Current and Future Immunotherapy-Based Treatments for Oesophageal Cancers.

Oesophageal cancer is a disease that causes significant morbidity and mortality worldwide, and the prognosis of this condition has hardly improved in the past few years. Standard treatment includes a combination of chemotherapy, radiotherapy and surgery; however, only a proportion of patients go on to treatment intended to cure the disease due to the late presentation of this disease. New treatment options are of utmost importance, and immunotherapy is a new option that has the potential to transform the landscape of this disease. This treatment is developed to act on the changes within the immune system caused by cancer, including checkpoint inhibitors, which have recently shown great promise in the treatment of this disease and have recently been included in the adjuvant treatment of oesophageal cancer in many countries worldwide. This review will outline the mechanisms by which cancer evades the immune system in those diagnosed with oesophageal cancer and will summarize current and ongoing trials that focus on the use of our own immune system to combat disease.

Efficacy and tolerability of initiating, or switching to, infliximab biosimilar CT-P13 in inflammatory bowel disease (IBD): a large single-centre experience.

OBJECTIVES: Recently, the infliximab biosimilar (CT-P13) received market authorisation for inflammatory bowel disease (IBD), allowing cost benefits when switching to CT-P13. We aim to assess the efficacy and safety of switching from originator infliximab to CT-P13 for new and existing patients. MATERIAL AND METHODS: Treatment response, remission, primary and secondary loss of response rates, and adverse events in patients who initiated infliximab originator in the 12 months pre-switch (n = 53) were compared with the patients who initiated CT-P13 in the 12 months post-switch (n = 69). Sustained responses were compared for existing infliximab originator patients who switched to CT-P13 (n = 191) and those who continued with the originator (n = 19). RESULTS: There was no difference in remission (58.1% vs. 47.4%, p = .37), response (12.6% vs. 10.5%, p = .80), secondary loss of response (24.6% vs. 42.1%, p = .10), or adverse events (4.7% vs. 0% p = 1.0) between those who switched to CT-P13 and those who continued infliximab originator. There was no difference in remission (42.0% vs. 26.4%, p = .074), response (21.7% vs. 22.6%, p = .91), primary non-response (5.8% vs. 15.1%, p = .09), secondary loss of response (21.7% vs. 22.6%, p = .91), or adverse events (8.7% vs. 11.3%, p = .63) in those who initiated CT-P13 compared with infliximab originator. CONCLUSIONS: There was no difference in the efficacy and safety of infliximab originator and CT-P13 during the first 12 months after switching.

Enhancing Diagnostic Performance of Symptom-Based Criteria for Irritable Bowel Syndrome by Additional History and Limited Diagnostic Evaluation.

OBJECTIVES: Symptom-based criteria to diagnose irritable bowel syndrome (IBS) positively perform only modestly. Our aim was to assess whether including other items from the clinical history and limited diagnostic evaluation improves their performance. METHODS: We collected complete symptom, colonoscopy, and histology data from 318 consecutive, unselected adult patients with lower gastrointestinal (GI) symptoms in secondary care. All participants underwent colonoscopy, with relevant organic findings recorded. The reference standard used to define the presence of true IBS was patient-reported lower abdominal pain or discomfort associated with a change in bowel habit, in the absence of organic GI disease. Sensitivity, specificity, and positive and negative likelihood ratios (LRs), with 95% confidence intervals, were calculated for Rome III criteria, as well as for modifications, incorporating nocturnal stools, results of simple blood tests (hemoglobin and C-reactive protein (CRP)), measures of somatization, and/or affective disorders (hospital anxiety or depression scale (HADS) score). RESULTS: The sensitivity and specificity of the Rome III criteria for identifying IBS was 69.6%, and 82.0%, respectively, with positive and negative LRs of 3.87 and 0.37, respectively. Clinically useful enhancements in positive LRs were provided by combining Rome III criteria with: (a) high level of somatization (7.27); (b) normal hemoglobin and CRP with HADS score of ≥8 (5.04); (c) normal hemoglobin and CRP with a high level of somatization (7.56); or (d) no nocturnal passage of stool with a high level of somatization (17.3). Specificity was ≥95% with each of these modifications. CONCLUSIONS: Incorporating nocturnal stools, somatization, and affective disorders from the clinical history, and hemoglobin and CRP measurements, enhances the positive LR and specificity of symptom-based Rome III criteria for IBS.

Validation and modification of a diagnostic scoring system to predict microscopic colitis.

OBJECTIVE: Many patients with diarrhoea undergo colonoscopy. If this is macroscopically normal, random biopsies are obtained to rule out microscopic colitis (MC), but most patients have functional disease. Accurate predictors of MC could avoid the need to take biopsies in a substantial proportion of patients, saving money for the health service. We validated a previously described diagnostic scoring system for MC, and incorporated further variables to assess whether this improved performance. MATERIAL AND METHODS: Consecutive adults with loose stools undergoing colonoscopy in Leeds, UK were included. Demographic and symptom data were collected prospectively. The diagnostic scoring system described previously was applied. In addition, the incorporation of further variables, including drugs associated with MC, number of stools, nocturnal passage of stools, and duration of loose stools, into the scoring system was assessed. Sensitivities, specificities, and positive and negative predictive values were calculated. RESULTS: Among 242 patients (mean age 51.0 years, 163 (67.4%) female), 26 (10.7%) of whom had MC, a cut off of ≥4 on the original scoring system had a sensitivity of 92.3% and specificity of 35.2%. Nocturnal passage of stools and duration of loose stools <6 months were significant predictors of MC. Incorporating these variables in a new scoring system with a cut off of ≥6 identified MC with 95.7% sensitivity and 46.0% specificity. CONCLUSIONS: Incorporating nocturnal passage of stools and duration of loose stools into the scoring system may improve ability to predict MC, and avoid random colonic biopsies in a greater proportion of patients with loose stools.

Toll-like receptor 8 agonist and bacteria trigger potent activation of innate immune cells in human liver.

The ability of innate immune cells to sense and respond to impending danger varies by anatomical location. The liver is considered tolerogenic but is still capable of mounting a successful immune response to clear various infections. To understand whether hepatic immune cells tune their response to different infectious challenges, we probed mononuclear cells purified from human healthy and diseased livers with distinct pathogen-associated molecules. We discovered that only the TLR8 agonist ssRNA40 selectively activated liver-resident innate immune cells to produce substantial quantities of IFN-γ. We identified CD161(Bright) mucosal-associated invariant T (MAIT) and CD56(Bright) NK cells as the responding liver-resident innate immune cells. Their activation was not directly induced by the TLR8 agonist but was dependent on IL-12 and IL-18 production by ssRNA40-activated intrahepatic monocytes. Importantly, the ssRNA40-induced cytokine-dependent activation of MAIT cells mirrored responses induced by bacteria, i.e., generating a selective production of high levels of IFN-γ, without the concomitant production of TNF-α or IL-17A. The intrahepatic IFN-γ production could be detected not only in healthy livers, but also in HBV- or HCV-infected livers. In conclusion, the human liver harbors a network of immune cells able to modulate their immunological responses to different pathogen-associated molecules. Their ability to generate a strong production of IFN-γ upon stimulation with TLR8 agonist opens new therapeutic opportunities for the treatment of diverse liver pathologies.