母体胚胎亮氨酸拉链激酶（maternal embryo leucine zipper kinase ,MELK）在多数恶性肿瘤中高表达，其通过与各种类 型蛋白相互作用和使其磷酸化后调节靶蛋白的生物活性，影响细胞周期调控和细胞增殖、凋亡、侵袭与转移等，促进癌细胞增殖 和肿瘤形成，因此，MELK功能失调成为癌细胞逃避人体正常免疫监视的重要机制。深入了解MELK在肿瘤中的表达和作用机 制，为完善肿瘤诊断分子标志物体系、肿瘤靶向治疗方案具有一定的临床意义。本文就MELK的生物学功能、对恶性肿瘤的治疗 情况及其作为候选靶向分子的潜质进行综述。

Objective: To analyze the clinical manifestations, diagnosis, treatment and prognosis of intestinal lymphangiectasia (IL) in children in order to improve the skills of diagnosis and treatment of IL. Method: Clinical manifestations, laboratory findings, gastroscopic findings, histopathological examinations and lymphatic radionuclide imaging assessments were analyzed retrospectively among 47 IL patients who were hospitalized in the Gastroenterology Department of Beijing Children's Hospital Affiliated to Capital Medical University from June 2007 to December 2015. All patients were followed up by telephone. According to the various causes, the patients were divided into the primary intestinal lymphangiectasia (PIL) group and secondary IL group, and their clinical manifestations were compared by t test, Rank sum test or Chi-square test. Result: In 47 IL patients, there were 38 children (81%) younger than 3 years old. There were 43 PIL patients (91%) and 4 secondary IL patients (9%). Between PIL and secondary IL, there were statistical differences in serum albumin (t=-3.950, P<0.005) , globulin(t=-2.850, P=0.007), age of onset(U=27.000, P=0.024), age at diagnosis(U=29.000, P=0.030) and course of disease(U=26.500, P=0.023), whereas there were no statistical differences in lymphocyte count, IgG, lymphatic radionuclide imaging, histopathology and gender(all P>0.05). Edema (44 cases, 94%), diarrhea (42 cases, 89%), accompanied with infection (35 cases, 74%) and ascites (30 cases, 64%) were the main clinical manifestations. In 47 IL patients, 45 patients were done gastroscopy and histopathological examinations, and there were 31 patients' histopathological examinations(69%) were positive. Forty patients were done lymphatic radionuclide imaging, and there was evidence of protein losing from gut via lymphatic radionuclide imaging in 39 patients(98%). Among 47 patients, 35 patients (74%) were followed up, 32 patients had good prognosis, 2 patient failed to show evidence of improvement, 1 patient died and no patient experienced a relapse till the end of the follow-up. In 35 patients, 28 patients were treated with medium chain triglycerides (MCT) dietary therapy, 26 patients showed improvement in symptoms, and 2 patients had no improvement. Among 35 patients with follow-up, there were 6 patients received surgical treatment, and their symptoms were improved. Conclusion PIL are the majority of IL in children younger than 3 years old. The main clinical manifestations are edema, diarrhea, accompanied with infection and ascites. For the patients without the evidence of lymphangiectasia from duodenum histopathological examination, further consideration of lymphatic radionuclide imaging, clinical manifestations, and laboratory studies are needed to make a final diagnosis. MCT dietary therapy is the cornerstone of IL medical management.

Objective To summarize the clinical data of the children with inflammatory bowel diseases (IBD),including Crohn's disease (CD) and ulcerative colitis (UC),and to analyze and compare the clinical features of very early-onset IBD (VEO-IBD) and late-onset IBD (LO-IBD).Methods A retrospective analysis of the clinical data of 184 cases of IBD hospitalized children diagnosed at Beijing Children's Hospital,Capital Medical University from January 2000 to December 2014.According to their ages of onset,the patients were divided into VEO-IBD group (＜6 years old) and LO-IBD group (6-16 years old);the patients with CD were divided into VEO-CD group (＜ 6 years old) and LO-CD group (6-16 years old);UC were divided into VEO-UC group (＜ 6 years old) and LO-UC group (6-16 years old).The clinical features among each group were analyzed and compared.Results A total of 184 IBD patients were included in the study,77 cases(41.8％) were VEO-IBD and 107 cases(58.2％) were LO-IBD.Comparison between VEO-CD group and LO-CD group indicated that abdominal pain was more common in LO-CD group (P ＜ 0.05),while diarrhea and hematochezia were more common in VEO-CD group (all P ＜ 0.05).In addition,comparison between VEO-UC group and LO-UC group indicated that abdominal pain was more common in LO-UC group(P ＜ 0.001),while diarrhea,fever,and oral ulcers were more common in VEO-UC group (all P ＜0.05).Both VEO-CD and LO-CD group were mainly ileocolonic[15/27 cases (55.6％),20/47 cases (42.6％)],non-narrow,non-penetrating [20/27 cases (74.1％),30/47 cases (63.8％)] and moderate-to-severe activity[23/27 cases(85.2％),37/47 cases (78.7％)].The incidence of perianal lesions in the VEO-CD group was as high as 51.9％ (14/27 cases),which was significantly higher than that in the LO-CD group (9/47 cases,19.1％) (P ＜ 0.05).Left-sided UC and severe UC were more common in VEO-UC group(all P ＜ 0.05),while pancolitis and mild UC were more common in LO-UC group (all P ＜ 0.05).The incidence of intestinal perforation in the VEO-UC group was significantly higher than that in the LO-UC group (P ＜0.05).The incidence of surgical rate,intestinal obstruction,and intestinal perforation in the LO-CD group were significantly higher than those in the LO-UC group (all P ＜ 0.05).Conclusions Compared between VEO-IBD and LO-IBD,VEO-IBD patients are more severe,with perianal lesions more common,and the incidence of intestinal perforation is higher.

Objective: To investigate the clinical data of children with inflammatory bowel disease (IBD) retrospectively, including Crohn′s disease (CD) and ulcerative colitis (UC) and identify the clinical characteristics and trends of change. Method: Clinical data of hospitalized patients diagnosed as IBD in Beijing Children′s Hospital from January 2000 to December 2014 were collected and retrospectively analyzed. Patients were divided into six groups based on type of disease and year of admission: Group A1(CD, 2000-2004) included 12 patients, Group B1(CD, 2005-2009) included 11, Group C1(CD, 2010-2014) included 51; Group A2(UC, 2000-2004) included 17, Group B2(UC, 2005-2009) included 25, Group C2(UC, 2010-2014) included 68. Result: A total of 184 IBD patients were included in the study, 74 had CD and 110 had UC. The hospitalization constituent ratio of CD increased from 0.6/10 000 in Year 2000 to 2.9/10 000 in Year 2014. The hospitalization constituent ratio of UC increased from 0.5/10 000 in Year 2001 to 3.9/10 000 in Year 2014. The hospitalization constituent ratios of CD and UC both increased gradually(P<0.05). Up to 61.4%(113/184) of IBD patients belong to early onset IBD, furthermore the very early onset IBD and infantile IBD accounted for 41.8%(77/184) and 26.6%(49/184) respectively. For CD, ileocolonic type(47.3%, 35/74) and non-structuring, non-penetrating type (67.6%, 50/74) were more common. Perianal disease occured in 31.1%(23/74) of CD patients; 81.1%(60/74) of CD patients had moderate/severe activity. For UC, pancolitis type(59.1%, 65/110) was more common. There were no significant changes for location of pathological change, disease behavior, activity degree of CD, extent of UC lesion and incidence of surgery, intestinal perforation and hemorrhage of gastrointestinal tract for IBD in the past 15 years(P>0.05). Severe UC(S3) was more common in Group A2(64.7%, 11/17), but moderate UC(S2) was more common in Group C2(48.5%, 33/68), the difference was statistically significant (P=0.001 7). Conclusion During the past 15 years, the hospitalization constituent ratio for IBD in our hospital showed a growing trend. The ratio of infantile IBD and very early onset IBD was high. For CD, perianal disease was commonly seen and most patients had moderate/severe activity. The surgery rate and incidence of intestinal obstruction and perforation were higher in the CD patients than UC patients. For UC, the lesions were more extensively combined with higher disease activity.

Objective: To study the feasibility of ¹⁸F-fluoro-L-dihydroxyphenylalanine positron emission tomography/Computed tomography (¹⁸F-DOPA PET/CT) scanning in the localization and differential diagnosing of focal versus diffuse form of pancreas lesions in patients with hyperinsulinemic hypoglycemia (HH). Method: Twenty-four patients were diagnosed with HH between January, 2016 and February, 2017 in the Department of Pediatric Endocrinology and Inherited Metabolic Diseases, Children′s Hospital of Fudan University using an integrated clinical and biochemical diagnostic protocol, domestic ¹⁸F-DOPA PET/CT imaging technique were applied after MRI and ultrasound failed to detect pancreas lesions. Pancreas ¹⁸F-DOPA standardized uptake values (SUV) were measured, and pancreas′ lesions were dually analyzed via visual method and pancreas percentage SUV method. Among these patients, 9 patients received surgical pancreatic lesion resections, the correlations among surgical outcomes, histopathological findings and ¹⁸F-DOPA PET/CT scan results were analyzed. Result: Seven patients were detected with focal form of pancreas lesions, the mean peak of SUV was 4.7±1.7(2.6-7.1), and 17 patients were found to have diffuse form lesions after ¹⁸F-DOPA-PET/CT scanning. Among the 24 cases, 9 patients (7 showed focal and 2 showed diffuse ¹⁸F-DOPA PET/CT pancreatic uptake)were euglycemic without any medical support after surgery; the resected pancreatic tissue histopathological results were consistent with that of PET/CT imaging. Only one patient, who responded to medical treatment before surgery, had temporary hyperglycemia after operation. Conclusion Domestic ¹⁸F-DOPA PET/CT could successfully locate and differentiate the pancreatic lesions and thus improve the success of surgery.

Objective:To investigate the clinical features and risk factors of the extraintestinal manifestations(EIM)in children with ulcerative colitis(UC).Methods:A retrospective case-control study was conducted.The clinical data of 99 children with UC diagnosed in Department of Gastroenterology, Beijing Children′s Hospital, Capital Medical University from January 2016 to December 2021 were analyzed.According to whether the patients had EIM or not, they were divided into EIM-positive group and EIM-negative group.Rank sum test, χ2test or Fisher′s exact test were used to compare the variables between the 2 groups, including the clinical features, laboratory examination results and treatments.The Logistic regression was used to analyze the risk factors of EIM in children with UC. Results:A total of 99 children with UC were enrolled, including 57 males and 42 females; the age of onset was 10.3(6.4, 12.6)years, and the course of disease was 4.2(1.6, 10.1)months.The patients were mainly characterized by extensive disease(E3)and pancolitis(E4)(69/99, 69.7%), moderate to severe activity(63/99, 63.6%)and moderate to severe inflammation of colonic mucosa(89/99, 89.9%). There were 77 patients(77.8%)in the EIM-negative group and 22 patients(22.2%)in the EIM-positive group, of which 5 patients had two types of EIMs; the most common EIMs were oral ulcers(9 cases), joint lesions(7 cases), and skin lesions(6 cases). Compared with the EIM-negative group, those in the EIM-positive group, such as the E4 type(77.3% vs 44.2%, χ2=7.513, P=0.006), moderate to severe activity(81.8% vs 58.4%, χ2=4.041, P=0.044), pediatric ulcerative colitis activity index score[47.5(35.0, 57.5)score vs 35.0(25.0, 50.0)score, Z=-2.260, P=0.024], the proportion of C-reactive protein≥8mg/L at diagnosis(54.5% vs 19.5%, χ2=10.607, P=0.001), erythrocyte sedimentation rate[30.0(13.8, 47.8)mm/h vs 10.0(4.0, 19.5)mm/h, Z=-3.918, P<0.001], the proportion of glucocorticoid treatment within one year after diagnosis(77.3% vs 49.4%, χ2=5.403, P=0.020)and the proportion of biological agents treatment(45.5% vs 23.4%, χ2=4.112, P=0.043)were significantly higher; the E3 type were significantly lower than those in the EIM-negative group(0 vs 23.4%, χ2=4.813, P=0.028), and the differences were statistically significant.Multivariate Logistic regression analysis showed that erythrocyte sedimentation rate at diagnosis was an independent risk factor of EIM in children with UC( OR=1.063, 95% CI: 1.025~1.103, P=0.001). Conclusion:The UC patients with EIM had more extensive lesions, more severe disease activity, significantly increased inflammatory indicators, and more commom glucocorticoid and biologic therapy.Increased erythrocyte sedimentation rate was an high risk factor of EIM in children with UC.

Objective:To compare the efficacy of combination therapy on cyclic vomiting syndrome(CVS)in children, and improve the efficacy of CVS treatment in the future.Methods:This study retrospectively analyzed patients′ medical records of CVS, which were admitted to Digestive Department of Beijing Children′s Hospital from 2012 to 2019.The treatment regimen was A(Cyproheptadine+ Doxepin+ Valproate), B(Propranolol+ Cyproheptadine), or C(Propranolol+ Amitriptyline). Meanwhile, the patients should take drugs more than three months.The clinical data of 42 cases were analyzed retrospectively, and the treatment effect after discharge was followed up by telephone until October, 2020.Results:Among the 42 cases, 17 were male and 25 were female, whose mean age of onset was (4.65±3.23) years, and the age of diagnosis was (6.79±3.58) years.The main accompanied symptoms were abdominal pain and upper gastrointestinal bleeding.Forty-two patients were moderate/severe CVS.The regimens A, B and C were observed in 7, 11, and 24 patients, respectively.The age at improvement was(8.17±4.12)years.The course of treatment was(1.37±0.96)years.The age at follow-up was(10.32±4.03)years.During the 1-year follow-up, 35 cases were effective, and the efficiency was 83.3%.Among them, 23 cases had no paroxysmal vomiting and 7 cases had no effect.There was no significant difference in therapy effects among group A, B and C. Between the effective group and non-effective group, there were statistical differences in the personal history of hiatus hernia( P=0.024), the weight at follow-up ( P=0.042), and the course of medication( P=0.020). Conclusion:The combination regimen has a higher effective rate in the treatment of CVS.There was no significant difference among the three regimens in the treatment of CVS.For children with refractory CVS, who can not be treated with combination therapy, individualized therapy should be further developed.

Objective:To evaluate the efficacy and safety of Adalimumab(ADA) in the treatment of pediatric Crohn′s disease (CD).Methods:The clinical data of 20 CD patients treated with ADA at Beijing Children′s Hospital, Capital Medical University from September 2016 to September 2021 were retrospectively analyzed.The disease activity status and mucosal inflammation in CD patients were evaluated using the Pediatric Crohn′s Disease Activity Index (PCDAI) and Crohn′s Disease Endoscopic Severity Index(CDEIS). Data were compared between groups using the rank sum test or Fisher′ s exact test. Results:A total of 20 CD patients were recruited, including 12 males and 8 females.The mean age at diagnosis of CD was (9.5 ± 4.9) years old, ranging from 0.9-15.1 years old.The mean age of the first use of ADA was (10.4 ± 4.8) years old, ranging from 1.2-16.7 years old.The median duration of CD symptoms before ADA treatment was 0.9 (0.4, 1.7) years.The mean PCDAI score of 20 CD patients before ADA treatment was (28.5±19.8) points (range: 0-65.0 points). Of the 20 cases, 8 cases (40.0%) had severe disease activity, and 4 cases (20.0%) were in remission.A total of 15 CD patients underwent CDEIS assessment.The results showed that 9 patients had moderate to severe disease activity, and the symptoms were improved in 1 case under endoscopy.Ten patients (10/20 cases, 50.0%) received Infliximab (IFX) treatment preceding ADA treatment.IFX discontinuation was due to the loss of response(8/10 cases, 80.0%) and allergic reactions (2/10 patients, 20.0%). After 6 weeks of ADA treatment, the median PCDAI score of the 20 CD patients was 5.0 (0, 10.0) points, which was significantly lower than that before ADA treatment ( P<0.001). The clinical remission rate and clinical response rate of 16 patients with active CD treated with ADA for 6 weeks were 62.5% (10/16 cases) and 87.5% (14/16 cases), respectively.There were no significant differences in the clinical remission rate and clinical response rate between the patients who did not receive IFX and those who had previously received IFX(all P> 0.05). The median ADA treatment period was 5.5 (2.6, 17.8) months.During the follow-up period, 6 patients (6/20 cases, 30.0%) suffered from clinical recurrence of CD.At the end of the follow-up visit, seventeen patients(17/20 cases, 85.0%) maintained clinical remission, one had primary non-response and two experienced secondary non-response.Adverse events were reported in 7 patients, mainly including pneumonia (4 cases) or upper respiratory tract infection (2 cases). No tumor or other serious adverse events were recorded. Conclusions:ADA has good efficacy in inducing and maintaining clinical remission in pediatric CD patients, and does not cause serious adverse events.

Objective:To evaluate the efficacy and safety of infliximab(IFX)in pediatric patients with ulcerative colitis(UC).Methods:The clinical data of 17 UC patients who received IFX treatment at Beijing Children′s Hospital, Capital Medical University from January 2017 to December 2021 were retrospectively analyzed, and the pediatric ulcerative colitis activity index(PUCAI)and laboratory data were compared before and after treatment to evaluate the efficacy and safety of IFX.Results:A total of 17 UC patients were included, and among them there were 9 boys and 8 girls.The age of onset was 12.1(10.7, 12.8)years old, and median age at IFX initiation was 12.5(11.8, 13.6)years old.The duration of IFX medication was 46.1(17.4, 56.9)weeks, and the times of IFX injections was 8.0(4.5, 10.5). The mean PUCAI score of the 17 UC patients at start of IFX treatment was (50.6±21.2) points, and the Mayo endoscopic score showed: ten severe activity, six moderate activity, and one mild activity.IFX efficacy analysis: the clinical response rate was 87.5%(14/16), and the clinical remission rate was 56.3%(9/16) at the 14th week.The sustained response rate was 81.8%(9/11), and the sustained remission rate was 36.4%(4/11) at the 30th week.At the 14th week of IFX treatment, PUCAI score[2.5(0, 10.0)points vs.50.0(41.3, 70.0)points] and white blood cell count[5.7(4.8, 8.6)×10 9/L vs.8.7(6.4, 13.5)×10 9/L] significantly decreased(all P<0.05), hemoglobin[(113.8±20.4)g/L vs.(99.3 ± 19.4)g/L] and albumin level[42.2(40.0, 44.4)g/L vs.36.6(28.6, 40.2)g/L] significantly increased compared with those before IFX treatment, and the differences were statistically significant(all P<0.05). The Mayo endoscopic scores at 14 weeks of IFX treatment in 12 active UC patients showed: only 2 patients achieved mucosal healing, 5 patients had reduced from severe to moderate mucosal inflammation, and 5 patients had no improvement.Seven patients had 10 adverse events, 2 cases had 4 times acute infusion reactions, and 5 cases had 6 times infections. Conclusion:IFX is effective and relatively safe in inducing and maintaining clinical remission in pediatric UC patients.

Objective: To summarize the clinical data including manifestations, diagnosis, treatment and prognosis of eosinophilic gastroenteritis (EGE) in children. Methods: A retrospective analysis was performed in 71 patients with pathologically proven EGE at Beijing Children's Hospital Affiliated to Capital Medical University from January 2008 to January 2017. Their clinical manifestations, laboratory and imaging examinations, endoscopic findings, histopathological examinations, and treatment were collected and analyzed. Results: Among 71 EGE cases, 47 (66%) cases were male and 24 (34%) cases were female, and the median age was 9.2 (0.2-16.5) years old. The main clinical manifestations included abdominal pain (76%, 54/71), vomiting (68%, 48/71), anorexia (54%, 38/71), weight loss (38%, 27/71), and diarrhea (37%, 26/71). There were 27 cases (38%) with a history of allergic diseases or family history. The median absolute value of eosinophil in peripheral blood of the 71 patients was 0.4 (0-36.8)×10⁹/L, and 27 cases (38%) showed an increase in eosinophil counts. Serum IgE was measured in 52 patients (104.3 (3.4- 3 000.0)×10³ U/L), and 30 patients (58%) showed an increase in serum IgE. A large number of eosinophils ((41.0±8.5)/HP) were found in 3 patients' ascites. The endoscopic examination of upper gastrointestinal tract revealed hyperemic edema in 62 cases (87%), plaque in 44 cases (62%), erosion in 17 cases (24%) and ulceration in 16 cases (23%). Histopathologically, in 8 cases (11%) the disease involved both stomach and duodeneum, in 21 cases (30%) involved stomach only, and in 37 cases (52%) involved duodeneum only. In addition, in 6 cases (8%) the disease involved esophagus and in 10 cases (14%) involved colorectum. Microscopically, eosinophil counts averaged 67/HP, 33/HP, 40/HP and 38/HP in esophageal, gastric, duodenal and colorectal mucosa respectively. A total of 34 cases were treated with glucocorticoid, and all these patients had alleviation of symptoms, which occurred within 14.9 days on average, but EGE recurred in 11 cases (32%). Conclusions The clinical symptoms and endoscopic findings of EGE are diverse and nonspecific. Histopathological examination of gastrointestinal mucosa is particularly important for the diagnosis. Glucocorticoid treatment is effective, but the patients with EGE are prone to relapse.