Comparison and development of machine learning for thalidomideinduced peripheral neuropathy prediction of refractory Crohn’s disease in Chinese population

BACKGROUND Thalidomide is an effective treatment for refractory Crohn’s disease(CD).However,thalidomide-induced peripheral neuropathy(TiPN),which has a large individual variation,is a major cause of treatment failure.TiPN is rarely predictable and recognized,especially in CD.It is necessary to develop a risk model to predict TiPN occurrence.AIM To develop and compare a predictive model of TiPN using machine learning based on comprehensive clinical and genetic variables.METHODS A retrospective cohort of 164 CD patients from January 2016 to June 2022 was used to establish the model.The National Cancer Institute Common Toxicity Criteria Sensory Scale(version 4.0)was used to assess TiPN.With 18 clinical features and 150 genetic variables,five predictive models were established and evaluated by the confusion matrix receiver operating characteristic curve(AUROC),area under the precision-recall curve(AUPRC),specificity,sensitivity(recall rate),precision,accuracy,and F1 score.RESULTS The top-ranking five risk variables associated with TiPN were interleukin-12 rs1353248[P=0.0004,odds ratio(OR):8.983,95%confidence interval(CI):2.497-30.90],dose(mg/d,P=0.002),brainderived neurotrophic factor(BDNF)rs2030324(P=0.001,OR:3.164,95%CI:1.561-6.434),BDNF rs6265(P=0.001,OR:3.150,95%CI:1.546-6.073)and BDNF rs11030104(P=0.001,OR:3.091,95%CI:1.525-5.960).In the training set,gradient boosting decision tree(GBDT),extremely random trees(ET),random forest,logistic regression and extreme gradient boosting(XGBoost)obtained AUROC values>0.90 and AUPRC>0.87.Among these models,XGBoost and GBDT obtained the first two highest AUROC(0.90 and 1),AUPRC(0.98 and 1),accuracy(0.96 and 0.98),precision(0.90 and 0.95),F1 score(0.95 and 0.98),specificity(0.94 and 0.97),and sensitivity(1).In the validation set,XGBoost algorithm exhibited the best predictive performance with the highest specificity(0.857),accuracy(0.818),AUPRC(0.86)and AUROC(0.89).ET and GBDT obtained the highest sensitivity(1)and F1 score(0.8).Overall,compared with other state-of-the-art classifiers such as ET,GBDT and RF,XGBoost algorithm not only showed a more stable performance,but also yielded higher ROC-AUC and PRC-AUC scores,demonstrating its high accuracy in prediction of TiPN occurrence.CONCLUSION The powerful XGBoost algorithm accurately predicts TiPN using 18 clinical features and 14 genetic variables.With the ability to identify high-risk patients using single nucleotide polymorphisms,it offers a feasible option for improving thalidomide efficacy in CD patients.

ZHANG Ren＇s Needling Experience in Treating Refractory Diseases

Chief doctor ZHANG Ren has been engaged in acupuncture practice and literature research for about forty years, with abundant knowledge and clinical experience, particularly in the application of needling techniques. This article presents his experience in the treatment of refractory diseases.

Refractory celiac disease and sprue-like intestinal disease

Celiac disease is a gluten-dependent small intestinal mucosal disorder that causes malabsorption, often with diarrhea and weight loss. Diagnosis is based on detection of typical biopsy changes in the proximal small bowel, followed by evidence for an unequivocal response to a gluten-free diet. Refractoriness in celiac disease may be due to poor diet compliance, sometimes intentional, or consumption of ubiquitious sources of gluten. Alternatively, the original diagnosis may not be correct (eg., duodenal Crohn's disease), or a second cause for symptoms may be present (eg., collagenous colitis, functional bowel disorder). In some with recurrent symptoms, a complication may be present (eg., collagenous sprue, small bowel carcinoma, lymphoma). In some, a response to a gluten-free diet can not be unequivocally defined, and more precise historical terms have been used including "sprue-like intestinal disease" or "unclassified sprue". Although a "wastebasket diagnosis", these likely represent a heterogeneous group, and some, but not all, may develop lymphoma. Precise definition will be critical in the future as an array of new treatments, including biological agents, may emerge.

Abdominal computed tomography in refractory coeliac disease and enteropathy associated T-cell lymphoma

AIM： To evaluate computed tomography （CT） findings, useful to suggest the presence of refractory celiac disease （RCD） and enteropathy associated T cell lymphoma （EATL）. METHODS： Coeliac disease （CD） patients were divided into two groups. Group Ⅰ ： uncomplicated CD （n = 14） and RCD type Ⅰ （n = 10）. Group Ⅱ ： RCD type Ⅱ （n = 15） and EATL （n = 7）. RESULTS： Both groups showed classic signs of CD on CT. Intussusception was seen in 1 patient in group Ⅰ vs 5 in group Ⅱ （P = 0.06）. Lymphadenopathy was seen in 5 patients in group Ⅱ vs no patients in group Ⅰ （P = 0.01）. Increased number of small mesenteric vessels was noted in 20 patients in group Ⅰ vs Ⅱ in group 11 （P = 0.02）. Eleven patients （50%） in group 11 had a splenic volume 〈 122 cm^3 vs 4 in group Ⅰ （14%）, 10 patients in group Ⅰ had a splenic volume 〉 196 cm^3 （66.7%） vs 5 in group Ⅱ （33.3%） P = 0.028. CONCLUSION： CT scan is a useful tool in discriminating between CD and （Pre） EATL. RCD Ⅱ and EATL showed more bowel wall thickening, lymphadenopathy and intussusception, less increase in number of small mesenteric vessels and a smaller splenic volume compared with CD and RCD Ⅰ.

Evaluation of Cladribine treatment in refractory celiac disease type Ⅱ

AIM: To evaluate cladribine [2-chlorodeoxyadenosine (2-CdA)] therapy in refractory celiac disease (RCD) Ⅱ. METHODS: An open-label cohort-study of RCD Ⅱ patients treated with 2-CdA was performed between 2000 and 2010. Survival rate, enteropathy associated T-cell lymphoma (EATL) occurrence, clinical course, and histological and immunological response rates were evaluated. RESULTS: Overall, 32 patients were included with a median follow-up of 31 mo. Eighteen patients responded well to 2-CdA. Patients responsive to 2-CdA had a statistically significant increased survival compared to those who were unresponsive. The overall 3- and 5-year survival was 83% in the responder and 63% and 22% in the non-responder group, respectively. The overall 2-year clinical, histological and immunological response rates were 81%, 47% and 41%, respectively. Progression into EATL was reported in 16%, all of these patients died. CONCLUSION: Treatment of RCD Ⅱ with 2-CdA holds promise, showing excellent clinical and histological response rates, and probably less frequent transition into EATL.

Possible relationship between refractory celiac disease and malignancies

Celiac disease(CeD)is a chronic autoimmune disorder that is triggered by gluten in genetically susceptible individuals,and that is characterized by CeD-specific antibodies,HLA-DQ2 and/or HLA-DQ8 haplotypes,enteropathy and different clinical pictures related to many organs.Intestinal lymphoma may develop as a result of refractory CeD.If a patient diagnosed with CeD is symptomatic despite a strict gluten-free diet for at least 12 months,and does not improve with severe villous atrophy,refractory CeD can be considered present.The second of the two types of refractory CeD has abnormal monoclonal intraepithelial lymphocytes and can be considered as pre-lymphoma,and the next picture that will emerge is enteropathy-associated T-cell lymphoma.This manuscript addresses"CeD and malignancies"through a review of current literature and guidelines.

A meta-analysis of the efficacy of traditional Chinese medicine alone in the treatment of refractory gastroesophageal reflux disease

Background:To systematically evaluate the efficacy and safety of traditional Chinese medicine in the treatment of refractory gastroesophageal reflux.Methods:PubMed,The Cochrane Library,Embase,Web of Science,China National Knowledge Infrastructure,Wanfang Database,China Science and Technology Journal Database and Chinese BioMedical Literature Database were searched for randomized controlled trials of traditional Chinese medicine in the treatment of refractory gastroesophageal reflux from database establishment time to December 2020.After two researchers independently screened the literature,extracted data and evaluated the bias risk included in the study,RevMan5.3 software was used for meta-analysis.Results:A total of 12 randomized controlled trials,were included,including 893 patients.The results of meta-analysis showed that the total effective rate of the treatment group(relative risk=1.28,95%confidence interval(CI)(1.19,1.38),P<0.00001),RGERDQ(refractory gastroesophageal reflux disease)score(mean difference(MD)=−3.35,95%CI(−4.13,−2.57),P<0.00001],acid reflux(acid in the stomach comes out of the mouth)[MD=−0.30,95%CI(−0.45,−0.15),P<0.00001],heartburn(the feeling that the heart is burned)(MD=−0.44,95%CI(−0.60,−0.29),P<0.00001,and retrosternal pain(MD=−0.27,95%CI(−0.44,−0.10),P<0.00001,belching(MD=−0.40,95%CI(−0.57,−0.24),P<0.00001],endoscopic mucosal score(MD=−0.62,95%CI(−0.78,−0.46),P<0.00001],the differences were statistically significant,and the effective rate of mucosal improvement under endoscopy was P=0.93>0.05,with no statistically significant difference.Conclusion:The current evidence shows that traditional Chinese medicine in the treatment of refractory gastroesophageal reflux disease is better than that of western medicine in the total effective rate,relieving acid reflux,heartburn,retrosternal pain and belching symptoms,but it is impossible to judge the improvement of mucosa under endoscope.Due to the limitations of the quality and quantity of included studies,more high-quality studies are needed to confirm the above conclusions.

Laparoscopic fundoplication for gastroesophageal reflux disease

Gastroesophageal reflux disease (GERD) is a condition that develops when the reflux of gastric contents into the esophagus leads to troublesome symptoms and/or complications. Heartburn is the cardinal symptom, often associated with regurgitation. In patients with endoscopy-negative heartburn refractory to proton pump inhibitor (PPI) therapy and when the diagnosis of GERD is in question, direct reflux testing by impedance-pH monitoring is warranted. Laparoscopic fundoplication is the standard surgical treatment for GERD. It is highly effective in curing GERD with a 80% success rate at 20-year follow-up. The Nissen fundoplication, consisting of a total (360&#x000b0;) wrap, is the most commonly performed antireflux operation. To reduce postoperative dysphagia and gas bloating, partial fundoplications are also used, including the posterior (Toupet) fundoplication, and the anterior (Dor) fundoplication. Currently, there is consensus to advise laparoscopic fundoplication in PPI-responsive GERD only for those patients who develop untoward side-effects or complications from PPI therapy. PPI resistance is the real challenge in GERD. There is consensus that carefully selected GERD patients refractory to PPI therapy are eligible for laparoscopic fundoplication, provided that objective evidence of reflux as the cause of ongoing symptoms has been obtained. For this purpose, impedance-pH monitoring is regarded as the diagnostic gold standard.

Celiac disease:Management of persistent symptoms in patients on a gluten-free diet

AIM:To investigate all patients referred to our center with non-responsive celiac disease (NRCD),to establish a cause for their continued symptoms.METHODS:We assessed all patients referred to our center with non-responsive celiac disease over an 18-mo period.These individuals were investigated to establish the eitiology of their continued symptoms.The patients were first seen in clinic where a thorough history and examination were performed with routine blood work including tissue transglutaminase antibody measurement.They were also referred to a specialist gastroenterology dietician to try to identift any lapses in the diet and sources of hidden gluten ingestion.A repeat small intestinal biopsy was also performed and compared to biopsies from the referring hospital where possible.Colonoscopy,lactulose hydrogen breath testing,pancreolauryl testing and computed tomography scan of the abdomen were undertaken if the symptoms persisted.Their clinical progress was followed over a minimum of 2 years.RESULTS:One hundred and twelve consecutive patients were referred with NRCD.Twelve were found not to have celiac disease (CD).Of the remaining 100 patients,45% were not adequately adhering to a strict gluten-free diet,with 24 (53%) found to be inadvertently ingesting gluten,and 21 (47%) admitting noncompliance.Microscopic colitis was diagnosed in 12% and small bowel bacterial overgrowth in 9%.Refractory CD was diagnosed in 9%.Three of these were diagnosed with intestinal lymphoma.After 2 years,78 patients remained well,eight had continuing symptoms,and four had died.CONCLUSION:In individuals with NRCD,a remediable cause can be found in 90%:with continued gluten ingestion as the leading cause.We propose an algorithm for investigation.

Hematopoietic stem cell transplantation for non-malignant gastrointestinal diseases

Both, autologous and allogeneic hematopoietic stem cell transplantation (HSCT) can be used to cure or ameliorate a variety of malignant and non-malignant diseases. The rationale behind this strategy is based on the concept of immunoablation using high-dose chemotherapy, with subsequent regeneration of naive T-lymphocytes derived from reinfused hematopoietic progenitor cells. In addition, the use of HSCT allows for the administration of high-dose chemotherapy (whether or not combined with immunomodulating agents such as antithymocyte globulin) resulting in a prompt remission in therapy-refractory patients. This review gives an update of the major areas of successful uses of HSCT in non-malignant gastrointestinal disorders. A Medline search has been conducted and all relevant published data were analyzed. HSCT has been proved successful in treating refractory Crohn&#x02019;s disease (CD). Patients with refractory celiac disease type II and a high risk of developing enteropathy associated T-cell lymphoma have shown promising improvement. Data concerning HSCT and mesenchymal SCT in end-stage chronic liver diseases are encouraging. In refractory autoimmune gastrointestinal diseases high-dose chemotherapy followed by HSCT seems feasible and safe and might result in long-term improvement of disease activity. Mesenchymal SCT for a selected group of CD is promising and may represent a significant therapeutic alternative in treating fistulas in CD.

Application of vascular endothelial cells in stem cell medicine

Stem cell medicine is gaining momentum in the development of therapy for various end-stage diseases.The search for new seed cells and exploration of their application prospects are topics of interest in stem cell medicine.In recent years,vascular endothelial cells(VECs)have attracted wide attention from scholars.VECs,which form the inner lining of blood vessels,are critically involved in many physiological functions,including permeability,angiogenesis,blood pressure regulation,immunity,and pathological development,such as atherosclerosis and malignant tumors.VECs have significant therapeutic effects and broad application prospects in stem cell medicine for the treatment of various refractory diseases,including atherosclerosis,myocardial infarction,diabetic complications,hypertension,coronavirus disease 2019,and malignant tumors.On the one hand,VECs and their extracellular vesicles can be directly used for the treatment of these diseases.On the other hand,VECs can be used as therapeutic targets for some diseases.However,there are still some obstacles to the use of VECs in stem cell medicine.In this review,advances in the applications and challenges that come with the use of these cells are discussed.

Efficacy and safety of thalidomide in the treatment of 29 refractory Crohn's disease patients

Objective To evaluate the efficacy and safety of thalidomide(100 to 200 mg per day)in the treatment of adult refractory Crohn’s disease(CD).Methods From July 2008 to February 2013,29 refractory CD patients were enrolled in thalidomide(100 to 200 mg per day)cohort study.The clinical activity was evaluated by

Professor HE Jin-sen＇s Experience in Treating Difficult and Complicated Diseases by Acupuncture-Moxibustion

Professor HE Jin-sen has been engaged in acupuncture practice, scientific researches and teaching for more than thirty years and won enormous achievements. In particular, he works a lot on the clinical study of acupuncture in the regulation of hypothalamic-pituitary-thyroid axis（HPT axis） and hypothalamic-pituitary-gonad axis（HPG axis） and the associated diseases, such as hyperthyroidism, male sterility and female climacteric syndrome.