Bile acid alterations associated with indolent course of inflammatory bowel disease.

BACKGROUND: The indolent course of treatment-naive patients with inflammatory bowel disease (IBD) is confirmed predictable based on clinical characteristics. Current evidences supported that bile acids (BAs) alteration might be promising biomarkers in the field of IBD. We aimed to analyze the alterations of BAs as the disease progresses and explore their predictive value for indolent course of IBD. METHODS: The indolent course of IBD was defined as a disease course without need for strict interventions throughout the entire follow-up. A targeted metabolomics method was used to detect the concentration of 27 BAs from serum sample in treatment-naive patients with IBD (Crohn's disease [CD], n = 27; ulcerative colitis [UC], n = 50). Patients with CD and UC were individually divided into two groups for further study according to the median time of indolent course. The overall BAs profile and the clinical value of BAs in predicting indolent course of IBD were identified between different groups. RESULTS: For CD, the levels of deoxycholic acid, glycodeoxycholic acid, taurodeoxycholic acid, glycolithocholic acid-3-sulfate disodium salt and iso-lithocholic acid were significantly increased in patients with indolent course > 18 M (p < 0.05). These five BAs owned 83.5% accuracy for predicting indolent course over 18 months in CD. For UC, the concentration of deoxycholic acid and glycodeoxycholic acid were significantly higher, while dehydrocholic acid were lower in patients with indolent course > 48 M (p < 0.05). These three BAs predicted indolent course over 48 months of 69.8% accuracy in UC. CONCLUSION: The specific BAs alterations might be potential biomarkers in predicting disease course of IBD patients.

The usefulness of three-dimensional ultrasound fusion imaging for precise needle placement in liver thermal ablation: a phantom and an in vivo simulation study.

PURPOSE: To investigate the value of three-dimensional ultrasound fusion imaging (3DUS-FI) in real-time guiding needle placement by phantom models and in vivo simulations. MATERIALS AND METHODS: Two radiologists (beginner and expert) performed needle placement using two-dimensional ultrasound (2DUS) and 3DUS-FI, respectively. In the phantom study, single-needle placement was performed by puncturing the center point of each ball and assessed based on the specimen length. Multiple-needles placement was performed by placing three needles in each ball, and their locations were confirmed by computed tomography, and assessed based on the distance deviation between needles. In the in vivo simulation study, simulated-needle placement was performed by placing a virtual ablation needle in each liver tumor and assessed by the simulated ablative cover rate and margin. RESULTS: Specimen length was significantly longer with 3DUS-FI in the beginner, whereas no significant difference was observed in the expert (2DUS vs. 3DUS-FI: beginner, 14.60 ± 2.60 mm vs. 16.25 ± 1.38 mm, p = .017; expert, 16.78 ± 1.40 mm vs. 16.95 ± 1.15 mm, p = .668). Distance deviation between needles was significantly smaller with 3DUS-FI (2DUS vs. 3DUS-FI: beginner, 25.06 ± 16.07 mm vs. 3.72 ± 1.99 mm, p < .001; expert, 11.70 ± 7.79 mm vs. 2.89 ± 1.52 mm, p < .001). The simulated ablative cover rate and margin were significantly larger with 3DUS-FI for the beginner, whereas only the latter was significantly larger for the expert (2DUS vs. 3DUS-FI: beginner, 73.55 ± 8.73% vs. 81.38 ± 11.84%, p = .001, 0.82 ± 0.97 mm vs. 2.65 ± 1.23 mm, p < .001; expert, 78.60 ± 9.91% vs. 83.24 ± 11.69%, p = .059; 1.65 ± 1.15 mm vs. 2.95 ± 1.13 mm, p < .001). CONCLUSIONS: 3DUS-FI is useful for real-time guiding precise needle placement and may be further use to improve the efficacy of liver thermal ablation.

Alterations of gut microbiota in patients with irritable bowel syndrome: A systematic review and meta-analysis.

BACKGROUND AND AIMS: Alterations of gut microbiota were assumed to be the etiology and pathogenesis of irritable bowel syndrome (IBS) in some studies. However, alterations of gut microbiota in IBS patients had not been systematically assessed with a meta-analysis. We performed a mate-analysis to explore and compare the alterations of gut microbiota in IBS patients from China and other regions around the world. METHODS: Case-control studies detecting gut microbiota in IBS patients were identified through English and Chinese databases. The standardized mean difference (SMD) with 95% confidence interval (CI) of bacterial counts was calculated. RESULTS: Ten studies from China and seven studies from other regions around the world were included in our study. As compared with healthy controls, the SMDs of Bifidobacteria, Lactobacillus, Escherichia Coli, and Enterobacter in Chinese IBS patients were -1.42 (CI: -2.10, -0.75), -0.91 (95% CI: -1.31, -0.52), 0.83 (95% CI: 0.26, 1.40), and 0.57 (95% CI: 0.33, 0.82), respectively. But the SMDs of Bacteroides and Enterococcus were found no significant differences in Chinese IBS patients. However, the SMDs of Bifidobacteria and Bacteroides in IBS patients from other regions were -0.76 (CI: -1.43, -0.09) and 1.17 (CI: 0.00, 2.35), while the SMDs of Lactobacillus, E. Coli, Enterobacter, and Enterococcus were found no significant differences. CONCLUSIONS: There were alterations of gut microbiota in IBS patients, and it implied that alterations of gut microbiota might be involved in the pathogenesis of IBS. However, the species-specific alterations of gut microbiota were different between IBS patients from China and other regions.

[Clinical characteristics and risk factors of refractory Crohn's disease].

OBJECTIVE: To analyze the clinical characteristics and risk factors of refractory Crohn's disease (CD). METHODS: All clinical data of confirmed consecutive CD patients were collected from our hospital between January 2003 and June 2013. The patients' demographic data, clinical features, therapeutic regimens and laboratory examinations were analyzed. A multivariate Logistic regression was performed to identify the risk factors of refractory CD. RESULTS: (1) A total of 402 confirmed CD patients were recruited for analysis. The prevalence of refractory CD was 33.8% (136/402). The rates of steroid-dependency was 37.0% (97/262) in 262 patients with a history of steroid use and the rate of thiopurines ineffectiveness was 26.9% (79/294) in 294 patients with a history of thiopurines-use; (2) Univariate analysis showed that disease location (L3 type), abdominal pain, diarrhea, fever, abdominal tenderness, perianal lesion, steroid use, AZA/6-MP use, leucocyte, hemoglobin (Hb), platelet level and high-sensitivity C-reactive protein (HsCRP) were significantly different between refractory and non-refractory CD patients (all P < 0.05) . Multivariate Logistic regression showed that steroid use (OR = 6.516, 95% CI: 2.884-14.722, P = 0.000) and low Hb (OR = 1.023, 95% CI: 1.008-1.037, P = 0.002) were independent risk factors related to refractory CD; (3) Univariate analysis showed that Hb level, erythrocyte sedimentation rate (ESR) were significantly different between steroid-dependent and non-steroid-dependent groups (all P < 0.05) . Multivariate Logistic regression showed that only low Hb level (OR = 1.021, 95% CI: 1.006-1.036, P = 0.005) was an independent risk factor related to steroid-dependency; (4) Univariate analysis showed that disease location (L3 type), perianal lesion, abdominal pain, diarrhea, fever, abdominal tenderness, platelet level, steroid use, steroid-dependency were significantly different between thiopurines-ineffective and thiopurines-effective groups (all P < 0.05) . Multivariate Logistic regression showed that perianal lesion (OR = 2.085, 95% CI: 1.007-4.039, P = 0.029), abdominal tenderness (OR = 2.943, 95% CI: 1.452-5.964, P = 0.003) and steroid-dependency (OR = 3.599, 95% CI: 1.847-7.013, P = 0.000) were independent risk factors related to thiopurines-ineffectiveness. CONCLUSIONS: Nearly one third CD patients became refractory during the course of disease. Low Hb and steroid use are independent risk factors. Low Hb is an independent risk factor related to steroid-dependency. Perianal disease, abdominal tenderness and steroid-dependency are independent risk factors related to thiopurines- ineffectiveness.

Using four-point subcutaneous injection of lymphatic contrast-enhanced ultrasound to diagnose lymphedema of lower extremity.

Background: The diagnosis of lymphedema primarily relies on the clinical symptoms, signs, medical history and imaging. Objective lymphatic imaging helps improving the diagnosis of lymphedema. This study aimed to develop an effective imaging tool to diagnose lymphedema. Methods: This is a single-center retrospective study. From September 2022 to November 2023, we enrolled thirty-two patients, involving 40 lower extremities who underwent lymphatic contrast-enhanced ultrasound (CEUS) following a subcutaneous injection of contrast agent at four points in the First Affiliated Hospital of Sun Yat-sen University. Cohen's kappa value, sensitivity, specificity, positive predictive value, negative predictive value and accuracy were calculated. Lymphoscintigraphy was the reference standard. Results: Successful lymphatic-CEUS detection was defined as the situation that lymphatic drainage of medial or lateral lower limbs were observed. The successful detection rate was 100% (40 of 40). The diagnosis of lymphedema was based on the presence of either medial or lateral lymphatic obstructions, or subcutaneous lymphatic enhancement. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy for diagnosing lymphedema by lymphatic-CEUS were as follows: 91.2% (31 of 34), 100% (6 of 6), 100% (31 of 31), 66.7% (6 of 9) and 92.5% (37 of 40), respectively. The Cohen's Kappa value was 0.756. The area under the receiver operating characteristic curve (AUC) for the subcutaneous injection of four-point lymphatic-CEUS was 0.956. Conclusions: This study put forward a novel four-point lymphatic-CEUS method to detect the functions of the lymphatics of lower extremities and established a lymphatic-CEUS standard for diagnosing lymphedema of lower extremities. Four-point lymphatic-CEUS is a considerable option for diagnosing lymphedema of lower extremities.

Bowel Stiffness Assessed by Shear-Wave Ultrasound Elastography Predicts Disease Behavior Progression in Patients With Crohn's Disease.

INTRODUCTION: There is a lack of reliable predictors of disease behavior progression in patients with Crohn's disease (CD). Real-time shear-wave elastography (SWE) is a novel method for evaluating tissue stiffness. However, its value for assessing CD has not yet been investigated. We aimed to explore the value of SWE and other ultrasound parameters at diagnosis in predicting CD behavior progression. METHODS: We retrospectively collected data from patients with CD with the nonstenotic nonpenetrating disease (B1 phenotype based on the Montreal classification). All patients underwent intestinal ultrasound at baseline and were followed up. The end point was defined as disease behavior progression to stricturing (B2) or penetrating (B3) disease. Cox regression analysis was performed for the association between baseline characteristics and subsequent end points. In addition, a multivariate nomogram was established to predict the risk of disease behavior progression quantitatively. RESULTS: A total of 130 patients with CD with B1 phenotype were enrolled. Twenty-seven patients (20.8%) developed B2 or B3 disease, with a median follow-up of 33 months. Multivariate analysis identified that SWE was the only independent predictor of disease behavior progression (hazard ratio 1.08, 95% confidence interval 1.03-1.12, P = 0.001). A reverse of the HR appeared at the cutoff 12.75 kPa. The nomogram incorporating SWE and other clinical characteristics showed a good prediction performance (area under the curve = 0.792). DISCUSSION: Intestinal stiffness assessed using SWE is an independent predictor of disease behavior progression in patients with CD. Patients with CD with SWE >12.75 kPa at diagnosis are prone to progress toward stricturing or penetrating diseases.

Measurement of the stiffness of the normal terminal ileum mesentery using shear-wave elastography.

OBJECTIVE: To investigate the feasibility of using shear-wave elastography (SWE) to measure the stiffness of the normal terminal ileum mesentery, and to establish its normal reference range. METHODS: Ninety-five normal subjects and 22 patients with mesentery-related disease were included. The average Young's modulus of the normal terminal ileal mesentery was measured by SWE ultrasound. The thickness and the extent to which mesenteric fat extended around the intestinal circumference of the normal terminal ileum were also recorded. The normal reference range was established and the SWE values of normal and diseased subjects were compared. RESULTS: Transabdominal SWE examination of the terminal ileum mesentery was successfully performed on 91 subjects (95.8 %). The mean extent range, thickness, and SWE value of the normal terminal ileum mesentery were 1/4 (1/5-1/3), 6.8 ± 2.4 mm, and 4.3 ± 2.1 kPa, respectively. These parameters did not differ significantly between genders, and across age and body mass index groups (all P > 0.05). The intra- and inter-operator consistencies were excellent for the replicated SWE measurements (0.801 [95 % confidence interval: 0.560-0.916] and 0.751 (95 % confidence interval: 0.388-0.900], respectively). The mean mesenteric elasticity in diseased subjects was 21.9 ± 10.7 kPa, which was significantly higher than that in normal subjects (P < 0.001). The cut-off value for mesenteric elasticity was 9.3 kPa, with a sensitivity of 90 % and a specificity of 100 % (P < 0.001). CONCLUSION: SWE can be used to reliably evaluate the stiffness of the terminal ileum mesentery in normal subjects.

The application of contrast-enhanced ultrasound for sentinel lymph node evaluation and mapping in breast cancer patients.

Background: To retrospectively investigate the application of contrast-enhanced ultrasound on sentinel lymph node (SLN-CEUS) for SLN evaluation and mapping in breast cancer patients. Methods: Patients diagnosed with breast cancer at the First Affiliated Hospital of Sun Yat-sen University from June 2019 to March 2021 were conveniently evaluated by SLN-CEUS. The results of SLN-CEUS and B mode-ultrasound (BUS) were collected and compared. For patients who only underwent SLN-CEUS, we conducted a 1:1 propensity score matching (PSM). The diagnostic parameters, including sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), false negative rate (FNR), false positive rate (FPR), and proportion of undetermined diagnoses were compared between the SLN-CEUS and BUS cohorts. The identification rate and FNR of sentinel lymph node biopsy (SLNB) were also assessed. Results: There were 327 patients in each of the SLN-CEUS and BUS cohorts. Among the entire cohort, both NPV [90.2% (95% CI, 85.4-93.5%) vs. 83.5% (95% CI, 77.8-88.0%), P=0.048] and accuracy [80.7% (95% CI, 76.5-85.0%) vs. 73.7% (95% CI, 68.9-78.5%), P<0.001] of SLN-CEUS were significantly higher than those of BUS. In non-neoadjuvant treatment (NAT) patients, the NPV [94.7% (95% CI, 89.9-97.4%) vs. 85.5% (95% CI, 79.1-90.2%), P=0.007] and accuracy [87.6% (95% CI, 83.2-92.0%) vs. 76.0% (95% CI, 70.4-81.5%), P<0.001] of SLN-CEUS were significantly higher than those of BUS. In NAT patients, no difference in diagnostic efficacy was found. The proportion of undetermined diagnoses of SLN-CEUS was significantly lower than that of BUS (5.8% vs. 15.3%, P<0.001). The identification rate of SLN-CEUS in overall patients, non-NAT patients, and NAT patients was 94.2%, 96.3%, and 89.9%, respectively. The FNR of SLNB with the blue-dye tracer in combination with SLN-CEUS in overall patients, non-NAT patients, and NAT patients was 7.3%, 4.0%, and 12.5%, respectively. Conclusions: Compared to BUS, SLN-CEUS is a better technique for diagnosing SLNs in early breast cancer patients, showing superiority in multiple diagnostic parameters. However, the diagnostic value of SLN-CEUS in NAT patients is still undetermined. SLN-CEUS is a promising mapping method in SLNB, with a high identification rate and a low FNR when used in combination with a blue-dye tracer.

Recent developments on BMPs and their antagonists in inflammatory bowel diseases.

Inflammatory bowel diseases (IBDs), including ulcerative colitis, and Crohn's disease, are intestinal disorders characterized by chronic relapsing inflammation. A large proportion of patients with IBD will progress to develop colitis-associated colorectal cancer due to the chronic intestinal inflammation. Biologic agents that target tumour necrosis factor-α, integrin α4ß7, and interleukin (IL)12/23p40 have been more successful than conventional therapies in treating IBD. However, drug intolerance and loss of response are serious drawbacks of current biologics, necessitating the development of novel drugs that target specific pathways in IBD pathogenesis. One promising group of candidate molecules are bone morphogenetic proteins (BMPs), members of the TGF-ß family involved in regulating morphogenesis, homeostasis, stemness, and inflammatory responses in the gastrointestinal tract. Also worth examining are BMP antagonists, major regulators of these proteins. Evidence has shown that BMPs (especially BMP4/6/7) and BMP antagonists (especially Gremlin1 and follistatin-like protein 1) play essential roles in IBD pathogenesis. In this review, we provide an updated overview on the involvement of BMPs and BMP antagonists in IBD pathogenesis and in regulating the fate of intestinal stem cells. We also described the expression patterns of BMPs and BMP antagonists along the intestinal crypt-villus axis. Lastly, we synthesized available research on negative regulators of BMP signalling. This review summarizes recent developments on BMPs and BMP antagonists in IBD pathogenesis, which provides novel insights into future therapeutic strategies.

Protocadherin 20 maintains intestinal barrier function to protect against Crohn's disease by targeting ATF6.

BACKGROUND: Intestinal barrier dysfunction plays a central role in the pathological onset of Crohn's disease. We identify the cadherin superfamily member protocadherin 20 (PCDH20) as a crucial factor in Crohn's disease. Here we describe the function of PCDH20 and its mechanisms in gut homeostasis, barrier integrity, and Crohn's disease development. RESULTS: PCDH20 mRNA and protein expression is significantly downregulated in the colonic epithelium of Crohn's disease patients and mice with induced colitis compared with controls. In mice, intestinal-specific Pcdh20 knockout causes defects in enterocyte proliferation and differentiation, while causing morphological abnormalities. Specifically, the deletion disrupts barrier integrity by unzipping adherens junctions via ß-catenin regulation and p120-catenin phosphorylation, thus aggravating colitis in DSS- and TNBS-induced colitis mouse models. Furthermore, we identify activating transcription factor 6 (ATF6), a key chaperone of endoplasmic reticulum stress, as a functional downstream effector of PCDH20. By administering a selective ATF6 activator, the impairment of intestinal barrier integrity and dysregulation of CHOP/ß-catenin/p-p120-catenin pathway was reversed in Pcdh20-ablated mice with colitis and PCDH20-deficient colonic cell lines. CONCLUSIONS: PCDH20 is an essential factor in maintaining intestinal epithelial homeostasis and barrier integrity. Specifically, PCDH20 helps to protect against colitis by tightening adherens junctions through the ATF6/CHOP/ß-catenin/p-p120-catenin axis.

Nanodroplet-enhanced sonodynamic therapy potentiates immune checkpoint blockade for systemic suppression of triple-negative breast cancer.

Immune checkpoint blockade (ICB) has shown great promise in treating various advanced malignancies including triple-negative breast cancer (TNBC). However, only limited number of patients could benefit from it due to the low immune response rate caused by insufficient matured dendritic cells (DCs) and inadequate tumor infiltration of cytotoxic T lymphocytes (CTLs). Here, we report a combination therapeutic strategy which integrates STING pathway activation, hypoxia relief and sonodynamic therapy (SDT) with anti-PD-L1 therapy to improve the therapeutic outcome. The synthesized nanodroplet consisted of a O2-filled Perfluorohexane (PFH) core and a lipid membrane carrying sonosensitizer IR-780 and STING agonist Vadimezan (DMXAAs). It released O2 inside the hypoxic tumor tissue, thereby enhancing SDT which relied on O2 to generate cytotoxic reactive oxygen species (ROS). The co-delivered STING agonist DMXAAs promoted the maturation and tumor antigen cross-presenting of DCs for priming of CTLs. Moreover, SDT induced immunogenic cell death (ICD) of tumor to release abundant tumor-associated antigens, which increased tumor immunogenicity to promote tumor infiltration of CTLs. Consequently, not only a robust adaptive immune response was elicited but also the immunologically "cold" TNBC was turned "hot" to enable a potent anti-PD-L1 therapy. The nanodroplet demonstrated strong efficacy to systemically suppress TNBC growth and mimic distant tumor in vivo. STATEMENT OF SIGNIFICANCE: Only a limited number of triple-negative breast cancer (TNBC) patients can benefit from immune checkpoint blockade therapy due to its low immune response rate caused by insufficient matured DCs and inadequate tumor infiltration of cytotoxic T lymphocytes (CTLs). Interestingly, compelling evidence has shown that sonodynamic therapy (SDT) not only directly kills cancer cells but also elicits immunogenic cell death (ICD), which promotes tumor infiltration of cytotoxic T lymphocytes to transform an immunosuppressive "cold" tumor into a "hot" one. However, the hypoxic tumor microenvironment severely restricts the therapeutic efficiency of SDT, wherein, oxygen is indispensable in the process of ROS generation. Here, we report an O2-filled nanodroplet-enhanced sonodynamic therapy that significantly potentiated immune checkpoint blockade for systemic suppression of TNBC.

Ultrasound combined with biochemical parameters can be used to differentiate parathyroid carcinoma from benign tumors in patients with primary hyperparathyroidism.

BACKGROUND: Primary hyperparathyroidism (PHPT) results from excessive secretion of parathyroid hormone from parathyroid tumors. Differentiating parathyroid tumors can be challenging before operation. OBJECTIVES: To differentiate parathyroid carcinoma from benign tumors in patients with PHPT by the application of ultrasound and biochemical parameters. METHODS: This study is a retrospective study. The study enrolled 17 patients with parathyroid carcinoma (PC) and 57 patients with parathyroid adenoma (PA), confirmed by postoperative pathology, between September 2010 and July 2017. This study retrospectively compared the ultrasonic features of the tumors included echotexture, maximum lesion diameter, shape, margin, blood flow inside the mass, intralesional calcifications, cysts in the mass, and biochemical parameters included serum calcium, phosphorus, parathyroid hormone (PTH), alkaline phosphatase (ALP) levels, gender distribution and age of patients between patients with PC and those with PA. RESULTS: In the US images, the two groups showed significant differences in heterogeneity, the appearance of a taller-than-wide shape, irregular or lobulated margins, and intralesional calcifications (p < #x003C;< #x200A;0.05). However, no significant difference was found in echogenicity, maximum lesion diameter, blood flow, and cystic components of the mass (p > #x003E;> #x200A;0.05). The mean PTH levels were significantly different between the two groups (p < #x003C;< #x200A;0.05). The PC and PA patients did not differ significantly in terms of mean serum calcium, mean serum phosphorus, and mean ALP levels (p > #x003E;> #x200A;0.05). There were significant differences to distinguish PC from PA in calcifications in mass or/and taller-than-wide shape combine with PTH > #x003E;> #x200A;1000 pg/mL (p < #x003C;< #x200A;0.05). Significant difference existed in the age between the two groups (p < #x003C;< #x200A;0.001). No significant difference existed in the gender distribution between the two groups (p > #x003E;> #x200A;0.05). CONCLUSION: Ultrasound features especially intralesional calcifications and taller-than-wide shape combine with an extremely high serum PTH (>1000 pg/mL) are helpful in differentiating between benign and parathyroid tumors in patients with PHPT.

Fecal Microbiota Alterations Associated With Clinical and Endoscopic Response to Infliximab Therapy in Crohn's Disease.

BACKGROUND: Gut microbiota dysbiosis is associated with the occurrence and development of Crohn disease (CD). Currently, infliximab (IFX) is used more and more to treat CD; however, gut microbiota alterations during IFX therapy are variable and sometimes even contradictory. We longitudinally identified microbial changes during IFX therapy associated with the clinical and endoscopic response to IFX treatment in CD. METHODS: Fecal-associated microbiota was analyzed using 16S sequencing in 49 patients with active CD who were prospectively recruited at baseline, week 6, and week 30, respectively. Moreover, a model trained on the gut microbiota alterations at week 6 was developed to investigate their potential to predict clinical and endoscopic responses to IFX therapy at weeks 14 and 30. RESULTS: Characteristics of fecal microbiota composition in patients with CD after IFX treatment displayed an increased diversity and richness, a significant gain in short-chain fatty acid -producing bacteria, and a loss of pathogenic bacteria. Furthermore, certain functional profiles of Kyoto Encyclopedia of Genes and Genomes pathways were predictably altered during the treatment period. Increased proportions of Lachnospiraceae and Blautia were associated with IFX efficacy; the combined increase of these taxa at week 6 showed 83.4% and 84.2% accuracy in predicting clinical response at weeks 14 and 30, respectively, with a predictive value of 89.1% in predicting endoscopic response at week 30. CONCLUSIONS: We found that IFX diminished CD-related gut microbial dysbiosis by modifying microbiota composition and function. Specifically, increased Lachnospiraceae and Blautia at week 6 are associated with the clinical and endoscopic response to IFX, providing potentially predictive biomarkers for IFX treatment decision-making.

Thalidomide Combined With Azathioprine as Induction and Maintenance Therapy for Azathioprine-Refractory Crohn's Disease Patients.

The combination therapy of thalidomide and azathioprine (AZA) offers an alternative in clinical practice for Crohn's disease (CD) patients experiencing a loss of response to AZA monotherapy. However, little is known about the efficacy and safety of this combination therapy for patients with CD. This was a retrospective study of 122 consecutive CD patients who lost response to AZA therapy and had switched to a combination therapy of thalidomide and AZA. The primary outcomes were clinical response and clinical remission rates at week 24. Patients who had an initial response to combination therapy were continued on the treatment for remission maintenance. The secondary outcomes were the proportion of clinical relapse throughout maintenance. The Kaplan-Meier method was used to calculate cumulative rates, and Cox regression analysis was used for multivariate analysis. During induction, 80.3% (98/122) patients achieved clinical response within a median duration of 6.5 weeks, (interquartile range, 4.3-8.1 weeks). The rate of clinical remission at 24 weeks was 70.5%. During follow-up, 22.4% (22/98) of the patients that were maintained on combination therapy experienced clinical relapse. The proportions of patients in remission status at 12, 24, and 36 months were 85.1, 78.3, and 70.1%, respectively. Multivariate analysis revealed C-reactive protein >10 mg/L at disease relapse on AZA monotherapy [adjusted hazard ratio (HR), 4.72; 95% CI, 1.19-18.75, P = 0.027] and 6-thioguanine nucleotides level ≥235 pmol/8 × 108 erythrocytes at AZA monotherapy (adjusted HR, 5.32; 95% CI, 1.40-20.14, P = 0.014) were associated with disease relapse on combination therapy. The endoscopic remission rate was 63.6%. Mucosal healing was achieved in 23.6% of the patients. Both Crohn's Disease Endoscopic Index of Severity (13.4 ± 4.92 vs. 6.12 ± 5.24, P < 0.001) and Rutgeerts scores (3.23 ± 0.73 vs. 1.77 ± 1.59, P = 0.003) were significantly decreased with the use of combination therapy. Adverse events occurred in 62 (50.8%) patients, but only 13 (10.7%) necessitated therapy discontinuation. Thalidomide combined with AZA was effective in inducing clinical remission and sustaining long-term steroid-free remission in CD patients who lost response to AZA monotherapy.

Value of multimodality imaging in the diagnosis of breast lesions with calcification: A retrospective study.

PURPOSE: To assess the value of conventional ultrasound (US), contrast-enhanced ultrasound (CEUS) and mammography in the diagnosis of breast lesions with calcifications. METHODS: A total of 87 breast lesions with calcification were subjected to US, CEUS and mammography and divided into 3 groups: Group A (all cases), Group A1 (31 cases who underwent US and CEUS first followed by mammography), and Group A2 (56 cases who underwent mammography first followed by US and CEUS). A receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic efficacy of different methods in different groups. RESULTS: In Group A, the area under the ROC curve (AUROC) of CEUS were 0.937, which were significantly higher than that of mammography (p < 0.05). In Group A1, the AUROC of CEUS were 0.842, which were not significantly different from that of US and mammography (p > 0.05). In Group A2, the AUROC of CEUS were 0.987, which were significantly higher than that of mammography and US (p < 0.05). CONCLUSION: Based on the mammography results, the combination of US and CEUS might improve the diagnostic efficacy in breast lesions with calcification.

Systematic Review and Meta-analysis: Short-Chain Fatty Acid Characterization in Patients With Inflammatory Bowel Disease.

BACKGROUND: Alterations in gut microbiota and short-chain fatty acids (SCFAs) have been reported in inflammatory bowel disease (IBD), but the results are conflicting. The aim of this study was to perform a meta-analysis to explore the characterization of SCFAs in IBD patients and their potential role in the occurrence and development of IBD. METHODS: Case-control studies investigating SCFAs in IBD patients were identified from several English databases. The standardized mean difference (SMD) with 95% confidence interval (CI) was calculated using the random-effects model. RESULTS: The SMDs of acetate, valerate, and total SCFAs in ulcerative colitis (UC) patients were -0.51 (95% CI, -0.90 to -0.13), -0.65 (95% CI, -1.02 to -0.28), and -0.51 (95% CI, -0.95 to -0.07), respectively. The SMDs of acetate, propionate, and butyrate in patients with active UC were -1.74 (95% CI, -3.15 to -0.33), -2.42 (95% CI, -4.24 to -0.60), and -1.99 (95% CI, -3.39 to -0.60), respectively. However, the SMD of butyrate in UC patients in remission was 0.72 (95% CI, 0.34 to 1.11). In addition, the SMDs of acetate, butyrate, and valerate in Crohn's disease (CD) patients were -1.43 (95% CI, -2.81 to -0.04), -0.77 (95% CI, -1.39 to -0.14), and -0.75 (95% CI, -1.47 to -0.02), respectively. Finally, the SMDs of acetate, propionate, butyrate, valerate, and lactate in IBD patients were -2.19 (95% CI, -3.98 to -0.39), -1.64 (95% CI, -3.02 to -0.25), -1.98 (95% CI, -3.93 to -0.03), -0.55 (95% CI, -0.93 to -0.18), and 4.02 (95% CI, 1.44 to 6.61), respectively. CONCLUSIONS: There were alterations of SCFAs in IBD patients, and inconsistent SCFA alterations were found in CD and UC. More importantly, inverse SCFA alterations existed in patients with active UC and those in remission.

Patients with Gastric Polyps need Colonoscopy Screening at Younger Age: A Large Prospective Cross-Sectional Study in China.

Background To date, it is not clarified whether patients with gastric polyps without any alarming symptoms for colorectal neoplasia need colonoscopy screening. The objective of this study is to prospectively determine the association between gastric polyps and colorectal neoplasia. Methods A multicenter prospective cross-sectional study was performed from July 2012 to December 2014. We compared patients with and without gastric polyps for prevalence of colorectal adenomas. The odds ratios (OR) were computed by logistic regression analysis after multivariable adjustments. Results Totally 1546 patients were included, with 770 patients in the gastric polyp group and 776 in the age- and sex- matched control group. Patients with gastric polyps had greater odds of having any colorectal adenoma (adjusted OR=2.34, 95% confidence interval [CI]: 1.79 to 3.06, p<0.001) and advanced colorectal adenomas (adjusted OR=2.71, 95% CI: 1.74 to 4.23, p<0.001) than those without. The positive association between gastric polyps and colorectal adenomas remained significant in both women (OR=2.34, 95% CI: 1.66 to 3.29, p<0.001) and men (OR=1.87, 95% CI: 1.31 to 2.66, p=0.001). Patients over the age of 40 with gastric polyps had a higher prevalence of colorectal adenomas than those without (40-49yr: OR=1.81, 95% CI=1.02-3.21, p=0.04; 50-59yr: OR=1.88, 95% CI=1.26-2.81, p<0.001; 60-74yr: OR=2.62, 95% CI=1.73-3.98, p<0.001). Conclusions The presence of gastric polyps is significantly associated with a higher prevalence of colorectal adenomas, especially advanced colorectal adenomas. Colonoscopy might be considered in patients with gastric polyps, of any gender, and over the age of 40.

Relationship between carotid intima-media thickness and carotid artery stiffness assessed by ultrafast ultrasound imaging in patients with type 2 diabetes.

OBJECTIVES: To evaluate the relationship between carotid stiffness and carotid intima-media thickness (CIMT) in patients with type 2 diabetes (T2DM). MATERIALS AND METHODS: Carotid properties were evaluated in 317 consecutive subjects (98 volunteers for controls, 105 patients with normal CIMT for T2DM group 1, and 114 patients with thickened CIMT for T2DM group 2). The CIMT and carotid pulse wave velocity at the beginning (PWV-BS) and at the end of systole (PWV-ES) were measured. RESULTS: Apart from PWV-BS in T2DM group 1, CIMT and PWV-ES were significant higher in patients groups than those of in controls. In multiple regression analysis, diabetes was independently associated with PWV-ES and not with PWV-BS. Moreover, when adjusting for baseline covariates, only PWV-ES (odds ratio = 4.27, P < 0.001) distinguished carotid in T2DM group 1 from that of controls. Concerning the relationship between log(CIMT) and PWV-ES, when adjusting for baseline covariates, the association were still significant in controls and T2DM group 1, whereas it was no longer present in T2DM group 2 (P = 0.091). Additionally, the slope (ß) after adjustment for the PWV-ES to log(CIMT) was significantly steeper in T2DM group 1 than that of in controls (ß= 8.35 vs. 3.31, P < 0.01). CONCLUSIONS: The PWV-ES seem to be a better biomarker candidate than PWV-BS to assess the carotid stiffness in diabetic patients. Compared with controls, diabetic patients showed more advanced functional changes than morphological changes despite normal CIMT, whereas the relationship trend was not present when thickened CIMT emerged.

Upregulation of miR-665 promotes apoptosis and colitis in inflammatory bowel disease by repressing the endoplasmic reticulum stress components XBP1 and ORMDL3.

MicroRNAs are critical post-transcriptional regulators of gene expression and key mediators of pathophysiology of inflammatory bowel disease (IBD). This study is aimed to study the role of miR-665 in the progression of IBD. Real-time PCR analysis was used to determine miR-665 expression in 89 freshly isolated IBD samples and dextran sulfate sodium (DSS)-induced colonic mucosal tissues. The role of miR-665 in inducing apoptosis and colitis were examined by Annexin V, TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling) staining, colony formation in vitro and DSS-induced colitis mice model in vivo. Moreover, luciferase reporter assay, western blot analysis and microribonucleoprotein immunoprecipitation were performed to determine that miR-665 directly repressed XBP1 (X-box-binding protein-1) and ORMDL3 expression. Herein, our results revealed that miR-665 was markedly upregulated in active colitis. Gain-of-function and loss-of-function studies showed that ectopic expression of miR-665 promoted apoptosis under different inflammatory stimuli. Importantly, delivery of miR-665 mimic promoted, while injection of antagomiR-665 markedly impaired DSS-induced colitis in vivo. Mechanistically, we demonstrated that miR-665 induced apoptosis by inhibiting XBP1 and ORMDL3. Taken together, our findings reveal a new regulatory mechanism for ER stress signaling and suggest that miR-665 might be a potential target in IBD therapy.

Systematic review with meta-analysis: the efficacy and safety of stem cell therapy for Crohn's disease.

BACKGROUND AND AIMS: Stem cell therapy (SCT) for the treatment of Crohn's disease (CD) is still in its infancy, and whether SCT is associated with improved outcomes is unclear. We performed a meta-analysis to evaluate the efficacy and safety of patients receiving SCT. METHODS: Electronic databases were searched for studies that reported the use of stem cells for the treatment of patients with CD. Raw data from included studies were pooled for effect estimates. Subgroup analyses were performed for exploration of heterogeneity regarding all outcomes. RESULTS: We analyzed 21 studies comprising 514 patients with active CD. A random-effects meta-analysis of studies of SCT as systemic infusion showed 56% (95% confidence interval (CI) 33-76, n = 150) of patients achieved clinical response. Similarly, random-effects pooled rates of clinical or endoscopic remission were 46% (95% CI 25-69, n = 116) and 15% (95% CI 0-50, n = 48), respectively. A random-effects meta-analysis of all perianal CD studies showed that 57% (95% CI 44-69%, n = 251) of patients had healed fistula with SCT, with an odds ratio of 3.83 (95% CI 1.06-13.86, n = 121, P = 0.04) versus control. The pooled rate of clinical recurrence was high at 16% (95% CI 4-34, n = 101) with follow-up >12 months. The pooled rates of severe adverse events (SAEs) and SAEs related to SCT were 12% (95% CI 6-23, n = 378) and 8% (95% CI 3-18, n = 378), respectively. The Egger test suggests no publication bias existed for fistula healing (P = 0.36), but did for clinical response (P = 0.003). CONCLUSIONS: SCT seems potentially effective and may serve as an alternative treatment for refractory active CD. Toxicity will remain the most significant barrier to systemic SCT in patients with CD.