Gastric neuroendocrine neoplasms type 1: A systematic review and meta-analysis

BACKGROUND To date, the histopathological parameters predicting the risk of lymph node (LN) metastases and local recurrence, associated mortality and appropriateness of endoscopic or surgical resection in patients with gastric neuroendocrine neoplasms type 1 (GNENs1) have not been fully elucidated. AIM To determine the rate of LN metastases and its impact in survival in patients with GNEN1 in relation to certain clinico-pathological parameters. METHODS The PubMed, EMBASE, Cochrane Library, Web of Science and Scopus databases were searched through January 2019. The quality of the included studies and risk of bias were assessed using the Newcastle-Ottawa Scale (NOS) in accordance with the Cochrane guidelines. A random effects model and pooled odds ratios (OR) with 95%CI were applied for the quantitative meta-analysis. RESULTS We screened 2933 articles. Thirteen studies with 769 unique patients with GNEN1 were included. Overall, the rate of metastasis to locoregional LNs was 3.3%(25/769). The rate of LN metastases with a cut-off size of 10 mm was 15.3% for lesions > 10 mm (vs 0.8% for lesions < 10 mm) with a random-effects OR of 10.5 (95%CI: 1.4 -80.8;heterogeneity: P = 0.126;I2 = 47.5%). Invasion of the muscularis propria was identified as a predictor for LN metastases (OR: 17.2;95%CI: 1.8-161.1;heterogeneity: P = 0.165;I2 = 44.5%), whereas grade was not clearly associated with LN metastases (OR: 2;95%CI: 0.3-11.6;heterogeneity: P = 0.304;I2 = 17.4%). With regard to GNEN1 local recurrence, scarce data were available. The 5-year disease-specific survival for patients with and without LN metastases was 100% in most available studies irrespective of the type of intervention. Surgical resection was linked to a lower risk of recurrence (OR: 0.3;95%CI: 0.1-1.1;heterogeneity: P = 0.173;I2 = 31.9%). The reported complication rates of endoscopic and surgical intervention were 0.6 and 3.8%, respectively. CONCLUSION This meta-analysis confirms that tumor size ≥ 10 mm and invasion of the muscularis propria are linked to a higher risk of LN metastases in patients with GNEN1. Overall, the metastatic propensity of GNEN1 is low with favorable 5- year disease-specific survival rates reported;hence, no clear evidence of the prognostic value of LN positivity is available. Additionally, there is a lack of evidence supporting the prediction of local recurrence in GNEN1, even if surgery was more often a definitive treatment.

Histidine decarboxylase and urinary methylimidazoleacetic acid in gastric neuroendocrine cells and tumours

AIM: To study histidine decarboxylase(HDC) expression in normal and neoplastic gastric neuroendocrine cells in relationship to the main histamine metabolite. METHODS: Control tissues from fundus(n = 3) and corpus(n = 3) mucosa of six patients undergoing operations for gastric adenocarcinoma, biopsy and/or gastric surgical specimens from 64 patients with primary gastric neuroendocrine tumours(GNETs), as well as metastases from 22 of these patients, were investigated using conventional immunohistochemistry and double immunofluorescence with commercial antibodies vs vesicular monoamine transporter 2(VMAT-2), HDC and ghrelin. The urinary excretion of the main histamine metabolite methylimidazoleacetic acid(U-Me Im AA) was determined using highperformance liquid chromatography in 27 of the 64 patients.RESULTS: In the gastric mucosa of the control tissues, co-localization studies identified neuroendocrine cells that showed immunoreactivity only to VMAT-2 and others with reactivity only to HDC. A third cellpopulation co-expressed both antigens. There was no co-expression of HDC and ghrelin. Similar results were obtained in the foci of neuroendocrine cell hyperplasia associated with chronic atrophic gastritis type A and also in the tumours. The relative incidence of the three aforementioned markers varied in the tumours that were examined using conventional immunohistochemistry. All of these GNETs revealed both VMAT-2 and HDC immunoreactivity, and their metastases showed an immunohistochemical pattern and frequency similar to that of their primary tumours. In four patients, increased U-Me Im AA excretion was detected, but only two of the patients exhibited related endocrine symptoms. CONCLUSION: Human enterochromaffin-like cells appear to partially co-express VMAT-2 and HDC. Coexpression of VMAT-2 and HDC might be required for increased histamine production in patients with GNETs.

A Toxicological Assessment of Endocrine Disrupting Chemicals Found in the BMW (Border, Midland and Western) Region of Ireland

A battery of tests was established to determine the oestrogenic, mutagenic and genotoxic potential of two categories of endocrine disrupting chemicals (EDCs), phthalates and alkylphenols. Diisononylphthalate (DINP), diethylhexylphthalate (DEHP), dibutylphthalate (DBP), diisododecylphthalate (DIDP) and 4-nonylphenol (4-NP) were oestrogenic in the yeast estrogen screen (YES) assay and potently oestrogenic in the MVLN and E-SCREEN assays at environmentally relevant concentrations. DINP and 4-NP were mutagenic in the Ames assay and also induced significant levels of unscheduled DNA synthesis and DNA strand breakage. Significant induction in the percentage of cells containing micronuclei was observed after treatment with DINP, DEHP and 4-NP. In addition, sewage effluents from sewage treatment plants (STPs) in the Border, Midlands and Western (BMW) region of Ireland were significantly oestrogenic in the YES assay. Moreover, analysis of levels of phthalates and alkylphenol identified in Irish rivers receiving treated effluent showed potent oestrogenicity in the YES assay. The proliferative and genotoxic ability of the phthalates and alkylphenol, and the oestrogenicity of the treated effluents reported here, is significant as these EDCs and EDCs within the effluent may play a role in the etiology of human abnormalities.

Screening for Genotoxicity and Oestrogenicity of Endocrine Disrupting Chemicals <i>in Vitro</i>

A diverse range of endocrine disrupting chemicals (EDCs) was examined, using an in vitro test system, for critical events required for the onset of carcinogenesis in vivo. The initiation stage of carcinogenesis is a genotoxic process. 4-Octylphenol (alkylphenol), bisphenol A (plasticiser), coumestrol and genistein (phytoestrogens), 2,4-dichlorophe- noxyacetic acid and toxaphene (pesticides) and ethinylestradiol (synthetic hormone) were investigated for potential mutagencicity, DNA strand breakage, clastogenicity and DNA repair. Significant induction in the percentage of cells containing micronuclei was observed for all the EDCs. Toxaphene and coumestrol were mutagenic in the Ames assay. They also induced significant levels of unscheduled DNA synthesis and DNA strand breakage. Bisphenol A induced low level DNA strand breakage in HepG2 cells in the comet assay. The EDCs, with the exception of toxaphene, induced transcriptional activation in the yeast estrogen screen (YES) assay. They were potently oestrogenic in the mammalian based MVLN (transactivation) and E-SCREEN (proliferation) assays. This report on the transactivational, proliferative and genotoxic ability of the EDCs suggests that these chemicals may play a role in the etiology of male and female reproductive cancers.

A Case of Ectopic Growth Hormone Releasing Hormone (GHRH) from Pancreatic Neuroendocrine Tumor Resistant to Therapy

Introduction: Ectopic secretion of GHRH is a rare cause of acromegaly. However, its recognition is clinically important because different therapeutic approaches are required. Case Presentation: We present a challenging case of acromegaly secondary to ectopic GHRH secretion from pancreatic neuroendocrine tumor in a 52-year-old female. The patient is treated with different modalities which include pegvisomant in an attempt to control the stimulated GH-axis considering the limited data about its use in treatment of ectopic acromegaly. Conclusion: GHRH-secreting tumor is a rare cause of acromegaly. Surgical resection of the tumor is the therapy of choice whenever possible. However, further studies are warranted for unresectable tumor or resistant cases.

Advanced small-bowel well-differentiated neuroendocrine tumours:An international survey of practice on 3rd-line treatment

BACKGROUND Somatostatin analogues are an established first-line therapy for well differentiated small bowel neuroendocrine tumours(Wd-SBNETs),while and peptide receptor radionuclide therapy(PRRT)is frequently used as a second-line therapy.Adequate treatment selection of third-line treatment remains challenging due to the limited prospective data currently available on the best therapeutic sequence.AIM To understand current practice and rationale for decision-making by physicians in the 3rd-line setting by building an online survey.METHODS Weighted average(WA)of likelihood of usage between responders(1 very unlikely;4 very likely)was used to reflect the relevance of factors explored.RESULTS Replies from representatives of 28 centers were received(5/8/2020-21/9/2020);medical oncologist(53.6%),gastroenterologist(17.9%);United Kingdom(21.4%),Spain(17.9%),Italy(14.3%).Majority from European Neuroendocrine Tumor Society(ENETS)Centres of Excellence(57.1%),who followed ENETS guidelines(82.1%).Generally speaking,3rd-line treatment for Wd-SBNETs was:everolimus(EVE)(66.7%),PRRT(18.5%),liver embolization(LE)(7.4%)and interferon-alpha(IFN)(3.7%);chemotherapy(0%);decision was based on clinical trial data(59.3%),or personal experience(22.2%).EVE was most likely used if Ki-67<10%(WA 3.27/4)or age<70 years(WA 3.23/4),in the 3rd-line setting(WA 3.23/4);regardless of presence/absence of carcinoid syndrome(CS),rate of progression or extent of disease.Chemotherapy was mainly utilised only if rapid progression(within 6 mo)(WA 3.35/4),Ki-6710%-20%(WA 2.77/4),negative somatostatin receptor imaging(WA 2.65/4)or high tumour burden(WA 2.77/4);temozolomide or streptozocin was used with capecitabine or 5-fluorouracil(5-FU)(57.7%),FOLFOX(5-FU combined with oxaliplatin)(23.1%).LE was selected if presence of CS(WA 3.24/4)or Ki-67<10%(WA 2.8/4),after progression to other treatments(WA 2.8/4).IFN was rarely used(WA 1.3/4).CONCLUSION Everolimus was the most frequently used therapeutic option in the third-line setting.The most important factors for decision-making included Ki-67,rate of progression,functionality and tumour burden;since this decision is based on multiple factors,it highlights the need for a multidisciplinary assessment.

THE ENDOCRINE CELLS OF EXTRATUMORAL MUCOSA IN RELATION TO THE CARCINOMA IN STOMACH

One hundred and sixty-one surgically resected gastric carcinomas and 5 stomachs obtained at necropsy were evaluated using anti chromogranin A (CgA). CgA-Positive cells were found in 55 of 161 gastric carcinoma. Endocrine cells (EC) of the 55 cases of rumors and extratumoral mucosa and 5 normal gastric mucosa were distinguished by immunoreastive gastrin (CAST), somatostatin (SS), serotonin (SERO), calcitonin (CT), ACTH, human chorionic gonadotropin (HCG) , glucagon (GLU) , pancreatic polypeptide (PP), bombesin (BOM). Each type EC in extratumoral mucosa was quantitated by Image analyser. TWO variants of changes of EC were identified on the basis of presence or absence of associated antral atrophy. In the group of antral atrophy, amount of G cells decreases than normal control (58. 7mm2, P<0. 001); D cells and BOM-positive cell also decrease; GLU-positive cells distributing in glands of intestinal metaplasia increase (18. 6/mm2, P<0. 001) in antral mucosa. There is not obvious change in the average thickness of fundic mucosa (1. 42mm, P>0. 05). Intestinal type carcinoma was more found in this group. G cell hyperplasia was observed in nontrophic antral extratumorel mucosa (211/mm2, P< 0. 001). G cell and D cell is in a ratio of about 14 to 1, however It is about 7. 6 to 1 in normal gastric antrum. BOM-positive cells are hyperplasia. The average thickness of fundic mucosa was found to be increased (1. 92mm, P<0.05). Diffuse type carcinoma was more found in this group. PP, ACTH, HCG-positive cells were discovered in the two groups. It suggests that endocrine substances may act as promoters of tumor growth and that different kinds of hormones may play a effect on different type of gastric carcinoma.

Management of incidentally discovered appendiceal neuroendocrine tumors after an appendicectomy

Appendiceal neuroendocrine tumors(aNETs)are an uncommon neoplasm that is relatively indolent in most cases.They are typically diagnosed in younger patients than other neuroendocrine tumors and are often an incidental finding after an appendectomy.Although there are numerous clinical practice guidelines on management of a NETs,there is continues to be a dearth of evidence on optimal treatment.Management of these tumors is stratified according to risk of locoregional and distant metastasis.However,there is a lack of consensus regarding tumors that measure 1-2 cm.In these cases,some histopathological features such as size,tumor grade,presence of lymphovascular invasion,or mesoappendix infiltration must also be considered.Computed tomography or magnetic resonance imaging scans are recommended for evaluating the presence of additional disease,except in the case of tumors smaller than 1 cm without additional risk factors.Somatostatin receptor scintigraphy or positron emission tomography with computed tomography should be considered in cases with suspected residual or distant disease.The main point of controversy is the indication for performing a completion right hemicolectomy after an initial appendectomy,based on the risk of lymph node metastases.The main factor considered is tumor size and 2 cm is the most common threshold for indicating a colectomy.Other factors such as mesoappendix infiltration,lymphovascular invasion,or tumor grade may also be considered.On the other hand,potential complications,and decreased quality of life after a hemicolectomy as well as the lack of evidence on benefits in terms of survival must be taken into consideration.In this review,we present data regarding the current indications,outcomes,and benefits of a colectomy.

Acute coronary syndrome: a rare case of multiple endocrine neoplasia syndromes with pheochromocytoma and medullary thyroid carcinoma

Pheochromocytoma is a tumor arising from neuroectodermal chromaffin tissues in the adrenal gland or extra-adrenal paraganglia(paragangliomas). The prevalence of the tumor is 0.1%-0.6% in the hypertensive population, of which 10%-20% are malignant. Pheochromocytoma produces, stores, and secretes catecholamines, as well as leads to hypertensive crisis, arrhythmia, angina, and acute myocardial infarction without coronary artery diseases. We report a case of acute coronary syndrome(ACS) with a final diagnosis of multiple endocrine neoplasia with pheochromocytoma and medullary thyroid carcinoma(MTC).

A NOVEL Ser73Gly VARIATION OF SUCCINATE DEHYDROGENASE,SUBUNIT D AND A Cys634Gly MUTATION IN Ret PROTO-ONCOGENE OBSERVED IN A CHINESE MULTIPLE ENDOCRINE NEOPLASIA TYPE 2A PATIENT

Multiple endocrine neoplasia type 2A(MEN2A)is an autosomal dominant cancer syndrome that is characterized by medullary thyroid carcinoma(MTC),pheochromocytoma(50%-60% of cases),and hyperplasia of the parathyroid glands(20%-30% of cases).MEN2A comprises a heterogeneous group of neoplastic disorders that most commonly have a single missense substitution of the Ret proto-oncogene(RET)involving exons 10 and 11.Here,we reported a novel case of MEN2A associated with two variations in two distinct genes,Cys634Gly in RET and a rare Ser73Gly substitution in succinate dehydrogenase,subunit D(SDHD).Because the patient presented with medullary thyroid carcinoma and pheochromocytoma but without parathyroid gland involvement,we speculated that this clinical feature could be correlated with the two substitutions.This is the first report of a MEN2A case involving two different changes one in the RET gene and the other in the SDHD gene.

Virilizing Ovarian Leydig Cell Tumor with Multiple Non-Functional Endocrine Neoplasias: A Case Report

Ovarian Leydig cell tumor, a sub-type of ovarian steroid cell tumor, accounts for less than 0.1% of all ovarian tumors. It can affect women of any age group but is most common in postmenopausal women. We here report a case of virilizing ovarian Leydig cell tumor with multiple non-functional endocrine neoplasias (pituitary and adrenal adenomas) in a 48-year-old woman. She first presented with sub-abdominal pain and hirsutism since menopause three years ago. Subsequently, she had slight facial acne, voice deepening, breast atrophy, and a prominent Adam’s apple. Her hormone profile showed an elevated level of testosterone, high free androgen index, low levels of luteinizing hormone and follicle stimulating hormone, and normal levels of random cortisol, androstenedione, 17-hydroxyprogesterone and dehydroepiandrosterone sulfate. A pelvic enhanced magnetic resonance imaging (MRI) scan showed nodules in the right ovary, and a pituitary enhanced MRI revealed a microadenoma. An enhanced computerized tomography scan of the adrenal gland revealed left adrenal nodules, possibly adenomas. After a right cystectomy and right fallopian tube resection, her testosterone level declined to 0.38 nmol/L and the symptoms associated with hyperandrogenism improved. This is a rare case of virilizing ovarian Leydig cell tumor with multiple non-functional endocrine neoplasias. We believe our findings will be helpful in the clinical diagnosis and treatment of hyperandrogenism.

Surgical treatment of non-functioning pancreatic neuroendocrine tumors:current controversies and challenges

There has been a rising trend in the incidence and prevalence of non-functioning pancreatic neuroendocrine tumors(NFPanNETs).While a significant number of the newly diagnosed NFPanNETs are asymptomatic,a majority of patients will present with liver metastasis(LM)at the time of diagnosis.Surgical resection remains the only curative treatment,especially for localized NFPanNETs.While a majority of small NFPanNETs are indolent,some are not.This heterogeneity in tumor biology presents the surgeon with the unique challenge of determining which patient will benefit from surgery,given the morbidity of pancreatic surgery.There has been a recent push for a more aggressive approach to the care of these patients,given the emergence of data supporting such measures.However,the risk of over or under treatment has generated immense debate amongst experts in the field.The heterogeneity of current practice guidelines and institutional practices around the world is a reflection of the disparate opinion on the management of NFPanNET.In this review,we set out to examine the evidence regarding some of the most controversial and challenging aspects of the surgical treatment of NFPanNET.We evaluate the following questions;should patients with small NFPanNETs≤2 cm in size be resected;should patients with metastatic NFPanNETs undergo surgical debulking,and should there be resection of the primary tumor in the setting of non-resectable metastatic disease?Although there are currently no Level 1 data to answer these questions conclusively,we believe that the current literature supports a more aggressive approach to the management of NFPanNET.

Chemosensitization role of endocrine hormones in cancer chemotherapy

The endocrine changes of cancer patients on initial confirmed diagnosis and during chemotherapy havebeen gradually realized and clarified, as well as the dependences of different tumors on corresponding hormones. The prevalent endocrinotherapy suppresses tumor progression through downregulating dependent hormone level or completely inhibitting its combination with receptors. Because of the different and even antagonistic mechanisms, endocrinotherapy should not be used with chemotherapy at the same time, or it will reduce the chemotherapeutic efficacy, which is a widely accepted principle in clinic.

MicroRNAs in thyroid cancer with focus on medullary thyroid carcinoma:potential therapeutic targets and diagnostic/prognostic markers and web based tools

This review aimed to describe the inculpation of microRNAs(miRNAs)in thyroid cancer(TC)and its subtypes,mainly medullary thyroid carcinoma(MTC),and to outline web-based tools and databases for bioinformatics analysis of miRNAs in TC.Additionally,the capacity of miRNAs to serve as therapeutic targets and biomarkers in TC management will be discussed.This review is based on a literature search of relevant articles on the role of miRNAs in TC and its subtypes,mainly MTC.Additionally,web-based tools and databases for bioinformatics analysis of miRNAs in TC were identified and described.MiRNAs can perform as oncomiRs or antioncoges,relying on the target mRNAs they regulate.MiRNA replacement therapy using miRNA mimics or antimiRs that aim to suppress the function of certain miRNAs can be applied to correct miRNAs aberrantly expressed in diseases,particularly in cancer.MiRNAs are involved in the modulation of fundamental pathways related to cancer,resembling cell cycle checkpoints and DNA repair pathways.MiRNAs are also rather stable and can reliably be detected in different types of biological materials,rendering them favorable diagnosis and prognosis biomarkers as well.MiRNAs have emerged as promising tools for evaluating medical outcomes in TC and as possible therapeutic targets.The contribution of miRNAs in thyroid cancer,particularly MTC,is an active area of research,and the utility of web applications and databases for the biological data analysis of miRNAs in TC is becoming increasingly important.

WNT5A Regulated by miR154-5p is Associated with Angiopoiesis and Invasion of Placental Site Trophoblastic Tumor (PSTT)

Placental site trophoblastic tumor(PSTT),a rare gestational trophoblastic neoplasm(GTN),exhibits slow growth,late-onset metastasis,and chemotherapy insensitivity[1,2].The invasive capacity of trophoblasts induces angiogenesis in PSTT,yet the specific mechanism remains unclear[3].PSTT is typically resistant to chemotherapy and hysterectomy stands as the primary therapeutic choice for patients with an overall cure rate of approximately 75%-80%[4,5].Therefore,investigating the precise emergence and progression of PSTT is crucial,aiming to identify novel targets for diagnosis and therapy.

Enzyme-linked immunosorbent assay of 3 Screen Islet Cell Autoantibody in patients with autoimmune thyroid disease

BACKGROUND In recent years,the emergence of multiplex technology that can simultaneously measure multiple anti-islet autoantibodies has become particularly valuable for the staging and early diagnosis of immune-mediated type 1 diabetes(T1D).While it has been established that 20%-30%of T1D patients suffer from autoimmune thyroid disease(AITD),there is limited available data regarding the presence of anti-islet autoantibodies in AITD patients.Among commercially available anti-islet autoantibodies,glutamic acid decarboxylase 65 autoantibodies(GADAs)are often the first marker measured in general clinical practice.AIM To investigate the frequency of anti-islet autoantibodies in AITD patients.METHODS Our study involved four hundred ninety-five AITD patients,categorized into three distinct groups:AITD with T1D(n=18),AITD with phenotypic type 2 diabetes(T2D)(n=81),and AITD without diabetes(n=396),and the enzyme-linked immunosorbent assay(ELISA)was employed to determine the frequencies of 3 Screen Islet Cell Autoantibody(3 Screen ICA),GADA,insulinoma-associated antigen-2 autoantibodies(IA-2As),and zinc transporter 8 autoantibodies(ZnT8As)within these groups.RESULTS The frequency of 3 Screen ICA in AITD patients with T1D,T2D,and those without diabetes were 88.9%,6.2%,and 5.1%,respectively,with no significant difference seen between the latter two groups.Notably,the frequency of 3 Screen ICA was 11.1%higher in AITD patients with T1D,1.3%higher in AITD patients with T2D,and 1.1%higher in AITD patients without diabetes compared to GADA,respectively.Furthermore,12.5%,20.0%,and 20.0%of the 3 Screen ICA-positive patients were negative for GADA.Additionally,1.3%of the AITD patients who tested negative for 3 Screen ICA in both the AITD with T2D and non-diabetic AITD groups were found to be positive for individual autoantibodies.Among the 3 Screen ICA-positive patients,there was a significantly higher proportion of individuals with multiple autoantibodies in AITD patients with T1D compared to those without diabetes(37.5%vs 5.0%,P<0.05).However,this proportion was similar to that in AITD patients with T2D(20.0%).Nevertheless,there was no significant difference in 3 Screen ICA titers between AITD patients with T1D and those without diabetes(436.8±66.4 vs 308.1±66.4 index).Additionally,no significant difference in 3 Screen ICA titers was observed between Graves’disease and Hashimoto’s thyroiditis in any of the groups.CONCLUSION Our findings reveal that some AITD patients without diabetes exhibit 3 Screen ICA titers comparable to those in AITD patients with T1D.Thus,3 Screen ICA outperforms GADA in identifying latent anti-islet autoantibody-positive individuals among AITD patients.

Novel insights into immune-related genes associated with type 2 diabetes mellitus-related cognitive impairment

BACKGROUND The cognitive impairment in type 2 diabetes mellitus(T2DM)is a multifaceted and advancing state that requires further exploration to fully comprehend.Neu-roinflammation is considered to be one of the main mechanisms and the immune system has played a vital role in the progression of the disease.AIM To identify and validate the immune-related genes in the hippocampus associated with T2DM-related cognitive impairment.METHODS To identify differentially expressed genes(DEGs)between T2DM and controls,we used data from the Gene Expression Omnibus database GSE125387.To identify T2DM module genes,we used Weighted Gene Co-Expression Network Analysis.All the genes were subject to Gene Set Enrichment Analysis.Protein-protein interaction network construction and machine learning were utilized to identify three hub genes.Immune cell infiltration analysis was performed.The three hub genes were validated in GSE152539 via receiver operating characteristic curve analysis.Validation experiments including reverse transcription quantitative real-time PCR,Western blotting and immunohistochemistry were conducted both in vivo and in vitro.To identify potential drugs associated with hub genes,we used the Comparative Toxicogenomics Database(CTD).RESULTS A total of 576 DEGs were identified using GSE125387.By taking the intersection of DEGs,T2DM module genes,and immune-related genes,a total of 59 genes associated with the immune system were identified.Afterward,machine learning was utilized to identify three hub genes(H2-T24,Rac3,and Tfrc).The hub genes were associated with a variety of immune cells.The three hub genes were validated in GSE152539.Validation experiments were conducted at the mRNA and protein levels both in vivo and in vitro,consistent with the bioinformatics analysis.Additionally,11 potential drugs associated with RAC3 and TFRC were identified based on the CTD.CONCLUSION Immune-related genes that differ in expression in the hippocampus are closely linked to microglia.We validated the expression of three hub genes both in vivo and in vitro,consistent with our bioinformatics results.We discovered 11 compounds associated with RAC3 and TFRC.These findings suggest that they are co-regulatory molecules of immunometabolism in diabetic cognitive impairment.

Hepatocellular carcinoma presenting as an extrahepatic mass:A case report and review of literature

BACKGROUND Hepatocellular carcinoma(HCC)is a primary liver tumor generally diagnosed based on radiographic findings.Metastatic disease is typically associated with increased tumor diameter,multifocality,and vascular invasion.We report a case of a patient who presented with extrahepatic HCC metastasis to a portocaval lymph node with occult hepatic primary on computed tomography(CT).We review the literature for cases of extrahepatic HCC presentation without known hepatic lesions and discuss strategies to differentiate between metastatic and ectopic HCC.CASE SUMMARY A 67-year-old male with remotely treated hepatis C was referred for evaluation of an enlarging portocaval,mixed cystic-solid mass.Serial CT evaluations demonstrated steatosis,but no cirrhosis or liver lesions.Endoscopic ultrasound demonstrated a normal-appearing pancreas,biliary tree,and liver.Fine needle aspiration yielded atypical cells.The differential diagnosis included duodenal or pancreatic cyst,lymphoproliferative cyst,stromal or mesenchymal lesions,nodal involvement from gastrointestinal or hematologic malignancy,or duodenal gastrointestinal stromal tumor.After review by a multidisciplinary tumor board,the patient underwent open surgical resection of a 5.2 cm×5.5 cm retroperitoneal mass with pathology consistent with moderately-differentiated HCC.Magnetic resonance imaging(MRI)subsequently demonstrated a 1.2 cm segment VIII hepatic lesion with late arterial enhancement,fatty sparing,and intrinsic T1 hyperintensity.Alpha fetoprotein was 23.3 ng/mL.The patient was diagnosed with HCC with portocaval nodal involvement.Review:We surveyed the literature for HCC presenting as extrahepatic masses without history of concurrent or prior intrahepatic HCC.We identified 18 cases of extrahepatic HCC ultimately found to represent metastatic lesions,and 30 cases of extrahepatic HCC found to be primary,ectopic HCC.CONCLUSION Hepatocellular carcinoma can seldomly present with extrahepatic metastasis in the setting of occult primary.In patients with risk factors for HCC and lesions suspicious for metastatic disease,MRI may be integral to identifying small hepatic lesions and differentiating from ectopic HCC.Tumor markers may also have utility in establishing the diagnosis.

Emerging significance of butyrylcholinesterase

Butyrylcholinesterase(BChE;EC 3.1.1.8),an enzyme structurally related to acetylcholinesterase,is widely distributed in the human body.It plays a role in the detoxification of chemicals such as succinylcholine,a muscle relaxant used in anesthetic practice.BChE is well-known due to variant forms of the enzyme with little or no hydrolytic activity which exist in some endogamous communities and result in prolonged apnea following the administration of succinylcholine.Its other functions include the ability to hydrolyze acetylcholine,the cholinergic neurotransmitter in the brain,when its primary hydrolytic enzyme,acetylcholinesterase,is absent.To assess its potential roles,BChE was studied in relation to insulin resistance,type 2 diabetes mellitus,cognition,hepatic disorders,cardiovascular and cerebrovascular diseases,and inflammatory conditions.Individuals who lack the enzyme activity of BChE are otherwise healthy,until they are given drugs hydrolyzed by this enzyme.Therefore,BChE is a candidate for the study of loss-of-function mutations in humans.Studying individuals with variant forms of BChE can provide insights into whether they are protected against metabolic diseases.The potential utility of the enzyme as a biomarker for Alzheimer’s disease and the response to its drug treatment can also be assessed.