Histologic Features of Liver Injury Associated With SARS-CoV-2 Messenger RNA Vaccines.

CONTEXT.­: Many drugs can induce liver injury; however, vaccine-induced liver injury is a rare phenomenon. SARS-CoV-2 messenger RNA (mRNA) vaccines are now widely administered, and clinical evidence of liver injury has been reported. OBJECTIVE.­: To characterize the histologic features of SARS-CoV-2 mRNA vaccine-associated liver injury. DESIGN.­: Thirteen liver biopsies from 12 patients with elevated liver enzymes clinically favored to be secondary to SARS-CoV-2 mRNA vaccine were identified between 2021 and 2022. Demographics, clinical information, and histologic features of liver biopsies were reviewed. RESULTS.­: All patients (median age, 58 years; M:F = 4:8) received at least 1 dose of SARS-CoV-2 mRNA vaccines (7 Pfizer and 5 Moderna). Four patients had a history of liver disease. Nine patients developed symptoms between 1 day and 2 months after receiving the vaccine dose. Viral serologies were negative. Drug-induced liver injury was thought to be less likely clinically in the 3 patients who had started new medications. Autoimmune antibodies were detected in 9 patients. Moderate to severe active hepatitis was the dominant histologic pattern of injury (9 of 13 biopsies; 69%). Resolving hepatitis, cholestatic hepatitic injury, and bile duct injury were identified in 1 biopsy each. All patients recovered spontaneously or with steroid therapy except one patient who developed autoimmune hepatitis. CONCLUSIONS.­: Moderate to severe active hepatitis is commonly observed in SARS-CoV-2 mRNA vaccine-associated liver injury, and female patients may be more susceptible to injury. Liver injury resolves spontaneously or with steroid treatment. In rare cases, these vaccines may trigger an underlying immune condition.

Imaging of Biliary Tree Abnormalities.

Pathologic conditions of the biliary system, although common, can be difficult to diagnose clinically. Challenges in biliary imaging include anatomic variants and the dynamic nature of the biliary tract, which can change with age and intervention, blurring the boundaries of normal and abnormal. Choledochal cysts can have numerous appearances and are important to diagnose given the risk of cholangiocarcinoma potentially requiring surgical resection. Choledocholithiasis, the most common cause of biliary dilatation, can be difficult to detect at US and CT, with MRI having the highest sensitivity. However, knowledge of the imaging pitfalls of MRI and MR cholangiopancreatography is crucial to avoid misinterpretation. Newer concepts in biliary tract malignancy include intraductal papillary biliary neoplasms that may develop into cholangiocarcinoma. New paradigms in the classification of cholangiocarcinoma correspond to the wide range of imaging appearances of the disease and have implications for prognosis. Accurately staging cholangiocarcinoma is imperative, given expanding curative options including transplant and more aggressive surgical options. Infections of the biliary tree include acute cholangitis or recurrent pyogenic cholangitis, characterized by obstruction, strictures, and central biliary dilatation. Inflammatory conditions include primary sclerosing cholangitis, which features strictures and fibrosis but can be difficult to differentiate from secondary causes of sclerosing cholangitis, including more recently described entities such as immunoglobulin G4-related sclerosing cholangitis and COVID-19 secondary sclerosing cholangitis. The authors describe a wide variety of benign and malignant biliary tract abnormalities, highlight differentiating features of the cholangitides, provide an approach to interpretation based on the pattern of imaging findings, and discuss pearls and pitfalls of imaging to facilitate accurate diagnosis. ©RSNA, 2024 Supplemental material is available for this article.

Small bowel pyloric metaplasia is associated with lower rates of earlier recurrence of Crohn's disease after resection.

Recurrence within one or two years is common after Crohn's disease (CD) resection. In this study, we seek to identify histologic features in CD resections that may predict earlier (≤18 months) recurrence to potentially guide post-operative management. A single-institution, retrospective review was performed on patients with first-time CD bowel resection specimens (2002-2007). Patient demographics and CD course were also documented. Slides were reviewed for inflammatory distribution and composition, small bowel (SB) pyloric metaplasia (PM), and presence and characteristics of submucosal fibrosis and granulomas. In our cohort, 14 of 41 patients experienced earlier clinical or endoscopic recurrence after initial resection. In the 38 patients who underwent SB resection (3 were colon only), PM was less common in those with earlier recurrence (6/12 [50%]) compared to those with later (>18 months) or no known recurrence (22/26 [85%]) (P = 0.045). PM was present even in patients with <1 year of known CD. Additionally, therapy with anti-tumor necrosis factor (TNF) prior to surgery was more common in earlier recurrence patients (7/14 [50%]) than later or no recurrence patients (4/27 [15%]) (P = 0.026). There was no significant difference in age, sex, smoking status, duration of CD, post-operative CD medication, distribution or features of inflammation, granulomas, or fibrosis. Overall, our results indicate that SB PM and pre-surgical anti-TNF therapy are possible helpful clinicopathologic features to evaluate for recurrence risk.

Is Type 2 Diabetes Mellitus Associated with Spinal Degenerative Disorders?: Evidence from Observational and 2-Sample Mendelian Randomization Analyses.

BACKGROUND: Type 2 diabetes mellitus (T2DM) and spinal degenerative disorders (SDD) are common diseases that frequently coexist. However, both traditional observational studies and recent Mendelian randomization (MR) studies have demonstrated conflicting evidence on the association between T2DM and SDD. This comparative study explored and compared the association between T2DM and SDD using observational and MR analyses. METHODS: For observational analyses, cross-sectional studies (44,972 participants with T2DM and 403,095 participants without T2DM), case-control studies (38,234 participants with SDD and 409,833 participants without SDD), and prospective studies (35,550 participants with T2DM and 392,046 participants without T2DM with follow-up information until 2022) were performed to test the relationship between T2DM and SDD using individual-level data from the U.K. Biobank from 2006 to 2022. For MR analyses, the associations between single-nucleotide polymorphisms with SDD susceptibility obtained using participant data from the U.K. Biobank, which had 407,938 participants from 2006 to 2022, and the FinnGen Consortium, which had 227,388 participants from 2017 to 2022, and genetic predisposition to T2DM obtained using summary statistics from a pooled genome-wide association study involving 1,407,282 individuals were examined. The onset and severity of T2DM are not available in the databases being used. RESULTS: Participants with T2DM were more likely to have SDD than their counterparts. Logistic regression analysis identified T2DM as an independent risk factor for SDD, which was confirmed by the Cox proportional hazard model results. However, using single-nucleotide polymorphisms as instruments, the MR analyses demonstrated no causal relationship between T2DM and SDD. The lack of such an association was robust in the sensitivity analysis, and no pleiotropy was seen. CONCLUSIONS: Our results suggest that the association between T2DM and SDD may be method-dependent. Researchers and clinicians should be cautious in interpreting the association, especially the causal association, between T2DM and SDD. Our findings provide fresh insights into the association between T2DM and SDD by various analysis methods and guide future research and clinical efforts in the effective prevention and management of T2DM and SDD. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Clinicopathologic Features of Gastrointestinal Tract Langerhans Cell Histiocytosis.

Gastrointestinal (GI) tract involvement by Langerhans cell histiocytosis (LCH) is rare and its clinicopathologic characteristics have only been described in case reports and small series. We reviewed hematoxylin and eosin and CD1a, S100, and Langerin immunohistochemical-stained slides from 47 patients with well-documented demographic and clinical findings. Our cases included 8 children and 39 adults, with a mean follow-up of 63 months. All pediatric patients had concurrent multisystem LCH, presented with GI symptoms, and showed nonpolypoid lesions. Seven (88%) showed multifocal GI disease, including 5 with multiple GI organ involvement. All sampled lesions from children exhibited infiltrative growth. More than half had died of the disease or manifested persistent LCH at last follow-up. Twenty-five of 39 (64%) adults had LCH involving only the GI tract (single system), with the remaining 14 (36%) exhibiting multisystem disease. Adult single-system GI LCH was typically encountered incidentally on screening/surveillance endoscopy (72%). Most exhibited isolated colorectal involvement (88%) as a solitary polyp (92%), with a well-demarcated/noninfiltrative growth pattern (70%), and excellent prognosis (100%). In comparison, adult patients with multisystem LCH more frequently presented with GI symptoms (92%, P < .001), noncolorectal GI site involvement (50%, P = .02), multifocal GI lesions (43%, P = .005), nonpolypoid lesions (71%, P < .001), infiltrative histologic growth pattern (78%, P = .04), and persistent disease (57%, P < .001). Adult patients with multisystem LCH appear to exhibit similar clinicopathologic features to those of pediatric patients. These results demonstrated that adults with single-system LCH involving the GI tract have an excellent prognosis, whereas multisystem LCH occurring at any age carries an unfavorable prognosis. High-risk features of GI LCH include pediatric age, GI symptomatology, noncolorectal GI involvement, multifocal GI disease, nonpolypoid lesions, and infiltrative growth pattern.

Imaging of pancreatic serous cystadenoma and common imitators.

Pancreatic cystic neoplasms are lesions comprised of cystic components that show different biological behaviors, epidemiology, clinical manifestations, imaging features, and malignant potential and management. Benign cystic neoplasms include serous cystic neoplasms (SCAs). Other pancreatic cystic lesions have malignant potential, such as intraductal papillary mucinous neoplasms and mucinous cystic neoplasms. SCAs can be divided into microcystic (classic appearance), honeycomb, oligocystic/macrocystic, and solid patterns based on imaging appearance. They are usually solitary but may be multiple in von Hippel-Lindau disease, which may depict disseminated involvement. The variable appearances of SCAs can mimic other types of pancreatic cystic lesions, and cross-sectional imaging plays an important role in their differential diagnosis. Endoscopic ultrasonography has helped in improving diagnostic accuracy of pancreatic cystic lesions by guiding tissue sampling (biopsy) or cyst fluid analysis. Immunohistochemistry and newer techniques such as radiomics have shown improved performance for preoperatively discriminating SCAs and their mimickers.

Integrating single-cell and spatial transcriptomics reveals endoplasmic reticulum stress-related CAF subpopulations associated with chordoma progression.

BACKGROUND: With cancer-associated fibroblasts (CAFs) as the main cell type, the rich myxoid stromal components in chordoma tissues may likely contribute to its development and progression. METHODS: Single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, bulk RNA-seq, and multiplexed quantitative immunofluorescence (QIF) were used to dissect the heterogeneity, spatial distribution, and clinical implication of CAFs in chordoma. RESULTS: We sequenced here 72 097 single cells from 3 primary and 3 recurrent tumor samples, as well as 3 nucleus pulposus samples as controls using scRNA-seq. We identified a unique cluster of CAF in recurrent tumors that highly expressed hypoxic genes and was functionally enriched in endoplasmic reticulum stress (ERS). Pseudotime trajectory and cell communication analyses showed that this ERS-CAF subpopulation originated from normal fibroblasts and widely interacted with tumoral and immune cells. Analyzing the bulk RNA-seq data from 126 patients, we found that the ERS-CAF signature score was associated with the invasion and poor prognosis of chordoma. By integrating the results of scRNA-seq with spatial transcriptomics, we demonstrated the existence of ERS-CAF in chordoma tissues and revealed that this CAF subtype displayed the most proximity to its surrounding tumor cells. In subsequent QIF validation involving 105 additional patients, we confirmed that ERS-CAF was abundant in the chordoma microenvironment and located close to tumor cells. Furthermore, both ERS-CAF density and its distance to tumor cells were correlated with tumor malignant phenotype and adverse patient outcomes. CONCLUSIONS: These findings depict the CAF landscape for chordoma and may provide insights into the development of novel treatment approaches.

Human neutrophil elastase inhibitors: Classification, biological-synthetic sources and their relevance in related diseases.

BACKGROUND: Human neutrophil elastase is a multifunctional protease enzyme whose function is to break the bonds of proteins and degrade them to polypeptides or amino acids. In addition, it plays an essential role in the immune mechanism against bacterial infections and represents a key mediator in tissue remodeling and inflammation. However, when the extracellular release of this enzyme is dysregulated in response to low levels of its physiological inhibitors, it ultimately leads to the degradation of proteins, in particular elastin, as well as other components of the extracellular matrix, producing injury to epithelial cells, which can promote sustained inflammation and affect the innate immune system, and, therefore, be the basis for the development of severe inflammatory diseases, especially those associated with the cardiopulmonary system. OBJECTIVE: This review aims to provide an update on the elastase inhibitory properties of several molecules, either synthetic or biological sources, as well as their classification and relevance in related pathologies since a clear understanding of the function of these molecules with the inhibitory capacity of this protease can provide valuable information for the development of pharmacological therapies that manage to modify the prognosis and survival of various inflammatory diseases. METHODS: Collected data from scientific databases, including PubMed, Google Scholar, Science Direct, Nature, Wiley, Scopus, and Scielo. Articles published in any country and language were included. RESULTS: We reviewed and included 132 articles conceptualizing neutrophil elastase activity and known inhibitors. CONCLUSION: Understanding the mechanism of action of elastase inhibitors based on particular aspects such as their kinetic behavior, structure-function relationship, chemical properties, origin, pharmacodynamics, and experimental progress has allowed for a broad classification of HNE inhibitors.

Cardiovascular-specific mortality and risk factors in colorectal Cancer patients: A cohort study based on registry data of over 500,000 individuals in the US.

BACKGROUND: Colorectal cancer (CRC) is one of the most common cancers worldwide, and recent studies have found that CRC patients are at increased risk for cardiovascular disease (CVD). This study aimed to investigate competing causes of death and prognostic factors among a large cohort of CRC patients and to describe cardiovascular-specific mortality in relation to the US standard population. METHODS: This registry-based cohort study identified patients diagnosed with CRC between 1973 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database in the US. Cumulative mortality functions, conditional standardized mortality ratios, and cause-specific hazard ratios were calculated. RESULTS: Of the 563,298 eligible CRC patients included in this study, 407,545 died during the follow-up period. CRC was the leading cause of death, accounting for 49.8% of all possible competing causes of death. CVD was the most common non-cancer cause of death, accounting for 17.8% of total mortality. This study found that CRC patients have a significantly increased risk of cardiovascular-specific mortality compared to the US standard population, with the risk increasing with age and extended survival time. CONCLUSION: This study highlights the need to develop multidisciplinary prevention and management strategies for CRC and CVD to improve CRC patients' survival and quality of life.

A breast cancer classification and immune landscape analysis based on cancer stem-cell-related risk panel.

This study sought to identify molecular subtypes of breast cancer (BC) and develop a breast cancer stem cells (BCSCs)-related gene risk score for predicting prognosis and assessing the potential for immunotherapy. Unsupervised clustering based on prognostic BCSC genes was used to determine BC molecular subtypes. Core genes of BC subtypes identified by non-negative matrix factorization algorithm (NMF) were screened using weighted gene co-expression network analysis (WGCNA). A risk model based on prognostic BCSC genes was constructed using machine learning as well as LASSO regression and multivariate Cox regression. The tumor microenvironment and immune infiltration were analyzed using ESTIMATE and CIBERSORT, respectively. A CD79A+CD24-PANCK+-BCSC subpopulation was identified and its spatial relationship with microenvironmental immune response state was evaluated by multiplexed quantitative immunofluorescence (QIF) and TissueFAXS Cytometry. We identified two distinct molecular subtypes, with Cluster 1 displaying better prognosis and enhanced immune response. The constructed risk model involving ten BCSC genes could effectively stratify patients into subgroups with different survival, immune cell abundance, and response to immunotherapy. In subsequent QIF validation involving 267 patients, we demonstrated the existence of CD79A+CD24-PANCK+-BCSC in BC tissues and revealed that this BCSC subtype located close to exhausted CD8+FOXP3+ T cells. Furthermore, both the densities of CD79A+CD24-PANCK+-BCSCs and CD8+FOXP3+T cells were positively correlated with poor survival. These findings highlight the importance of BCSCs in prognosis and reshaping the immune microenvironment, which may provide an option to improve outcomes for patients.

A novel immune checkpoint-related signature for prognosis and immune analysis in breast cancer.

Breast cancer is one of the most prevailing forms of cancer globally. Immunotherapy has demonstrated efficacy in improving the overall survival of breast cancer. The aim of us was to formulate a novel signature predicated on immune checkpoint-related genes (ICGs) that could anticipate the prognosis and further analyze the immune status of patients with breast cancer. After acquiring data, we pinpointed the definitive ICGs for constructing the prognostic model of breast cancer. We constructed a novel prognostic model and created a fresh risk score called Immune Checkpoint-related Risk Score in breast cancer (ICRSBC). The nomogram was constructed to evaluate the accuracy of the model, and the new web-based tool was created to be more intuitive for predicting prognosis. We also investigated immunotherapy responsiveness and analyzed the tumor mutational burden (TMB) in ICRSBC subgroups. The ICRSBC was found to have significant correlations with the immune environment, immunotherapy responsiveness, and TMB. The expression levels of the 9 ICGs that construct the prognostic model and their promoter methylation levels are significantly different between breast cancer and normal tissues. Furthermore, the mutation profiles, the copy number alterations, and the levels of protein expression also exhibit marked disparities among the 9 ICGs. We have identified and validated a novel signature related to ICGs that is strongly associated with breast cancer progression. This signature enables us to create a risk score for prognosticating the survival and assessing the immune status of individuals affected by breast cancer.

Ultrasound identification of the cricothyroid membrane. Systematic review and meta-analysis

Introduction: The no-ventilation no-oxygenation situation is extremely important due to its high mortality. In these cases, open cricothyroidotomy is indicated. Around fifty percent of the difficulties are the result of inadequate identification of the cricothyroid membrane (CTM). Objective: To determine whether ultrasonography is superior to palpation to identify the CTM at the first attempt. Methods: A systematic review and a meta-analysis were conducted on the identification of the cricothyroid membrane versus palpation in Medline/Central and Embase. Clinical controlled trials and observational studies were included. Two authors independently and in duplicate selected the studies, assessed the biases and extracted the data; a random effects meta-analysis was successfully conducted for the correct identification of the CTM. The risk of bias was assessed and the certainty of the evidence was qualified. CRD42021223961. Results: 464 studies were included of which 15 met the eligibility criteria; 6 were clinical trials y 9 were observational. Ultrasound is superior to palpation in the detection of the CTM (RR 1.88, 95 % CI 1.05-3.36) according to the clinical trials, and it was also superior in observational studies (RR 1.76, 95 % CI 1.36-2.28). The association was preserved in the sensitivity analyses. Conclusions: Ultrasonography is superior to palpation for the correct identification of the TCM, though the certainty of the evidence is low. Further studies with better methodology are needed to improve both certainty and precision.

Introducción: La situación de no ventilación-no oxigenación es de gran importancia dada su elevada mortalidad. En dichos casos, la cricotiroidotomía abierta está indicada. Cerca de la mitad de las dificultades son causadas por inadecuada identificación de la membrana cricotiroidea (MCT). Objetivo: Determinar si la ultrasonografía es superior a la palpación para identificar la MCT al primer intento. Métodos: Se realizó una revisión sistemática y metaanálisis de identificación de membrana cricotiroidea versus palpación en Medline/Central y Embase. Se incluyeron ensayos clínicos controlados y estudios observacionales. Dos autores de manera independiente y por duplicado realizaron la selección de estudios, la evaluación de sesgos y la extracción de datos, se efectuó un metaanálisis de efectos aleatorios con el éxito de identificación correcta de la MCT. Se evaluó el riesgo de sesgos y se calificó la certeza de la evidencia. CRD42021223961. Resultados: Se incluyeron 464 estudios de los cuales 15 cumplieron criterios de elegibilidad, 6 fueron ensayos clínicos y 9 observacionales. La ecografía es superior a la palpación para detección de la MCT (RR 1,88, IC 95 % 1,05-3,36) según los ensayos clínicos y, similarmente, fue superior para los estudios observacionales (RR 1,76, IC 95 % 1,36-2,28); la asociación se conservó en los análisis de sensibilidad. Conclusiones: La ultrasonografía es superior a la palpación para detectar correctamente la MCT, aunque con baja certeza de la evidencia. Se requieren más estudios con mejor calidad metodo-lógica para mejorar la certeza y la precisión.

HER2+ esophageal carcinoma leptomeningeal metastases treated with intrathecal trastuzumab regimen.

Materials & methods: We recently reported the largest trial of breast cancer patients with HER2 positive leptomeningeal metastases (LM) treated with trastuzumab. An additional treatment indication was explored as part of a single institution retrospective case series of HER2 positive esophageal adenocarcinoma LM (n = 2). Results: One patient received intrathecal trastuzumab (80 mg twice weekly) as part of their treatment regimen with durable long-term response and clearance of circulating tumor cells in the cerebral spinal fluid. The other patient demonstrated rapid progression and death as previously described in the literature. Conclusion: Intrathecal trastuzumab is a well-tolerated and reasonable therapeutic option worthy of further exploration for patients with HER2 positive esophageal carcinoma LM. An associative, but not a causal relationship, can be made regarding therapeutic intervention.

Cancer of the esophagus, the tube that connects the mouth to the stomach, tends to be aggressive. Very rarely, this cancer can spread to the lining that surrounds your brain, called the leptomeninges. Previous reports of patients who have experienced this specific spreading pattern of esophageal cancer to the leptomeninges are quite grim, with patients experiencing rapid decline and death within weeks to months. However, we write with two cases of esophageal cancer with this leptomeningeal spreading pattern, one of which involves a patient treated with a medication known as trastuzumab. As part of his long and complex course of treatment, this patient was given trastuzumab through a tube traveling directly to the area of the leptomeninges. This patient, now almost 2 years out from his initial diagnosis, has responded well to the treatment. As such, we believe that this specific treatment regimen as well as the ways in which our clinical team tracked this patient's response to medications are worth exploring further.

High-Density IgG4+ Plasma Cells Infiltration Is Associated With Fibroplasia in Fibrostenotic Crohn's Disease.

Transmural fibrosis and stricture formation are key pathogenic processes for Crohn's disease that underlies clinical refractoriness, resulting in severe morbidity. The mechanisms for fibroplasia in Crohn's are not fully elucidated. In this study, we identified a cohort of refractory Crohn's disease with surgically resected bowel specimens including cases with bowel stricture and age-/sex-matched refractory disease without bowel stricture. Via immunohistochemistry, density and distribution of IgG4+ plasma cells in resected cases were analyzed. The histologic severity of fibrosis and association with gross evidence of stricture formation and IgG4+ plasma cells were comprehensively analyzed. Our results showed that density of IgG4+ plasma cells/high-power field (IgG4+ PCs/HPF) was significantly associated with increasing histologic fibrosis score (15 IgG4+ PCs/HPF in specimens with fibrosis score 0 vs 31 IgG4+ PC/HPF in fibrosis score 2 and 3, P = .039). Patients with gross evidence of stricture had significantly higher fibrosis scores compared to those without gross evidence of stricture (P = .044). There was a trend that mean IgG4+ plasma cell count was higher in Crohn's disease with gross stricture formation (P = .26), although it did not reach statistical significance (likely due to multiple pathogenesis events involved in bowel stricture formation besides IgG4+ plasma cells; such as transmural fibrosis, muscular hypertrophy, transmural ulcer/scar formation, and muscular-neural dysfunction). Our findings indicate IgG4+ plasma cells are associated with increasing histologic fibrosis in Crohn's. Further research is needed to establish a role for IgG4+ plasma cells in fibroplasia with an eye toward potential medical therapies targeting IgG4+ plasma cells to prevent transmural fibrosis.

Immunomodulatory Activity of Diterpenes over Innate Immunity and Cytokine Production in a Human Alveolar Epithelial Cell Line Infected with Mycobacterium tuberculosis.

BACKGROUND: Mexico has the largest number of the genus salvia plant species, whose main chemical compounds of this genus are diterpenes, these chemical compounds have shown important biological activities such as: antimicrobial, anti-inflammatory and immunomodulatory. OBJECTIVE: This study aimed to evaluate the immunomodulatory activity of three diterpenes: 1) icetexone, 2) anastomosine and 3) 7,20-dihydroanastomosine, isolated from Salvia ballotiflora, over innate immunity and cytokine production in a human alveolar epithelial cell line infected with Mycobacterium tuberculosis. METHODS: The immunomodulatory activity of diterpenes over innate immunity included reactive oxygen and nitrogen species (ROS and RNS) induction in response to infection; cytokine production included TNF-α and TGF-ß induction in response to infection. RESULTS: The diterpenes anastomosine and 7,20-dihydroanastomosine showed a statically significant (p < 0.01) increase of RNS after 36 h of infection and treatment of 2.0 µg/mL. Then, the ROS induction in response to infection showed a consistent statically significant (p < 0.01) increase after 12 h of diterpenes treatments. The cell cultures showed an anti-inflammatory effect, in the case of TGF-ß induction, in response to infection when treated with the diterpenes. On the other hand, there was not any significant effect on TNF-α release. CONCLUSION: The diterpenes anastomosine and 7,20-dihydroanastomosine increased the production of RNS after 36 h of infection and treatment. Besides, the three diterpenes increased the production of ROS after 12 h. This RNS and ROS modulation can be considered as an in vitro correlation of innate immunity in response to Mycobacterium tuberculosis infection; and an indicator of the damage of epithelial lung tissue. This study also showed an anti-inflammatory immune response by means of TGF-ß modulation when compared with control group.

"Imaging Findings of Eosinophilic Gastrointestinal Diseases in Adults".

Eosinophilic gastrointestinal (GI) disorders are a group of conditions marked by pathologic eosinophilic infiltration of one or multiple locations in the GI tract. Conditions include eosinophilic esophagitis, eosinophilic gastritis, eosinophilic enteritis, and eosinophilic colitis. The site and depth of eosinophilic infiltration of the GI tract usually determines clinical presentation. These conditions should be considered in the differential diagnosis for several GI symptoms, such as food impaction or dysphagia. Histopathology is the gold standard for diagnosis of eosinophilic disorders. Nevertheless, findings from endoscopy, barium studies, computed tomography or magnetic resonance imaging, can aid in the diagnosis, by allowing for earlier diagnosis as well as proper management. Eosinophilic gastrointestinal disorders are typically managed with corticosteroids or dietary elimination. A high index of suspicion is required for diagnosis as it can often be challenging.

Histologic Variants of Kaposi Sarcoma in the Gastrointestinal Tract: A Contemporary Multi-institutional Clinicopathologic Analysis of 46 Cases.

Kaposi sarcoma (KS) can pose diagnostic challenges in biopsy specimens. Multiple histologic variants of cutaneous KS have been described; however, the histomorphologic spectrum of gastrointestinal (GI) KS has not been systematically studied. This large series comprehensively evaluated 46 cases of KS involving the GI tract and identified 7 histomorphologic variants, some that have not been previously described. Five of them are inconspicuous but have unique morphologic patterns, including lymphangioma/lymphangiectatic-like (n=17), mucosal hemorrhage/telangiectatic-like (n=17), mucosal inflammation-like (n=15), granulation tissue-like (n=13), and mucosal prolapse-like (n=4) variants. These variants can be easily misdiagnosed or misinterpreted on routine examination if KS is not considered, and if the immunohistochemical stain for human herpesvirus-8 is not performed. The other 2 morphologic variants present as spindle cell proliferations and are the GI stromal tumor-like (n=8) and inflammatory myofibroblastic tumor-like (n=2). These variants raise a broad differential diagnosis of spindle cell tumors of the GI tract and could pose diagnostic challenges. In summary, GI KS lesions exhibit variable, often unconventional histomorphologic patterns. KS should be included in the differential diagnosis even if features of conventional KS are not seen, particularly in limited biopsies in immunocompromised patients, such as those with human immunodeficiency virus infection. Although the clinical significance of these morphologic variants is yet to be determined, they are nonetheless important from a diagnostic standpoint. Misdiagnosis and delay in appropriate management can be avoided by recognizing the morphologic diversity of GI KS and appropriately utilizing the human herpesvirus-8 immunohistochemical stain.

Overexpression of programmed death ligand 1 in refractory inflammatory bowel disease.

Programmed death ligand 1 (PD-L1) dysregulation has been implicated in chronic inflammatory diseases, but its role in regulating intestinal mucosa inflammation is still unclear. The aim of this study was to assess PD-L1 expression in the intestinal mucosa of patients with refractory inflammatory bowel disease (IBD) compared to controls. We evaluated PD-L1 expression by immunohistochemistry in colectomy specimens of patients with ulcerative colitis (UC) and Crohn disease (CD) compared to controls. PD-L1 expression was assessed in colonic epithelium and inflammatory cells, along with the location of the inflammatory cells expressing PD-L1. All cases were stained with CD3, CD4, CD8, FOXP3, CD20, CD68, and CD90 immunostains to determine the types of cells expressing PD-L1. The UC group showed significantly higher PD-L1 expression in the colonic epithelium than both CD and control groups (both P < 0.001), and CD was also significantly higher than the control group (P = 0.004). Both UC and CD groups showed similar PD-L1 expression in the inflammatory infiltrate but significantly higher than the control group (both P < 0.001). Among both IBD groups, higher IBD activity was associated with higher levels of PD-L1 expression in the colonic epithelium (P < 0.05) and inflammatory infiltrate (P < 0.001). When comparing PD-L1 expression to lineage-specific markers, CD3+, CD4+ T cells, CD68+ macrophages, and CD90+ colonic stromal cells appeared to be expressing PD-L1. These findings implicate a role for PD-L1 in the dysregulation of the immune response in refractory IBD. Further studies are warranted to better understand the role of the immune regulatory pathways in intestinal mucosa.

The Possible Pathogenic Role of IgG4-Producing Plasmablasts in Stricturing Crohn's Disease.

BACKGROUND: Crohn's disease (CD) is a condition on the spectrum of inflammatory bowel disease that affects up to 20 people per 100,000 in the US annually, and with incidence increasing. One of the most significant sources of morbidity in CD is the formation of strictures, with resultant intestinal blockage a common indication for hospitalization and surgical intervention in these patients. The pathophysiology of stricture formation is not fully understood. However, the fibroplasia that leads to fibrostenotic stricture formation may have shared pathophysiology with IgG4-related fibrosis. SUMMARY: Initial intestinal inflammation recruits innate immune cells, such as neutrophils, that secrete IL-1ß and IL-23, which induces a type 17 CD4+ T-helper T-cell (Th17)-mediated adaptive immune response. These CD4+ Th17 T cells also contribute to inflammation by secreting proinflammatory cytokines such as IL-17 and IL-21. IL-21 recruits and stimulates CD4+ T follicular helper (Tfh) cells, which secrete more IL-21. This causes ectopic germinal center formation, recruiting and stimulating naïve B cells. The IL-17 and IL-21 produced by Th17 cells and Tfh cells also induce IgG4 plasmablast differentiation. Finally, these IgG4-producing plasmablasts secrete platelet-derived growth factor (PDGF), which activates local PDGF-receptor expressing fibroblasts and myofibroblasts, resulting in uncontrolled fibroplasia.