Submucosal Epstein-Barr Virus Positive Polymorphic B-cell Lymphoproliferative Disorder of the Larynx: A Case Report.

Epstein-Barr virus (EBV) belongs to the group of human herpes virus and can cause clinical and subclinical infections. Although EBV-related disease presentations are similar, they can lead to oncogenic transformation with various clinical manifestations. A thorough workup with morphology, immunohistochemistry, and molecular studies is crucial for the diagnosis of EBV-positive polymorphic B-cell lymphoproliferative disorder, not otherwise specified (NOS), which is a new entity introduced by International Consensus Classification in 2022. We describe an interesting presentation of EBV-positive polymorphic B-cell lymphoproliferative disorder with laryngeal involvement to bring awareness to this entity and we would like to address the need for more accessible treatment options.

Clinical Outcomes After Endoscopic Management of Low-Risk and High-Risk T1a Esophageal Adenocarcinoma: A Multicenter Study.

INTRODUCTION: Endoscopic eradication therapy (EET) is standard of care for T1a esophageal adenocarcinoma (EAC). However, data on outcomes in high-risk T1a EAC are limited. We assessed and compared outcomes after EET of low-risk and high-risk T1a EAC, including intraluminal EAC recurrence, extraesophageal metastases, and overall survival. METHODS: Patients who underwent EET for T1a EAC at 3 referral Barrett's esophagus endotherapy units between 1996 and 2022 were included. Patients with submucosal invasion, positive deep margins, or metastases at initial diagnosis were excluded. High-risk T1a EAC was defined as T1a EAC with poor differentiation and/or lymphovascular invasion, with low-risk disease being defined without these features. All pathology was systematically assessed by expert gastrointestinal pathologists. Baseline and follow-up endoscopy and pathology data were abstracted. Time-to-event analyses were performed to compare outcomes between groups. RESULTS: One hundred eighty-eight patients with T1a EAC were included (high risk, n = 45; low risk, n = 143) with a median age of 70 years, and 84% were men. Groups were comparable for age, sex, Barrett's esophagus length, lesion size, and EET technique. Rates of delayed extraesophageal metastases (11.1% vs 1.4%) were significantly higher in the high-risk group ( P = 0.02). There was no significant difference in the rates of intraluminal EAC recurrence ( P = 0.79) and overall survival ( P = 0.73) between the 2 groups. DISCUSSION: Patients with high-risk T1a EAC undergoing successful EET had a substantially higher rate of extraesophageal metastases compared with those with low-risk T1a EAC on long-term follow-up. These data should be factored into discussions with patients while selecting treatment approaches. Additional prospective data in this area are critical.

Iatrogenic Acute Ascending Aortic Dissection During Combined Heart/Liver Transplant for Amyloidosis.

We report a case of iatrogenic acute type A aortic dissection (ATAAD) during a combined heart-liver transplant in a patient with amyloid-associated cardiac and hepatic failure. The patient developed ATAAD of the recipient's aorta during the heart transplantation. Because there was no sign of malperfusion or proximal extension into the donor aorta, we proceeded with the liver transplantation and continued medical management for ATAAD. The patient was discharged uneventfully 30 days after the transplant, and computed tomography coronary angiogram after 4 months showed stable dissection. During a heart transplant, ATAAD of the native aorta without malperfusion syndrome can be managed conservatively with close progress monitoring.

Pyomyositis presenting as myonecrosis secondary to methicillin-resistant Staphylococcus aureus bacteremia in chronic lymphocytic leukemia.

The incidence of pyomyositis in immunocompromised patients with HIV, diabetes, myelodysplastic syndromes, and acute lymphocytic leukemia is well documented. However, there are only a few reports of pyomyositis and myonecrosis in patients with chronic lymphocytic leukemia (CLL). We present a rare case of pyomyositis presenting as myonecrosis secondary to methicillin-resistant Staphylococcus aureus bacteremia in a 72-year-old patient with CLL. Pyomyositis, although rare, warrants increased provider awareness and management, especially among CLL patients who pose diagnostic and treatment challenges.

Prkci Regulates Autophagy and Pancreatic Tumorigenesis in Mice.

Protein kinase C iota (PKCι) functions as a bonafide human oncogene in lung and ovarian cancer and is required for KrasG12D-mediated lung cancer initiation and progression. PKCι expression is required for pancreatic cancer cell growth and maintenance of the transformed phenotype; however, nothing is known about the role of PKCι in pancreas development or pancreatic tumorigenesis. In this study, we investigated the effect of pancreas-specific ablation of PKCι expression on pancreatic cellular homeostasis, susceptibility to pancreatitis, and KrasG12D-mediated pancreatic cancer development. Knockout of pancreatic Prkci significantly increased pancreatic immune cell infiltration, acinar cell DNA damage, and apoptosis, but reduced sensitivity to caerulein-induced pancreatitis. Prkci-ablated pancreatic acinar cells exhibited P62 aggregation and a loss of autophagic vesicles. Loss of pancreatic Prkci promoted KrasG12D-mediated pancreatic intraepithelial neoplasia formation but blocked progression to adenocarcinoma, consistent with disruption of autophagy. Our results reveal a novel promotive role for PKCι in pancreatic epithelial cell autophagy and pancreatic cancer progression.

Extent of eosinophilic esophagitis predicts response to treatment.

Background and study aim The clinical impact of eosinophilic esophagitis (EoE) limited to the distal esophagus (Lim-EE) vs. diffuse involvement (Dif-EE) is unknown. This study compared clinical characteristics and outcomes of Lim-EE vs. Dif-EE. Patients and methods This retrospective, single-center study of patients with EoE between December 2011 and December 2019 evaluated treatment response based on repeated pathology and/or clinical improvement using comparative statistics. Results 479 patients were identified (126 Lim-EE, 353 Dif-EE). Lim-EE patients had a higher incidence of endoscopically identified esophagitis (23.0 % vs. 14.7 %; P  = 0.04), were older (50.8 [SD 16.2] vs. 46.4 [SD 15.3] years; P  = 0.007), and were more likely to present with iron deficiency anemia (5.6 % vs. 1.7 %; P  = 0.05), dyspepsia (15.1 % vs. 8.8 %; P  = 0.06) or for Barrett's surveillance (10.3 % vs. 3.7 %; P  = 0.02). Patients with Dif-EE presented more frequently with dysphagia (57.2 % vs. 45.2 %; P  = 0.02). Both groups had similar proton pump inhibitor (87.2 % vs. 83.3 %; P  = 0.37) and steroid (12.8 % vs. 21.4 %; P  = 0.14) use. Patients with Lim-EE had a better clinicopathologic response (61.5 % vs. 44.8 %; P  = 0.009). On multivariate analysis, EoE extent predicted treatment response with an odds ratio of 1.89 (95 % confidence interval 1.13-3.20; P  = 0.02). However, treatment response based only on repeat biopsy results showed no statistical difference between Lim-EE (52.5 %) and Dif-EE (39.7 %; P  = 0.15). Conclusions Lim-EE may represent a distinct phenotype separate from Dif-EE, with more overlap with gastroesophageal reflux disease and better treatment response.

Lymphocytic Esophagitis: Assessing Risk Factors and Clinical Outcomes.

BACKGROUND: Lymphocytic esophagitis is a rare esophageal condition. Our knowledge of potential risk factors and treatment outcomes of lymphocytic esophagitis is limited. AIM: To investigate potential risk factors associated with the development of lymphocytic esophagitis and compare clinical characteristics and treatment outcomes of patients diagnosed with lymphocytic esophagitis to patients diagnosed with eosinophilic esophagitis. METHODS: This is a multicenter retrospective study. Lymphocytic esophagitis patients were identified based on pathology results between 1997 and 2019. Control groups consisted of patients with normal esophageal biopsies and patients diagnosed with eosinophilic esophagitis. Thirteen potential risk factors for lymphocytic esophagitis were analyzed using univariate and multivariate models including IBD, achalasia, hyperlipidemia, hypothyroidism, celiac sprue, CVID, H. pylori, thymoma, aspirin, opioids, ACE-I, metformin, and statin use. Comparative statistics were performed. RESULTS: Ninety-four adult patients with lymphocytic esophagitis, 344 with eosinophilic esophagitis, and 5202 control patients with normal esophageal biopsies were analyzed. Age older than 60 [adjusted odd ratio (AOR) 1.03, 95% CI 1.02-1.05, p = 0.001], aspirin use (2.7, 95% CI 1.4-4.9, p = 0.001), statin use (2.2, 95% CI 1.2-4.2, p = 0.01), or a diagnosis of achalasia (2.4, 95% 1.08-5.67, p = 0.03) were associated with lymphocytic esophagitis. Compared to eosinophilic esophagitis, lymphocytic esophagitis patients were more likely to respond to medical treatment (95% CI 2.54-12.8, p = 0.0001). CONCLUSIONS: Our data suggests that lymphocytic esophagitis is more likely to be found in older female patients and is significantly associated with achalasia, statin, and aspirin use. Compared to eosinophilic esophagitis, lymphocytic esophagitis is more likely to respond to treatment with medical therapy.

Modeling and Simulation of the Pharmacokinetics and Target Engagement of an Antagonist Monoclonal Antibody to Interferon-γ-Induced Protein 10, BMS-986184, in Healthy Participants to Guide Therapeutic Dosing.

BMS-986184 is a human, second-generation, anti-interferon-γ-induced protein 10 (IP-10) monoclonal antibody. In this study the pharmacokinetics and target engagement (TE) of BMS-986184 in healthy participants were characterized using population-based target-mediated drug disposition (TMDD) modeling and data from a first-in-human study (NCT02864264). The results of the first-in-human study and the model generated were used to conduct stochastic simulations of a virtual population of healthy participants to predict pharmacokinetic exposures and TE responses for different dosage regimens. A 2-compartment, 2-target, TMDD structural model, assuming quasi-steady-state and stimulated production on treatment, was developed by simultaneous fitting of the total drug, serum-free IP-10, and serum total IP-10 concentration data, with the second unobservable target contribution to drug elimination described by the Michaelis-Menten elimination term. Model evaluation confirmed agreement between model predictions and observed data. Simulation of a virtual population of healthy individuals demonstrated that steady state was reached at the eighth dosing interval, and that around 150 mg subcutaneously every other week could be a suitable target dosage regimen for future clinical trials. Integrated modeling strategies such as this can be used to help guide rational clinical trial development of drugs with TMDD, leading to improved dose selection and greater patient benefits.

Biopsy-proven progressive multifocal leukoencephalopathy in a renal transplant patient.

Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease that affects immunocompromised hosts. Most often the disease is reported in association with leukemia, lymphoma, and AIDS. With recent advancements in immunosuppressive medications and subsequent rise in solid organ transplantations, it is becoming more prevalent in this population. Both the diagnosis and treatment of PML remains a challenge to the transplant community. The disease remains mostly underreported and undertreated. The diagnostic uncertainty in a renal transplant patient leads us to do the brain biopsy for suspicion and confirmation of PML.

Volumetric laser endomicroscopy in the biliary and pancreatic ducts: a feasibility study with histological correlation.

BACKGROUND: Volumetric laser endomicroscopy (VLE) provides circumferential images 3 mm into the biliary and pancreatic ducts. We aimed to correlate VLE images with the normal and abnormal microstructure of these ducts. METHODS: Samples from patients undergoing hepatic or pancreatic resection were evaluated. VLE images were collected using a low-profile VLE catheter inserted manually into the biliary and pancreatic ducts ex vivo. Histological correlation was assessed by two unblinded investigators. RESULTS: 25 patients (20 liver and 5 pancreatic samples) and 111 images were analyzed. VLE revealed three histological layers: epithelium, connective tissue, and parenchyma. It identified distinctive patterns for primary sclerosing cholangitis (PSC), pancreatic cysts, neuroendocrine tumor, and adenocarcinoma adjacent to the pancreatic duct or ampulla. VLE failed to identify dysplasia in a dominant stricture and inflammatory infiltrates in PSC. Reflectivity measurements of the liver parenchyma diagnosed liver cirrhosis with high sensitivity. CONCLUSIONS: VLE can identify histological changes in the biliary and pancreatic ducts allowing real-time diagnosis. Further studies are needed to measure the accuracy of VLE in a larger sample and to validate our findings in vivo.

Association Between Programmed Death-Ligand 1 Expression and the Vascular Endothelial Growth Factor Pathway in Angiosarcoma.

Angiosarcoma is a vascular malignancy associated with a poor prognosis and chemotherapy resistance. The tumor immune microenvironment of angiosarcoma has not been characterized. We investigated the expression of programmed death-ligand 1 (PD-L1) and programmed death 1 (PD-1) in angiosarcoma and correlated these findings with vascular endothelial growth factor (VEGF)-related gene expression and survival. Using archived formalin-fixed paraffin-embedded tissues of primary and metastatic angiosarcoma specimens, we characterized the immunohistochemical (IHC) expression of PD-L1 and PD-1. In addition, we extracted RNA from each tumor and quantified the expression of VEGF-related genes, and then tested if these genes were associated with PD-L1 and PD-1 expression and clinical outcomes. Retrospective review identified 27 angiosarcoma specimens collected between 1994 and 2012. IHC expression of tumor PD-L1, tumor-infiltrating immune cell PD-L1, and tumor-infiltrating immune cell PD-1 expression was identified in 5 (19%), 9 (33%), and 1 (4%) specimens, respectively. Expression of PD-L1 and PD-1 was not associated with VEGF-related gene expression or survival. PD-L1 tumor and tumor-infiltrating immune cells expression was identified in a large proportion of patients. Though neither was associated with VEGF-related gene expression or prognosis, targeting PD-1/PD-L1 may be of benefit for a significant proportion of angiosarcomas that do not respond to surgery, chemotherapy, or radiation.

Depth of Muscularis Propria Invasion Does Not Prognosticate Survival in T2 Esophageal Adenocarcinoma.

AIM: Although tumor depth of invasion is strongly associated with risk of lymph node metastasis and long-term survival in patients with esophageal adenocarcinoma, the significance of differential T2 invasion (inner circular layer versus outer longitudinal layer) is unknown. The current study was undertaken to explore the hypothesis that greater T2-specific depth of invasion is associated with inferior long-term outcomes in patients with esophageal adenocarcinoma treated with esophagectomy. PATIENTS AND METHODS: Demographic, treatment, and outcome data were collected for patients with resected pT2N0-3M0 esophageal adenocarcinoma treated between 2005 and 2015 pooled from four U.S. academic medical centers. Two blinded pathologists evaluated depth of muscularis propria tumor invasion. Univariate and Cox proportional hazard regression analyses were performed to identify prognostic factors for overall (OS) and disease-free (DFS) survival, and Kaplan-Meier analysis to compare survival differences specific to prognostic factors. RESULTS: A total of 84 patients were identified for analysis (53 with circular invasion; 31 with longitudinal invasion), with a median age of 66 years. Sixty percent of patients (50/84) received induction therapy prior to esophagectomy. The median OS and DFS was 58 months (95% confidence interval(CI)=42 months-not reached) and 27 months (95% CI=13.7-66 months) respectively. Depth of muscularis propria invasion did not correlate with OS or DFS on univariate (p=0.42; and p=0.34, respectively) or multivariate (p=0.15 and p=0.21, respectively) analysis after adjustment for age, nodal status, perineural invasion, and tumor grade. These findings did not vary by induction therapy status. CONCLUSION: Depth of muscularis propria invasion does not appear to correlate with survival in patients with esophageal adenocarcinoma.

Thermal ablation of pancreatic cyst with a prototype endoscopic ultrasound capable radiofrequency needle device: A pilot feasibility study.

BACKGROUND AND OBJECTIVES: Pancreatic cysts are evaluated by endoscopic ultrasound and fine needle aspiration (EUS). The only accepted treatment is pancreatectomy, which is associated with morbidity and mortality. This study evaluated the optimal thermal dosimetry of a novel radiofrequency ablation device using a standard electrosurgical unit in ex vivo cyst models. METHODS: A modified EUS 22-gauge monopolar needle prototype with a tip electrode connected to a standard electrosurgical unit (Erbe USA, Marietta, GA, USA) was used to induce a subboiling point temperature. A cyst model was created using 2-cm sections of porcine small intestine ligated and filled with saline. After ablation, the cyst models were prepared for pathological evaluation. The epithelial layers were measured in at least two different sites with a micrometer and compared with the corresponding control sample. RESULTS: Thirty-two cyst models were ablated with maximum temperatures of 50°C, 60°C, 90°C, and 97°C in 8, 11, 11, and 2 cysts, respectively. Longer ablation times were required to induce higher temperatures. A trend in the reduction in thickness of the measured layers was observed after exposure to higher temperatures. A temperature over 50°C was required for the ablation of the muscularis, submucosa, and villi, and over 60°C was required to ablate the mucosal crypts. CONCLUSIONS: In a preclinical model, a novel radiofrequency EUS-capable needle connected to a standard electrosurgical unit using standard low-voltage coagulation provided ablation in a temperature-dependent fashion with a threshold of at least 60°C and a safe cyst margin below 97°C. This potentially will allow low-cost, convenient cyst ablation.

Predictors of Progression in Barrett's Esophagus with Low-Grade Dysplasia: Results from a Multicenter Prospective BE Registry.

OBJECTIVES: Low-grade dysplasia (LGD) is a risk factor for progression in Barrett's esophagus (BE). Progression estimates however vary and predictors of progression are not well established. We aimed to assess predictors of progression in a multicenter BE-LGD cohort. METHODS: All subjects with LGD (diagnosed by a GI pathologist) in a prospective BE registry were identified. Progression was defined development of HGD/EAC more than 12 months after index date of LGD diagnosis. Clinical, endoscopic factors and impact of histologic review by an independent panel of two GI pathologists were assessed as predictors of progression. Cox proportional hazard models were used to assess their association with risk of progression. RESULTS: 244 BE-LGD subjects met inclusion criteria. Their mean age was 63.2 years. 205 (84%) were males. The median follow up was 4.8 years. Fifty six patients were diagnosed with HGD/EAC in less than 12 months, while 14 progressed to HGD/EAC after 12 months, with an overall annual risk of progression of 1.2%. 29% of LGD subjects were downgraded to non-dysplastic and the remaining re-confirmed as LGD or indefinite dysplasia. The risk of progression in the reconfirmed LGD group was eight fold higher (hazards ratio: 7.6, 95% CI: 1.5-139.4) in a propensity score stratified model. CONCLUSIONS: In this large BE-LGD cohort, progression risk increased substantially when an additional panel of two expert GI pathologists re-confirmed a LGD diagnosis. These BE subjects may be candidates for endoscopic therapy. LGD was a marker of prevalent HGD/EAC in 18% of patients.