Nasopharyngeal Carcinoma: Connecting Antemortem and Postmortem Findings to Highlight a Rare Case of EBV and HPV Negativity.

Nasopharyngeal carcinoma is an endemic entity with a strong association with Epstein-Barr virus and a new recognition of human papilloma virus-mediated effects in nonendemic areas. Here, we discuss a nasopharyngeal carcinoma suspected as based on imaging results with metastasis to the lymph nodes, lung, spleen, bone, and liver. Gross and microscopic findings from the autopsy were clinicopathologically correlated with antemortem clinical studies and investigations. The authors report a case of EBV- and HPV-negative nonendemic, multisite metastatic nasopharyngeal carcinoma, shown to be nonkeratinizing undifferentiated subtype.

An Autopsy Case of Saphenous Vein Graft Rupture.

ABSTRACT: Saphenous vein graft aneurysms are rare complications after coronary artery bypass grafting that carry serious complications. Less than 10 case reports of autopsy findings consistent with ruptured saphenous vein grafts exist in the literature. We report a case of a female presenting at autopsy who, after coronary artery bypass grafting 20 years prior, demonstrated findings of a saphenous vein graft aneurysm and rupture. With limited evidence from medical records, this case highlights a need for patients with previous coronary artery bypass grafting to be properly monitored to detect minute graft changes before aneurysm formation and rupture as seen in our decedent.

Do Not Turn a Blind Eye on Forensic Biochemistry: Using Vitreous Electrolytes to Reveal Renal Insufficiency as Cause of Death.

ABSTRACT: In both medical and forensic autopsy, the kidneys may be overlooked grossly and histologically. As both acute and chronic kidney dysfunction have major implications on morbidity and mortality, it is essential to consider the kidneys as a pathologic source for both immediate and proximate cause of death. For decades, vitreous humor has been used as a measure of postmortem electrolyte analysis to help understand ionic disturbances carried over from the antemortem period. Renal insufficiency from both acute and chronic kidney dysfunction can be ascertained from vitreous investigations and should be a consideration for cause of death. Here, we present 4 cases in which vitreous analysis was used to determine the cause of death. In highlighting these cases, we support the use of biochemical testing in autopsy while demonstrating how it can help elucidate an often overlooked means of mortality. Importantly, it can help with the formulation of clinicopathologic correlations between antemortem and postmortem findings.

Mucin-producing urothelial-type adenocarcinoma of the prostate with sarcomatoid features and novel molecular phenotype.

Introduction: Mucin-producing urothelial-type adenocarcinoma of the prostate is a rare tumor that may not elevate serum prostate-specific antigen, creating significant diagnostic and monitoring challenges. We evaluate our case in detail and review prior studies to demonstrate that the pathologic and molecular features of this tumor are distinct from conventional prostate adenocarcinoma. Case presentation: Our patient had a remote history of radiation-treated conventional prostate adenocarcinoma and presented many years later with an abscess-like prostate mass leading to urinary obstruction and hematuria. Biopsy revealed mucin-producing urothelial-type adenocarcinoma of the prostate with concurrent sarcomatoid features. Molecular studies showed a unique phenotype involving alterations in the KRAS, PTEN, RAD21, and TP53 genes. Conclusions: To our knowledge, this is the first report that describes sarcomatoid features and molecular mutations in mucin-producing urothelial-type adenocarcinoma of the prostate.

An Autopsy Case of Abdominal Aortic Aneurysm in a Pediatric Decedent With Tuberous Sclerosis Complex.

ABSTRACT: Vascular involvement in tuberous sclerosis complex (TSC) is uncommon and even more so in pediatric patients. When asymptomatic, these vascular abnormalities carry increased risk of rupture with increased morbidity and mortality. Here, we describe a case of a ruptured unrecognized abdominal aortic aneurysm in an 11-month-old patient with a history of TSC. The abdominal aortic aneurysm was discovered at autopsy and highlights the rarity of abdominal aortic aneurysm in pediatric patients diagnosed with TSC and the importance of screening for associated aneurysmal disease in the pediatric population with TSC. Furthermore, the extensive retroperitoneal hemorrhage seen in this case also highlights a rare but potential mimic of abuse in the pediatric population.

Therapeutic leukocytapheresis for leukostasis in chronic lymphocytic leukemia: A case report and literature review.

Chronic lymphocytic leukemia (CLL) is a clonal mature B-cell neoplasm with a typically indolent clinical course. Though most clinicians follow these neoplasms through observation alone, an aggressive transformation to prolymphocytic leukemia, diffuse large-B-cell lymphoma (Richter transformation) or classical Hodgkin lymphoma requires immediate attention. We present a case of extreme leukocytosis (>1 million/µL) in a previously diagnosed CLL patient. Due to symptomatic leukostasis, she was started on cytoreductive therapies including leukocytapheresis. After three rounds of leukocytapheresis (LCP) and concurrent chemotherapy, her white blood cell count decreased from a maximum 1262 × 103 /µL to 574 × 103 /µL. To our knowledge, CLL with symptomatic leukostasis that required therapeutic LCP is rarely reported in literature. We propose that therapeutic LCP is of value in such rare, yet dangerous settings like our case.

Invasive urothelial carcinoma with squamous differentiation and associated high-risk human papilloma virus infection: Clinical, cytologic, and histologic features of a rare entity.

We correlate the fine needle aspiration (FNA) cytologic findings with the histologic features of an invasive high-grade urothelial carcinoma showing squamous differentiation in the setting of high-risk Human Papilloma Virus (hrHPV) infection. To our knowledge, only extensive urinary bladder catheterization has been associated with hrHPV-positive urothelial carcinoma with squamous differentiation, and rarely at that. Herein, we present a case arising in a patient with only sparse and intermittent catheterization. A 69-year-old woman presented with voiding difficulties, and after continued symptoms, a Foley catheter was placed, and a cystoscopy procedure revealed two 1-2 cm inflammatory masses. Excisional biopsies were interpreted as papillary urothelial carcinoma. One month follow-up pelvic imaging demonstrated a new mass involving the urinary bladder neck, with irregular wall thickening and perivesical fat stranding, as well as probable vaginal involvement. CT-guided FNA (CT-FNA) to collect smears and core biopsies revealed an invasive urothelial carcinoma with squamous differentiation. HPV-cytopathic changes amid squamous metaplasia and dysplasia were noted on FNA smears with HPV E6/E7 RNA in situ hybridization (ISH) showing on the FNA core biopsy specimen. Immunostains showed that the tumor cells were positive for P16 (strong, diffuse), CK7, p63, ER, and GATA3 (patchy). Subsequent radical cystectomy revealed the extent of the patient's carcinoma, with direct extension to the vaginal wall, and involvement of the radial soft tissue resection margins. Describing the cytomorphologic features of a hrHPV positive urothelial carcinoma with squamous differentiation, without an extensive history of urinary catheterization or prior known history of HPV infection, emphasizes the role of cytopathology as a powerful diagnostic tool for recognizing a unique and unexpected lesion.

FKBP11 rewires UPR signaling to promote glucose homeostasis in type 2 diabetes and obesity.

Chronic endoplasmic reticulum (ER) stress and sustained activation of unfolded protein response (UPR) signaling contribute to the development of type 2 diabetes in obesity. UPR signaling is a complex signaling pathway, which is still being explored in many different cellular processes. Here, we demonstrate that FK506-binding protein 11 (FKBP11), which is transcriptionally regulated by XBP1s, is severely reduced in the livers of obese mice. Restoring hepatic FKBP11 expression in obese mice initiates an atypical UPR signaling pathway marked by rewiring of PERK signaling toward NRF2, away from the eIF2α-ATF4 axis of the UPR. This alteration in UPR signaling establishes glucose homeostasis without changing hepatic ER stress, food consumption, or body weight. We conclude that ER stress during obesity can be beneficially rewired to promote glucose homeostasis. These findings may uncover possible new avenues in the development of novel approaches to treat diseases marked by ER stress.

Antisense oligonucleotide-mediated knockdown of Mpzl3 attenuates the negative metabolic effects of diet-induced obesity in mice.

Previously, we demonstrated that global knockout (KO) of the gene encoding myelin protein zero-like 3 (Mpzl3) results in reduced body weight and adiposity, increased energy expenditure, and reduced hepatic lipid synthesis in mice. These mice also exhibit cyclic and progressive alopecia which may contribute to the observed hypermetabolic phenotype. The goal of the current study was to determine if acute and peripherally restricted knockdown of Mpzl3 could ameliorate the negative metabolic effects of exposure to a high-fat and sucrose, energy-dense (HED) diet similar to what was observed in global Mpzl3 KO mice in the absence of a skin phenotype. Mpzl3 antisense oligonucleotide (ASO) administration dose-dependently decreased fat mass and circulating lipids in HED-fed C57BL/6N mice. These changes were accompanied by a decrease in respiratory exchange ratio, a reduction in energy expenditure and food intake, a decrease in expression of genes regulating de novo lipogenesis in white adipose tissue, and an upregulation of genes associated with steroid hormone biosynthesis in liver, thermogenesis in brown adipose tissue and fatty acid transport in skeletal muscle. These data demonstrate that resistance to the negative metabolic effects of HED is a direct effect of Mpzl3 knockdown, rather than compensatory changes that could be associated with deletion of Mpzl3 during development in global KO mice. Inhibiting MPZL3 could be a potential therapeutic approach for the treatment of obesity and associated dyslipidemia.

Lipocalin 2 Does Not Play A Role in Celastrol-Mediated Reduction in Food Intake and Body Weight.

Celastrol is a leptin-sensitizing agent with profound anti-obesity effects in diet-induced obese (DIO) mice. However, the genes and pathways that mediate celastrol-induced leptin sensitization have not been fully understood. By comparing the hypothalamic transcriptomes of celastrol and vehicle-treated DIO mice, we identified lipocalin-2 (Lcn2) as the gene most strongly upregulated by celastrol. LCN2 was previously suggested as an anorexigenic and anti-obesity agent. Celastrol increased LCN2 protein levels in hypothalamus, liver, fat, muscle, and bone marrow, as well as in the plasma. However, genetic deficiency of LCN2 altered neither the development of diet-induced obesity, nor the ability of celastrol to promote weight loss and improve obesity-associated dyshomeostasis. We conclude that LCN2 is dispensable for both high fat diet-induced obesity and its therapeutic reduction by celastrol.

IL1R1 is required for celastrol's leptin-sensitization and antiobesity effects.

Celastrol, a pentacyclic triterpene, is the most potent antiobesity agent that has been reported thus far1. The mechanism of celastrol's leptin-sensitizing and antiobesity effects has not yet been elucidated. In this study, we identified interleukin-1 receptor 1 (IL1R1) as a mediator of celastrol's action by using temporally resolved analysis of the hypothalamic transcriptome in celastrol-treated DIO, lean, and db/db mice. We demonstrate that IL1R1-deficient mice are completely resistant to the effects of celastrol in leptin sensitization and treatment of obesity, diabetes, and nonalcoholic steatohepatitis. Thus, we conclude that IL1R1 is a gatekeeper for celastrol's metabolic actions.

PGC-1α functions as a co-suppressor of XBP1s to regulate glucose metabolism.

OBJECTIVE: Peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α) promotes hepatic gluconeogenesis by activating HNF4α and FoxO1. PGC-1α expression in the liver is highly elevated in obese and diabetic conditions, leading to increased hepatic glucose production. We previously showed that the spliced form of X-box binding protein 1 (XBP1s) suppresses FoxO1 activity and hepatic gluconeogenesis. The shared role of PGC-1α and XBP1s in regulating FoxO1 activity and gluconeogenesis led us to investigate the probable interaction between PGC-1α and XBP1s and its role in glucose metabolism. METHODS: We investigated the biochemical interaction between PGC-1α and XBP1s and examined the role of their interaction in glucose homeostasis using animal models. RESULTS: We show that PGC-1α interacts with XBP1s, which plays an anti-gluconeogenic role in the liver by suppressing FoxO1 activity. The physical interaction between PGC-1α and XBP1s leads to suppression of XBP1s activity rather than its activation. Upregulating PGC-1α expression in the liver of lean mice lessens XBP1s protein levels, and reducing PGC-1α levels in obese and diabetic mouse liver restores XBP1s protein induction. CONCLUSIONS: Our findings reveal a novel function of PGC-1α as a suppressor of XBP1s function, suggesting that hepatic PGC-1α promotes gluconeogenesis through multiple pathways as a co-activator for HNF4α and FoxO1 and also as a suppressor for anti-gluconeogenic transcription factor XBP1s.