Pen2/ErbB4 signaling regulates stemness of pancreatic ductal carcinoma.

Cancer stem cells (CSCs) are critical for progression, invasion, metastasis, and chemotherapy resistance of pancreatic ductal adenocarcinoma (PDAC). Presenilin enhancer 2 (Pen2), a vital component of the gamma-secretase complex, is overexpressed in various cancers and plays a significant role in carcinogenesis. Here, we investigated the association between Pen2 expression and the stem-like properties of PDAC cells. We analyzed Pen2 and its downstream target, Erb-B2 Receptor Tyrosine Kinase 4 (ErbB4), using public databases. The expression of Pen2 in CSC populations, marked by CD133+, CD44+, or epithelial cell adhesion molecule (EpCAM)+, was evaluated. Pen2-positive cells were sorted from Pen2-negative ones in PDAC cells transduced with a vector designed to express green fluorescent protein (GFP) under the Pen2 promoter. Stemness was examined in vitro and in vivo in Pen2-positive versus Pen2-negative cells. Our results showed that Pen2 was significantly upregulated, while ErbB4 was significantly downregulated in PDAC tissues compared to adjacent non-tumorous tissues, with an inverse relationship between Pen2 and Erbb4 levels. PDACs with high Pen2 expression are associated with considerably poorer patient survival. The CSC populations identified by CD133+, CD44+, and EpCAM+ markers displayed significantly higher Pen2 and lower EpCAM levels. Compared to Pen2-negative PDAC cells, Pen2-positive cells formed more tumor spheres, were more invasive and migratory, and showed significantly increased resistance to chemotherapy-induced apoptosis. Altering Pen2 levels reversed these oncogenic effects. In vivo, Pen2-positive cells formed larger tumors in immunodeficient mice. Overall, our findings suggest that Pen2 is highly expressed in CSCs within PDAC cells, being a novel therapeutic target.

Urinary peptidomic liquid biopsy for non-invasive differential diagnosis of chronic kidney disease.

BACKGROUND AND HYPOTHESIS: Specific urinary peptides hold information on disease pathophysiology, which, in combination with artificial intelligence, could enable non-invasive assessment of chronic kidney disease (CKD) aetiology. Existing approaches are generally specific for the diagnosis of single aetiologies. We present the development of models able to simultaneously distinguish and spatially visualize multiple CKD aetiologies. METHODS: The urinary peptide data of 1850 healthy control (HC) and CKD [diabetic kidney disease (DKD), immunoglobulin A nephropathy (IgAN) and vasculitis] participants were extracted from the Human Urinary Proteome Database. Uniform manifold approximation and projection (UMAP) coupled to a support vector machine algorithm was used to generate multi-peptide models to perform binary (DKD, HC) and multiclass (DKD, HC, IgAN, vasculitis) classifications. This pipeline was compared with the current state-of-the-art single-aetiology CKD urinary peptide models. RESULTS: In an independent test set, the developed models achieved 90.35% and 70.13% overall predictive accuracies, respectively, for the binary and the multiclass classifications. Omitting the UMAP step led to improved predictive accuracies (96.14% and 85.06%, respectively). As expected, the HC class was distinguished with the highest accuracy. The different classes displayed a tendency to form distinct clusters in the 3D space based on their disease state. CONCLUSION: Urinary peptide data present an effective basis for CKD aetiology differentiation using machine learning models. Although adding the UMAP step to the models did not improve prediction accuracy, it may provide a unique visualization advantage. Additional studies are warranted to further validate the pipeline's clinical potential as well as to expand it to other CKD aetiologies and also other diseases.

Somatostatin Receptor PET Imaging in Diffuse Pancreatic Neuroendocrine Tumor.

ABSTRACT: Somatostatin receptor imaging findings of pancreatic neuroendocrine tumor with diffuse involvement of the pancreas are rarely reported. We present somatostatin receptor PET imaging findings in 3 cases of diffuse pancreatic neuroendocrine tumor. One case showed diffuse swelling and diffusely intense activity of the pancreas with multiple metastases in the peripancreatic lymph nodes and liver. The other 2 cases showed diffusely intense activity of the pancreas without metastasis. The pancreatic tumor extended into the duodenum in all the 3 cases. Familiarity with this rare pattern of radiotracer uptake in pancreatic neuroendocrine tumor may be helpful for the diagnosis.

The bromodomain protein TRIM28 controls the balance between growth and invasiveness in melanoma.

Melanoma tumors are highly metastatic partly due to the ability of melanoma cells to transition between invasive and proliferative states. However, the mechanisms underlying this plasticity are still not fully understood. To identify new epigenetic regulators of melanoma plasticity, we combined data mining, tumor models, proximity proteomics, and CUT&RUN sequencing. We focus on the druggable family of bromodomain epigenetic readers and identify TRIM28 as a new regulator of melanoma plasticity. We find that TRIM28 promotes the expression of pro-invasive genes and that TRIM28 controls the balance between invasiveness and growth of melanoma cells. We demonstrate that TRIM28 acts via the transcription factor JUNB that directly regulates the expression of pro-invasive and pro-growth genes. Mechanistically, TRIM28 controls the expression of JUNB by negatively regulating its transcriptional elongation by RNA polymerase II. In conclusion, our results demonstrate that a TRIM28-JUNB axis controls the balance between invasiveness and growth in melanoma tumors and suggest that the bromodomain protein TRIM28 could be targeted to reduce tumor spread.

Role of hypoxia in the tumor microenvironment and targeted therapy.

Tumor microenvironment (TME), which is characterized by hypoxia, widely exists in solid tumors. As a current research hotspot in the TME, hypoxia is expected to become a key element to break through the bottleneck of tumor treatment. More and more research results show that a variety of biological behaviors of tumor cells are affected by many factors in TME which are closely related to hypoxia. In order to inhibiting the immune response in TME, hypoxia plays an important role in tumor cell metabolism and anti-apoptosis. Therefore, exploring the molecular mechanism of hypoxia mediated malignant tumor behavior and therapeutic targets is expected to provide new ideas for anti-tumor therapy. In this review, we discussed the effects of hypoxia on tumor behavior and its interaction with TME from the perspectives of immune cells, cell metabolism, oxidative stress and hypoxia inducible factor (HIF), and listed the therapeutic targets or signal pathways found so far. Finally, we summarize the current therapies targeting hypoxia, such as glycolysis inhibitors, anti-angiogenesis drugs, HIF inhibitors, hypoxia-activated prodrugs, and hyperbaric medicine.

Systemic therapy and perioperative management improve the prognosis of pancreatic ductal adenocarcinoma: A retrospective cohort study of 2000 consecutive cases.

OBJECTIVE: This study aimed to explore patterns of the treatment strategies of pancreatic ductal adenocarcinoma based on 2000 consecutive cases of a prospective database since 2012 to obtain new insights for future directions. METHODS: Among 2000 patients enrolled in this study, 210 patients were excluded, and 710, 521, and 559 patients were treated between 2012 and 2015 (group 1), between 2016 and 2017 (group 2), and between 2018 and 2019 (group 3), respectively. Patient clinicopathologic and biological factors, and perioperative outcomes were used to assess the prognostic factors. RESULTS: The median survival for all patients with pancreatic ductal adenocarcinoma was 21.7 months (1-year survival, 75.0%; 2-year survival, 43.7%; 5-year survival, 19.7%). Group 3 had a better survival outcome than groups 1 and 2 (median survival time: 23 versus 20.5 and 21.1 months). The proportion of patients younger than 65 gradually increased over time, as did the use of systemic chemotherapy and postoperative adjuvant radiotherapy. The tendency for early diagnosis (lower CA19-9 and CEA levels, smaller size, and earlier N stage), use of chemotherapy and radiotherapy, early recovery (lesser hospital stay and Clavien-Dindo grade <3), absence of abdominal pain, younger age, length of operation ≤3 h, and pathological factors (absence of lymphovascular invasion, peripancreatic fat infiltration and neural invasion, higher differentiation) were related to patients' survival. Multivariable analysis for prognosis revealed that tumor biological factors (increased preoperative serum CA19-9 level, tumor size, tumor differentiation, N stage, and presence of lymphovascular invasion and neural invasion), chemotherapy, radiotherapy, abdomen pain, operation period, length of stay, and length of operation correlated with patients' survival. CONCLUSIONS: Systemic therapy, including chemotherapy and radiotherapy, has gradually improved the prognosis after operative resection for pancreatic ductal adenocarcinoma. Neoadjuvant therapy is also beneficial to improve the prognosis to a certain extent. The enhanced recovery after surgery (ERAS) policies and the specific assessment of postoperative pancreatic fistula (POPF) risk may be related to reduced hospital stays and the reduction of serious complications. These advancements show that the concept of systemic therapy has been accepted and actively applied by Chinese medical institutions.

Nomogram predicts CR-POPF in open central pancreatectomy patients with benign or low-grade malignant pancreatic neoplasms.

Introduction: Central pancreatectomy (CP) is a standard surgical procedure for benign and low-grade malignant pancreatic neoplasms in the body and neck of the pancreas. Higher incidence of clinically relevant postoperative pancreatic fistula (CR-POPF) after CP than after pancreaticoduodenectomy (PD) or distal pancreatectomy (DP) has been reported, but no nomogram for prediction of CR-POPF after open CP has been previously established. Methods: Patients undergoing open CP for benign or low-grade malignant pancreatic neoplasms in the department of Hepatobiliary and Pancreatic (HBP) surgery of Shanghai Changhai Hospital affiliated to Naval Medical University between January 01, 2009 and December 31,2020 were enrolled. Pre-, intra- and post-operative parameters were analyzed retrospectively. Results: A total of 194 patients, including 60 men and 134 women, were enrolled with median age of 52 years (21~85 years). 84 patients (43.3%) were overweight (BMI>23.0 Kg/m2) and 14 (7.2%) were obese (BMI>28.0 Kg/m2). Pathological diagnoses ranged from serous cystic neoplasm (32.5%), solid pseudopapillary neoplasm (22.2%), pancreatic neuroendocrine tumor (20.1%), intraductal papillary mucinous neoplasm (18.0%) to mucinous cystic neoplasm (5.2%). All patients had soft pancreatic texture. Main pancreatic duct diameters were ≤0.3cm for 158 patients (81.4%) and were ≥0.5cm in only 12 patients (6.2%). A stapler (57.7%) or hand-sewn closure (42.3%) were used to close the pancreatic remnant. The pancreatic anastomosis techniques used were duct to mucosa pancreaticojejunostomy (PJ)-interrupted suture (47.4%), duct to mucosa PJ-continuous suture (43.3%), duct to mucosa "HO" half-purse binding PJ (5.2%) and invaginating pancreaticogastrostomy (4.1%). Post-surgical incidences of CR-POPF of 45.9%, surgical site infection of 28.9%, postpancreatectomy hemorrhage of 7.7% and delayed gastric emptying of 2.1% were found. Obesity and pancreatic anastomosis technique were independent risk factors of CR-POPF, with a concordance index of 0.675 and an Area Under the Curve of 0.678. Discussion: This novel nomogram constructed according to obesity and pancreatic anastomosis technique showed moderate predictive performance of CR-POPF after open CP.

The short-term efficacy of DEB-TACE loaded with epirubicin and raltitrexed in the treatment of intermediate and advanced primary hepatocellular carcinoma.

OBJECTIVE: To investigate the short-term efficacy of drug-eluting bead transarterial chemoembolization (DEB-TACE) loaded with epirubicin and raltitrexed in the treatment of intermediate and advanced primary hepatocellular carcinoma (PHC). METHODS: One hundred patients with intermediate or advanced PHC were randomly divided into a control group (the CG, n=50) and an observation group (the OG, n=50). The CG was treated with conventional TACE (cTACE), and the OG was treated with DEB-TACE loaded with epirubicin and raltitrexed. The overall efficiency, the liver function indices, the tumor markers, the macrophage migration inhibitory factor (MIF) levels , the lesion diameters, the Child-Pugh scores, the adverse reactions, the median times to disease progression, the 1-year and 2-year recurrence rates, and the survival rates were compared between the two groups. RESULTS: At 6 months after the surgery, the overall response rate in the OG (82.00%) was higher than it was in the CG (62.00%) (P<0.05). The serum alanine aminotransferase, total bilirubin, and aspartate aminotransferase levels were elevated in both groups after the intervention, but they were lower in the OG than they were in the CG (P<0.05). The serum alpha-fetoprotein, carcinoembryonic antigen, and MIF levels, and the lesion diameters were lower in both groups at one month after the intervention, and they were lower in the OG than they were in the CG (P<0.05). The incidence of abnormal blood test results in the OG was lower than it was in the CG (P<0.05). The OG also exhibited a longer median time to disease progression, lower 1-year and 2-year recurrence rates, and higher 1- and 2-year survival rates than the CG (P<0.05). CONCLUSION: DEB-TACE loaded with epirubicin and raltitrexed improves the short-term outcomes, reduces the tumor load, decreases the incidence of adverse events, and improves the survival rate in patients with intermediate and advanced PHC.

CD99 and polymeric immunoglobulin receptor peptides deregulation in critical COVID-19: A potential link to molecular pathophysiology?

Identification of significant changes in urinary peptides may enable improved understanding of molecular disease mechanisms. We aimed towards identifying urinary peptides associated with critical course of COVID-19 to yield hypotheses on molecular pathophysiological mechanisms in disease development. In this multicentre prospective study urine samples of PCR-confirmed COVID-19 patients were collected in different centres across Europe. The urinary peptidome of 53 patients at WHO stages 6-8 and 66 at WHO stages 1-3 COVID-19 disease was analysed using capillary electrophoresis coupled to mass spectrometry. 593 peptides were identified significantly affected by disease severity. These peptides were compared with changes associated with kidney disease or heart failure. Similarities with kidney disease were observed, indicating comparable molecular mechanisms. In contrast, convincing similarity to heart failure could not be detected. The data for the first time showed deregulation of CD99 and polymeric immunoglobulin receptor peptides and of known peptides associated with kidney disease, including collagen and alpha-1-antitrypsin. Peptidomic findings were in line with the pathophysiology of COVID-19. The clinical corollary is that COVID-19 induces specific inflammation of numerous tissues including endothelial lining. Restoring these changes, especially in CD99, PIGR and alpha-1-antitripsin, may represent a valid and effective therapeutic approach in COVID-19, targeting improvement of endothelial integrity.

Urinary peptides in heart failure: a link to molecular pathophysiology.

AIMS: Heart failure (HF) is a major public health concern worldwide. The diversity of HF makes it challenging to decipher the underlying complex pathological processes using single biomarkers. We examined the association between urinary peptides and HF with reduced (HFrEF), mid-range (HFmrEF) and preserved (HFpEF) ejection fraction, defined based on the European Society of Cardiology guidelines, and the links between these peptide biomarkers and molecular pathophysiology. METHODS AND RESULTS: Analysable data from 5608 participants were available in the Human Urinary Proteome database. The urinary peptide profiles from participants diagnosed with HFrEF, HFmrEF, HFpEF and controls matched for sex, age, estimated glomerular filtration rate, systolic and diastolic blood pressure, diabetes and hypertension were compared applying the Mann-Whitney test, followed by correction for multiple testing. Unsupervised learning algorithms were applied to investigate groups of similar urinary profiles. A total of 577 urinary peptides significantly associated with HF were sequenced, 447 of which (77%) were collagen fragments. In silico analysis suggested that urinary biomarker abnormalities in HF principally reflect changes in collagen turnover and immune response, both associated with fibrosis. Unsupervised clustering separated study participants into two clusters, with 83% of non-HF controls allocated to cluster 1, while 65% of patients with HF were allocated to cluster 2 (P < 0.0001). No separation based on HF subtype was detectable. CONCLUSIONS: Heart failure, irrespective of ejection fraction subtype, was associated with differences in abundance of urinary peptides reflecting collagen turnover and inflammation. These peptides should be studied as tools in early detection, prognostication, and prediction of therapeutic response.

Peptides in Plasma, Urine, and Dialysate: Toward Unravelling Renal Peptide Handling.

PURPOSE: The peptidomes of spent hemodialysate, urine, and plasma are investigated, to shed light on peptide handling in the kidney. EXPERIMENTAL DESIGN: Fifteen plasma, 15 urine, and 13 spent hemodialysate samples are collected from age- and sex-matched subjects with chronic kidney disease. Peptide identification and quantification are performed with capillary electrophoresis-coupled mass spectrometry. RESULTS: A total of 6278 urinary peptides, 1743 plasma peptides, and 1727 peptides from spent hemodialysate are detected. Of these, sequences can be assigned to 1580, 419, and 352 peptides, respectively. A strong correlation in peptide abundance between urine and spent hemodialysate (p = 3 × 10-21 , Rho = 0.52), a moderately strong correlation between spent hemodialysate and plasma (p = 4.5 × 10-5 , Rho = 0.30), and no significant correlation between urine and plasma (p = 0.11, Rho = 0.094) are found. Collagen and fibrinogen alpha peptides are highly abundant in all three body fluids. In spent hemodialysate, thymosin ß4 is one of the most abundant peptides, which is shown to be negatively associated with the estimated glomerular filtration rate (Rho = -0.39, p-value = 3.9 × 10-81 ). CONCLUSION AND CLINICAL RELEVANCE: The correlation of peptide abundance in these three body fluids is lower than expected, supporting the hypothesis that tubular reabsorption has a major impact on urinary peptide content. Further investigation of thymosin ß4 in hemodialysis is thus warranted.

Gambogic Acid Inhibits the Progression of Gastric Cancer via circRNA_ASAP2/miR-33a-5p/CDK7 Axis.

BACKGROUND: Gastric cancer (GC) is a major cancer-related mortality disease. Gambogic acid (GA) has been investigated to inhibit cancer progression. In the present study, the molecular mechanism of GA in regulating GC progression was studied. METHODS: The expression levels of circular RNA ASAP2 (circ_ASAP2), miR-33a-5p and cyclin-dependent kinases 7 (CDK7) were detected by quantitative real-time polymerase reaction (qRT-PCR). CDK7 protein level was evaluated by Western blot. Cell colony formation assay, 3-(4,5-Dimethylthazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, transwell assay and flow cytometry analysis were employed to reveal the functional effects among circ_ASAP2, miR-33a-5p and CDK7 on GA-induced GC progression. Mechanistically, the binding relationship between miR-33a-5p and circ_ASAP2 or CDK7 was predicted with starBase v3.0 online database and verified by dual-luciferase reporter assay. In vivo tumor formation assay was used to explain the impacts of GA treatment on GC growth in vivo. RESULTS: Circ_ASAP2 and CDK7 expression were downregulated in GA-induced GC cells compared with GC cells. MiR-33a-5p expression was upregulated in GA-induced GC cells relative to GC cells. The protein expression level of CDK7 was lower in GA-induced GC cells than that in GC cells. Further, circ_ASAP2 overexpression decreased GA-induced inhibition effects on cell proliferation, migration and invasion and GA-induced promotion effect on cell apoptosis in both AGS and HGC-27 cells, whereas this phenomenon was reversed by miR-33a-5p. In addition, circ_ASAP2 functioned as a sponge of miR-33a-5p and miR-33a-5p was associated with CDK7. Furthermore, GA treatment inhibited GC growth in vivo. CONCLUSION: Circ_ASAP2 overexpression promoted cell proliferation, migration and invasion, whereas inhibited cell apoptosis by upregulating CDK7 expression through binding to miR-33a-5p in GA-induced GC cells. This study provided a theoretical basis in GC treatment with GA.

Radical antegrade modular pancreatosplenectomy versus standard distal pancreatosplenectomy for pancreatic cancer, a dual-institutional analysis.

BACKGROUND: Radical antegrade modular pancreatosplenectomy (RAMPS) has been adopted by some surgeons in the treatment of left-sided pancreatic cancer (PDAC). Low disease incidence and heterogenous disease biology make robust prospective comparison of RAMPS and standard distal pancreatosplenectomy (DPS) difficult. METHODS: Consecutive cases of chemo-naïve patients undergoing open RAMPS and DPS for PDAC between 2010-2017 at two international high-volume pancreatectomy centers were compared. Cox proportional hazard modeling was utilized for multivariate analysis. RESULTS: We identified 193 DPS and 253 RAMPS during the study period. DPS was associated with higher rates of median estimated blood loss (500 vs. 300 cc, P<0.001), median total harvested lymph nodes (18 vs. 12, P<0.001) and R0 resection (94.3% vs. 88.9%, P=0.013). There were no differences in rates of postoperative pancreatic fistula (16.5% vs. 17.8%, P=1) or postoperative hemorrhage (5.9% vs. 3.6%, P=0.385) (DPS vs. RAMPS). After controlling for significant clinical pathological parameters, RAMPS was associated with non-superior recurrence-free survival (RFS) (HR 0.29; 95% CI, 0.07-1.27, P=0.101) and overall-survival (HR 1.03; 95% CI, 0.71-1.49, P=0.895) compared with DPS. Similar results were observed in node-positive patients. CONCLUSIONS: RAMPS is safe and effective in the treatment of PDAC, but is not associated with an improvement in either RFS or overall-survival over DPS.

Associations of urinary polymeric immunoglobulin receptor peptides in the context of cardio-renal syndrome.

The polymeric immunoglobulin receptor (pIgR) transports immunoglobulins from the basolateral to the apical surface of epithelial cells. PIgR was recently shown to be associated with kidney dysfunction. The immune defense is initiated at the apical surface of epithelial cells where the N-terminal domain of pIgR, termed secretory component (SC), is proteolytically cleaved and released either unbound (free SC) or bound to immunoglobulins. The aim of our study was to evaluate the association of pIgR peptides with the cardio-renal syndrome in a large cohort and to obtain information on how the SC is released. We investigated urinary peptides of 2964 individuals available in the Human Urine Proteome Database generated using capillary electrophoresis coupled to mass spectrometry. The mean amplitude of 23 different pIgR peptides correlated negatively with the estimated glomerular filtration rate (eGFR, rho = -0.309, p < 0.0001). Furthermore, pIgR peptides were significantly increased in cardiovascular disease (coronary artery disease and heart failure) after adjustment for eGFR. We further predicted potential proteases involved in urinary peptide generation using the Proteasix algorithm. Peptide cleavage site analysis suggested that several, and not one, proteases are involved in the generation of the SC. In this large cohort, we could demonstrate that pIgR is associated with the cardio-renal syndrome and provided a more detailed insight on how pIgR can be potentially cleaved to release the SC.

Robot-assisted distal pancreatectomy improves spleen preservation rate versus laparoscopic distal pancreatectomy for benign and low-grade malignant lesions of the pancreas.

BACKGROUND: The aim of this retrospective study was to compare robot-assisted distal pancreatectomy (RDP) with laparoscopic distal pancreatectomy (LDP) for patients with benign and low-grade malignant lesions of the pancreas. METHODS: This study included 166 patients who underwent RDP (n=63) or LDP (n=103) for benign or low-grade malignant lesions of the pancreas from January 2011 to October 2018 in Changhai Hospital. A retrospective analysis was performed between the two groups. The primary points were operation time, operative blood loss, hospital stay, pancreatic fistula and spleen preservation. RESULTS: There were no significant differences in patient characteristics or indications between RDP and LDP. Notably, among all patients, RDP was associated with a significantly higher rate of spleen preservation than that for LDP (30.2% vs. 6.8%, P<0.001), while other intraoperative variables were similar between the two groups. No death cases in the study group within 30 days were reported in either group. Referring to postoperative outcomes, postoperative pancreatic fistula (POPF) was 22% for the RDP group and 33% for the LDP group. In addition, the rate of clinically significant grade B/C pancreatic fistula was 5% and 7%, respectively. There were also no significant differences in hospital stay (6.0±3.0 vs. 6.4±2.5, P=0.404). Furthermore, the univariate analysis demonstrated that tumor size (P=0.001) and surgery group (RDP/LDP) (P=0.002) were associated with SP rate independent factor for spleen preservation. CONCLUSIONS: RDP is an effective and safe technique with significant advantage in spleen preservation for patients with benign and low-grade malignant lesions in the distal pancreas.

Menin Coordinates C/EBPß-Mediated TGF-ß Signaling for Epithelial-Mesenchymal Transition and Growth Inhibition in Pancreatic Cancer.

Menin displays either tumor suppression or promotion functions in a context-dependent manner. Previously, we proposed that Menin acts as a tumor suppressor by inhibiting cell growth in pancreatic ductal adenocarcinoma (PDAC), whereas the relationship between the Menin expression and overall survival rate of PDAC patients has not been completely elucidated, indicating the complexity of Menin functions in PDAC progression. Here, we identify Menin as a promoter of epithelial-mesenchymal transition (EMT), which is largely associated with cell migration or metastasis, with modest activity in cell growth inhibition. Ectopic expression of Menin suppresses the expression of CCAAT/enhancer-binding protein beta (CEBPB) and epithelial-specific genes by histone deacetylation and further enhances the TGF-ß signaling-related EMT process. We also demonstrate that CCAAT/enhancer binding protein (C/EBP) beta (C/EBPß; encoded by CEBPB) acts downstream of Menin and TGF-ß signaling for balancing growth inhibition and EMT, and C/EBPß overexpression could restore the anti-cancer functions of Menin in pancreatic cancer by cooperatively activating CDKN2A/B genes and antagonizing EMT processes. Taken together, our results suggest that Menin functions as an oncogene for cancer metastasis upon C/EBPß depletion or acts as a tumor suppressor by cooperation with C/EBPß to activate CDKN2A transcription.

FDG PET/CT in Primary Splenic Angiosarcoma With Diffuse Involvement of the Spleen.

Primary splenic angiosarcoma is rare. A 44-year-old man presented with abdominal distension and malaise for 7 months. Laboratory tests showed anemia. Abdominal ultrasound showed enlargement of the spleen with multiple hypoechoic nodules. These nodules showed progressive enhancement on dynamic enhanced CT. Lymphoma was suspected. FDG PET/CT showed increased nonuniform FDG uptake with SUVmax of 11.6 of the entire spleen. Laparoscopic splenectomy was performed. The pathologic findings were consisted with angiosarcoma with replacement of the spleen. Eight months after surgery, multiple hepatic metastases were detected by follow-up abdominal CT.

Abdominal Kaposiform Hemangioendothelioma Associated With Lymphangiomatosis Involving Mesentery and Ileum: A Case Report of MRI, CT, and 18F-FDG PET/CT Findings.

Kaposiform hemangioendothelioma (KH) is a rare vascular tumor of intermediate malignancy that occurs mainly in the childhood. Adult patients with KH are rare. Imaging findings of KH have rarely been reported before. We present magnetic resonance imaging (MRI), computed tomography (CT), and fluorine-18-fluorodeoxyglucose (F-FDG) positron emission tomography (PET)/CT findings in an adult patient with KH associated with lymphangiomatosis involving mesentery and ileum.A 22-year-old female complained of a 9-month history of intermittent melena, weakness, and palpitation. Laboratory tests revealed anemia and hypoproteinemia. Fecal occult blood test was positive. Abdominal enhanced MRI and CT showed a large abdominal mass involving mesentery and ileum. On enhanced MRI, there were many hypervascular nodules in the mass. On FDG PET/CT, the mass and the nodules showed slight FDG uptake. Small bowel capsule endoscopy showed numerous grape-shaped red nodules in the luminal wall of the involved ileum. The patient underwent resection of the abdominal mass and a segment of the ileum invaded by the abdominal mass. KH arising within lymphangiomatosis involving mesentery and ileum was confirmed by pathology. After surgery, the patient's symptoms improved.This is the first case of KH associated with lymphangiomatosis involving mesentery and ileum. In this case, the lymphangiomatosis overshadowed the small tumor nodules resulting in unusual imaging findings. Familiarity with these imaging findings is helpful for diagnosis and differential diagnosis of KH.

FDG PET/CT Findings of Ménétrier Disease.

Ménétrier disease is a very rare chronic gastric disorder characterized by gastric mucosal hypertrophy. We present a case of Ménétrier disease with CT, MRI, and FDG PET/CT findings. Enhanced CT and MRI showed diffuse thickened mucosa of the greater curvature and elongated mucosa of the antrum with remarkable enhancement. The early and delayed FDG PET/CT showed increased FDG uptake of these thickened mucosa. The increased FDG uptake may be due to the mucosal inflammation. This case indicates Ménétrier disease should be included in the differential diagnosis of abnormal gastric FDG accumulation along with tumor and nontumor processes.

Diffuse Infantile Hepatic Hemangioendothelioma With Early Central Enhancement in an Adult: A Case Report of CT and MRI Findings.

Infantile hepatic hemangioendothelioma (IHH) is the most common vascular tumor of the liver in infancy. Adult with IHH is extremely rare. We presented a diffuse IHH in an adult patient with computed tomography (CT) and magnetic resonance image (MRI) findings.A 39-year-old man was admitted to our hospital because of a 2-year history of abnormal liver function tests and a 7-day history of jaundice. Physical examination revealed enlarged liver. Unenhanced abdominal CT showed enlargement of the liver with diffuse hypodensity. Enhanced CT on the arterial phase revealed multiple centrally enhanced lesions diffusely involved the enlarged liver. The enhanced areas of the lesions became larger on the portal phase and all the lesions became homogeneous enhanced on the delayed phase. These lesions showed heterogeneously hyperintense on T2-weighted image, hypointense on T1-weighted image, and early centrally enhanced on dynamic gadolinium-enhanced MRI, with complete tumor enhancement after 180 s. The patient underwent orthotopic liver transplantation. IHH type 2 was confirmed by pathology. The patient died of tumor recurrence in the liver 4 months after transplantation.Unlike the previously described imaging appearances of IHH, this case showed diffuse nodules with early central enhancement on CT and MRI. Considering the importance of the ability to differentiate IHH from other hepatic tumors, radiologists should be aware of these imaging appearances to establish knowledge of the entire spectrum of IHH.