Unusual Presentation of a Hepatic Neuroendocrine Tumor With Elevated CEA and CA 19-9: A Case Report.

Neuroendocrine tumors (NETs) of the gastrointestinal tract (GIT) are rare malignancies, which may have unique presentations. The diagnostic process predominantly relies on immunohistochemical analysis. While tumor markers are extensively utilized in diagnosing and monitoring GI malignancies, their specific role in NETs has not been fully explored. This case describes an 83-year-old male presenting with jaundice and general weakness. Diagnostic imaging through MRI and CT angiography (CTA) revealed a nodular texture on the liver's surface suggesting cirrhosis. The presence of elevated tumor markers, specifically carcinoembryonic antigen (CEA) and cancer antigen 19-9 (CA 19-9), raised suspicions of malignancy. A subsequent liver biopsy confirmed the diagnosis of small-cell high-grade neuroendocrine carcinoma accompanied by reactive fibrosis. As per our knowledge, this case is the first recorded instance of a liver neuroendocrine tumor (NET) exhibiting elevated levels of both CEA and CA 19-9, with no abnormalities detected in the gallbladder, biliary tree, and bowel in the MRI with magnetic resonance cholangiopancreatography (MRCP) and CTA. This is an atypical presentation of a liver NET, mimicking cirrhotic liver morphology, and underscores the potential diagnostic relevance of tumor markers CEA and CA 19-9 in such cases.

A Novel Presentation of Autoimmune Hepatitis with IgG1 Elevation.

Autoimmune hepatitis (AIH) is a common and debilitating pathology that has acute, subacute, and chronic presentation, requiring prompt diagnosis and early intervention. Several serologic markers are found to be associated with the pathogenesis and progression of autoimmune hepatitis, most notably antinuclear antibodies and anti-smooth muscle antibodies [Front Immunol. 2018;9:609]. In addition, AIH is also characterized by the elevation of gamma globulin levels, mainly immunoglobulin G (IgG) [World J Gastroenterol. 2015;21(1):60-83]. Although the literature has well established the presence of increased IgG levels in AIH, few studies have evaluated the subtypes of IgG and their differential levels associated with AIH. Here, we present a rare case of AIH that lacks the common serologic markers but instead reveals an elevation in IgG1 level. Our patient was subsequently placed on corticosteroids, and her symptoms quickly resolved. We intend to introduce this case to the medical community in the hope of aiding in the proper diagnosis and timely intervention of subsequent cases with similar presentations.

Aberrant p53 expression is associated with neoplastic progression in Barrett oesophagus diagnosed as indefinite for dysplasia.

The aim of this study was to investigate the role of immunohistochemical (IHC) expression of p53 and other potential clinical parameters as prognostic markers for predicting neoplastic progression in Barrett oesophagus (BE) patients diagnosed as indefinite for dysplasia (IND). The study included patients with established BE of any extent who had a diagnosis of IND accompanied by concurrent p53 immunohistochemistry (IHC) stain at the index endoscopic procedure and at least one follow-up examination between 2000 and 2021. Correlation between disease progression from IND to higher-grade dysplasia [low-grade dysplasia (LGD), high-grade dysplasia (HGD) and oesophageal adenocarcinoma (EAC)] and clinicopathological parameters were analysed. A total of 149 patients (99 males; mean age 63.3 ± 10.0 years, range = 35-89) were included in the final analysis. Median follow-up was 37.1 months [interquartile range (IQR) = 20.5-59.1 months]. Progression rates from IND to LGD and HGD were 12.1% (18 of 149) and 2.7% (four of 149), respectively. On multivariate analysis, the number of IND diagnoses was significantly associated with progression to both LGD and HGD (P = 0.016 and P < 0.001, respectively). Cox regression analysis showed that aberrant p53 expression was significantly associated with progression to LGD [hazard ratio (HR) = 4.87, 95% confidence interval (CI) = 1.91-12.45, P = 0.001] and HGD (HR = 21.81, 95% CI = 1.88-253.70, P = 0.014). Kaplan-Meier survival analysis also demonstrated that aberrant p53 expression was significantly associated with progression to LGD (P < 0.001) and HGD (P = 0.001). Our results suggest that frequency of IND diagnoses and status of p53 expression can help to stratify risk of neoplastic progression in BE patients with IND.

Electroacupuncture at Zusanli (ST36), Guanyuan (CV4), and Qihai (CV6) Acupoints Regulates Immune Function in Patients with Sepsis via the PD-1 Pathway.

Objective: The present study is aimed at investigating the biochemical and clinical effects of electroacupuncture in patients with sepsis. Methods: Patients with sepsis treated at Guangdong Provincial Hospital of Chinese Medicine from July 2019 to December 2020 were included. Patients were randomly assigned to treatment with routine Western medicine (WM group) or treatment with Western medicine plus electroacupuncture based on Western medicine (EA group). Indices associated with immune function and clinical efficacy were determined before and at 3 and 5 days after treatment. Indicators of immune function included the percentage of T lymphocyte subsets, natural killer (NK) cells, and soluble programmed death protein 1 (sPD-1) levels. Indicators of clinical efficacy included infection-related indicators in whole blood; levels of tumor necrosis factor-α (TNF-α), C-reactive protein (CRP), and interferon-γ (INF-γ); and assessments using acute physiology and chronic health evaluation-II (APACHE-II) and sequential organ failure assessment (SOFA) scores. Results: Baseline data were not different between WM (N = 30) and EA groups (N = 30). At day 5 following treatment, the level of sPD-1 in the EA group was lower than that in the WM group. Proportions of CD3 + T lymphocytes, CD4 + T lymphocytes, and NK cells, the percentage of lymphocytes, and INF-γ levels in the EA group were significantly higher than those in the WM group. Compared with the WM group, the white blood cell count (WBC), percentage and count of neutrophils, ratio of neutrophils to lymphocytes, and levels of CRP and TNF-α were significantly decreased in the EA group 5 days after treatment. The APACHE-II score of the EA group was significantly lower than that of the WM group 5 days after treatment. Conclusion: Electroacupuncture may regulate the immune function of patients with sepsis through the PD-1 pathway to achieve an anti-inflammatory state and improve clinical symptoms.

A case report on a large, peduncular intra-abdominal hepatocellular carcinoma extending into the retroperitoneum.

Here, we discuss a relatively uncommon presentation of a hepatocellular carcinoma and discuss its preoperative planning and surgical intervention required to reach complete resection.

Colorectal carcinomas with mucinous differentiation are associated with high frequent mutation of KRAS or BRAF mutations, irrespective of quantity of mucinous component.

BACKGROUND: Mucinous adenocarcinoma (MAC) is a distinct type of colorectal cancer (CRC) associated with poor response to treatment and poorer prognosis. MAC is diagnosed by WHO definition when the extracellular mucin is more than 50% of the lesion. We aimed at assessing the gene expression profiles of the CRCs with any mucinous features (> 5%) in a retrospective study. METHODS: The data of a 50-gene next generation sequencing (NGS) panel of 166 CRCs was analyzed and the gene mutational profile with morphologic features was correlated. RESULTS: We identified the different genetic mutation profiles between CRCs with and without mucinous component, but noticed a similar genetic profile between MACs and CRCs with mucinous component, irrespective of the percentage (if mucinous component more than 5%). The different genetic mutation profile related to MSI status was also identified between two groups of tumors. The most frequent mutations in CRCs with mucinous component are KRAS (28/49, 57.1%) and BRAF (19/49, 38.7%), PIK3CA (16/49, 32.6%), followed by APC (12/49, 24.5%) and TP53 (11/49, 22.5%). The combined mutation frequency of the two key factors in the EGFR signaling pathway, KRAS and BRAF, in the CRCs with and without mucinous component is 95.9 and 52.1%, respectively. CONCLUSIONS: The dysregulation of EGFR pathway plays a critical role in the development of CRCs with mucinous component, irrespective of the percentage. The result suggested that the current cut off of 50% mucin component to define mucinous adenocarcinoma might be challengeable.

Impact of EUS-guided microforceps biopsy sampling and needle-based confocal laser endomicroscopy on the diagnostic yield and clinical management of pancreatic cystic lesions.

BACKGROUND AND AIMS: EUS-guided microforceps biopsy sampling (MFB) and needle-based confocal laser endomicroscopy (nCLE) are emerging diagnostic tools for pancreatic cystic lesions (PCLs). There is a paucity of data regarding their performance and impact. The aim of this study was to compare diagnostic outcomes and changes in clinical management resulting from MFB and nCLE use in PCLs. METHODS: This was a single-center retrospective study of patients with PCLs who underwent combined EUS-guided FNA, MFB, and nCLE. Primary outcomes included diagnostic yield (specific PCL type) and change in clinical management for each modality compared with the current "composite standard" (CS) obtained by combining clinical, morphologic, cyst fluid cytology, and chemical analysis. RESULTS: Forty-four cysts were studied in 44 patients. Technical success was 100% for EUS-FNA, 88.6% for MFB, and 97.7% for nCLE. Of 44 procedures, there was 1 adverse event (2.3%, an infected pseudocyst). Diagnostic yield for each individual modality was 34.1% for CS, 75.0% for MFB (P < .05 vs CS), and 84.1% for nCLE (P < .05 vs CS). Diagnostic yield for combined tests was 79.5% for CS/MFB, 88.6% for CS/nCLE, and 93.2% for CS/MFB/nCLE (P = not significant). Compared with the CS, the use of MFB, nCLE, and their combination led to overall change in clinical management in 38.6%, 43.2%, and 52.3% of cases, respectively. MFB and nCLE led to an overall increase in discontinuation of surveillance (MFB, 34.1% [P < .05]; nCLE, 31.8% [P < .05]), led by a reduction in the indication for follow-up radiologic or endoscopic studies (MFB, 34.1% [P < .05]; nCLE, 38.6% [P < .05]). Based on MFB and nCLE, 2 of 28 (7.1%) and 3 of 28 (10.7%) patients who would have undergone further surveillance were referred for surgery. CONCLUSIONS: In the evaluation of PCLs, the use of combined EUS-guided FNA, MFB, and nCLE is safe. MFB and nCLE led to significant improvements in specific PCL diagnosis, which in turn has major impacts in clinical management.

Green Tea Consumption and Esophageal Cancer Risk: A Meta-analysis.

Background: The protective role of green tea against cancer is still unknown.Objectives: To investigate the association between green tea consumption and esophageal cancer risk through meta-analysis.Methods: We searched MEDLINE, EMBASE, Web of Science and Cochrane Library for studies on the relationship between green tea and esophageal cancer risk. We assessed heterogeneity (I2) and publication bias (Begg's and Egger's tests). Pooled relative risks (RRs) or odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using random effects models.Results: A total of 20 studies were included. The RRs for all studies was 0.65 (95% CI: 0.57-0.73), with I2 = 75.3% and P = 0. In the subgroup analysis, the following variables showed marked heterogeneity: Asian (RR: 0.64; 95% CI: 0.56-0.73) and non-Asian countries (RR: 0.74; 95% CI: 0.45-1.03), female (RR: 0.55; 95% CI: 0.39-0.71) and male + female (RR: 0.64; 95% CI: 0.54-0.75), case-control study (RR: 0.62; 95% CI: 0.52-0.71), impact factor >3 (RR: 0.65; 95% CI: 0.56-0.75), impact factor <3 (RR: 0.64; 95% CI: 0.48-0.80), Newcastle-Ottawa Scale >7 (RR: 0.82; 95% CI: 0.66-0.97) and Newcastle-Ottawa Scale ≤7 (RR: 0.59; 95% CI: 0.49-0.68).Conclusion: Green tea consumption could be a protective factor for esophageal cancer.

Gastric Neuroendocrine Tumor and Duodenal Gastrinoma With Chronic Autoimmune Atrophic Gastritis.

Our group observed the first case of synchronous gastric neuroendocrine tumor (NET) and duodenal gastrinoma with autoimmune chronic atrophic gastritis (CAG), in the absence of Helicobacter pylori infection. Demographic, clinical, endoscopic, and pathologic data were abstracted from the electronic medical record at Mount Sinai Hospital from 2013 to 2015. The patient's anonymity was carefully protected, and informed consent was obtained for publication of protected health information. A 53-year-old woman with hypertension presented to Mount Sinai Hospital in June 2013 for a second opinion for management of gastric and duodenal NETs. After evaluation by gastroenterology and surgery, repeat upper endoscopy with ultrasound and fine-needle aspiration revealed multiple diminutive type I gastric NETs and 2 duodenal NETs, against a background of autoimmune CAG, with biopsy pathology negative for H. pylori. She subsequently underwent a transduodenal resection of the duodenal NETs, confirming low-grade, gastrin-positive, stage T2 duodenal NET. On routine follow-up over the next 2 years, clinical, radiographic, and endoscopic surveillance revealed no recurrent or metastatic gastric or duodenal disease. This first report of synchronous duodenal gastrinoma and gastric NET in the setting of autoimmune CAG can broaden our understanding of gastric NET pathophysiology.

Polypoid Undifferentiated Carcinoma With Osteoclast-like Giant Cells Arising in the Distal Common Bile Duct: A Rare Case Report.

BACKGROUND: Undifferentiated carcinoma with osteoclast-like giant cells (UC-OGC) in distal common bile duct (CBD) is a rare entity. CASE REPORT: This case report describes a 45-year-old male with a history of a choledochal cyst status post partial excision and cholecystectomy who presented with a mass in the remaining distal/intrapancreatic common bile duct. It was initially mistaken for post-surgery hematoma; however, the rapid growth raised concern for malignancy, and prompted a pancreaticoduodenectomy (Whipple) procedure. Macroscopic examination revealed a 5.5 cm polypoid mass grossly confined in the lumen of the distal CBD. Histology was consistent with UC-OGC, with minimal invasion into the polyp stalk and adjacent CBD wall. Immunohistochemistry demonstrated co-expression of CK7 and p40, normal/wild-type p53, and retained SMAD4 expression in tumor cells. Next-generation sequencing detected mutations at p.Q61H (c.183A>C) of KRAS and p.E545K (c.1633G>A) of PIK3CA, keeping in line with similarity to conventional cholangiocarcinoma. The patient remained disease-free after two years of follow-up without chemotherapy. CONCLUSION: To our knowledge, this is the first case report of UC-OGC presented as a polypoid mass in the distal CBD. It highlights the complex dynamism and controversial pathogenesis of this unique entity, which should be made aware to avoid diagnostic pitfalls.

Interobserver Agreement in the Diagnosis of Inflammatory Bowel Disease-Associated Neoplasia in China in Comparison to Subspecialized American Gastrointestinal Pathologists.

BACKGROUND: The aim of this study was to evaluate the interobserver variability in diagnosing inflammatory bowel disease (IBD)-associated neoplasia among practicing pathologists from China using telepathology, a practice of remote diagnostic consultation increasingly used nationally and internationally, and its comparison with the interpretation of subspecialized gastrointestinal (GI) pathologists from the United States (US). METHODS: Eight GI pathologists from the US and 4 pathologists from China with an interest in GI pathology participated in this study. A total of 50 colonic biopsies from patients with a clinical history of IBD from 8 medical centers in China were included. All microscopic slides in each case were digitized using an Aperio system. One pathologist (XL) reviewed the digitized full-slide images, and selected areas of interest were captured at low, medium, and high magnifications at a resolution of 1712 × 1072 pixels and saved as tagged image file format (TIFF) files on read-only DVD. Each pathologist evaluated the images and selected the most appropriate diagnostic category for each case (negative, indefinite, low-grade dysplasia [LGD], high-grade dysplasia [HGD], and carcinoma). A Fleiss' kappa coefficient (K) analysis was performed to determine interobserver agreement and the agreement of each pathologist from China with the consensus diagnosis (defined as diagnostic agreement by at least 4 participating US GI pathologists). RESULTS: There was substantial interobserver agreement among 4 pathologists from China on the interpretation of IBD-associated neoplasia (kappa value 0.68, 95% confidence interval: 0.56-0.78). A consensus diagnosis included negative (n = 22), LGD (n = 22), HGD (n = 3), carcinoma (n = 2), and indefinite for dysplasia (n = 1). Using consensus diagnoses as references, the agreement between each pathologist from China and the consensus diagnosis was substantial with kappa values ranging from 0.75 to 0.80. CONCLUSIONS: This study reveals substantial interobserver agreement for the interpretation of colonic neoplasia in IBD using digitized images among Chinese pathologists as well as between each Chinese pathologist and a consensus diagnosis generated by US GI pathologists.

Prediction of the histopathologic findings of intrahepatic cholangiocarcinoma: qualitative and quantitative assessment of diffusion-weighted imaging.

OBJECTIVE: To correlate qualitative and quantitative diffusion weighted imaging (DWI) characteristics of intrahepatic cholangiocarcinoma (ICC) with histopathologic tumour grade and fibrosis content. METHODS: Fifty-one patients (21M/30F; mean age 61y) with ICC and MRI including DWI were included in this IRB-approved multicentre retrospective study. Qualitative tumour features were assessed. Tumour apparent diffusion coefficient (ADC) mean, minimum, and normalized (nADCliver) values were computed. Tumour grade [well(G1), moderately(G2), or poorly differentiated(G3)] and tumour fibrosis content [minimal(1), moderate(2), or abundant(3)] were categorized pathologically. Imaging findings and ADC values were compared with pathologic measures. Utility of ADC values for predicting tumour grade was assessed using ROC analysis. RESULTS: 51 ICCs (mean size 6.5±1.1 cm) were assessed. 33/51(64%) of ICCs demonstrated diffuse hyperintensity and 15/51(29%) demonstrated target appearance on DWI. Infiltrative morphology (p=0.02) and tumour size (p=0.04) were associated with G3. ADCmean and nADCmean of G3 (1.32±0.47x10-3 mm2/sec and 0.97±0.95) were lower than G1+G2 (1.57±0.39x10-3 mm2/sec and 1.24±0.49; p=0.03 and p=0.04). ADCmean and nADCmean were inversely correlated with tumour grade (p<0.025). No correlation was found between ADC and tumour fibrosis content. AUROC, sensitivity and specificity of nADCmean for G3 versus G1+G2 were 0.71, 89.5% and 55.5%. CONCLUSION: ADC quantification has reasonable accuracy for predicting ICC grade. KEY POINTS: • ADC quantification was useful for predicting ICC tumour grade. • Infiltrative tumour morphology and size were associated with poorly differentiated ICCs. • ADC values depended more on ICC tumour grade than fibrosis content. • Ability to predict ICC tumour grade non-invasively could impact patient management.

Clinical Benefit from Trametinib in a Patient with Appendiceal Adenocarcinoma with a GNAS R201H Mutation.

We report the case of a patient with appendiceal adenocarcinoma with mucinous peritoneal carcinomatosis who was treated with trametinib upon identification of a GNAS R201H mutation by comprehensive genomic profiling. The molecular pathology of appendiceal neoplasms is reviewed, and the mechanistic basis underlying the clinical benefit as well as the subsequent course on trametinib that were observed in this patient are discussed.

Post-obstructive cyst formation in pancreas and cystic acinar transformation: Are they same?

Pancreatic "acinar cell cystadenoma" (PACA) is a rare benign pancreatic cystic lesion showing acinar cell differentiation. The neoplastic nature of PACA has been questioned and its exact pathogenesis remains unclear. To investigate that acinar cell differentiation is a non-specific metaplastic phenomenon that can occur in pancreatic ductal system, especially when chronically inflamed and dilated, and doesn't necessarily imply an acinar cell neoplasm, we retrospectively analyzed cases diagnosed as PACA and cases with post-obstructive cystic dilatation of pancreatic ducts for acinar cell differentiation using immunohistochemistry for trypsin. The etiology of obstruction was microscopic periductal pancreatic neuroendocrine tumors (PanNET) and pancreatic ductal adenocarcinomas (PDAC). All cases of post-obstructive cystic dilatation showed multiple varying sized cysts distal to the obstruction with histologic findings virtually identical to PACAs. The cysts in both conditions were lined by a single layer of non-dysplastic flattened to columnar ductal-type epithelium with areas of acinar cell differentiation. Trypsin immunohistochemistry confirmed presence of acinar cell differentiation in all cases of post-obstructive cysts and PACAs. Our results suggest that acinar cell differentiation is common in post-obstructive cyst formation, and changes are identical to PACAs. These findings further support the notion that PACA is a benign non-neoplastic cystic lesion with acinar cell differentiation. The findings also suggest that in cases with histology resembling "PACA" or showing diffuse ductal cystic dilation, careful gross examination should be carried out for a proximal obstructive lesion, which can be subtle and easily be missed on initial examination.

Gastrointestinal stromal tumor presenting as a right adnexal mass with histopathologic correlation.

The authors report and discuss a rare case of a gastrointestinal stromal tumor (GIST) in a 35-year-old female, which was pre-procedurally characterized as a right ovarian mass by magnetic resonance imaging (MRI) features. This manuscript reviews the imaging and clinical features of GISTs with pathologic correlation, and emphasizes how this entity may present a diagnostic challenge in certain anatomic regions owing in large part to its exophytic nature. This case is unique among similarly reported cases in that there was a "claw sign" with the right ovary, which provided convincing evidence of its point of origin.

Quantification of hepatocellular carcinoma heterogeneity with multiparametric magnetic resonance imaging.

Tumour heterogeneity poses a significant challenge for treatment stratification. The goals of this study were to quantify heterogeneity in hepatocellular carcinoma (HCC) using multiparametric magnetic resonance imaging (mpMRI), and to report preliminary data correlating quantitative MRI parameters with advanced histopathology and gene expression in a patient subset. Thirty-two HCC patients with 39 HCC lesions underwent mpMRI including diffusion-weighted imaging (DWI), blood-oxygenation-level-dependent (BOLD), tissue-oxygenation-level-dependent (TOLD) and dynamic contrast-enhanced (DCE)-MRI. Histogram characteristics [central tendency (mean, median) and heterogeneity (standard deviation, kurtosis, skewness) MRI parameters] in HCC and liver parenchyma were compared using Wilcoxon signed-rank tests. Histogram data was correlated between MRI methods in all patients and with histopathology and gene expression in 14 patients. HCCs exhibited significantly higher intra-tissue heterogeneity vs. liver with all MRI methods (P < 0.030). Although central tendency parameters showed significant correlations between MRI methods and with each of histopathology and gene expression, heterogeneity parameters exhibited additional complementary correlations between BOLD and DCE-MRI and with histopathologic hypoxia marker HIF1α and gene expression of Wnt target GLUL, pharmacological target FGFR4, stemness markers EPCAM and KRT19 and immune checkpoint PDCD1. Histogram analysis combining central tendency and heterogeneity mpMRI features is promising for non-invasive HCC characterization on the imaging, histologic and genomics levels.

BET N-terminal bromodomain inhibition selectively blocks Th17 cell differentiation and ameliorates colitis in mice.

T-helper 17 (Th17) cells have important functions in adaptor immunity and have also been implicated in inflammatory disorders. The bromodomain and extraterminal domain (BET) family proteins regulate gene transcription during lineage-specific differentiation of naïve CD4+ T cells to produce mature T-helper cells. Inhibition of acetyl-lysine binding of the BET proteins by pan-BET bromodomain (BrD) inhibitors, such as JQ1, broadly affects differentiation of Th17, Th1, and Th2 cells that have distinct immune functions, thus limiting their therapeutic potential. Whether these BET proteins represent viable new epigenetic drug targets for inflammatory disorders has remained an unanswered question. In this study, we report that selective inhibition of the first bromodomain of BET proteins with our newly designed small molecule MS402 inhibits primarily Th17 cell differentiation with a little or almost no effect on Th1 or Th2 and Treg cells. MS402 preferentially renders Brd4 binding to Th17 signature gene loci over those of housekeeping genes and reduces Brd4 recruitment of p-TEFb to phosphorylate and activate RNA polymerase II for transcription elongation. We further show that MS402 prevents and ameliorates T-cell transfer-induced colitis in mice by blocking Th17 cell overdevelopment. Thus, selective pharmacological modulation of individual bromodomains likely represents a strategy for treatment of inflammatory bowel diseases.

Synchronous pancreatic adenocarcinoma and intrahepatic cholangiocarcinoma arising in the context of intraductal papillary neoplasms.

Field cancerization theory provides rationale for the development of multiple pancreatic ductal and biliary lesions in a single patient through the development and accumulation of multiple genetic changes. Genetic alterations result in the development of precursor lesions including intraductal papillary mucinous neoplasms of the pancreas (IPMN), intraductal papillary neoplasm of the bile duct (IPN-B), and their malignant counterparts, pancreatic adenocarcinoma and cholangiocarcinoma. Although IPMN are frequently encountered, IPN-B are uncommon and the synchronous occurrence of both lesions is rare. We present a case of synchronous pancreatic adenocarcinoma and intrahepatic cholangiocarcinoma with histopathologic evidence of underlying precursor lesions, IPMN-P and IPN-B.

5-Fluorouracil targets thymidylate synthase in the selective suppression of TH17 cell differentiation.

While it is well established that treatment of cancer patients with 5-Fluorouracil (5-FU) can result in immune suppression, the exact function of 5-FU in the modulation of immune cells has not been fully established. We found that low dose 5-FU selectively suppresses TH17 and TH1 cell differentiation without apparent effect on Treg, TH2, and significantly suppresses thymidylate synthase (TS) expression in TH17 and TH1 cells but has a lesser effect in tumor cells and macrophages. Interestingly, the basal expression of TS varies significantly between T helper phenotypes and knockdown of TS significantly impairs TH17 and TH1 cell differentiation without affecting the differentiation of either Treg or TH2 cells. Finally, low dose 5-FU is effective in ameliorating colitis development by suppressing TH17 and TH1 cell development in a T cell transfer colitis model. Taken together, the results highlight the importance of the anti-inflammatory functions of low dose 5-FU by selectively suppressing TH17 and TH1 immune responses.