Mortality and Autopsy Findings in Patients with Pyoderma Gangrenosum: A Multi-Institutional Series.

INTRODUCTION: Pyoderma gangrenosum (PG) is a rare ulcerative skin condition with an increased risk of mortality compared to the general population. The causes of this increased risk are not well understood. Misdiagnosis is common in PG, and many studies are limited by the inclusion of misdiagnosed cases. The goal of this study was to review autopsy findings, identify causes of death, and identify factors that may worsen outcomes among deceased patients confirmed to have PG. METHODS: Data was retrospectively reviewed from the electronic medical records at five academic hospitals. A search was conducted for deceased patients with a diagnosis of PG who had an autopsy performed between 2010 and 2020. We report a descriptive analysis of 11 patients and their clinical characteristics, causes of death, and autopsy findings. RESULTS: The average age of death was 62.9 years. Seven patients had at least one underlying condition known to be associated with PG including inflammatory bowel disease, inflammatory arthritis, or a hematologic disorder. The most common cause of death was infection (n = 6, 54.5%), followed by pulmonary embolism (n = 3, 27.3%), and myelodysplastic syndrome (n = 2, 18.2%). Six patients (54.5%) were taking systemic steroids at the time of death. CONCLUSION: The development of PG may shorten life expectancy among those with underlying conditions associated with PG, and common treatments for PG may contribute to the risk of fatal complications. Awareness of the risk of infection, thrombosis, and malignancy among those with PG is necessary for proper management. Further research is needed to explore the relationship between PG and thromboembolism.

Multi-modality imaging assessment of microbubbles and cerebral emboli in left ventricular pulsed field ablation.

BACKGROUND: Pulsed field ablation (PFA) may have a superior safety profile compared to other technologies, but it has the potential to cause gaseous microbubbles (MB), which may be associated with cerebral emboli. Limited relative safety data has been published regarding PFA in the left ventricle (LV). METHODS: Healthy and chronic myocardial infarction (MI) swine underwent PFA (monopolar, biphasic, 25 Amps) in the LV using an irrigated focal catheter under intra-cardiac echocardiography (ICE) guidance for MB monitoring. Two control swine received air MBs through the lumen of the ablation catheter. Swine underwent brain MRI before and after PFA (or control air MB injection). Gross pathology and histology of brains with abnormal MRI findings were performed. RESULTS: Four healthy and 5 chronic MI swine underwent 124 left ventricular PFA applications. No PFA-related MB formation was noted on ICE. Both control swine developed multiple acute emboli in the thalamus and caudate on DWI, ADC, and FLAIR brain MRI images in response to air MB injection. Of the 9 PFA swine, there were no abnormalities on ADC or FLAIR images. There was one hyperintense focus in the left putamen on the DWI trace image, but the absence of ADC or FLAIR affirmation suggested it was artifact. Gross pathology and histopathology of this region did not detect any abnormalities. CONCLUSIONS: Focal monopolar biphasic PFA of both healthy and chronically infarcted left ventricular myocardium does not generate any MB or cerebral emboli observable on ICE and brain MRI.

A neonatal nonhuman primate model of gestational Zika virus infection with evidence of microencephaly, seizures and cardiomyopathy.

Zika virus infection during pregnancy is associated with miscarriage and with a broad spectrum of fetal and neonatal developmental abnormalities collectively known as congenital Zika syndrome (CZS). Symptomology of CZS includes malformations of the brain and skull, neurodevelopmental delay, seizures, joint contractures, hearing loss and visual impairment. Previous studies of Zika virus in pregnant rhesus macaques (Macaca mulatta) have described injury to the developing fetus and pregnancy loss, but neonatal outcomes following fetal Zika virus exposure have yet to be characterized in nonhuman primates. Herein we describe the presentation of rhesus macaque neonates with a spectrum of clinical outcomes, including one infant with CZS-like symptoms including cardiomyopathy, motor delay and seizure activity following maternal infection with Zika virus during the first trimester of pregnancy. Further characterization of this neonatal nonhuman primate model of gestational Zika virus infection will provide opportunities to evaluate the efficacy of pre- and postnatal therapeutics for gestational Zika virus infection and CZS.

Nod2 Deficiency Augments Th17 Responses and Exacerbates Autoimmune Arthritis.

Arthritis in a genetically susceptible SKG strain of mice models a theoretical paradigm wherein autoimmune arthritis arises because of interplay between preexisting autoreactive T cells and environmental stimuli. SKG mice have a point mutation in ZAP-70 that results in attenuated TCR signaling, altered thymic selection, and spontaneous production of autoreactive T cells that cause arthritis following exposure to microbial ß-glucans. In this study, we identify Nod2, an innate immune receptor, as a critical suppressor of arthritis in SKG mice. SKG mice deficient in Nod2 (Nod2-/-SKG) developed a dramatically exacerbated form of arthritis, which was independent of sex and microbiota, but required the skg mutation in T cells. Worsened arthritis in Nod2-/-SKG mice was accompanied by expansion of Th17 cells, which to some measure coproduced TNF, GM-CSF, and IL-22, along with elevated IL-17A levels within joint synovial fluid. Importantly, neutralization of IL-17A mitigated arthritis in Nod2-/-SKG mice, indicating that Nod2-mediated protection occurs through suppression of the Th17 response. Nod2 deficiency did not alter regulatory T cell development or function. Instead, Nod2 deficiency resulted in an enhanced fundamental ability of SKG CD4+ T cells (from naive mice) to produce increased levels of IL-17 and to passively transfer arthritis to lymphopenic recipients on a single-cell level. These data reveal a previously unconsidered role for T cell-intrinsic Nod2 as an endogenous negative regulator of Th17 responses and arthritogenic T cells. Based on our findings, future studies aimed at understanding a negative regulatory function of Nod2 within autoreactive T cells could provide novel therapeutic strategies for treatment of patients with arthritis.

Increased Wnt and Notch signaling: a clue to the renal disease in Schimke immuno-osseous dysplasia?

BACKGROUND: Schimke immuno-osseous dysplasia (SIOD) is a multisystemic disorder caused by biallelic mutations in the SWI/SNF-related matrix-associated actin-dependent regulator of chromatin, subfamily A-like 1 (SMARCAL1) gene. Changes in gene expression underlie the arteriosclerosis and T-cell immunodeficiency of SIOD; therefore, we hypothesized that SMARCAL1 deficiency causes the focal segmental glomerulosclerosis (FSGS) of SIOD by altering renal gene expression. We tested this hypothesis by gene expression analysis of an SIOD patient kidney and verified these findings through immunofluorescent analysis in additional SIOD patients and a genetic interaction analysis in Drosophila. RESULTS: We found increased expression of components and targets of the Wnt and Notch signaling pathways in the SIOD patient kidney, increased levels of unphosphorylated ß-catenin and Notch1 intracellular domain in the glomeruli of most SIOD patient kidneys, and genetic interaction between the Drosophila SMARCAL1 homologue Marcal1 and genes of the Wnt and Notch signaling pathways. CONCLUSIONS: We conclude that increased Wnt and Notch activity result from SMARCAL1 deficiency and, as established causes of FSGS, contribute to the renal disease of most SIOD patients. This further clarifies the pathogenesis of SIOD and will hopefully direct potential therapeutic approaches for SIOD patients.

A Patient-Derived Xenograft Model of Parameningeal Embryonal Rhabdomyosarcoma for Preclinical Studies.

Embryonal rhabdomyosarcoma (eRMS) is one of the most common soft tissue sarcomas in children and adolescents. Parameningeal eRMS is a variant that is often more difficult to treat than eRMS occurring at other sites. A 14-year-old female with persistent headaches and rapid weight loss was diagnosed with parameningeal eRMS. She progressed and died despite chemotherapy with vincristine, actinomycin-D, and cyclophosphamide plus 50.4 Gy radiation therapy to the primary tumor site. Tumor specimens were acquired by rapid autopsy and tumor tissue was transplanted into immunodeficient mice to create a patient-derived xenograft (PDX) animal model. As autopsy specimens had an ALK R1181C mutation, PDX tumor bearing animals were treated with the pan-kinase inhibitor lestaurtinib but demonstrated no decrease in tumor growth, suggesting that single agent kinase inhibitor therapy may be insufficient in similar cases. This unique parameningeal eRMS PDX model is publicly available for preclinical study.

Abundant hepatic Gaucher-like cells following chemotherapy and bone marrow transplantation for hematologic malignancy: report of two cases.

Cells with a resemblance to Gaucher cells, sometimes called pseudo-Gaucher cells, are seen in the bone marrow of some patients with hematologic malignancy or anemia. These cells are derived from cells of the monocytic lineage but do not show the characteristic inclusions of true Gaucher cells when examined by electron microscopy. Large numbers of Gaucher-like cells were found in the livers at autopsy of 2 patients with hematologic malignancy treated with chemotherapy and bone marrow transplant. Knowledge of this phenomenon may be useful in the interpretation of liver biopsy done on a patient with bone marrow transplant.

Reduced elastogenesis: a clue to the arteriosclerosis and emphysematous changes in Schimke immuno-osseous dysplasia?

BACKGROUND: Arteriosclerosis and emphysema develop in individuals with Schimke immuno-osseous dysplasia (SIOD), a multisystem disorder caused by biallelic mutations in SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1). However, the mechanism by which the vascular and pulmonary disease arises in SIOD remains unknown. METHODS: We reviewed the records of 65 patients with SMARCAL1 mutations. Molecular and immunohistochemical analyses were conducted on autopsy tissue from 4 SIOD patients. RESULTS: Thirty-two of 63 patients had signs of arteriosclerosis and 3 of 51 had signs of emphysema. The arteriosclerosis was characterized by intimal and medial hyperplasia, smooth muscle cell hyperplasia and fragmented and disorganized elastin fibers, and the pulmonary disease was characterized by panlobular enlargement of air spaces. Consistent with a cell autonomous disorder, SMARCAL1 was expressed in arterial and lung tissue, and both the aorta and lung of SIOD patients had reduced expression of elastin and alterations in the expression of regulators of elastin gene expression. CONCLUSIONS: This first comprehensive study of the vascular and pulmonary complications of SIOD shows that these commonly cause morbidity and mortality and might arise from impaired elastogenesis. Additionally, the effect of SMARCAL1 deficiency on elastin expression provides a model for understanding other features of SIOD.

Diagnosis of autoimmune pancreatitis vs neoplasms in children with pancreatic mass and biliary obstruction.

Autoimmune pancreatitis (AIP) is a rare autoimmune disorder that resembles pancreatic neoplasia and occurs primarily in adults. Management strategies and diagnostic criteria are being revised for adult patients; there are no clear diagnostic criteria for pediatric patients. We describe 3 cases of AIP in children, on the basis of clinical and pathology records. We also performed a literature review to determine the incidence of biliary obstruction in pediatric patients with pancreatic tumors. We found that children with AIP present with a variety of symptoms, and that diagnostic and therapeutic strategies also vary. Furthermore, on the basis of the many studies published on pediatric patients with pancreatic tumors, only a small percentage of the patients have biliary obstructions. Cytologic analysis of samples collected by fine-needle aspiration cytology does not accurately identify AIP in children. However, frozen section needle core biopsy samples can be used to distinguish children with AIP from those with neoplasia. Children with pancreatic mass and biliary obstruction are more likely to have AIP than neoplasms.

Penetrance of biallelic SMARCAL1 mutations is associated with environmental and genetic disturbances of gene expression.

Biallelic mutations of the DNA annealing helicase SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1) cause Schimke immuno-osseous dysplasia (SIOD, MIM 242900), an incompletely penetrant autosomal recessive disorder. Using human, Drosophila and mouse models, we show that the proteins encoded by SMARCAL1 orthologs localize to transcriptionally active chromatin and modulate gene expression. We also show that, as found in SIOD patients, deficiency of the SMARCAL1 orthologs alone is insufficient to cause disease in fruit flies and mice, although such deficiency causes modest diffuse alterations in gene expression. Rather, disease manifests when SMARCAL1 deficiency interacts with genetic and environmental factors that further alter gene expression. We conclude that the SMARCAL1 annealing helicase buffers fluctuations in gene expression and that alterations in gene expression contribute to the penetrance of SIOD.

Primary seminal vesicle carcinoma.

Criteria for the very rare diagnosis of primary seminal vesicle carcinoma have traditionally been highly stringent but may be relaxed with the application of immunohistochemistry to the diagnosis of mass lesions that occur in the male pelvis. The authors report a case of disseminated carcinoma with a clinically occult primary site that apparently had its origin in the seminal vesicle. Autopsy revealed a 10-cm tumor enveloping the prostate and seminal vesicles without involvement of colonic or urothelial mucosa. Much smaller tumors were present in other sites outside the pelvis. The tumor was composed of poorly formed glands and sheets of malignant-appearing cells, involved the seminal vesicle, and had the immunohistochemical profile of seminal vesicle carcinoma, notably strong immunoreactivity for CA-125 and no immunoreactivity for cytokeratin-20 or prostate-specific markers.

Life-threatening adenovirus infections in the setting of the immunocompromised allogeneic stem cell transplant patients.

A single institution case series of adenovirus infections after allogeneic hematopoietic stem cell transplantation is presented to highlight the consideration for adenovirus infections as an etiology in patients with rapid hepatic or other sudden organ deterioration in the setting of apparent GVHD stabilization. The series also highlights that survival is limited with these infections often due in part to concomitant opportunistic infections. In addition, the pathophysiological events, such as GVHD and hepatic dysfunction, may complicate the clinical picture and delay therapy of an opportunistic infection. This is particularly true for adenoviral infections as they also have a distinct clinical picture in immunocompromised patients when compared to immune competent patients. Adenovirus infections also have the additional challenge that its treatment, cidofovir, has associated toxicities that can delay its administration. Recent developments has yielded an assay that can be used in the early detection and for serial determinations of adenovirus in patients with advanced GVHD, as well as a new therapeutic agent currently undergoing clinical trials.

Acute graft-versus-host disease of the heart.

Graft-versus-host disease (GVHD) is a frequent cause of morbidity and mortality after bone marrow transplantation. Acute GVHD most commonly involves the skin, gastrointestinal tract, and liver. Involvement of other organ systems is rare and remains controversial. We report a patient with GVHD who suffered a fatal ventricular arrhythmia shortly after bone marrow transplantation. Autopsy of the heart showed lymphocyte infiltration. Investigations for cardiotrophic viruses were negative, and chimerism analysis of the heart showed both donor and recipient DNA. We conclude that the cause of death was possibly graft-versus-host disease of the heart. A review of the literature revealed a total of 14 cases of possible cardiac GVHD. All but one of the reported cases have occurred in pediatric patients and six of those patients died, suggesting that this may be a rare but frequently fatal complication of pediatric allogeneic stem cell transplant.

Postmortem screening for fatty acid oxidation disorders by analysis of Guthrie cards with tandem mass spectrometry in sudden unexpected death in infancy.

A protocol was developed for the detection of fatty acid oxidation disorders (FOD) in cases of sudden unexpected death in infancy (SUDI). Tandem mass spectrometry blood acylcarnitine analysis of Guthrie card blood spots was performed. In the first 5 years, 1.2% of Oregon's 247 SUDI cases were identified with FOD, 2 with medium-chain acyl-CoA dehydrogenase deficiency, and one with very long-chain acyl-CoA dehydrogenase deficiency.