Combination treatment of inflammatory bowel disease:Present status and future perspectives

The treatment of patients with inflammatory bowel disease(IBD),especially those with severe or refractory disease,represents an important challenge for the clinical gastroenterologist.It seems to be no exaggeration to say that in these patients,not only the scientific background of the gastroenterologist is tested,but also the abundance of“gifts”that he should possess(insight,intuition,determ-ination,ability to take initiative,etc.)for the successful outcome of the treatment.In daily clinical practice,depending on the severity of the attack,IBD is treated with one or a combination of two or more pharmaceutical agents.These combin-ations include not only the first-line drugs(e.g.,mesalazine,corticosteroids,antibiotics,etc)but also second-and third-line drugs(immunosuppressants and biologic agents).It is a fact that despite the significant therapeutic advances there is still a significant percentage of patients who do not satisfactorily respond to the treatment applied.Therefore,a part of these patients are going to surgery.In recent years,several small-size clinical studies,reviews,and case reports have been published combining not only biological agents with other drugs(e.g.,immunosuppressants or corticosteroids)but also the combination of two biologi-cal agents simultaneously,especially in severe cases.In our opinion,it is at least a strange(and largely unexplained)fact that we often use combinations of drugs in a given patient although studies comparing the simultaneous administration of two or more drugs with monotherapy are very few.As mentioned above,there is a timid tendency in the literature to combine two biological agents in severe cases unresponsive to the applied treatment or patients with severe extraintestinal manifestations.The appropriate dosage,the duration of the administration,the suitable timing for checking the clinical and laboratory outcome,as well as the treatment side-effects,should be the subject of intense clinical research shortly.In this editorial,we attempt to summarize the existing data regarding the already applied combination therapies and to humbly formulate thoughts and suggestions for the future application of the combination treatment of biological agents in a well-defined category of patients.We suggest that the application of biomarkers and artificial intelligence could help in establishing new forms of treatment using the available modern drugs in patients with IBD resistant to treatment.

Immunotherapy of gastric cancer:Present status and future perspectives

In this editorial,we comment on the article entitled“Advances and key focus areas in gastric cancer immunotherapy:A comprehensive scientometric and clinical trial review(1999-2023),”which was published in the recent issue of the World Journal of Gastroenterology.We focused on the results of the authors’bibliometric analysis concerning gastric cancer immunotherapy,which they analyzed in depth by compiling the relevant publications of the last 20 years.Before that,we briefly describe the most recent data concerning the epidemiological parameters of gastric cancer(GC)in different countries,attempting to give an interpretation based on the etiological factors involved in the etiopathogenesis of the neoplasm.We then briefly discuss the conservative treatment(chemotherapy)of the various forms of this malignant neoplasm.We describe the treatment of resectable tumors,locally advanced neoplasms,and unresectable(advanced)cases.Special attention is given to modern therapeutic approaches with emphasis on immunotherapy,which seems to be the future of GC treatment,especially in combination with chemotherapy.There is also a thorough analysis of the results of the study under review in terms of the number of scientific publications,the countries in which the studies were conducted,the authors,and the scientific centers of origin,as well as the clinical studies in progress.Finally,an attempt is made to draw some conclusions and to point out possible future directions.

Early-onset gastrointestinal cancer:An epidemiological reality with great significance and implications

During the last few years,epidemiological data from many countries suggest that the incidence and prevalence of many cancers of the digestive system are shifting from the older to the younger ages,the so-called“early-onset cancer”.This is particularly evident in colorectal cancer and secondarily in other malignant digestive neoplasms,mainly stomach and in a lesser degree pancreas,and biliary tract.It should be emphasized that data concerning digestive neoplasms,except for those referring to the colon and stomach,could be characterized as rather insufficient.The exact magnitude of the shift in younger ages is expected to become clearer shortly,as long as relevant epidemiological data from many parts of the world would be available.The most important question concerns the etiology of this phenomenon,since its magnitude cannot be explained solely by the better diagnostic methodology and the preventive programs applied in many countries.The existing data support the assumption that a number of environ-mental factors may play a primary role in influencing carcinogenesis,sometimes from childhood.Changes that have appeared in the last decades related mainly to eating habits,consistency of gut microbiome and an increase of obese people interacting with genetic factors,ultimately favor the process of carcinogenesis.Even these factors however,are not entirely sufficient to explain the age-related changes in the frequency of digestive neoplasms.Studies of the individual effect of each of the already known factors or factors likely to be involved in the etiology of this phenomenon and studies using state-of-the-art technologies to accurately determine the degree of the population exposure to these factors are required.In this article,we attempt to describe the epidemiological data supporting the age-shifting of digestive malignancies and their possible pathogenesis.Finally,we propose some measures regarding the attitude of the scientific community to this alarming phenomenon.

Sedation in gastrointestinal endoscopy: Current issues

Diagnostic and therapeutic endoscopy can successfully be performed by applying moderate(conscious) sedation.Moderate sedation,using midazolam and an opioid,is the standard method of sedation,although propofol is increasingly being used in many countries because the satisfaction of endoscopists with propofol sedation is greater compared with their satisfaction with conventional sedation.Moreover,the use of propofol is currently preferred for the endoscopic sedation of patients with advanced liver disease due to its short biologic half-life and,consequently,its low risk of inducing hepatic encephalopathy.In the future,propofol could become the preferred sedation agent,especially for routine colonoscopy.Midazolam is the benzodiazepine of choice because of its shorter duration of action and better pharmacokinetic profile compared with diazepam.Among opioids,pethidine and fentanyl are the most popular.A number of other substances have been tested in several clinical trials with promising results.Among them,newer opioids,such as remifentanil,enable a faster recovery.The controversy regarding the administration of sedation by an endoscopist or an experienced nurse,as well as the optimal staffing of en-doscopy units,continues to be a matter of discussion.Safe sedation in special clinical circumstances,such as in the cases of obese,pregnant,and elderly individuals,as well as patients with chronic lung,renal or liver disease,requires modification of the dose of the drugs used for sedation.In the great majority of patients,sedation under the supervision of a properly trained endoscopist remains the standard practice worldwide.In this review,an overview of the current knowledge concerning sedation during digestive endoscopy will be provided based on the data in the current literature.

Effects of mycophenolate mofetil vs cyclosporine administration on graft survival and function after islet allotransplantation in diabetic rats

AIM: To develop an experimental model of islet allotransplantation in diabetic rats and to determine the positive or adverse effects of MMF as a single agent. METHODS: Thirty-six male Wistar rats and 18 male Lewis rats were used as recipients and donors respectively. Diabetes was induced by the use of streptozotocin (60 mg/kg) intraperitoneally. Unpurified islets were isolated using the collagenase digestion technique and transplanted into the splenic parenchyma. The recipients were randomly assigned to one of the following three groups: group A (control group) had no immunosuppression; group B received cyclosporine (CsA) (5 mg/kg); group C receivedmycophenolate mofetil (MMF) (20 mg/kg). The animalswere killed on the 12th d. Blood and grafted tissues were obtained for laboratory and histological assessment. RESULTS: Median allograft survival was significantly higher in the two therapy groups than that in the controls (10 and 12 d for CsA and MMF respectively vs 0 d for the control group, P＜0.01). No difference in allograft survival between the CsA and MMF groups was found. However,MMF had less renal and hepatic toxicity and allowed weight gain.CONCLUSION: Monotherapy with MMF for immunosu ppression was safe in an experimental model of islet allotransplantation and was equally effective with cyclosporine, with less toxicity.

Favorable response to subcutaneous administration of infliximab in rats with experimental colitis

AIM： To investigate the influence of infliximab （Remicade） on experimental colitis produced by 2,4,6,trinitrobenzene sulfonic add （TNBS） in rats. METHODS： Thirty-six Wistar rats were allocated into four groups （three groups of six animals each and a fourth of 12 animals）. Six more healthy animals served as normal controls （Group 5）. Group 1： colitis was induced by intracolonic installation of 25 mg of TNBS dissolved in 0.25 mL of 50% ethanol and infliximab was subcutaneously administered at a dose of 5 mg/kg BW; Group 2： colitis was induced and infliximab was subcutaneously administered at a dose of 10 mg/kg BW; Group 3： colitis was induced and infliximab was subcutaneously administered at a dose of 15 mg/kg BW; Group 4： colitis was induced without treatment with infliximab. Infliximab was administered on d 2-6. On the 7^th d, all animals were killed. The colon was fixed in 10% buffered formalin and examined by light microscopy for the presence and activity of colitis and the extent of tissue damage. Tumor necrosis factor-alpha （TNF-α） and malondialdehyde （MDA） were also measured. RESULTS： Significant differences concerning the presence of reparable lesions and the extent of bowel mucosa without active inflammation in all groups of animals treated with infliximab compared with controls were found. Significant reduction of the tissue levels of TNF-α in all groups of treated animals as compared with the untreated ones was found （0.47＋0.44, 1.09＋0.86, 0.43＋0.31 vs 18.73＋10.53 respectively）. Significant reduction in the tissue levels of MDA was noticed in group 1 as compared to group 4, as well as between groups 2 and 4. CONCLUSION： Subcutaneous administration of infliximab reduces the inflammatory activity as well as tissue TNF-α and MDA levels in chemical colitis in rats. Infliximab at a dose of 5 mg/kg BW achieves better histological results and produces higher reduction of the levels of TNF-α than at a dose of 10 mg/kg BW. Infliximab at a dose of 5 mg/kg BW produces higher reduction of tissue MDA levels than at a dose of 15 mg/ kg BW.