Anesthesia Choice and Its Potential Impact on Endoluminal Functional Lumen Imaging Probe Measurements in Esophageal Motility Disorders.

BACKGROUND AND AIMS: The widespread use of peroral endoscopic myotomy (POEM) has revolutionized the management of esophageal motility disorders (EMDs). The introduction of an endoluminal functional lumen imaging probe (EndoFLIP) can serve as a complimentary diagnostic tool to assess the mechanical properties (i.e., pressure, diameter, distensibility and topography) of the esophagus. During EndoFLIP measurements, different anesthesia techniques may induce variable degrees of neuromuscular blockade, potentially affecting esophageal motility and altering the results of EndoFLIP metrics. Our study aimed to compare the impact of using total intravenous anesthesia (TIVA) versus general anesthesia with inhalational anesthetics (GAIA) on diagnostic EndoFLIP measurements. METHODS: We conducted a retrospective study of all adult patients (≥18 years) undergoing EndoFlip during the POEM procedure at our institution between February 2017 and February 2022. We obtained the differences in pressure, diameter, and distensibility index using propofol-based TIVA vs sevoflurane-based GAIA with a 30ml and 60ml balloon. The differences were divided into terciles and compared between diagnoses using univariate comparisons and logistic regression models. RESULTS: 49 patients were included (39% Type 1 achalasia, 43% Type 2 or 3 achalasia, and 18% jackhammer esophagus (JE)). Compared to spastic disorders (Type 2, 3 and JE), Type 1 had lower values of pressure differences at 60 mL in univariate (3.75 vs 15.20 p=0.001) and multivariate (aOR 0.89 95%CI 0.82-0.978) analyses. Compared to Type 1, Type 2 and 3 had higher rates of pressure differences at 60 mL in univariate (9.85 vs 3.75 p=0.04); and nearly reached significance in multivariate analysis (1.09 95%CI 1-1.20). Compared to Type 1, JE demonstrated higher values in pressure differences at 60 mL (27.7 vs 3.75 p<0.001) CONCLUSION: Esophageal pressure, as measured by EndoFLIP, was significantly reduced when patients were sedated with sevoflurane-based GAIA. The use sevoflurane-based GAIA for diagnostic EndoFLIP may potentially lead to the misclassification of spastic disorders as Type I achalasia. Therefore, propofol-based TIVA should be considered over sevoflurane-based GAIA for sedation during the diagnostic test.

Isolated Gastritis Secondary to Immune Checkpoint Inhibitors Complicated by Superimposed Cytomegalovirus Infection.

Immune checkpoint inhibitors such as nivolumab increase the T-cell destruction of malignancies but can also trigger a broad variety of immune-related adverse events (irAEs). Colitis as an irAE is well-documented, but upper gastrointestinal tract involvement is primarily unrecognized. We present a patient who developed gastritis as an irAE after multiple cycles of nivolumab and initially responded well to steroid therapy but then developed superimposed cytomegalovirus infection. The similarity between both presentations highlights the importance of having a broad differential diagnosis in patients with gastrointestinal complaints treated with immune checkpoint inhibitors and the need for further studies to better characterize gastritis as an irAE.

IL4 receptor ILR4α regulates metastatic colonization by mammary tumors through multiple signaling pathways.

IL4, a cytokine produced mainly by immune cells, may promote the growth of epithelial tumors by mediating increased proliferation and survival. Here, we show that the type II IL4 receptor (IL4R) is expressed and activated in human breast cancer and mouse models of breast cancer. In metastatic mouse breast cancer cells, RNAi-mediated silencing of IL4Rα, a component of the IL4R, was sufficient to attenuate growth at metastatic sites. Similar results were obtained with control tumor cells in IL4-deficient mice. Decreased metastatic capacity of IL4Rα "knockdown" cells was attributed, in part, to reductions in proliferation and survival of breast cancer cells. In addition, we observed an overall increase in immune infiltrates within IL4Rα knockdown tumors, indicating that enhanced clearance of knockdown tumor cells could also contribute to the reduction in knockdown tumor size. Pharmacologic investigations suggested that IL4-induced cancer cell colonization was mediated, in part, by activation of Erk1/2, Akt, and mTOR. Reduced levels of pAkt and pErk1/2 in IL4Rα knockdown tumor metastases were associated with limited outgrowth, supporting roles for Akt and Erk activation in mediating the tumor-promoting effects of IL4Rα. Collectively, our results offer a preclinical proof-of-concept for targeting IL4/IL4Rα signaling as a therapeutic strategy to limit breast cancer metastasis.

Epithelial interleukin-4 receptor expression promotes colon tumor growth.

Inflammatory mediators are of considerable interest as potential therapeutic targets in various cancers. Here we investigate whether interleukin (IL)-4 receptor alpha (IL4Ralpha), a component of the receptor complex for the T helper 2 cytokines IL4 and IL13, plays a role in colonic tumorigenesis. IL4Ralpha protein expression was seen in tumor cells of 28/48 human colon adenocarcinomas on a tissue microarray. In human and murine colon tumor cell lines analyzed in vitro, all of which expressed IL4Ralpha, treatment with exogenous ligand resulted in dose-dependent increases in proliferation. IL4 decreased apoptosis only in HCT116 cells. An orthotopic allograft model was used to determine in vivo effects of tumor cell-specific IL4Ra ablation. MC38 murine tumor cells with the IL4Ra gene knocked down showed reduced proliferation but no difference in apoptosis compared with controls after implantation in ceca of syngeneic mice. Mice null for IL4Ra and wild-type controls were treated with azoxymethane and dextran sulfate sodium to induce tumor formation. Mice with global deletion of IL4Ra had significantly fewer and smaller tumors. Reduced tumorigenicity correlated with decreased proliferation and increased apoptosis. Systemic blockade of IL4Ralpha-IL4 interactions with a chimeric soluble receptor protein gave similar results in the cecal implant model. Thus, IL4Ralpha, a component of the IL4R and IL13R, contributes to tumor formation in a mouse model of colitis-associated cancer. Proliferation appears to be directly mediated via IL4Ralpha on the epithelial tumor cells. Survival may be an indirect response mediated via other host cells. Our results support therapeutic targeting of IL4Ralpha in colon cancer.