Thalidomide for Recurrent Bleeding Due to Small-Intestinal Angiodysplasia.

BACKGROUND: Recurrent bleeding from the small intestine accounts for 5 to 10% of cases of gastrointestinal bleeding and remains a therapeutic challenge. Thalidomide has been evaluated for the treatment of recurrent bleeding due to small-intestinal angiodysplasia (SIA), but confirmatory trials are lacking. METHODS: We conducted a multicenter, double-blind, randomized, placebo-controlled trial to investigate the efficacy and safety of thalidomide for the treatment of recurrent bleeding due to SIA. Eligible patients with recurrent bleeding (at least four episodes of bleeding during the previous year) due to SIA were randomly assigned to receive thalidomide at an oral daily dose of 100 mg or 50 mg or placebo for 4 months. Patients were followed for at least 1 year after the end of the 4-month treatment period. The primary end point was effective response, which was defined as a reduction of at least 50% in the number of bleeding episodes that occurred during the year after the end of thalidomide treatment as compared with the number that occurred during the year before treatment. Key secondary end points were cessation of bleeding without rebleeding, blood transfusion, hospitalization because of bleeding, duration of bleeding, and hemoglobin levels. RESULTS: Overall, 150 patients underwent randomization: 51 to the 100-mg thalidomide group, 49 to the 50-mg thalidomide group, and 50 to the placebo group. The percentages of patients with an effective response in the 100-mg thalidomide group, 50-mg thalidomide group, and placebo group were 68.6%, 51.0%, and 16.0%, respectively (P<0.001 for simultaneous comparison across the three groups). The results of the analyses of the secondary end points supported those of the primary end point. Adverse events were more common in the thalidomide groups than in the placebo group overall; specific events included constipation, somnolence, limb numbness, peripheral edema, dizziness, and elevated liver-enzyme levels. CONCLUSIONS: In this placebo-controlled trial, treatment with thalidomide resulted in a reduction in bleeding in patients with recurrent bleeding due to SIA. (Funded by the National Natural Science Foundation of China and the Shanghai Municipal Education Commission, Gaofeng Clinical Medicine; ClinicalTrials.gov number, NCT02707484.).

Influence of early colorectal cancer component on the positive margins after endoscopic resection: a retrospective study.

BACKGROUND: Endoscopic treatment methods for early colorectal cancer (ECRC) mainly depend on the size and morphology. It is unclear whether different endoscopic resection methods could achieve curative resection for ECRC confined in the mucosa. The study was designed to compare the rate of positive vertical margin (VM) of ECRC with advanced adenomas (AAs) including adenoma > 1 cm, villous adenoma, high-grade intraepithelial neoplasia/dysplasia stratified by different endoscopic resection methods. METHODS: Rate of positive VM for 489 ECRCs including Intramucosal (pTis) and superficial submucosal invasion (pT1) carcinomas were compared with those of 753 AAs stratified by different endoscopic resection methods using Chi-squared test. Multivariate logistic model was performed to investigate the risk factors of positive VM for different endoscopic resection methods. RESULTS: The pTis ECRC exhibited a similar rate of positive VM as that of AAs for en bloc hot snare polypectomy (HSP, 0% Vs. 0.85%, P = 0.617), endoscopic mucosal resection (EMR, 0.81% vs. 0.25%, P = 0.375) and endoscopic submucosal dissection (ESD, 1.82% Vs. 1.02%, P = 0.659). The pTis carcinoma was not found to be a risk factor for positive VM by en bloc EMR (P = 0.349) or ESD (P = 0.368). The en bloc resection achieved for pT1a carcinomas exhibited similar to positive VM achieved through ESD (2.06% Vs. 1.02%, P = 1.000) for AAs. Nonetheless, EMR resulted in higher risk of positive VM (5.41% Vs. 0.25%, P < 0.001) for pT1a carcinomas as compared to AAs. The pT1a invasion was identified as a risk factor for positive VM in polyps with en bloc EMR (odds ratio = 23.90, P = 0.005) but not ESD (OR = 2.96, P = 0.396). CONCLUSION: Collectively, the pTis carcinoma was not found to be a risk factor for positive VM resected by en bloc HSP, EMR or ESD. Additionally, ESD may be preferred over EMR for pT1a carcinomas with lower rate of positive VM.

The role of early video capsule endoscopy in the diagnosis and prognosis of obscure gastrointestinal bleeding: A multi-center propensity score matching study.

BACKGROUND AND AIM: Video capsule endoscopy (VCE) is a first-line procedure for the diagnosis of obscure gastrointestinal bleeding (OGIB). The opinions on the timing for such diagnostic evaluation remain unclear. We aimed to explore the role of early VCE in OGIB patients. METHODS: A total of 997 patients that underwent VCE at Renji Hospital and Nagoya University from May 15, 2002, to December 28, 2016, were included in this study. We matched patients that underwent early VCE within 14 days of bleeding (early group, n = 678) to patients that did not (late group, n = 319) via 1:1 propensity score matching (PSM). We then compared VCE diagnostic rates and the prevalence of post-VCE rebleeding in patients with initial negative VCE findings within 1 year between these groups before and after PSM. RESULTS: Following PSM, early VCE was associated with a significantly higher rate of OGIB diagnosis (56.4% vs 45.5%, P = 0.001) and with a significantly lower incidence of rebleeding within 1 year following treatment (24.7% vs 36.7%, P = 0.041). In univariate and multivariate analyses, VCE timing (odds ratio 0.648; 95% confidence interval 0.496-0.847, P = 0.001 and odds ratio 0.666; 95% confidence interval 0.496-0.894, P = 0.007, respectively) was found to be linked with a higher rate of positive findings. CONCLUSION: Early VCE can improve the reliability of OGIB diagnosis while also reducing rates of post-VCE rebleeding. This suggests that timely and accurate diagnosis can help to improve OGIB patient treatment and prognosis.

Thalidomide targets EGFL6 to inhibit EGFL6/PAX6 axis-driven angiogenesis in small bowel vascular malformation.

BACKGROUND: Small bowel vascular malformation disease (SBVM) is the most common cause of obscure gastrointestinal bleeding (OGIB). Several studies suggested that EGFL6 was able to promote the growth of tumor endothelial cells by forming tumor vessels. To date, it remains unclear how EGFL6 promotes pathological angiogenesis in SBVM and whether EGFL6 is a target of thalidomide. METHODS: We took advantage of SBVM plasma and tissue samples and compared the expression of EGFL6 between SBVM patients and healthy people via ELISA and Immunohistochemistry. We elucidated the underlying function of EGFL6 in SBVM in vitro and by generating a zebrafish model that overexpresses EGFL6, The cycloheximide (CHX)-chase experiment and CoIP assays were conducted to demonstrate that thalidomide can promote the degradation of EGFL6 by targeting CRBN. RESULTS: The analysis of SBVM plasma and tissue samples revealed that EGFL6 was overexpressed in the patients compared to healthy people. Using in vitro and in vivo assays, we demonstrated that an EMT pathway triggered by the EGFL6/PAX6 axis is involved in the pathogenesis of SBVM. Furthermore, through in vitro and in vivo assays, we elucidated that thalidomide can function as anti-angiogenesis medicine through the regulation of EGFL6 in a proteasome-dependent manner. Finally, we found that CRBN can mediate the effect of thalidomide on EGFL6 expression and that the CRBN protein interacts with EGFL6 via a Lon N-terminal peptide. CONCLUSION: Our findings revealed a key role for EGFL6 in SBVM pathogenesis and provided a mechanism explaining why thalidomide can cure small bowel bleeding resulting from SBVM.

Inverse Association of Age with Risk of Lymph Node Metastasis in Superficial Colorectal Cancer: A Large Population-Based Study.

BACKGROUND: Superficial colorectal cancer (SCRC) is defined as colorectal cancer (CRC) confined to the mucosa or submucosa. Endoscopic resection (ER) is widely used to resect differentiated SCRC from patients without lymph node metastasis (LNM). However, it is unclear whether ER is suitable for use with patients with differentiated early-onset SCRC because early-onset CRC is more aggressive. Therefore, we aimed to investigate the association between age of CRC onset and LNM. MATERIALS AND METHODS: We retrieved data for patients with surgically resected differentiated-type SCRCs from the Surveillance, Epidemiology, and End Results (SEER) database. Rate of LNM was compared among patients aged 18-39, 40-49, 50-59, 60-69, and ≥70 years. The association between age and LNM was further examined using multivariate logistic regression. RESULTS: We retrieved 34,506 records of differentiated SCRCs from the SEER database, including 667 patients aged 18-39 years, 2,385 aged 40-49, 8,075 aged 50-59 years, 9,577 aged 60-69 years, and 13,802 aged ≥70 years. Rates of LNM were 15.74%, 14.13%, 10.67%, 8.07%, and 6.76% for patients aged 18-39, 40-49, 50-59, 60-69, and ≥70 years, respectively. We found an inverse correlation between age at diagnosis and risk of LNM from the univariate analysis (p < .001). Compared with patients aged 18-39, the odds ratios with 95% confidence interval (CI) for patients aged 40-49, 50-59, 60-69, and ≥70 years were 0.90 (0.71-1.15, p = .376), 0.69 (0.56-0.87, p = .001), 0.54 (0.43-0.68, p < .001), and 0.47 (0.38-0.60, p < .001), respectively. CONCLUSION: In differentiated SCRCs, younger age at diagnosis was associated with higher risk of LNM. IMPLICATIONS FOR PRACTICE: Endoscopic resection (ER) is widely used to resect differentiated superficial colorectal cancer (SCRC) without lymph node metastasis (LNM). However, no study has ever investigated risk of LNM of early-onset SCRC compared with average onset SCRC to explore whether ER is suitable for early-onset SCRC. To the authors' knowledge, this population-based study is the first study to find inverse correlation between age at diagnosis and risk of LNM in differentiated SCRCs. This finding indicates that ER may not be suitable for young patients with differentiated SCRC. Because the 30-day operative mortality after surgery is higher but the risk of LNM is lower in older patients compared with younger patients, ER for differentiated SCRCs may be advantageous over surgery for older patients.

Low-dose and same day use of polyethylene glycol improves image of video capsule endoscopy: A multi-center randomized clinical trial.

BACKGROUND AND AIM: Clear visualization of the small bowel is a requirement for satisfactory video capsule endoscopy (VCE). The aim of this study was to identify the optimal dose and timing of polyethylene glycol (PEG) for small bowel preparation before VCE. METHODS: A total of 410 patients were enrolled in this prospective randomized trial. All patients fasted for 12 h and ingested 320 mg simethicone 30 min before swallowing the capsule. Patients were randomized into five groups: Group A (no PEG), Group B (1-L PEG, 12 h before VCE), Group C (2-L PEG, 12 h before VCE), Group D (1-L PEG, 4 h before VCE), and Group E (2-L PEG, 4 h before VCE). The primary endpoint was small bowel visualization quality (SBVQ), and the secondary endpoints were patient acceptability and diagnosis rate of VCE. RESULTS: Excellent SBVQ was achieved in 27 (32.5%) of Group A, 38 (46.3%) of Group B, 40 (48.2%) of Group C, 55 (66.3%) of Group D, and 43 (54.4%) of Group E. The percentage of excellent SBVQ in Group D was significantly more than in Group A (66.3% vs 32.5%, P < 0.001), and diagnostic rate in the distal segment was higher (28.9% vs 10.8%, P = 0.0035). Patient acceptance of 1-L PEG was better than of 2-L PEG (P < 0.005). CONCLUSION: Small bowel cleansing with 1-L PEG given 4 h before VCE was the optimal preparation for visualization of the bowel and patient acceptance (ClinicalTrials.gov, ID: NCT02486536).

Pseudopod-associated protein KIF20B promotes Gli1-induced epithelial-mesenchymal transition modulated by pseudopodial actin dynamic in human colorectal cancer.

Kinesin family member 20B (KIF20B) has been reported to have an oncogenic role in bladder and hepatocellular cancer cells, but its role in colorectal cancer (CRC) progression remains unclear. In this study, we assessed the mRNA and protein levels of KIF20B in CRC tissues using qRT-PCR and immunohistochemistry, respectively. KIF20B was overexpressed in CRC tissues and was associated with cancer invasion and metastasis. Mechanistically, KIF20B overexpression promoted the epithelial-mesenchymal transition (EMT) process mediated by glioma-associated oncogene 1 (Gli1) as well as CRC cell migration and invasion. Interestingly, KIF20B was localized in pseudopod protrusions of CRC cells and influenced the formation of cell protrusions, especially the EMT-related invadopodia. Moreover, intracellular actin dynamic participated in the modulation of the Gli1-mediated EMT and EMT-related cell pseudopod protrusion formation induced by KIF20B. We identified a role for KIF20B in CRC progression and revealed a correlation between KIF20B expression in CRC tissues and patient prognosis. The underlying mechanism was associated with the Gli1-mediated EMT and EMT-related cell protrusion formation modulated by intracellular actin dynamic. Thus, KIF20B may be a potential biomarker and promising treatment target for CRC.

Accuracy of Magnetically Controlled Capsule Endoscopy, Compared With Conventional Gastroscopy, in Detection of Gastric Diseases.

BACKGROUND & AIMS: Diseases of the stomach, including gastric cancer and peptic ulcer, are the most common digestive diseases. It is impossible to visualize the entire stomach with the passive capsule currently used in practice because of the large size of the gastric cavity. A magnetically controlled capsule endoscopy (MCE) system has been designed to explore the stomach. We performed a prospective study to compare the accuracy of detection of gastric focal lesions by MCE vs conventional gastroscopy (the standard method). METHODS: We performed a multicenter blinded study comparing MCE with conventional gastroscopy in 350 patients (mean age, 46.6 y), with upper abdominal complaints scheduled to undergo gastroscopy at a tertiary center in China from August 2014 through December 2014. All patients underwent MCE, followed by conventional gastroscopy 2 hours later, without sedation. We calculated the sensitivity, specificity, positive predictive value, and negative predictive value of detection of gastric focal lesions by MCE, using gastroscopy as the standard. RESULTS: MCE detected gastric focal lesions in the whole stomach with 90.4% sensitivity (95% confidence interval [CI], 84.7%-96.1%), 94.7% specificity (95% CI, 91.9%-97.5%), a positive predictive value of 87.9% (95% CI, 81.7%-94.0%), a negative predictive value of 95.9% (95% CI, 93.4%-98.4%), and 93.4% accuracy (95% CI, 90.83%-96.02%). MCE detected focal lesions in the upper stomach (cardia, fundus, and body) with 90.2% sensitivity (95% CI, 82.0%-98.4%) and 96.7% specificity (95% CI, 94.4%-98.9%). MCE detected focal lesions in the lower stomach (angulus, antrum, and pylorus) with 90.6% sensitivity (95% CI, 82.7%-98.4%) and 97.9% specificity (95% CI, 96.1%-99.7%). MCE detected 1 advanced gastric carcinoma, 2 malignant lymphomas, and 1 early stage gastric tumor. MCE did not miss any lesions of significance (including tumors or large ulcers). Among the 350 patients, 5 reported 9 adverse events (1.4%) and 335 preferred MCE over gastroscopy (95.7%). CONCLUSIONS: MCE detects focal lesions in the upper and lower stomach with comparable accuracy with conventional gastroscopy. MCE is preferred by almost all patients, compared with gastroscopy, and can be used to screen gastric diseases without sedation. Clinicaltrials.gov number: NCT02219529.

Long-term efficacy of modified retrievable stents for treatment of achalasia cardia.

AIM: To investigate the efficacy, safety and optimal duration of placement of modified retrievable metal stents for treatment of achalasia cardia. METHODS: Patients were randomly divided into groups A (N = 26, modified stents for 3 days), B (N = 26, modified stents for 2 days), C (N = 24, balloon dilation), and D (N = 25, regular stents for 2 days). Clinical symptom scores were recorded at baseline, 6 months, and during long-term follow-up. RESULTS: Seventy-seven patients with achalasia underwent stent placement (100 % success rate of implantation and extraction, no perforation). No stent migration or drop-off occurred in groups A and B. In group D, stent drop-off and migration was observed in 2 and 1 patients, respectively. Two patients in group C sustained esophageal perforation. Patients in the modified stent (A and B), balloon dilated (C) and regular stents (D) groups experienced significant improvement in dysphagia at 6 months, with recurrence in 1.92, 8.33 and 28 %, respectively. The clinical symptom score in the modified stent groups was significantly lower than that in the balloon dilated group (P = 0.01). During long-term follow-up, the symptom scores in modified stent groups were significantly lower than that in the balloon dilated (P < 0.01) and regular stent (P < 0.01) groups. CONCLUSION: Modified retrievable metal stents required an optimal placement duration of 2 days were safe with no incidence of migration or drop-off and had a lower recurrence of symptoms.

Carbon dioxide insufflation improves the intubation depth and total enteroscopy rate in single-balloon enteroscopy: a randomised, controlled, double-blind trial.

OBJECTIVE: The total enteroscopy rate of single-balloon enteroscopy (SBE) using air insufflation is not satisfactory, and whether carbon dioxide (CO2) insufflation increases the total enteroscopy rate of SBE is unknown. This randomised controlled trial aimed to determine whether CO2 insufflation facilitates the intubation depth and total enteroscopy rate of SBE. DESIGN: A total of 214 eligible patients referred for SBE were randomised to receive either air or CO2 insufflation, and included in the intention-to-test (ITT) analysis. In addition, 199 patients in whom enteroscopy was completed were included in the per-protocol (PP) analysis. Both the patients and endoscopists were blinded, and the intubation depth and total enteroscopy rate were defined as the primary outcomes. RESULTS: The CO2 group showed a superiority of intubation in the ITT analysis (oral route: 323.8±64.2 vs 238.3±68.6 cm; anal route: 261.6±74.2 vs 174.7±62.1 cm, both p<0.001), and the total enteroscopy rate (34.9% vs 17.6%, p=0.006). Similar results were obtained in a PP analysis for both outcomes. In addition, in the PP analysis, the addition of circumference after the procedure was less in the CO2 group (0.8±0.6 vs 3.3±1.8 cm, p=0.005) for the oral route. No serious complications were reported. The overall percentage of procedures with significant pathological findings was 52.8%; the rates were 58.5% and 47.2% (p=0.100, ITT analysis) in the CO2 and air groups, respectively. CONCLUSIONS: CO2 insufflation improves the intubation depth and total enteroscopy rate in SBE with a good safety profile and acceptability compared with that of air, and thus is recommended for clinical utilisation. TRIAL REGISTRATION NUMBER: ClinicalTrial.gov identifier: NCT01758900.

Inhibition of endothelial Slit2/Robo1 signaling by thalidomide restrains angiogenesis by blocking the PI3K/Akt pathway.

BACKGROUND: Thalidomide is effective in the treatment of angiodysplasia. The mechanisms underlying its activity may be associated with inhibition of angiogenic factors. It was recently shown that Slit2/Robo1 signaling plays a role in angiogenesis. PURPOSE: The aim of this study was to explore the expression and effects of Robo1 and Slit2 in angiodysplasia and to identify the possible therapeutic mechanisms of thalidomide. METHOD: Slit2 and Robo1 expression were analyzed in tissue samples and human umbilical vein endothelial cells (HUVECs) treated with thalidomide using a combination of laboratory assays that were able to detect functional activity. RESULTS: Slit2, Robo1 and vascular endothelial growth factor (VEGF) were strongly expressed in five angiodysplasia lesions out of seven cases, while expression was low in one out of seven normal tissues. Exposure of HUVECs to recombinant N-Slit2 resulted in an increase in VEGF levels and stimulated proliferation, migration and tube formation. These effects were blocked by an inhibitor of PI3K and thalidomide. CONCLUSIONS: Robo1 and Slit2 may have important roles in the formation of gastrointestinal vascular malformation. High concentrations of Slit2 increased the levels of VEGF in HUVECs via signaling through the PI3K/Akt pathway-an effect that could be inhibited by thalidomide.

Assessment of capsule endoscopy scoring index, clinical disease activity, and C-reactive protein in small bowel Crohn's disease.

BACKGROUND AND STUDY AIMS: Small bowel Crohn's disease (SBCD) patients are frequently assessed by capsule endoscopy (CE), which enables direct visualization of small bowel mucosal abnormalities; however, the correlations between CE scoring index (CESI), C-reactive protein (CRP), and disease activity indices remain undefined. We aimed to determine correlations between the CESI, clinical disease activity indices, and CRP in SBCD patients. PATIENTS AND METHODS: A prospective study was conducted between October 2008 and February 2011 on 58 established SBCD patients and suspected patients who received a definitive SBCD diagnosis during study. Patients underwent complete CE and were scored according to the CESI and Harvey-Bradshaw index (HBI). Statistical correlation among CESI, HBI, and CRP was assessed. RESULTS: Weak, but significant, correlations were found between CESI and HBI (r = 0.4, P < 0.01). The correlation between CESI and CRP was moderate (r = 0.58, P < 0.01). The median CRP value was significantly higher in patients with moderate to severe CESI compared with the mild group (22.60 ± 16.79 mg/L vs 11.88 ± 8.39 mg/L, P < 0.01). Changes between baseline and follow-up CESI failed to correlate with the delta-HBI or delta-CRP (both, P > 0.05). CONCLUSIONS: In this cohort of SBCD patients, clinical disease activity index was not reliable predictors of mucosal inflammation. CRP, however, might be a useful inflammatory marker for evaluating the moderate to severe CE activity in SBCD patients. Furthermore, therapy-induced clinical and biological improvement was not associated with repair of SBCD mucosal lesions.

Evaluation of narrow-band imaging in the diagnosis of colorectal lesions: is a learning curve involved?

BACKGROUND: The usefulness of endoscopy narrow-band imaging (NBI) in differentiating colorectal lesions has been demonstrated. However, the learning curve associated with this technique is a concern for endoscopists. METHODS: Prior to carrying out these colonoscopies, four endoscopists attended a training course designed to teach the principles of NBI and application of the Sano Capillary Pattern (CP) classification criteria. Following a pre-test, endoscopists used NBI with magnification and CP analysis for real-time colonoscopy exams to predict lesion histology. Three sets of 15 lesions were imaged. These three sets included both lesions requiring endoscopic treatment (e.g. target lesions) and lesions that were not, or could not be, treated by endoscopy (e.g. non-target lesions). The diagnostic accuracy of each endoscopist for each set of lesions was evaluated to assess the learning curve associated with the application of NBI. RESULTS: Overall accuracy, sensitivity, and specificity for differentiating neoplastic and non-neoplastic lesions were 95.4%, 98.0%, and 92.0%, respectively. For target lesions versus non-target lesions, the diagnostic accuracy associated with the second set of lesions was better than that achieved with the first set of lesions (78.3% vs 96.7% (P = 0.02) and 70.0% vs 96.7% ( P < 0.01), respectively in each case). In contrast, the difference in diagnostic accuracy between the second and third sets of lesions was not significant. CONCLUSION: NBI with magnification is a useful tool for the diagnosis of colorectal lesions. Moreover, following a short training program and with minimal clinic practice, less experienced endoscopists were able to become competent in the method.

The value of the neutrophil to lymphocyte ratio and PLT count for the diagnosis and prediction of COVID-19 severity.

BACKGROUND: COVID-19 and influenza A can cause severe respiratory illness. Differentiating between the two diseases and identifying critically ill patients in times of epidemics become a challenge for frontline medical staff. We sought to investigate whether both diseases and their severity could be recognized by routine blood parameters. METHODS: Our retrospective study analysed the clinical data and first-time routine blood parameters of 80 influenza A patients and 123 COVID-19 patients. COVID-19 patients were divided into three groups according to treatment modalities and outcomes: outpatient group, inpatient without invasive mechanical ventilation (IMV) group, and inpatient with IMV group. We used the Mann-Whitney and Kruskal-Wallis tests to analyze the differences in routine blood parameters between the two or three groups. Receiver operating characteristic (ROC) curve analysis and area under the curve (AUC) were used to assess the diagnostic accuracy. RESULTS: Compared with outpatient influenza A patients, outpatient COVID-19 patients had a higher neutrophil to lymphocyte ratio (NLR) (6.63 vs 3.55). ROC analysis showed that the NLR had a high diagnostic value for differentiating COVID-19 from influenza A (AUC = 0.739). The best cut-off point of the NLR was 6.48, the diagnostic sensitivity was 0.523, and the specificity was 0.925. The median platelet (PLT) count in the different COVID-19 groups was as follows: outpatient group (189×109/L), inpatient without IMV group (161×109/L), and inpatient with IMV group (94×109/L). Multivariate logistic regression analysis found a significant association between PLT and treatment modality and outcome in COVID-19 patients (p<0.001). CONCLUSIONS: NLR can be used as a potential biological indicator to distinguish COVID-19 and influenza A. Decreased PLT predicts the critical condition of COVID-19 patients and helps stratify the treatment of COVID-19 patients.

Efficacy of thalidomide for refractory gastrointestinal bleeding from vascular malformation.

BACKGROUND & AIMS: Patients with recurrent bleeding from gastrointestinal vascular malformations are a challenge to treat. We investigated the long-term efficacy and safety of thalidomide for refractory bleeding from gastrointestinal vascular malformations in an open-label, randomized study. METHODS: Eligible patients were randomly assigned to groups that were given either 100 mg thalidomide (n = 28) or 400 mg iron (n = 27, controls), daily for 4 months; patients were followed for at least 1 year (mean, 39 months). Bleeding was defined by a positive result from an immunoassay fecal occult blood test. The primary end point was the effective response rate, defined as the proportion of patients in whom bleeding episodes had decreased by ≥ 50% in the first year of the follow-up period. The secondary end points included the rates of cessation of bleeding, blood transfusion, overall hospitalization, and hospitalization for bleeding. We also quantified yearly bleeding episodes, bleeding duration, levels of hemoglobin, and yearly requirements for transfusions of red cells, numbers of hospitalizations for bleeding, and hospital stays. Plasma levels of vascular endothelial growth factor were measured in the group given thalidomide. RESULTS: Rates of response in the thalidomide and control groups were 71.4% and 3.7%, respectively (P < .001). All secondary end points differed significantly different between groups; thalidomide was more effective. No severe adverse effects were observed, although minor side effects were common among patients in the thalidomide group. Levels of vascular endothelial growth factor were significantly reduced by thalidomide (P < .001). CONCLUSIONS: Thalidomide is an effective and relatively safe treatment for patients with refractory bleeding from gastrointestinal vascular malformations. Mechanisms of thalidomide activity might involve vascular endothelial growth factor.

Role of vascular endothelial growth factor in angiodysplasia: an interventional study with thalidomide.

BACKGROUND AND AIM: The pathogenesis of angiodysplasia is still not fully understood and effective therapy is not available. Thalidomide was reported to be effective in the treatment of angiodysplasia, but the mechanisms underlying its activity are, as yet, unknown. We aimed to investigate the expression of vascular endothelial growth factor (VEGF) in angiodysplasia tissues, and the role of hypoxia-inducible factor-1α (HIF-1α) and basic fibroblast growth factor (bFGF) on VEGF expression in human umbilical vein endothelial cells (HUVEC). Additionally, we aimed to study the role of thalidomide in these parameters. METHODS: Immunohistochemistry was performed to visualize VEGF in angiodysplasia lesions. HUVEC were incubated under hypoxic conditions or in the presence of bFGF. Effects of exposure to thalidomide were studied. Cell growth was assessed in methylthiazolyte-trazolium assays. Enzyme-linked immunosorbent assays and real-time polymerase chain reaction were performed to assess the expression of VEGF at protein and mRNA levels. Western blot was performed to detect the expression of HIF-1α under hypoxic conditions. RESULTS: VEGF was strongly expressed in 75% of patients with angiodysplasia lesions, as compared to expression in patients without angiodysplasia lesions. VEGF was also induced in HUVEC under hypoxic conditions (P < 0.05). bFGF was found to stimulate the proliferation of HUVEC and enhance the expression of VEGF. Thalidomide suppressed bFGF-induced proliferation significantly and decreased VEGF expression, both at the protein and mRNA levels. Thalidomide also inhibited HIF-1α in a dose-dependent manner (P < 0.05). CONCLUSIONS: VEGF may play an important role in the pathogenesis of angiodysplasia. Thalidomide can suppress VEGF, either induced by HIF-1α or bFGF.

[The potential pathogenesis of gastrointestinal vascular malformation and the potential mechanism of thalidomide in the treatment of gastrointestinal vascular malformation].

OBJECTIVE: To study the pathogenesis of gastrointestinal vascular malformation (GIVM) and the potential mechanism of thalidomide in the treatment of gastrointestinal bleeding due to GIVM. METHODS: We collected the surgical intestinal specimens from 10 patients who suffered from massive hemorrhage of gastrointestinal tract owning to GIVM and the normal intestinal mucosa around the lesions, as well as normal intestinal mucosa from healthy subjects. Immunohistochemical (IHC) staining was carried out to investigate the differences of angiopoietin 2 (Ang2), Notch1 and delta like ligand 4 (Dll4) in the above three intestinal mucosa to find the relationship with the pathogenesis of GIVM. Human umbilical vein endothelial cells (HUVECs) were cultured with 0, 25, 50, 100 and 200 mg/L thalidomide for 24 or 48 hours to observe their mRNA and protein expressions of Ang2, Notch1, Dll4 by real-time PCR and Western blot. RESULTS: By IHC staining, more expressions of Ang2, Notch1 and Dll4 in the lesions were detected than those in the normal intestinal mucosa around the lesions and the normal intestinal mucosa in healthy people. The expressions of Ang2, Notch1 and Dll4 were significantly correlated (P = 0.016, r = 0.732), and the expressions of Notch1 and Dll4 were absolutely correlated (P = 0.000, r = 1.000). Real-time PCR and Western blot showed that thalidomide could down-regulate the expressions of them, which were in a concentration-dependent manner. CONCLUSION: Ang2, Notch1 and Dll4 may correlate with the pathogenesis of GIVM, while thalidomide can concentration-dependently down-regulate the expression of Ang2, Notch1 and Dll4, which may be one of the mechanism that thalidomide play a therapeutic role in GIVM.

Effectiveness of the immunofecal occult blood test for colorectal cancer screening in a large population.

BACKGROUND: Guaiac tests are the most widely used tests to detect colorectal cancer (CRC). However, their sensitivity is relatively low and results may be affected by various factors. Immunofecal occult blood test (IFOBT) is specific for human hemoglobin and does not require dietary restrictions. AIMS: The aim of this study was to evaluate the effectiveness of IFOBT for the screening of precancerous lesions and CRC. METHODS: From July 2006 to June 2007, IFOBT was performed on 5,919 adults who received periodic health examinations in our hospital. The positive cases were examined by colonoscopy and a double-contrast barium enema. Diagnosis was confirmed by histopathological analysis. RESULTS: Positive IFOBT was detected in 314 of 5,919 cases (5.30%). Further examinations were made in 264 IFOBT-positive cases. Of these, 116 cases with colorectal cancer (16 cases) or precancerous lesions (94 cases with colorectal adenomatous polyps and 6 cases with active ulcerative colitis) were detected. The total detection rate of CRC and precancerous lesions was 43.94% (116/264). TNM classification of 16 CRC cases was as follows: TNM I in eight cases (50.00%), TNM II in seven cases (43.75%) and TNM III in one case (6.25%), indicating IFOBT can detect CRC in the early stages. CONCLUSION: Regular IFOBT can detect precancerous lesions and CRC in early stages and can thus reduce mortality from CRC.

Long- and short-term outcomes of early gastric cancer after endoscopic resection: a retrospective study from China.

Background and study aims The aim of the study was to evaluate short- and long-term outcomes of endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) in China because no study has yet been conducted to confirm its effectiveness in EGC in China. Patients and methods A total of 570 EGC samples from 537 patients were collected for evaluation of en bloc, complete, and curative resection using ESD. Data from 302 patients with at least 3 years of active follow-up were collected for analysis of recurrence of EGC and occurrence of metachronous GC (MGC). Short- and long-outcomes of mixed-type and pure differentiated EGC were also compared. Results En bloc resection rates of 96.0 %, 98.7 %, and 95.2 %, complete resection rates of 91.2 %, 96.6 % and 90.8 %, and curative resection rates of 83.0 %, 96.2 % and 88.2 % were achieved in all EGCs included in the study, those with absolute indication, and those with expanded indication, respectively. As a long-term outcome, recurrence was observed in 1.3 % of patients, 3-year and 5-year recurrence rates being 0.7 % and 1.2 %, respectively. Thirteen patients (4.3 %) exhibited MGCs during follow-up, all of which were resected in a second ESD. Conclusions The effectiveness of ESD for EGC in China was confirmed, with satisfactory short- and long-term outcomes. With scheduled follow-up, the outcomes for mixed-type EGC can be similar to those for pure differentiated EGC after complete resection without development of lymphovascular invasion.

Patterns of Lymph Node Metastasis in Patients With T1/T2 Gastroduodenal Neuroendocrine Neoplasms: Implications for Endoscopic Treatment.

Guidelines have differed in their opinion regarding the indications for endoscopic resection of gastric-neuroendocrine neoplasms (g-NENs) and duodenal-NENs (d-NENs). We examined the association between size and lymph node metastasis (LNM) to identify candidates most suitable for endoscopic resection. We identified 706 patients with T1/T2 g-NENs and 621 patients with T1/T2 d-NENs from the SEER database. The prevalence of LNM and risk factors associated with LNM were analyzed. LNM was present in 8.1% of patients with gastroduodenal neuroendocrine tumors (NETs) and 31.6% of patients with neuroendocrine carcinomas (NECs). Multivariate logistic regression indicated that tumor size >10mm, greater invasion depth, and poor differentiation were independently associated with LNM. In addition, the percentage of g-NETs invading submucosa with LNM increased with tumor size (≤10 mm,3.9%;11-20 mm,8.6%;>20 mm,16.1%). However, in contrast to the low LNM risk in patients with small g-NETs (≤10 mm), we found that LNM rate exceeded 5% even for patients with small submucosal-infiltrating d-NETs. Among patients with nodal-negative g-NETs, the cause specific survival (CSS) was similar for those who received surgical resection and endoscopic resection. Among patients with d-NETs, the CSS was better for those who received endoscopic resection. In conclusion, patients with d-NETs had a higher probability of LNM than those with g-NETs. Endoscopic resection can be utilized for curative treatment of submucosa-infiltrating g-NETs and intramucosal d-NETs when the size is 10 mm or less. These results reinforce the need to search for LNM in lesions that are larger than 10 mm.