Postoperative cardiac homograft involvement in Erdheim-Chester disease.

Erdheim-Chester disease (ECD) is a rare multisystem disorder which is known to affect the skin, lungs, bone, pituitary gland, retroperitoneum and cardiovascular system. The case is described of a patient with ECD who had previously undergone a Ross procedure for presumed endocarditis involving the aortic valve and aortic root. The patient subsequently developed arthralgias, abdominal pain (requiring an exploratory laparotomy) and polydipsia. Furthermore, he developed progressive, symptomatic stenosis of the pulmonic homograft. A reoperative replacement of the homograft was required. The clinically suspected diagnosis of ECD was confirmed by a pathologic analysis of the explanted pulmonary homograft, and also (retrospectively) of previously resected mesenteric tissue. It is postulated that the patient may have developed ECD as a result of an immunologic reaction to the homograft tissue used for the Ross procedure.

Clinical and Intestinal Histopathological Findings in SARS-CoV-2/COVID-19 Patients with Hematochezia.

Gastrointestinal (GI) symptoms of SARS-CoV-2/COVID-19 in the form of anorexia, nausea, vomiting, abdominal pain and diarrhea are usually preceded by respiratory manifestations and are associated with a poor prognosis. Hematochezia is an uncommon clinical presentation of COVID-19, and we hypothesize that older patients with significant comorbidities (obesity and cardiovascular) and prolonged hospitalization are susceptible to ischemic injury to the bowel. We reviewed the clinical course, key laboratory data including acute-phase reactants, and drug/medication history in 2 elderly male patients admitted for COVID-19 respiratory failure. Both patients had a complicated clinical course and suffered from hematochezia, acute blood loss, and anemia which led to hemodynamic instability requiring blood transfusion around day 40 of their hospitalization. Colonoscopic impressions were correlated with the histopathological findings in the colonic biopsies that included changes compatible with ischemia and nonspecific acute inflammation, edema, and increased eosinophils in the lamina propria. Both patients were hemodynamically stable, on prophylactic anticoagulants, multiple antibiotics, and antifungal agents due to respiratory infections at the time of lower GI bleeding. Hematochezia resolved spontaneously with supportive care. Both patients eventually recovered and were discharged. Elderly patients with significant comorbid conditions are uniquely at risk for ischemic injury to the bowel. This case report highlights hematochezia as an uncommon GI manifestation of spectrum of COVID-19 complications. The causes of bleeding in these COVID-19 associated cases are likely multifactorial and can be attributed to concomitant etiologies based on their age, multiple comorbid conditions, prolonged hospitalization compounded by lung injury, and hypoxia precipitated by the virus. We hypothesize that rather than a direct viral cytopathic effect, ischemia and hypoperfusion may be unleashed due to the cytokine storm orchestrated by the virus that leads to abnormal coagulation profile. Additional factors that may contribute to ischemic injury are prophylactic use of anticoagulants and polypharmacy. There were no other causes to explain the brisk lower GI bleeding. Presentation of hematochezia was followed by hemodynamic instability that may further increase the mortality and morbidity of COVID-19 patients, and prompt consultation and management by gastroenterology is therefore warranted.

Screening coagulation testing using the APTT: which reagent to choose?

APTT testing is integral to hemostasis testing. A prolonged result, however, can be difficult to interpret, depending on the APTT reagent's sensitivity to the lupus anticoagulant. This often generates additional laboratory testing for both factor deficiencies and the presence of a lupus anticoagulant, and in so doing, delays patient management. We have found it useful to provide APTT testing with both a lupus anticoagulant sensitive and insensitive reagent, to facilitate the rapid exclusion of significant factor deficiencies. The following case report illustrates the utility of this approach and provides a backdrop for necessary discussions between laboratories and clinicians regarding which APTT reagent best meets their clinical need for screening hemostasis testing.

The significance of histologic examination of gastrectomy specimens: a clinicopathologic study of 511 cases.

BACKGROUND: Sleeve gastrectomy (SG) is quickly becoming the preferred procedure for bariatric surgery. According to the American Society for Metabolic and Bariatric Surgery guidelines, routine preoperative upper gastrointestinal endoscopies are not recommended universally for bariatric surgery. Some studies have shown that the histologic examination of SG specimens is insignificant and not a cost-effective practice. However, some speculate SG examination may unveil pertinent findings and prevent further progression of precursor lesions. OBJECTIVES: This study aims to explore the clinically significant or actionable lesions that can be revealed with SG examination. SETTING: Tufts Medical Center, Boston, USA. RESULTS: We analyzed 511 SG specimens obtained during bariatric surgery. Incidental findings were grouped in 2 categories: clinically significant/actionable and minor lesions. The clinically significant lesions accounted for 5.8%. This category included 5 cases of gastrointestinal stromal tumor; one case of MALT lymphoma; 4 cases of autoimmune gastritis with concomitant pancreatic metaplasia or neuroendocrine dysplasia. Intestinal metaplasia without dysplasia was identified in 3 cases; 14 cases of Helicobacter pylori associated active gastritis; 1 case of iron pill induced gastritis and 1 case of gastric glandular siderosis. The minor lesions accounted for 6.3%, showing findings other than chronic gastritis. This category included 19 cases of fundic polyps and 1 case of hyperplastic polyp; one case of leiomyoma; 11 cases of H pylori negative active gastritis. CONCLUSIONS: The majority of histopathology results after SG showed no significant changes. However, a few cases had clinically significant lesions in seemingly healthy patients, altering patient's postoperative management.

In vivo genome editing and organoid transplantation models of colorectal cancer and metastasis.

In vivo interrogation of the function of genes implicated in tumorigenesis is limited by the need to generate and cross germline mutant mice. Here we describe approaches to model colorectal cancer (CRC) and metastasis, which rely on in situ gene editing and orthotopic organoid transplantation in mice without cancer-predisposing mutations. Autochthonous tumor formation is induced by CRISPR-Cas9-based editing of the Apc and Trp53 tumor suppressor genes in colon epithelial cells and by orthotopic transplantation of Apc-edited colon organoids. ApcΔ/Δ;KrasG12D/+;Trp53Δ/Δ (AKP) mouse colon organoids and human CRC organoids engraft in the distal colon and metastasize to the liver. Finally, we apply the orthotopic transplantation model to characterize the clonal dynamics of Lgr5+ stem cells and demonstrate sequential activation of an oncogene in established colon adenomas. These experimental systems enable rapid in vivo characterization of cancer-associated genes and reproduce the entire spectrum of tumor progression and metastasis.

Corrigendum: In vivo genome editing and organoid transplantation models of colorectal cancer and metastasis.

This corrects the article DOI: 10.1038/nbt.3836.

Appendiceal Adenocarcinoma Presenting as a Rectal Polyp.

Appendiceal adenocarcinoma typically presents as an incidentally noted appendiceal mass, or with symptoms of right lower quadrant pain that can mimic appendicitis, but local involvement of adjacent organs is uncommon, particularly as the presenting sign. We report on a case of a primary appendiceal cancer initially diagnosed as a rectal polyp based on its appearance in the rectal lumen. The management of the patient was in keeping with standard practice for a rectal polyp, and the diagnosis of appendiceal adenocarcinoma was made intraoperatively. The operative strategy had to be adjusted due to this unexpected finding. Although there are published cases of appendiceal adenocarcinoma inducing intussusception and thus mimicking a cecal polyp, there are no reports in the literature describing invasion of the appendix through the rectal wall and thus mimicking a rectal polyp. The patient is a 75-year-old female who presented with spontaneous hematochezia and, on colonoscopy, was noted to have a rectal polyp that appeared to be located within a diverticulum. When endoscopic mucosal resection was not successful, she was referred to colorectal surgery for a low anterior resection. Preoperative imaging was notable for an enlarged appendix adjacent to the rectum. Intraoperatively, the appendix was found to be densely adherent to the right lateral rectal wall. An en bloc resection of the distal sigmoid colon, proximal rectum and appendix was performed, with pathology demonstrating appendiceal adenocarcinoma that invaded through the rectal wall. The prognosis in this type of malignancy weighs heavily on whether or not perforation and spread throughout the peritoneal cavity have occurred. In this unusual presentation, an en bloc resection is required for a complete resection and to minimize the risk of peritoneal spread. Unusual appearing polyps do not always originate from the bowel wall. Abnormal radiographic findings adjacent to an area of gastrointestinal pathology may signify locally advanced disease from a surrounding organ that secondarily involves the gastrointestinal tract. These findings warrant further investigation prior to any intervention to ensure appropriate treatment.

Hsp70 is a novel posttranscriptional regulator of gene expression that binds and stabilizes selected mRNAs containing AU-rich elements.

The AU-rich elements (AREs) encoded within many mRNA 3' untranslated regions (3'UTRs) are targets for factors that control transcript longevity and translational efficiency. Hsp70, best known as a protein chaperone with well-defined peptide-refolding properties, is known to interact with ARE-like RNA substrates in vitro. Here, we show that cofactor-free preparations of Hsp70 form direct, high-affinity complexes with ARE substrates based on specific recognition of U-rich sequences by both the ATP- and peptide-binding domains. Suppressing Hsp70 in HeLa cells destabilized an ARE reporter mRNA, indicating a novel ARE-directed mRNA-stabilizing role for this protein. Hsp70 also bound and stabilized endogenous ARE-containing mRNAs encoding vascular endothelial growth factor (VEGF) and Cox-2, which involved a mechanism that was unaffected by an inhibitor of its protein chaperone function. Hsp70 recognition and stabilization of VEGF mRNA was mediated by an ARE-like sequence in the proximal 3'UTR. Finally, stabilization of VEGF mRNA coincided with the accumulation of Hsp70 protein in HL60 promyelocytic leukemia cells recovering from acute thermal stress. We propose that the binding and stabilization of selected ARE-containing mRNAs may contribute to the cytoprotective effects of Hsp70 following cellular stress but may also provide a novel mechanism linking constitutively elevated Hsp70 expression to the development of aggressive neoplastic phenotypes.

Phosphorylation of p40AUF1 regulates binding to A + U-rich mRNA-destabilizing elements and protein-induced changes in ribonucleoprotein structure.

Messenger RNA turnover directed by A + U-rich elements (AREs) involves selected ARE-binding proteins. Whereas several signaling systems may modulate ARE-directed mRNA decay and/or post-translationally modify specific trans-acting factors, it is unclear how these mechanisms are linked. In THP-1 monocytic leukemia cells, phorbol ester-induced stabilization of some mRNAs containing AREs was accompanied by dephosphorylation of Ser83 and Ser87 of polysome-associated p40AUF1. Here, we report that phosphorylation of p40AUF1 influences its ARE-binding affinity as well as the RNA conformational dynamics and global structure of the p40AUF1-ARE ribonucleoprotein complex. Most notably, association of unphosphorylated p40AUF1 induces a condensed RNA conformation upon ARE substrates. By contrast, phosphorylation of p40AUF1 at Ser83 and Ser87 inhibits this RNA structural transition. These data indicate that selective AUF1 phosphorylation may regulate ARE-directed mRNA turnover by remodeling local RNA structures, thus potentially altering the presentation of RNA and/or protein determinants involved in subsequent trans-factor recruitment.