lesions of congenital hyperinsulinism. The latter are known to be associated with isodisomy for paternally transmitted ATP-sensitive potassium channel mutations on 11p15; however, the molecular basis for pediatric insulinomas is not well characterized. OBJECTIVE: The purpose of this study was to characterize the histopathological and molecular defects in a large group of 12 pediatric insulinomas seen at The Children's Hospital of Philadelphia. RESULTS: Twelve children with insulinomas were seen between 1971 and 2013, compared to 201 cases with focal congenital hyperinsulinism seen between 1997 and 2014. The age of insulinoma patients ranged from 4-16 years at the time of surgery. Features of MEN1 syndrome were present in five of the 12, including four cases with heterozygous mutations of MEN1 on 11q. Immunohistochemical analysis revealed nuclear loss of p57 staining consistent with loss of the maternal 11p15 allele in 11 of the 12 insulinomas, including all five MEN1-associated tumors. Imbalance of the paternal 11p allele was confirmed by single nucleotide polymorphism genotyping and methylation assays of the 11p imprinting control loci in four of five MEN1-associated tumors and six of seven sporadic insulinomas. In addition, single nucleotide polymorphism genotyping revealed extensive tumor aneuploidy beyond chromosome 11. CONCLUSIONS: These data indicate that MEN1 mutations are more common in insulinomas in children than in adults. Aneuploidy of chromosome 11 and other chromosomes is common in both MEN1 and non-MEN1 insulinomas. The novel observation of a paternal parent-of-origin effect in all MEN1 and most non-MEN1 tumors suggests a critical role for imprinted growth-regulatory genes in the 11p region in the genesis of ß-cell endocrine tumors in children.

Pathologic Findings in NEMO Deficiency: A Surgical and Autopsy Survey.

Hypomorphic mutations in nuclear factor κB (NF-κB) essential modulator (NEMO), encoded by IKBKG, lead to a variable combined immunodeficiency, which puts patients at risk of early death from infectious complications. The spectrum of clinical manifestations includes inflammatory disorders, especially colitis. Because of the multiple complications of NEMO deficiency, a variety of biopsy, excisional, and autopsy materials from these patients may be subject to pathologic examination. Therefore, using samples from a cohort of patients with this disorder, we aimed to survey the pathologic spectrum of NEMO deficiency and search for correlations between specific genotypes and phenotypes. Clinical and laboratory data, mutation analysis, and pathology from 13 patients were examined, including 6 autopsies. No specific genotype-pathology correlation was identified. However, we confirmed an association between ectodermal dysplasia and inflammatory conditions. We found no characteristic pathology to identify patients with NEMO deficiency; therefore, history, physical examination, and specific infections must remain the clues to suggest the diagnosis. Variability among patients and by infection makes the pathologic recognition of NEMO deficiency challenging.

Vincristine and Dactinomycin in Infantile Myofibromatosis With a Review of Treatment Options.

Although solitary presentations of infantile myofibromatosis tend toward spontaneous regression, multicentric forms fare worse. Previous case reports have depicted observation, surgical resection, and systemic therapies as treatment options. This paper reports well-tolerated, successful outcomes in a series of patients with high-risk infantile myofibromatosis in need of life-sustaining interventions treated with a combination of vincristine and dactinomycin. The clinical presentation, pathology, and radiographic findings are described.