Clinical and pathological characteristics of immune-mediated liver injury caused by immune checkpoint inhibitors / 中华内科杂志

Objective: Cancer immunotherapy can lead to various side effects, termed immune-related adverse events (irAE). This study summarized and analyzed the clinical and pathological characteristics of immune-mediated liver injury caused by immune checkpoint inhibitors (ILICI). Methods: This is a retrospective case series study involving 11 patients diagnosed with ILICI at the Peking Union Medical College Hospital from November 2019 to November 2021. Patient demographic information and clinical data, including gender, age, ILICI onset, clinical and radiological manifestations, pathological features, treatment, and resumption of ICI were retrospectively collected and analyzed. Results: The patients were primarily males (9/11) with a median age of 65 (range: 32-73) years. ICI mainly resulted in either partial remission (4/11) or stable disease (3/11). ILICI occurred after a median of two cycles of anti-programmed cell death-1 (PD-1) therapy, with a median time from the initial and last anti-PD-1 therapy to ILICI onset of 57 days and 17 days, respectively. ILICI was mostly severe (3/11) or very severe (6/11). While the clinical and radiological manifestations were non-specific, the pathological features were active lobular hepatitis and portal inflammation, with prominent CD8+T lymphocyte infiltration. The basic treatment was hepatoprotective drugs (10/11). Glucocorticoids were used as the primary therapy (9/11) but were ineffective in 4 of 9 cases. Of these, 3 of 9 cases received combined treatment with mycophenolate mofetil (MMF), only one of whom achieved remission. By the end of the study, 2 of 11 cases had resumed ICI and neither had experienced an ILICI relapse. Conclusion: The ILICI patients in this study had a corresponding history of ICI treatment and pathological features. The main treatment included hepatoprotective drugs and glucocorticoids. Immunosuppressive drugs were added for some cases but had poor efficacy.

Mentor-mentee dual evaluation of current clinical and translational research mentor competency and mentor training needs / 中华医学教育探索杂志

Objective:To investigate mentor-mentee dual evaluation of the current status of mentor competency of clinical and translational research mentors, and provide the basis for mentor training focused on the mentor competences.Methods:A total of 121 clinical and translational research mentors and 170 mentees from Peking Union Medical College Hospital were enrolled. The Chinese version of the Mentor Competency Assessment (MCA) questionnaire was used to evaluate the mentor competency, including maintaining effective communication, aligning expectations, assessing understanding, fostering independence, addressing diversity, promoting professional development total 6 parts with 26 sub-items. The Likert scale was used to quantitatively evaluate the clinical and translational research mentor competency by mentor-mentee dual evaluations. And the composition and training needs of clinical and translational research mentors were investigated. SPSS 25.0 was used for t-test. Results:Seventy percent (119/170) of mentees considered the mentor guidance was very helpful, and 78.5% (95/121) of the mentors considered it necessary to carry out the mentor training. The mentee evaluation of mentor competency was significantly higher than that of mentor self-evaluation [total score (162.35±23.59) vs. (154.80±19.81), P < 0.01]. And the excellent rate of 26 sub-items by mentees and mentors were 100.0%(170/170) and 46.3%(56/121) respectively. The mentors and mentees shared the agreement of the strengths on trust-based relationship and encouraging mentees, and weaknesses on taking into account the possible prejudices in mentor-mentee relationship. Conclusion:The clinical and translational research mentors have already had good competences, but mentor training is still highly warranted. It's expected that to carry out targeted mentor training and assessment according to the mentor's competences will help to improve the construction of the medical talents training system.

Clinical characteristics of eight cases of immune checkpoint inhibitor-related colitis / 中华消化杂志

Objective:Summarize and analyze the clinical features of immune checkpoint inhibitor (ICI)-related colitis.Methods:From January 2019 to September 2020, the clinical data of 8 patients with ICI-related colitis from Peking Union Medical College Hospital were retrospectively collected and including the onset of ICI-related colitis, clinical symptoms, endoscopic and pathological findings, treatment, comorbidities and resuming of ICI. Independent sample t test was used for statistical analysis. Results:Eight patients were all male, and the median age (range) was 66 years old (55 to 74 years old), 7 cases were diagnosed with stage Ⅳ lung cancer and 1 case was diagnosed with stage Ⅲc pyelo-carcinoma. Among 8 patients, 4 cases of ICI-related colitis occurred during combination of anti-programmed death-1 (PD-1) treatment and chemotherapy, 2 cases occurred during anti-PD-1 monotherapy after combination of anti-PD-1 treatment and chemotherapy, and 2 cases occurred after anti-PD-1 monotherapy. The median time (range) was 44 d (27 to 128 d) from initial anti-PD-1 treatment to the onset of ICI-related colitis and the median time (range) was 8 d (6 to 35 d) from last anti-PD-1 treatment to onset of ICI-related colitis. The ICI efficacy of 4 patients had partial response, 2 patients had stable disease, 1 patient had disease progression, and 1 patient′s condition was not assessed. All 8 patients had moderate to severe extensive colitis. The main clinical manifestation was diarrhea (5/8), 3 patients accompanied by abdominal pain. The endoscopic findings were diffuse mucosal erosion, accompanied by ulcer in 2 patients. The main pathologic findings were cryptitis or crypt abscess, accompanied by apoptosis in 2 patients. Eight patients were all treated with glucocorticoids, among them 2 patients were further treated with biologics, due to the insufficient efficacy of glucocorticoid treatment, 4 patients had opportunistic infections. The initial prednisone dose for patients with opportunistic infections and patients without opportunistic infections was (85.00±52.60) and (60.00±23.09) mg, respectively. The prednisone treatment course was (8.75±4.03) and (7.50±3.11) weeks, respectively, and the differences were not statistically significant (both P>0.05). The colitis relapsed in all 3 patients after resuming of ICI. Conclusions:ICI-related colitis had corresponding ICI treatment history and clinical, endoscopic, and histopathological features. Glucocorticoid is the main treatment, and it is prone to relapse after resuming of ICI.

Clinical characteristics and microbiome analysis in patients with anti-programmed cell death protein 1 related colitis / 中华内科杂志

Objective:To analyze clinical characteristics and monitor microbiome changes in patients with anti-PD-1 associated colitis.Methods:Two patients with non-small cell lung cancer who developed colitis after treated with anti-PD-1 antibodies were retrospectively analyzed in Peking Union Medical College Hospital from January 2019 to January 2020. The clinical symptoms, endoscopic and pathological manifestations, as well microbiome changes were analyzed and compared during pre-treatment, post-treatment and relapse.Results:The main clinical manifestations included diarrhea, elevated inflammatory indicators, colonic mucosal diffuse hyperemic edema with erosion by endoscopy. Changes in the structure of crypts were common pathological characteristics. Glucocorticoids were effective agents, which achieved clinical remission and mucosal healing. The microbiome composition of OTUs was different. After glucocorticoid treatment, the alpha diversity Observed species, Shannon, Simpson, Chao1, ACE indexes all decreased. The Firmicutesdecreased with Bacteroidetesincreasing in phylum level; while the Bacteroides increased with Ruminococcaceaedecreasing in genus level. Lactobacilluswas the potentially beneficial genus. Conclusion:Patients developing anti-PD-1 associated colitis have characteristic clinical and pathological manifestations. Glucocorticoids are effective treatment. The fecal microbiome diversity, relative abundance of major phylum and genus have changed after treatment.

Gastrointestinal Involvement in Systemic Diseases: Part / 胃肠病学

Digestive system is one of the major systems in human body. Many systemic diseases directly or indirectly affect the digestive system, resulting in corresponding structural and functional changes. Autoimmune diseases are the damages of organs caused by immune response to autoantigens. Involvement of gastrointestinal tract is prominent in connective tissue diseases, systemic vasculitis, spondyloarthropathy and autoinflammatory diseases. Oncologic diseases can also affect the digestive system through direct metastasis or indirect paraneoplastic syndrome. This article aimed to review the gastrointestinal involvement in autoimmune diseases and oncologic diseases.

Gastrointestinal Involvement in Systemic Diseases: Part Ⅱ / 胃肠病学

The main functions of gastrointestinal tract are intake, transport and digestion of food, absorption of nutrients and excretion of wastes. The structure and function of gastrointestinal tract can be influenced directly or indirectly by diseases originated from other systems such as endocrine system, nervous system, and other organs including kidney, heart, and lung etc. When approaching patients with gastrointestinal symptoms, besides gastrointestinal diseases, other organ and systemic diseases should also be considered. This article reviewed the gastrointestinal manifestations of diseases originated from endocrine system, nervous system, urinary system, respiratory system, circulation system, and some special diseases including critical illness and infiltrative diseases for improving the understanding of gastrointestinal involvement in systemic diseases.

Correlation between Vitamin D Status and Gut Microbiota in Patients with Inflammatory Bowel Disease / 中国医学科学院学报

Objective To investigate the correlation between serum total 25-hydroxyvitamin D[T-25(OH)D]level and fecal microbiota in patients with inflammatory bowel disease(IBD). Methods Twenty-three patients with IBD completed the tests for serum T-25(OH)D,and the fecal microbiota was studied using V4 hypervariable region of 16S ribosomal RNA(rRNA)gene sequencing.According to serum T-25(OH)D level,the patients were divided into three groups including vitamin D normal group(

Introduction to risk management plans in the Singapore context

A risk management plan (RMP) contains an overview of important safety concerns associated with the use of a therapeutic product (TP) and proposed pharmacovigilance activities to monitor and manage these safety concerns in the post-approval stage. The Health Sciences Authority (HSA) of Singapore has legislated its requirements for RMPs as part of its product life cycle approach in the management of safety concerns associated with TPs. Under the Health Product (Therapeutic Products) Regulations enacted in November 2016, companies may be required to implement RMPs under the direction of HSA to help ensure that the benefits of TPs outweigh their risks. In this commentary, we present a case study on the local RMP for Dengvaxia®, the world's first dengue vaccine, which has been approved for use in Singapore. We hope that this article raises awareness among healthcare professionals about the concept of RMPs and how RMPs are implemented locally.

Construction of three-dimensional finite element model and biomechanical study on patient with with cervical spondylotic myelopathy / 中南大学学报(医学版)

To establish a three-dimensional finite element model (FEM) of the neck, to analyze the differences in neck biomechanics between patient with cervical spondylotic myelopathy (CSM) and healthy subject and to provide biomechanics basis for the pathogenesis of CSM.
 Methods: A patient with CSM was enrolled in a mechanical simulation experiment. Three-dimensional CT scan was performed, and three-dimensional FEM of the neck was constructed. A heathy subject was selected as a control according to the patient's age, gender, height, and weight. Three-dimensional FEM was used to compare the stress differences in the vertebral body, intervertebral disc, ligament and spinal cord under the normal stress of the cervical spine and the maximum stress of the posterior reclining motion.
 Results: Successfully constructed FEM model of CSM patient and control, and performed mechanical analysis, the most obvious difference in cervical vertebral body force was at C5-C6 segment in CSM patients. The maximum stress site of control and patient was at the anterior edge of the vertebral body. The maximum stress of the vertebral body in the CSM patient was less than that of the control. The stress distribution of the intervertebral disc was irregular in the CSM patient, and the maximum stress was concentrated on both sides of the posterior edge of the intervertebral disc. The stress distribution of the ligaments of the CSM patient was uneven. The maximum stress was in the posterior longitudinal ligament. The range of neck movement in extension of the CSM patient was restricted.
 Conclusion: Compared with the healthy subject, the balance of the vertebral body, intervertebral disc, ligament and limited range of motion of the CSM patient has been changed, which may be related to the mechanical pathogenesis of cervical spondylotic myelopathy.

Efficacy of NICE classification with non-magnified endoscopy on diagnosis of colorectal tumor / 中华消化内镜杂志

Objective To evaluate the diagnostic efficacy of narrow band imaging (NBI) international colorectal endoscopic (NICE) classification in distinguishing neoplastic from non-neoplastic colorectal polyps during routine clinical practice. Methods A total of 224 lesions detected by white light colonoscopy by non-expert endoscopists were collected in this retrospective study. Each lesion was assessed by NBI and classified by NICE classification. The results were compared with pathological findings from endoscopic or surgical resected specimen. Results Among these 224 polyps, there were 59 of type 1, 159 of type 2 and 6 of type 3 according to NICE classification. There were 58 non-tumorous and 166 tumorous polyps according to pathological diagnosis. The total diagnostic sensitivity, specificity, positive predictive value, negative predictive value and accuracy of NICE classification for colorectal tumor were 91. 6%, 77. 6%, 92. 1%,76. 3%and 87. 9%, respectively.Diagnostic sensitivity and accuracy in big (＞10 mm in diameter), small (＞5-10 mm in diameter) and mini (≤5 mm in diameter) polyp groups were 100. 0%, 97. 0% and 80. 9%, as well as 95. 7%, 87. 8%, and 83. 3%, respectively. Diagnostic accuracy showed a decreasing tendency on polyp size, without significant difference between the three groups ( P＝0. 694). Conclusion NICE classification with non-magnified NBI is effective in distinguishing neoplastic and non-neoplastic colorectal polyps by non-expert endoscopists and is potentially worth popularizing for routine clinical practice.

Preoperative Corticosteroid Usage and Hypoalbuminemia Increase Occurrence of Short-term Postoperative Complications in Chinese Patients with Ulcerative Colitis / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Clarifying the risk factors for postoperative complications and taking measures to minimize these complications will improve the outcomes in patients with ulcerative colitis (UC). This study aimed to systemically explore the risk factors for short-term postoperative complications in Chinese UC patients undergoing ileocolorectal surgery.</p><p><b>METHODS</b>Forty-nine UC patients undergoing proctocolectomy or ileostomy were retrospectively enrolled. Univariate and multivariate logistic regression analyses were conducted to reveal the risk factors among the clinical, laboratory, and surgical variables as well as preoperative medications.</p><p><b>RESULTS</b>Twenty-two (44.9%) patients who suffered from at least one short-term postoperative event had more severe hypoalbuminemia (P = 0.007) and an increased prevalence of preoperative corticosteroid usage (prednisone more than 20 mg daily or equivalent) for more than 6 weeks (59.1% vs. 25.9%, P = 0.023) compared with patients without short-term postoperative complications. Based on the multivariate logistic regression analysis, the odds ratio (95% confidence interval) values of these two risk factors were 1.756 (0.889-3.470, P = 0.105) and 3.233 (0.916-11.406, P = 0.068), respectively. In 32 severe UC patients, prolonged preoperative hospital stay worsened the short-term postoperative outcomes.</p><p><b>CONCLUSIONS</b>Preoperative corticosteroids usage and hypoalbuminemia worsened the short-term outcomes following ileocolorectal surgery in Chinese UC patients.</p>

Clinical predictive factors of deep remission in Crohn′s disease treated with anti-tumor necrosis factorα / 中华消化杂志

Objective To investigate the predictors of deep remission in patients with Crohn′s disease (CD)treated with infliximab.Methods From February 2008 to February 2015 ,the clinical, laboratory and follow up data of 44 CD patients who received infliximab treatment and maintained clinical remission over six months were retrospectively analyzed.Mucosal healing was defined as no ulcer under endoscopy.Deep remission was defined as clinical remission with mucosal healing.According to results of endoscopy examination,the enrolled patients were divided into deep remission group and non-deep remission group.T test or Wilcoxon rank sum test was used for comparison of measurement data between groups,and chi square test was performed for the rate comparison.Multivariate analysis was made with Logistic regression.Results Median age of 44 patients was 19.5 yeares,39 males (88.6%),five females (11 .4%),and the median disease duration was 35 .0 months (18.5 to 73.5 months).Deep remission was achieved in 20 CD patients with long-time follow-up (median follow-up time 19 months,12 to 29 months). The mean duration of achieving deep remission was (28.9 ± 14.3 )weeks.There was no statistically significant difference between 20 patients with deep remission and 24 patients without deep remission in age of onset,disease duration,smoking status,Montreal phenotype,concurrent medications (mesalazine, steroids and azathioprine ), as well as body mass index (BMI ) and laboratory tests (erythrocyte sedimentation rate (ESR),high-sensitivity C-reactive protein (hsCRP),hemoglobin (Hb)and platelet (PLT)count)before administrating.The results of Logistic regression demonstrated that extraintestinal manifestations (arthralgia)(odds ratio (OR)=29.9,95 % confidence interval (CI )1 .26 -714.20,P =0.036),normalization of hs CRP at 14 th week after induced remission (OR=0.88,95 %CI 0.78-0.99, P =0.045)and thrombocytopenia (OR = 0.98,95 %CI 0.96 - 0.99,P = 0.016 )were independent predictive factors of deep remission.Conclusions Infliximab could effectively maintain long term deep remission in treatment of CD.Arthralgia,normalization of hsCRP and PLT counts at 14 th week after induced remission are predictive factor of deep remission.

Efficacy and safety of thalidomide in the treatment of 29 refractory Crohn's disease patients / 中华消化杂志

Objective To evaluate the efficacy and safety of thalidomide (100 to 200mg 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 simplified CD activity index.Patients in clinical remission underwent colon endoscope examination,and mucosal healing was assessed by simple endoscopic score for Crohn's disease (SES-CD).Adverse reactions (ADR) were also observed.Results Among the 29 CD patients,23 males and six females,the baseline of 19 patients (65.5％) were in clinical active period and 10 in clinical remission period.Among patients with baseline in clinical active period,three patients did not reach the target dose because of ADR,the left 16 patients were treated with thalidomide for one year and 14 patients achieved clinical remission.The median time of inducing clinical remission was one month.A totle of 24 patients with clinical remission induced by thalidomide and with baseline in clinical remission period were assessed in efficacy evaluation of mucosal healing.Thalidomide was withdrawn in three patients in six months because of ADR and colonoscopy evaluation did not complete,while the other 21 patients received colonoscopy evaluation among whom 33.3％ (7/21) achieved mucosal healing after two years of thalidomide treatment.Numbness of the hands,feet or mouth,somnolence and dermatitis were the top three ADR of thalidomide treatment.A total of nine patients withdrew the medication because of ADR (four (13.8％) with numbness of the hands,feet or mouth,four (13.8％) with dermatitis and one (3.4％) with leukopenia).Conclusions Thalidomide 100 to 200 mg per day can induce clinical remission and mucosal healing in refractory CD.However,it has some adverse reactions and close monitoring and follow up are required during treatment.

An analysis of adverse drug reactions of thalidomide in treatment of immune-related bowel diseases / 中华内科杂志

Objective To investigate the safety of thalidomide in the treatment of immune-related bowel diseases for providing clinical reference.Methods Thirty-five patients with immune-related bowel diseases (31 Crohn's disease,2 ulcerative colitis and 2 Behcet's disease) treated with thalidomide were enrolled in this study.The incidence,type,severity,duration of thalidomide related adverse drug reaction (ADR) and the dose-effect relationship of neurotoxicity were analyzed.Results All the patients were treated with a mean dose of thalidomide (109.29 ± 30.37) mg/d for (18.8 ± 12.4) months,and 33 occurred ADR.The three most frequent ADR were numbness [51.4％ (18/35)],somnolence [48.6％ (17/35)] and dermatitis [37.1％ (13/35)].The median time to development of these three ADR were 6.50,0.25,and 1.00 months,respectively.Severe ADR leading to withdrawal accounted for 20.0％ (7/35),including reasons of peripheral neuritis (3/7),dermatitis (2/7) and myelosuppression (2/7).The incidence of peripheral neuritis was not significantly related to the maximal and initial dose of thalidomide (P ＞ 0.05).Conclusions Although the incidence of ADR was relatively high during the treatment of thalidomide,most of them were mild and well tolerated.Thalidomide can be safely used in patients with immune-related bowel diseases under close monitoring.

Inflammatory bowel disease and nutrition support therapy / 中华临床营养杂志

Inflammatory bowel disease (IBD) is a group of diseases characterized by recurrent episodes of chronic intestinal inflammation including ulcerative colitis (UC) and Crohn's disease (CD).The prevalence of IBD has shown a rapid growth in China.Malnutrition is often seen in IBD patients,especially in those with CD.Appropriate diets and supplementation of trace elements,calcium,vitamin D,and probiotics are beneficial for disease remission and control.Nutrition support therapy can improve the nutritional status and meanwhile may facilitate the induction and maintenance of remission in CD patients.

The collagen metabolism and the expression of matrix metalloproteinase during atrial fibrillation / 中华老年医学杂志

Objective To quantify the expressions of collagen metabolic markers carboxy terminal propeptide of type I procollagen(PICP),nitrogen terminal propeptide of type I procollagen (PINP),nitrogen terminal propeptide of typeⅢprocollagen(PⅢNP),type I collagen carboxy terminal telopeptide (ICTP), matrix metalloproteinases(MMPs)and the tissue inhibitor of metalloproteinases(TIMPs)in the serum of atrial fibrillation patients by enzyme linked immunosorbent assay(ELISA),and to discuss the atrial structural remodeling during atrial fibrillation(AF).Methods 71 elderly patients were enrolled,24 patients had permanent AF,24 patients had paroxysmal AF,and 23 patients were in sinus rhythm.The serum levels of all markers were measured by ELISA. Results PICP was increased in permanent AF group versus the paroxysmal AF group and sinus rhythm group by 25.4%and 42.8%(all P<0.05),respectively.PⅢNP was increased in permanent AF group versus the paroxysmal AF group and sinus rhythm group by 17.9a% and 35.6%(all P<0.05),respectively,and was increased in the paroxysmal AF group versus the sinus rhythm group by 15.0%(P<0.05).PINP and ICTP did not differ significantly between the 3 groups(all P >0.05).MMP-1 was significantly increased by 25.6%(P<0.05)in the paroxysmal AF group versus the sinus rhythm group.MMP-2 was also significantly increased in permanent AF group versus the paroxysmal AF group and sinus rhythm group by 54.9%and 37.9%(all P<0.05),respectively.MMP-7,MMp-9 and TIMP-1 did not differ significantly between the 3 groups(P>0.05).TIMP-2was significantly decreased in the permanent AF group and paroxysmal AF group versus the sinus rhythm group by 21.8%and 11.8%(P<0.05),respectively. Conclusions Disturbance in the balance of MMP/TIMP system may perturb the balance of collagen synthesis and degradation during atrial fibrillation.This may be a contributing mechanism to atrial structural remodeling in atrial fibrillation,and may correlate with the initiation and maintenance of AF.