Necrotic debris and STING exert therapeutically relevant effects on tumor cholesterol homeostasis

Malignant tumors commonly display necrosis, which invariably triggers an inflammatory response that supports tumor growth. However, the effect on tumor cells of necrotic debris, or damage-associated molecular patterns (DAMPs) released by dying cells is unknown. Here, we addressed the effect of DAMPs on primary Ewing sarcoma (EwS) cells and cell lines grown in 3D (spheroids) and 2D culture. We show that DAMPs promote the growth of EwS spheroids but not 2D cultures and that the underlying mechanism implicates an increase in cholesterol load in spheroids. In contrast, stimulation of the nucleic acid sensor signaling platform STING by its ligand cyclic GMP-AMP decreases the tumor cell cholesterol load and reduces their tumor initiating ability. Overexpression of STING or stimulation with cyclic GMP-AMP opposes the growth stimulatory effect of DAMPs and synergizes with the cholesterol synthesis inhibitor simvastatin to inhibit tumor growth. Our observations show that modulation of cholesterol homeostasis is a major effect of necrotic cell debris and STING and suggest that combining STING agonists with statins may help control tumor growth.

Clinical, surgical, and pathological findings in client-owned rabbits with histologically confirmed appendicitis: 19 cases (2015–2019)

OBJECTIVE To report clinical, surgical, and pathological findings in client-owned rabbits with histologically confirmed appendicitis. ANIMALS 19 rabbits. PROCEDURES Medical records for client-owned rabbits that had a histologic diagnosis of appendicitis were reviewed. RESULTS Median age of the rabbits at presentation was 24.0 months (range, 4 to 84 months). Seventeen cases occurred during the summer and fall seasons. Decreased appetite (17/19 rabbits), abnormal rectal temperature (hyperthermia, 9/16 rabbits; hypothermia, 4/16 rabbits), hypocalcemia (8/11 rabbits), and hypoglycemia (7/15 rabbits) were common signs. Abdominal ultrasonography and CT findings were suggestive of appendicitis in 6 of 8 rabbits and in 1 of 2 rabbits, respectively. Of the 6 rabbits that received medical treatment, 3 died at 48 hours, 1 died at 24 hours after hospitalization, and 1 died at 10 days after presentation; 1 rabbit was alive at 1,030 days after presentation. Of the 8 rabbits that underwent appendectomy, 3 died before discharge from the hospital and 1 died 113 days after surgery; 4 rabbits were alive at 315, 334, 1,433, and 1,473 days after presentation. The remaining 5 rabbits either died or were euthanized before treatment could be instituted. In each of the 19 rabbits, the appendix had evidence of severe inflammation with mucosal ulceration, heterophilic inflammation, and necrotic debris. CLINICAL RELEVANCE For rabbits with decreased appetite and an apparently painful abdomen, hyperthermia, hypocalcemia, or hypoglycemia, appendicitis should be considered as a differential diagnosis. Further comparisons of medical and surgical treatments are required to establish treatment recommendations for rabbits with appendicitis.

Association Between the Morphological Features of Necrotizing Pancreatitis on Endoscopic Ultrasound and the Outcome of Endoscopic Transmural Step-Up Approach

BackgroundTo investigate the association between features of necrotic collections on endoscopic ultrasound (EUS) and outcomes of the endoscopic transmural step-up approach.MethodsThis was a retrospective cohort study analyzing patients with necrotic collections underwent endoscopic transmural step-up approach. According to the amount of solid necrotic debris quantified as a percentage of the total collection size, participants were divided into three groups: <30% (group 1), 30%-50% (group 2), and >50% (group 3).Results Out of a total of 134 patients, the mean necrotic collection size was 8.5 (7.0, 10.0) cm, with <30% (group 1), 30%-50% (group 2) and >50% (group 3) solid debris present in 52, 59, and 23 patients, respectively. Patients with more solid necrotic debris needed more sessions of necrosectomy (group 1, 1 (0, 1) time vs. group 2, 1 (1, 2) time vs. group 3, 2 (2, 3) times, P<0.001), more likely experienced stent occlusion (group 1, 9.6% vs. group 2, 16.9% vs. group 3, 34.8%; P<0.05), and had a longer hospital stay (group 1, 25.5 (17.3, 44.0) days vs. group 2, 28.0 (19.0, 41.0) days vs. group 3, 40.0 (30.0, 58.0) days; P<0.05). Procalcitonin (OR, 6.14; 95% CI, 1.40-26.94; P<0.05) and any organ failure (OR, 11.51; 95% CI, 2.42-54.78; P<0.01) were independently associated with clinical failure of the endoscopic transmural step-up approach.ConclusionsMore solid debris on EUS predicted more sessions of necrosectomy, stent occlusion, and hospital stay. Procalcitonin and organ failure are risk factors for clinical failure of the endoscopic transmural step-up approach.

A case of nontuberculous mycobacteria-associated thyroiditis mimicking subacute thyroiditis

We describe a case of nontuberculous mycobacteria infection in the thyroid gland in a 54-year-old woman who had painful thyroid enlargement. Ultrasonography showed ill-defined hypoechoic lesions without increased vascularity in both upper lobes of the thyroid gland. Fine needle aspiration biopsy was performed, and pathology showed granulomatous inflammation with necrotic debris that the pathologist suspected was subacute granulomatous thyroiditis or tuberculosis of the thyroid gland. Nontuberculous mycobacteria infection was confirmed after right hemithyroidectomy. Antimycobacterial therapy was initiated as the treatment of choice. Nontuberculous mycobacteria in the thyroid gland appear to be rare. In clinical practice, however, it should be considered as a differential diagnosis of a painful thyroid mass. For accurate diagnosis, clinical and radiological features plus histological examination are required.

Cystic Lesion of Dissected Pararectal Lymph Node in a Female Patient With Rectal Carcinoma: A Rare Pattern of Nodal Metastasis Mimicking a Serous Inclusion Cyst

Nodal metastatic foci of colorectal carcinoma are usually solid nodules. Serous inclusions are occasionally found in lymph nodes, particularly in female patients, and they occasionally form cysts. An 86-year-old woman was treated with laparoscopic low anterior resection and D3 lymph node dissection for advanced rectal carcinoma. A cyst with serous fluid and no necrotic debris was found within one of the dissected pararectal lymph nodes. Histologically, the cyst was lined by low columnar-to-cuboid epithelium with mild nuclear atypia, mimicking a serous inclusion cyst. Immunohistochemically, the epithelial cells were positive for caudal type homeobox 2 and negative for Wilms’ tumor suppressor gene1. Immunohistochemistry for p53 showed a diffuse strong positivity, indicating a mutant TP53 as seen in primary rectal carcinoma. Thus, the nodal cystic lesion was confirmed to be a metastatic lesion. It is important to carefully assess a nodal cystic lesion to confirm whether it is benign or malignant.

The Elusive Origin of Atherosclerotic Plaque Calcification

It has been known for decades or even centuries that arteries calcify as they age. Vascular calcification probably affects all adults, since virtually all have atherosclerotic plaques: an accumulation of lipids, inflammatory cells, necrotic debris, and calcium phosphate crystals. A high vascular calcium score is associated with a high cardiovascular mortality risk, and relatively recent data suggest that even microcalcifications that form in early plaques may destabilize plaques and trigger a cardiovascular event. If the cellular and molecular mechanisms of plaque calcification have been relatively well characterized in mice, human plaques appear to calcify through different mechanisms that remain obscure. In this context, we will first review articles reporting the location and features of early calcifications in human plaques and then review the articles that explored the mechanisms though which human and mouse plaques calcify.

Endoscopic eyebrow-eyelid sparing orbital exentration in mucormycosis

<p class="abstract">The intra-vascular invasion progressively halts the blood flow in the arterial distributaries and the venous tributaries and finally a “blue black”, wet gangrenous region is noted. Later the underlying bone too becomes fragile and crumbles off. Removal of necrotic debris remains the main stay of management. Removal of foci of infection, the orbital soft tissues utilizing high resolution endoscopic modality is elaborated upon.</p>

Barrett’s Esophageal Adenocarcinoma Involving a White Globe Appearance within the Long-Segment Barrett’s Esophagus

The diagnosis of Barrett’s esophageal adenocarcinoma (BEA) in patients with Barrett’s esophagus (BE) using endoscopy can be difficult and there are few specific endoscopic findings for BEA. However, white globe appearance (WGA) has been reported to be a specific endoscopic finding for early gastric cancer. We encountered a 51-year-old male patient with BEA exhibiting WGA. Esophagogastroduodenoscopy identified a red, depressed lesion of 10 mm within the long-segment BE (LSBE), while magnifying endoscopy with narrow-band imaging identified WGA. Endoscopic submucosal dissection (ESD) was performed based on our suspicion of BEA. Based on the ESD findings, we diagnosed adenocarcinoma accompanying LSBE histopathologically. WGA was identified, and intraglandular necrotic debris was discovered histologically at the same site. Therefore, WGA may be helpful in the diagnosis of BEA.