COVID-19 in recent heart transplant recipients: Clinicopathologic features and early outcomes.

BACKGROUND: The impact of COVID-19 on heart transplant (HTx) recipients remains unclear, particularly in the early post-transplant period. METHODS: We share novel insights from our experience in five HTx patients with COVID-19 (three within 2 months post-transplant) from our institution at the epicenter of the pandemic. RESULTS: All five exhibited moderate (requiring hospitalization, n = 3) or severe (requiring ICU and/or mechanical ventilation, n = 2) illness. Both cases with severe illness were transplanted approximately 6 weeks before presentation and acquired COVID-19 through community spread. All five patients were on immunosuppressive therapy with mycophenolate mofetil (MMF) and tacrolimus, and three that were transplanted within the prior 2 months were additionally on prednisone. The two cases with severe illness had profound lymphopenia with markedly elevated C-reactive protein, procalcitonin, and ferritin. All had bilateral ground-glass opacities on chest imaging. MMF was discontinued in all five, and both severe cases received convalescent plasma. All three recent transplants underwent routine endomyocardial biopsies, revealing mild (n = 1) or no acute cellular rejection (n = 2), and no visible viral particles on electron microscopy. Within 30 days of admission, the two cases with severe illness remain hospitalized but have clinically improved, while the other three have been discharged. CONCLUSIONS: COVID-19 appears to negatively impact outcomes early after heart transplantation.

Mutational load may predict risk of progression in patients with Barrett's oesophagus and indefinite for dysplasia: a pilot study.

BACKGROUND AND AIMS: Mutational load (ML) has been shown to help risk-stratify those that may progress from non-dysplastic Barrett's oesophagus (BE) to dysplastic disease. Management of patients with BE and indefinite for dysplasia (BE-IND) is challenging and risk stratification tools are lacking. The aim of this pilot study is to evaluate the utility of ML for risk stratification in patients with BE-IND. METHODS: This is a single-centre, retrospective pilot study evaluating ML quantification in patients with BE-IND. Histology at follow-up endoscopy at least 1 year after the baseline endoscopy was used to determine if a patient progressed to low or high dysplasia. The ML levels were then compared among patients who progressed to dysplasia versus those who did not. RESULTS: Thirty-five patients who met the inclusion criteria were identified, and seven met the exclusion criteria. Twenty-eight patients were analysed, of whom eight progressed to low-grade dysplasia (6) and high-grade dysplasia (2). Seven of these eight patients had some level of genomic instability detected in their IND biopsy (ML ≥0.5). Ten of the 20 (50%) who did not progress had no ML level. At an ML cut-off above 1.5, the risk of progression to high-grade dysplasia was 33% vs 0% (p=0.005), with a sensitivity of 100% and a specificity of 85%. CONCLUSION: These results indicate that ML may be able to risk-stratify progression to high-grade dysplasia in BE-IND. Larger studies are needed to confirm these findings.

Extra-osseous Ewing sarcoma of the pancreas: case report with radiologic, pathologic, and molecular correlation, and brief review of the literature.

In 2002, due to extensive histomorphologic, immunohistochemical, and cytogenetic similarities, the World Health Organization unified undifferentiated small round blue cell neoplasms of soft tissue and bone (previously segregated as Ewing sarcoma or Primitive Neuroectodermal tumor) into one category: Ewing family of tumors (EFT). Osseous EFT are more common, and while extra-osseous EFT can occur anywhere in the body, those of the pancreas are rare and likely to be seen in the second decade of life in the head of the pancreas. We report the case of a 39-year-old Caucasian male with a large heterogeneously enhancing mass in the pancreatic body. Pathologic examination showed a malignant round blue cell tumor diffusely positive for CD99, chromogranin, and synaptophysin; Ki-67 proliferation index was greater than 80%. FISH showed EWSR1 gene rearrangement in 90% of cells and Archer FusionPlexTM-targeted RNA sequencing analysis identified the EWSR1-FLI1 fusion transcript. The diagnosis of EFT of the pancreas was rendered. Unfortunately, the patient had minimal improvement and was transitioned to oral pain medications to continue care at a different institution.

Learning curve and competence for volumetric laser endomicroscopy in Barrett's esophagus using cumulative sum analysis.

BACKGROUND AND STUDY AIMS: Little is known about the learning curve for image interpretation in volumetric laser endomicroscopy (VLE) in Barrett's esophagus (BE). The goal of this study was to calculate the learning curve, competence of image interpretation, sensitivity, specificity, and accuracy of VLE among novice users. METHODS: 31 novice users viewed 96 VLE images electronically at three academic institutions after a brief training session. There were 24 images of each histologic type: normal gastric cardia, normal esophageal squamous epithelium, non-neoplastic BE, and neoplastic BE. The users were asked to identify the correct tissue type and level of confidence. The cumulative summation (CUSUM) technique was used to construct a learning curve. RESULTS: 22 (71 %) of the physicians achieved VLE interpretation competency during their 96-slide review. Half of the physicians achieved competency at 65 images (95 % confidence interval [CI] 45 - 85). There was a statistically significant association between confidence in diagnosis and selecting the correct histologic tissue type (P < 0.001). The median accuracy for esophageal squamous epithelium, normal gastric cardia, non-neoplastic BE, and neoplastic BE was 96 % (95 %CI 95 % - 96 %), 95 % (95 %CI 94 % - 96 %), 90 % (95 %CI 88 % - 91 %), 96 % (95 %CI 95 % - 96 %). The overall accuracy was 95 % (95 %CI 93 % - 95 %). CONCLUSION: The majority of novice users achieved competence in image interpretation of VLE for BE, using a pre-selected image set, with a favorable learning curve after a brief training session. An electronic review of VLE images, prior to real-time use of VLE, is encouraged.

Volumetric laser endomicroscopy in Barrett's esophagus: interobserver agreement for interpretation of Barrett's esophagus and associated neoplasia among high-frequency users.

BACKGROUND AND AIMS: Targeting neoplasia in Barrett's esophagus (BE) is challenging. Volumetric laser endomicroscopy (VLE) is a new imaging technique that allows for real time cross-sectional microstructure imaging that can detect BE neoplasia. The interobserver agreement among users in practice is unknown. METHODS: Eight high-volume users of VLE from different academic centers in the United States evaluated 120 stored VLE images blinded to the endoscopic and clinical findings. There were 30 images for each tissue type: gastric cardia, esophageal squamous mucosa, nonneoplastic BE, and neoplastic BE. Each image with BE had corresponding histology confirming the tissue diagnosis. Each normal esophagus and gastric cardia had matching endoscopic images confirming normal mucosa. These were considered the criterion standard. Respondents were asked to classify the images into 1 of each category. Agreement among the users was measured. RESULTS: The overall agreement among users was almost perfect (kappa = 0.81; 95% confidence interval [CI], 0.79-0.83). For esophageal squamous and gastric cardia, the agreement was almost perfect (kappa 0.95 and 0.86, respectively [95% CI, 0.92-0.98 and 0.83-0.89]). For nonneoplastic BE and neoplastic BE, the agreement was strong (kappa 0.66 [95% CI, 0.63-0.69] and 0.79 [95% CI, 0.75-0.82], respectively). When compared with the criterion standard, the median accuracy for identifying normal squamous mucosa, normal gastric mucosa, nonneoplastic BE, neoplastic BE, and all tissue types was 99% (95% CI, 98%-100%), 97% (95% CI, 95%-99%), 93% (95% CI, 88%-98%), 95% (95% CI, 91%-99%), and 96% (95% CI, 94%-99%), respectively. CONCLUSIONS: VLE has a high level of agreement and accuracy among high-volume users.

Hepatitis C virus impairs TLR3 signaling and inhibits IFN-λ 1 expression in human hepatoma cell line.

Toll-like receptor 3 (TLR3) activation plays an important role in the innate immune responses to viral infections. We show here that the activation of TLR3 signaling pathway by poly I:C, a synthetic mimic of dsRNA, could induce high-level expression of interferon (IFN)-λ1 in a hepatoma cell line. The induced IFN-λ1 contributed to poly I:C-mediated inhibition of hepatitis C virus (HCV) Japanese fulminant hepatitis-1 (JFH-1) replication in Huh7 cells. This inhibitory effect of poly I:C on HCV replication, however, was compromised by HCV infection of Huh7 cells. Investigation of the mechanisms showed that HCV infection suppressed the expression of poly I:C-induced IFN-λ1 and IFN-stimulated genes [IFN-stimulated gene 56 (ISG-56), myxovirus resistance A (MxA) and 2'-5'-oligoadenylate synthetase 1 (OAS-1))], the key antiviral elements in IFN signaling pathway. Among the HCV nonstructural (NS) proteins tested, NS3/4A, NS5A and NS5B had the ability to inhibit poly I:C-induced IFN-λ1 expression in Huh7 cells. These observations provide the experimental evidence that HCV and its proteins impair TLR3 signaling and inhibit intracellular IFN-λ1/ISG expression in a hepatoma cell line, which may account for HCV persistence in the liver.

Multifocal Synchronous Granular Cell Tumors of the Gastrointestinal Tract.

Granular cell tumors (GCT) are rare and unusual tumors, which are usually benign and asymptomatic. Only 5-10% of cases involve the gastrointestinal tract, most commonly as singular, non-cancerous lesions in the esophagus. We report a rare case of symptomatic, multifocal, synchronous GCT involving the esophagus, stomach, and cecum.

Oriental cholangiohepatitis masquerading as cholangiocarcinoma: A rare presentation that surgeons need to know.

INTRODUCTION: The detection of an abnormal hepatic mass with ductal dilatation is highly concerning for malignancy. However, if such patients happen to be immigrants from endemic parts of Asia or South America, further investigations are necessary to rule out oriental cholangiohepatitis, a rare recurrent disease of the hepatobiliary system that can masquerade as cholangiocarcinoma. PRESENTATION OF CASE: We report a case of a patient of South Asian origin who presented to us with acute cholangitis and moderately dilated left hepatic ducts. The findings were highly suspicious for advanced hepatic malignancy; however the laboratory and pathological investigations remained normal. We suspected an unlikely etiology and proceeded with conservative hepatic resection. The histology revealed cholangiohepatitis without any evidence of malignancy. DISCUSSION: Cholangiohepatitis is a complex hepatobiliary disease that commonly manifests as recurrent cholangitis or overt biliary sepsis and can rarely present as an abnormal hepatic mass. It results from the development of intrahepatic or extrahepatic strictures that causes stone formation and biliary dilation in the absence of gallbladder disease. Although it is endemic in many parts of the world, it is rare in the western world, and therefore it can present as a significant diagnostic enigma. CONCLUSION: Cholangiohepatitis is a rare clinical entity that requires a multi-disciplinary team approach. Surgery plays a dominant role in the management of such patients and therefore surgeons need to be aware of this disease.

A Francisella tularensis SCHU S4 mutant deficient in γ-glutamyltransferase activity induces protective immunity: characterization of an attenuated vaccine candidate.

Francisella tularensis is an intracellular pathogen which causes tularaemia. There is no licensed vaccine currently available for prophylaxis. The γ-glutamyl transpeptidase (GGT) encoded by the ggt gene has been shown to be important for the intracellular survival of F. tularensis. In this study we have constructed a ggt deletion mutant in the highly virulent F. tularensis strain SCHU S4. Characterization of the mutant strain confirmed the function of ggt, and confirmed the role of GGT in cysteine acquisition. The mutant strain was highly attenuated both in vitro and in vivo using murine models of infection. Moreover, we have demonstrated that the attenuated mutant is able to induce protective immunity against an F. tularensis SCHU S4 challenge, and thus may be a candidate for the development of an attenuated vaccine.

Gastric neuromuscular pathology in gastroparesis: analysis of full-thickness antral biopsies.

BACKGROUND: Pathologic assessment of gastric tissue in patients with gastroparesis is limited. Aims To evaluate gastric histopathology in patients with gastroparesis. METHODS: Full-thickness antral biopsies were obtained in 28 patients with gastroparesis. Control specimens were obtained from patients undergoing gastric resection. H&E and immunohistochemical stained slides were reviewed for the presence of inflammation, ganglion cells, and interstitial cells of Cajal (ICCs). RESULTS: A mild lymphocytic infiltrate in the myenteric plexus was present in 6 out of 14 patients with diabetic gastroparesis (DG), one of 14 idiopathic gastroparesis (IG) and 0 of eight controls. Significant reductions in total nerve cell bodies were seen in gastroparesis patients (2.2 +/- 0.3 per hpf; p = 0.0002) compared to controls (3.2 +/- 0.12). This was seen in both DG (2.4 +/- 0.32) and IG (2.0 +/- 0.2). Sixteen patients (ten IG and six DG) had a reduction of ganglion cells (<2.3 cells/hpf). C-kit staining showed a reduction of ICCs in six patients (five IG and one DG). Four patients (three IG and one DG) had abnormal ICC morphology on C-kit staining with more rounded morphology and less dendritic processes. CONCLUSIONS: This study shows several pathologic abnormalities in the gastric tissue in some patients with refractory gastroparesis. An inflammatory infiltrate was present in nearly half of the patients with diabetic gastroparesis. There was a reduction in nerve cell bodies in both idiopathic and diabetic gastroparesis. A reduced number of ICCs were found in the myenteric plexus. Thus, histologic abnormalities in gastroparesis are heterogeneous and include myenteric inflammation, decreased innervation, and reduction of ICCs.

Unusually large extraintestinal GIST presenting as an abdomino-pelvic tumor.

BACKGROUND: Gastrointestinal stromal tumor (GIST) is a rare visceral tumor that may mimic ovarian tumor. CASE: A 56-year-old woman presented with a large abdomino-pelvic mass and moderately elevated CA-125. A large tumor occupying the whole abdominal cavity and pelvis was noted on laparotomy. In addition, multiple tumor nodules were seen from the ligament of Treitz to the terminal ileum involving only the surface intestine. The ovaries appeared normal. The tumor demonstrated spindle and epithelioid components and was found to be morphologically and immunohistochemically consistent with GIST. CONCLUSION: Gynecologists need to be cognizant of extra-ovarian pathology in the atypical presentation of a pelvic mass. Correct diagnosis is essential for proper management since GISTs specifically respond to the c-kit selective tyrosine kinase inhibitor, Imatinib mesylate.

Giant dermoid cyst of the neck can mimic a cystic hygroma: using MRI to differentiate cystic neck lesions.

OBJECTIVE: To describe differential features of giant cervical dermoid cysts and other cystic lesions of the head and neck. METHODS: Case report including magnetic resonance imaging, surgical excision, pathologic examination and correlation. RESULTS: We report the case of a 15-year-old boy who presented for evaluation of a slowly enlarging doughy submental mass. Ultrasound showed some features consistent with a cystic hygroma and both sclerotherapy and surgical excision were discussed with the family. However, an unusual solid component on magnetic resonance imaging (MRI) mitigated toward surgical excision. At surgery, the cystic mass was excised and measured 9.5 cm x 5.5 cm x 4.0cm. Histology showed a giant dermoid cyst similar to those seen in the ovary. The solid component was a smooth spherical collection of inspissated sebum. CONCLUSIONS: The unique MRI characteristics of giant dermoid cysts can help to separate these rare lesions from more common cystic hygromas. Fine needle aspiration should be considered for questionable lesions before treatment with OK 432 or similar agents.

Detection of JC virus DNA sequences and expression of viral T antigen and agnoprotein in esophageal carcinoma.

BACKGROUND: The human polyomavirus JC virus (JCV) causes progressive multifocal leukoencephalopathy. Subclinical infection with JCV occurs in 85-90% of the population worldwide. The virus usually remains latent but can reactivate under immunosuppressive conditions, resulting in progressive multifocal leukoencephalopathy. JCV is oncogenic in experimental animals and is associated with human brain tumors. JCV is found in normal mucosa of the gastrointestinal tract, and some colon carcinomas express the oncogenic JCV T-antigen protein. The objective of this study was to examine the presence of JCV DNA sequences and JCV protein expression in normal and malignant human esophageal tissues. METHODS: The authors examined the presence of JCV DNA sequences and protein expression in normal and malignant human esophageal tissues. Seventy well characterized biopsy specimens from patients with a spectrum of esophageal disorders were studied by immunohistochemistry, and 18 specimens were analyzed further by polymerase chain reaction amplification. RESULTS: JC viral DNA was isolated from 11 of 13 normal esophageal biopsy specimens (85%) and from 5 of 5 esophageal carcinomas (100%). Using immunohistochemistry, JCV T antigen was detected in 10 of 19 carcinomas (53%), agnoprotein was detected in 8 carcinomas (42%), p53 tumor suppressor was detected in 11 carcinomas (58%), and beta-catenin was detected in 4 carcinomas (21%). Zero of 51 normal, benign, and premalignant esophageal samples expressed viral proteins. Laser-capture microdissection verified the presence and specificity of JCV DNA sequences. beta-Catenin and p53 were colocalized with JCV T-antigen in the nuclei of neoplastic cells. CONCLUSIONS: The results provide evidence for infection of gastrointestinal tract cells by JCV and suggest a potential role of JCV in the development of upper digestive tract carcinomas.

Esophageal bacteria and Barrett's esophagus: a preliminary report.

The objective of this study was to investigate if esophageal bacteria are associated with Barrett's esophagus (BE). This study was comprised of a retrospective (Part 1) and a subsequent prospective (Part 2) study. In Part 1, Gram stains were performed on esophageal biopsy specimens obtained in 47 patients. Bacteria were quantitated from 0 to 4. In Part 2, Gram stains and cultured bacterial counts of esophageal biopsies were obtained in 18 GERD patients (9 with BE and 9 without BE). Part 1 results were as follows. Bacteria were found in 37 of 47 esophageal biopsies. Quantitative bacterial stain scores for BE (2.5 +/- 0.2) were higher than for non-BE (1.5 +/- 0.3; P = 0.02). The quantitative bacterial stain scores correlated with increasing severity of dysplasia (r = 0.37, P = 0.028). In Part 2, bacteria were found in 8 of 18 esophageal biopsies by Gram stain (6 of 9 patients with BE vs. 2 of 9 non-BE). The distal esophageal bacterial stain scores in BE patients (1.6 +/- 0.5) were higher than in those without BE (0.4 +/- 0.3; P = 0.07). Patients on proton pump inhibitors tended to have higher bacterial stain scores (1.2 +/- 0.4) than patients who were not (0.7 +/- 0.3; P = 0.45). Bacterial colony counts were similar in patients with BE compared to those without BE. In conclusion, bacteria in esophageal biopsies were detected more often in BE than non-BE. Increasing bacterial stain scores were associated with metaplasia and increasing dysplasia. Esophageal bacteria, possibly related to stasis or gastric acid suppression therapy, may play a role in the pathogenesis of BE and dysplasia.

Predictors of recurrent specialized intestinal metaplasia after complete laser ablation.

OBJECTIVES: The aim of this study was to determine whether specialized intestinal metaplasia recurs after complete laser ablation and to evaluate the persistence of colon epithelial protein in esophageal mucosa after laser ablation as a predictor of recurrence. METHODS: A total of 31 patients with specialized intestinal metaplasia (Barrett's esophagus) underwent laser photoablation. Investigators without knowledge of treatment status evaluated serial hematoxylin and eosin-stained slides, Alcian blue-stained slides, and immunohistochemistry for the detection of colon epithelial protein (mAb Das-1). RESULTS: Endoscopic ablation of specialized intestinal epithelium was accomplished in 21 patients after 6.5 +/- 1.2 laser sessions. Complications included one perforation, one UGI bleed and one stricture. Of eight post-laser recurrences, seven were successfully re-ablated; one developed adenocarcinoma requiring esophageal resection. Cardia-type mucosa was present by biopsy at the time of complete ablation in all eight recurrent cases despite a normal endoscopic appearance. Colon epithelial protein was detected in all 31 patients before ablation, six of 21 completely ablated patients before they recurred and all eight recurrences. Only two of 15 patients, colon epithelial protein negative at the time of complete ablation, developed recurrent Barrett's esophagus. Thus, cardia-type mucosa and persistent colon epithelial protein staining after complete ablation of specialized intestinal epithelium were predictors of future recurrence (p < 0.001). CONCLUSIONS: Specialized intestinal epithelium was ablated by neodymium:yttrium-aluminum-garnet laser but recurred in eight of 21 (38%) of patients. Colon epithelial protein was present in all primary (31 of 31) and all recurrent (eight of eight) Barrett's esophagus. Recurrent specialized intestinal metaplasia may be deep to squamous epithelium. Replacement of specialized intestinal mucosa by cardia-type mucosa and persistence of colonic epithelial protein are predictors of recurrent specialized intestinal mucosa before its endoscopic or histological detection. Laser ablation of Barrett's epithelium is an investigational intervention that should be restricted to research protocols.

Congenital salivary gland anlage tumor of the nasopharynx.

OBJECTIVE: Nasal and upper respiratory tract obstruction in the neonatal period can result from a variety of conditions, and may present with variable symptoms. In the absence of dysmorphic features or other abnormalities, causes of nasal obstruction may be difficult to differentiate on initial examination. We report an unexpected and potentially life-threatening condition arising during the work-up of this common neonatal complaint. DESIGN: Case report with literature review. RESULTS: A male neonate presented with complaints of nasal obstruction and feeding difficulties. A common diagnostic approach to neonatal nasal obstruction was performed, resulting in an unexpected and potentially life-threatening, albeit curative, result. Cannulation of the nasal cavity to rule out choanal atresia resulted in a burst of bleeding from the nose and mouth. A finger sweep of the oropharynx produced a dislodged mass lesion. Pathology revealed a salivary gland anlage tumor of the nasopharynx. CONCLUSIONS: The diagnosis of a nasopharyngeal mass lesion should be considered in neonates with nasal obstructive symptoms. It is wise to place an index finger in the oropharynx when passing catheters to rule out choanal atresia to feel a dislodged mass lesion before it can become an airway foreign body. Should passage of nasal catheters result in bleeding and/or respiratory distress, the possibility of a displaced mass lesion must be considered immediately to institute prompt intervention.