Tumor size and perineural invasion predict outcome of gastric high-grade neuroendocrine neoplasms.

A new subcategory, grade 3 neuroendocrine tumors, is incorporated into the grading system of pancreatic neuroendocrine neoplasms in the 2017 WHO classification in order to differentiate grade 3 neuroendocrine tumors from neuroendocrine carcinomas. The 2019 WHO classification extends the concept of grade 3 neuroendocrine tumors to gastrointestinal high-grade neuroendocrine neoplasms. However, there is still limited study focusing on the gastric grade 3 neuroendocrine tumors and gastric neuroendocrine carcinomas. We retrospectively enrolled 151 gastric high-grade neuroendocrine neoplasms patients, who underwent radical resection from January 2007 to December 2015. Clinicopathologic and prognostic features were studied. The Surveillance, Epidemiology, and End Results (SEER) database was used to verify the prognostic determinants found in the Zhongshan cohort. Neuroendocrine carcinomas showed a higher Ki67 index and higher mitotic count than grade 3 neuroendocrine tumors. We identified 109 (72.2%) patients with neuroendocrine carcinomas, 12 (7.9%) patients with grade 3 neuroendocrine tumors, and 30 (19.9%) patients with mixed neuroendocrine-non-neuroendocrine neoplasms. Although neuroendocrine carcinomas demonstrated higher Ki67 index (P = 0.004) and mitoses (P = 0.001) than grade 3 neuroendocrine tumors, their prognosis after radical resection did not demonstrate significant differences (P = 0.709). Tumor size, perineural invasion, and TNM stage were independent prognostic factors of gastric high-grade neuroendocrine neoplasms.

Imbalance of T-helper 1/T-helper 2 cytokines and impaired glucose tolerance among patient with acute coronary syndrome.

PURPOSE: The balance between T helper (Th) cells Th1- and Th2-related cytokines plays a key role in the clinical process of acute coronary syndrome (ACS) and type 2 diabetes mellitus (T2DM) or impaired glucose tolerance (IGT). The objective of this study was to assess the status of Th1/Th2 cytokines in patients with ACS and T2D or IGT. METHODS: A total of 201 ACS patients were enrolled in the study. All ACS patients were divided into three groups: Group I-patients with normal glucose tolerance (NGT), Group II-patients with IGT and Group III-patients with T2D. We measured circulating Th1/Th2-type cytokines (interleukin [IL]-4, IL-13, interferon-gamma [IFN-γ], and tumor-necrosis factor-alpha [TNF-α]) using enzyme-linked immunosorbent assay and calculated the ratio of Th1/Th2. RESULTS: Significant elevations in serum levels of IL-4, IL-13, IFN-γ, and TNF-α were found in ACS-T2D and ACS-IGT groups compared to that in both ACS-NGT group and healthy individuals. Higher serum levels of IL-4, IL-13, and TNF-α were found in ACS-NGT group than that in the control group. Furthermore, IL-4 and IFN-γ concentrations were significantly higher in ACS-T2D patients than in ACS-IGT patients. IFN-γ/IL-4, IFN-γ/IL-13, and TNF-α/IL-4 ratios as markers of Th1/Th2 ratio were significantly higher for the ACS-T2D group and ACS-IGT group as compared to that in the ACS-NGT group and control group (P < 0.05). CONCLUSION: Shifts in the balance of Th1/Th2 toward a predominance of Th1 may represent more severe inflammatory status in ACS patients with type T2D or IGT.

De novo SOX10 Nonsense Mutation in a Patient with Kallmann Syndrome, Deafness, Iris Hypopigmentation, and Hyperthyroidism.

Kallmann syndrome (KS) is a clinically and genetically heterogeneous disorder characterized by hypogonadotropic hypogonadism and olfactory dysfunction. Recently, mutations in SOX10, a well-known causative gene of Waardenburg syndrome (WS), have been identified in a few KS patients with additional developmental defects including hearing loss. However, the understanding of SOX10 mutation associates with KS and other clinical consequences remains fragmentary. A 30-year-old Chinese male patient presented with no pubertal sex development when he was at the age of twelve years. Additionally, he showed anosmia, sensory deafness, and blue irises. Last year, he developed clinical symptoms of hyperthyroidism with a fast heartbeat, heat intolerance and weight loss. Blood examinations revealed low levels of FSH, LH, and testosterone. Thyroid function showed high levels of FT3, FT4 and extremely low level of TSH. Molecular analysis detected a de novo (c.565G>T/p.E189X) mutation in SOX10, which has previously been reported in a patient with WS4 (WS with Hirschsprung). The mutation was predicted to be probably damaging. These results highlight the significance of SOX10 haploinsufficiency as a genetic cause of KS. Importantly, our result implies that the same SOX10 mutation can underlie both typical KS and WS, while the correlation between SOX10 and hyperthyroidism still needs to be clarified in the future.

[Van Wyk-Grumbach syndrome: A case report and literature review].

Van Wyk-Grumbach syndrome (VWGS) is a rare complication of prolonged untreated juvenile hypothyroidism characterized by precocious puberty and enlarged multicystic ovaries. A 13-year-old girl visited our outpatient clinic due to menstrual irregularities. She had precocious puberty, pituitary hyperplasia and multiple cystic ovaries in addition to clinical signs of severe congenital hypothyroidism. After the initiation of L-thyroxine therapy, the symptoms were alleviated in a short time. This rare syndrome is easy to be misdiagnosed as pituitary and ovarian tumor. High degree of suspicion and timely diagnosis can prevent unnecessary surgical procedures because the symptoms can be reversed with thyroid hormone supplementation.

Efficacy and Safety of Endoscopic Submucosal Dissection for Colorectal Carcinoids.

BACKGROUND & AIMS: Although endoscopic submucosal dissection (ESD) of colorectal carcinoids is increasing, little is known about long-term outcomes of patients. We investigated the efficacy and safety of ESD of colorectal carcinoids and evaluated long-term outcomes, including local recurrence and metastasis. METHODS: We performed a retrospective analysis of data collected from 239 consecutive patients with colorectal carcinoids <20 mm who underwent endoscopic ultrasonography (to evaluate the size of tumor and the depth of invasion), followed by ESD from January 2007 through October 2012 at the Zhongshan Hospital of Fudan University. Histology and patient data were collected during a median follow-up period of 52 months (range, 25-94 months) to determine tumor stage and type, completeness of resection, complications, tumor recurrence, and distant metastasis. RESULTS: En bloc resection was achieved for all of the 239 treated lesions; tumor tissues were completely resected for 216 of the lesions (90.38%). Eight patients had ESD-related complications (3.35%). As more ESDs were performed by endoscopists, the rate of complete tumor resection increased, and the rate of complications decreased. ESD of carcinoids in colon increased the risk of non-R0 resection and the rate of complications. During the follow-up period, all patients remained free from local recurrence. However, distant metastases were detected in 6 patients (2.51%); lymphovascular invasion was a risk factor for metastasis. CONCLUSIONS: ESD is effective for the resection of rectal carcinoids <20 mm and causes complications in less than 4% of patients. ESD for colonic carcinoids is feasible but associated with a higher non-R0 resection rate and a trend toward higher complications risk. Tumor features and stage determine risk for distant metastasis, so long-term follow-up is essential.

miR-125a-3p and miR-483-5p promote adipogenesis via suppressing the RhoA/ROCK1/ERK1/2 pathway in multiple symmetric lipomatosis.

Multiple symmetric lipomatosis (MSL) is a rare disease characterized by symmetric and abnormal distribution of subcutaneous adipose tissue (SAT); however, the etiology is largely unknown. We report here that miR-125a-3p and miR-483-5p are upregulated in the SAT of MSL patients, promoting adipogenesis through suppressing the RhoA/ROCK1/ERK1/2 pathway. TaqMan microRNA (miR) array analysis revealed that 18 miRs were upregulated in the SAT of MSL patients. Transfection of human adipose-derived mesenchymal stem cells (hADSCs) with the individual agomirs of these 18 miRs showed that miR-125a-3p and miR-483-5p significantly promoted adipogenesis. A dual-luciferase assay showed that RhoA and ERK1 were the targets of miR-125a-3p and miR-483-5p, respectively. Moreover, transfection of hADSCs with mimics of miR-125a-3p and miR-483-5p resulted in a pronounced decrease of ERK1/2 phosphorylation in the nucleus; conversely, transfection of hADSCs with inhibitors of miR-125a-3p and miR-483-5p led to a significant increase of ERK1/2 phosphorylation in the nucleus. Most importantly, we found that miR-125a-3p and miR-483-5p promoted de novo adipose tissue formation in nude mice. These results demonstrated that miR-125a-3p and miR-483-5p coordinately promoted adipogenesis through suppressing the RhoA/ROCK1/ERK1/2 pathway. Our findings may provide novel strategies for the management and treatment of MSL or obesity.

MR imaging of primary hepatic neuroendocrine neoplasm and metastatic hepatic neuroendocrine neoplasm: a comparative study.

PURPOSE: To investigate MR characteristics in differentiating primary hepatic neuroendocrine neoplasm (PHNEN) from metastatic hepatic neuroendocrine neoplasm (MHNEN). MATERIALS AND METHODS: Thirty-nine patients with histopathologically proven liver neuroendocrine neoplasm were retrospectively analyzed. The morphological and MR signal features on T1, T2-weighted, dynamic-enhanced, and diffusion-weighted imaging were evaluated and compared between the PHNEN group (n = 12) and the MHNEN group (n = 27). RESULTS: The tumor size (P = 0.0084), number (P = 0.017), distribution (P = 0.000), contour (P = 0.041), the presence of capsule-like enhancement (P = 0.034), tumor homogeneity (P = 0.018) and the apparent diffusion coefficient (ADC) values (P = 0.024) were different between PHNENs and MHNENs. Large, solitary or massive-growing nodules with lobulated or irregular contour, capsule-like enhancement, heterogeneous signals or lower ADC values supported the diagnosis of PHNEN compared with MHNEN. ROC analysis demonstrated an area under the curve of 0.746, when the optimal cutoff value of 1.049 × 10(-3) mm(2)/s was used, a sensitivity of 63.0 % (95 % CI, 44.2-79.4 %), a specitivity of 80.0 % (95 % CI, 50.1-96.4 %), a positive predictive value of 89.5 % (95 % CI, 70.9-98.2 %), and a negative predictive value of 44.4 % (95 % CI, 23.4-67.0 %) can be achieved. CONCLUSIONS: MRI may provide valuable information for the diagnosis and differential diagnosis of PHNENs and MHNENs.

A novel mutation of thyroid hormone receptor ß in exon 10 in a case of thyroid hormone-resistant non-Hodgkin's lymphoma of the thyroid.

Only a few previous studies have demonstrated an association between resistance to thyroid hormone (RTH) and thyroid cancer. The current study presents the case of a 67-year-old female who was referred to the Third Xiangya Hospital of Central South University with an enlargement of the neck that had grown gradually over two years and subsequently, rapidly enlarged over the two months prior to admission, alongside a slight sensation of shortness of breath. Laboratory data revealed a significantly increased level of thyroid-stimulating hormone (TSH), total triiodothyronine, total thyroxine, free triiodothyronine, free thyroxine, thyroprotein and thyroglobulin antibody; however, the levels of thyroperoxidase and TSH receptor antibody were within the normal ranges. A thyroid hormone suppression test revealed a TSH reduction of 32%, Magnetic resonance imaging of the pituitary gland was negative for abnormalities. The patient's thyroid pathology revealed a non-Hodgkin's lymphoma of the thyroid. CHOP + nimustine chemotherapy significantly reduced the clinical symptoms. The genetic analysis revealed a novel point mutation of the thyroid hormone receptor ß (THRB) gene in exon 10 (g1680 G to A) in the 3'-untranslated region of the patient. To the best of our knowledge, this is the first case report of RTH with thyroid non-Hodgkin's lymphoma, which involved a mutation (g1680 G to A) in exon 10 of THRB.

Overexpression of Insig-1 protects ß cell against glucolipotoxicity via SREBP-1c.

BACKGROUND: High glucose induced lipid synthesis leads to ß cell glucolipotoxicity. Sterol regulatory element binding protein-1c (SREBP-1c) is reported to be partially involved in this process. Insulin induced gene-1 (Insig-1) is an important upstream regulator of Insig-1-SREBPs cleavage activating protein (SCAP)-SREBP-1c pathway. Insig-1 effectively blocks the transcription of SREBP-1c, preventing the activation of the genes for lipid biosynthesis. In this study, we aimed to investigate whether Insig-1 protects ß cells against glucolipotoxicity. METHODS: An Insig-1 stable cell line was generated by overexpression of Insig-1 in INS-1 cells. The expression of Insig-1 was evaluated by RT-PCR and Western blotting, then, cells were then treated with standard (11.2 mM) or high (25.0 mM) glucose for 0 h, 24 h and 72 h. Cell viability, apoptosis, glucose stimulated insulin secretion (GSIS), lipid metabolism and mRNA expression of insulin secretion relevant genes such as IRS-2, PDX-1, GLUT-2, Insulin and UCP-2 were evaluated. RESULTS: We found that Insig-1 suppressed the high glucose induced SREBP-1c mRNA and protein expression. Our results also showed that Insig-1 overexpression protected ß cells from ER stress-induced apoptosis by regulating the proteins expressed in the IRE1α pathway, such as p-IRE1α, p-JNK, CHOP and BCL-2. In addition, Insig-1 up-regulated the expression of IRS-2, PDX-1, GLUT-2 and Insulin, down-regulated the expression of UCP-2 and improved glucose stimulated insulin secretion (GSIS). Finally, we found that Insig-1 inhibited the lipid accumulation and free fatty acid (FFA) synthesis in a time-dependent manner. CONCLUSIONS: There results suggest that Insig-1 may play a critical role in protecting ß cells against glucolipotoxicity by regulating the expression of SREBP-1c.

Multiple symmetric lipomatosis: substantial subcutaneous adipose tissue accumulation did not induce glucose and lipid metabolism dysfunction.

OBJECTIVE: To study whether substantial subcutaneous adipose tissue (SCAT) can induce glucose and lipid metabolism dysfunction and possible underlying mechanisms. METHODS: We report a male patient with multiple symmetrical lipomatosis (MSL) suffering from increased adipose tissue accumulation in abdomen and back for 7 years, accompanied by the gradual expansion of excess adipose tissue to the nuchal region, upper thorax, upper arms and shoulders. Four obese male adults of similar age and body mass index were chosen as controls (only 4 subjects consented to blood and tissue sampling).Blood samples were collected before anesthesia in the early morning after overnight fasting, and tissue samples from all subjects and the patient were obtained under general anesthesia. Glucose tolerance, insulin resistance in the oral glucose tolerance test and insulin-releasing test were studied. A pathologic examination was made and expression of SCAT-related genes was determined. RESULTS: Although adipose tissue mainly accumulated in SCAT, the patient had no impaired glucose tolerance, insulin resistance and dyslipidemia. Importantly, the circulating adiponectin concentration was higher than in the control group (50.3 +/- 3.2 vs. 28.4 +/- 2.2 microg/ml, p < 0.05). Accordingly, adiponectin and leptin mRNA expression in SCAT was higher than in the control group (1.83 and 3.75 times, p < 0.05) but TNF-alpha and IL-6 mRNA levels were lower (decreased by 79 and 45%, p < 0.05). Furthermore, pathologically, adipocyte size in the patient's SCAT was smaller than in the control group (66.2 +/- 6.1 vs. 78.9 +/- 6.6 and 98.6 +/- 12.8 microm in SCAT and omentum adipose tissue, respectively, p < 0.05). CONCLUSION: In spite of the patient's SCAT accumulation, glucose and lipid metabolism dysfunction was absent. The mechanism may involve the interaction of different factors, including the subcutaneous formation of small adipocytes, the secretion of protective adipokines such as adiponectin and anti-inflammatory effects of SCAT.

[Effect of glucagon like peptide-1 on proliferation and differentiation of endothelial progenitor cells and its mechanism].

OBJECTIVE: To investigate the effect and mechanism of glucagon like peptide 1(GLP-1)on the proliferation and differentiation of endothelial progenitor cells(EPCs)derived from the peripheral blood. METHODS: Mononuclear cells were isolated from human peripheral blood by density gradient centrifugation. After 7 days of culture,attached cells were stimulated with different cultures of 0.2% BSA,and GLP-1(1,10,and 20 nmol/L). Laser scanning confocal microscope was used to determine the EPCs from human peripheral blood.The activity of EPCs was observed under reverse microscope. MTT was used to determine the proliferation of EPCs. The expression of KDR,Flt-1,VE-cadherin,and eNOS mRNA was detected by RT-PCR.The concentration of serum VEGF was detected by ELISA. The expression of VEGF protein was detected by immunohistochemical SP method. The EPCs cultured in GLP-1 were intervened by VEGFmAb. RESULTS: EPCs was proliferated more in the GLP-1 group(1,10,and 20 nmol/L) than in the control group (P<0.05 or P<0.01). The expression of KDR,FLT-1,VE-cadherin,eNOS mRNA and VEGF protein was higher than that in the control group(P<0.05 or P<0.01). VEGFmAb(100 ng/mL)down-regulated the expression of KDR,Flt-1,VE-cadherin,and eNOS mRNA. CONCLUSION: GLP-1 can promote the proliferation and differentiation of EPCs derived from the peripheral blood by up-regulating VEGF autocrine.

[Expression of hCTLA4-Ig mediated by adeno-associated virus in porcine islets and their biological activity].

OBJECTIVE: To evaluate the expression of hCTLA4-Ig and their biological function in newborn porcine islets (NPIs) transfected with AAV-hCTLA4-Ig. METHODS: Cultured NPIs were transfected with AAV-hCTLA4-Ig. The expression of CTLA4-Ig in these NPIs was assayed by RT-PCR and immunocytochemistry. The levels of IL-2, IFN-gamma, and TNF-alpha in the culture medium were assayed by ELISA after these cells the co-cultured with human. The response of glucose-stimulated insulin secretion was observed in the transgene group and the control group. RESULTS: The expressions of CTLA4-Ig mRNA and protein were detected in the transgene group. The levels of cytokines were obviously lower in the transgene group than those in the control group (P<0.01). There was no significant difference in the response of glucose-stimulated insulin release between the transgene group and the control group (P>0.05). CONCLUSION: AAV mediated hCTLA4-Ig expression in NPIs could inhibit T lymphocyte to produce cytokines, while the endocrine functions of the NPIs were not significantly affected.