Benign Lymphoid Polyp of the Rectum Diagnosed and Treated With Endoscopic Submucosal Resection With a Ligation Device.

Benign lymphoid polyps of the rectum, also termed "Rectal tonsil" or "Pseudolymphoma," are submucosal tumor-like growths with localized hyperplasia of the lymphoid follicles and are often discovered incidentally during colonoscopy. Its diagnosis and differentiation from other submucosal tumors pose challenges owing to their similar endoscopic features. A 72-year-old woman presented with a positive fecal occult blood test, which led to the discovery of a 10-mm lower rectal tumor resembling a neuroendocrine tumor during colonoscopy. Upon closer examination, the lesion had a yellow submucosal appearance with dilated capillaries. Endoscopic submucosal resection with a ligation device (ESMR-L) was performed because the patient preferred immediate removal. Histopathological examination revealed lymphocytic infiltration with germinal center-containing lymphoid follicles, confirming the diagnosis of benign lymphoid polyp. Benign lymphoid polyps are often difficult to differentiate from carcinoid tumors and malignant lymphomas because the endoscopic findings are similar. Although preoperative endoscopic ultrasonography aids localization and characterization, definitive differentiation remains elusive and necessitates complete lesion resection. ESMR-L is a viable approach for diagnostic accuracy and therapeutic intervention, offering advantages in terms of procedural efficiency and patient care, particularly in cases involving submucosal rectal lesions.

Pazopanib-induced enteritis in a patient with renal cell carcinoma.

A 69-year-old woman presented to our department with the chief complaint of diarrhea. She had undergone left nephrectomy for renal cancer 14 years earlier. Three years earlier, metastasis was detected in the left retroperitoneal cavity, and pazopanib administration was initiated. In the 29th month after the start of chemotherapy, the patient developed diarrhea, and on the 31st month, computed tomography showed thickening of the intestinal wall. Colonoscopy revealed white villi, intramucosal hemorrhage in the terminal ileum, and rough inflammatory mucosa with inflammatory polyps extending from the transverse to the sigmoid colon. Suspecting pazopanib-induced enteritis, we discontinued the medication, and the diarrhea resolved within 3 days. On the 21st day after discontinuation, colonoscopy revealed that the inflammatory polyps had shrunk, and the inflammatory findings had improved. Biopsy of the white villi of the ileum revealed histiocytes. The patient resumed treatment with pazopanib at 400 mg/day and developed soft stool on the 7th day after resumption. Compared with other tyrosine-kinase inhibitor-induced enteritis cases, this case showed less bleeding and more extensive inflammatory findings. There are similarities as well as differences from cases of previously reported pazopanib-induced enteritis. The mechanisms and characteristics of this disease require further investigation.

Characteristics and Prognosis of Sporadic Neoplasias Detected in Patients with Ulcerative Colitis.

INTRODUCTION: Patients with ulcerative colitis (UC) develop not only UC-associated neoplasias but also sporadic neoplasias (SNs). However, few studies have described the characteristics of SNs in patients with UC. Therefore, this study aimed to evaluate the clinical features and prognosis of SNs in patients with UC. METHODS: A total of 141 SNs in 59 patients with UC, detected by surveillance colonoscopy at Hiroshima University Hospital between January 1999 and December 2021, were included. SNs were diagnosed based on their location, endoscopic features, and histopathologic findings along with immunohistochemical staining for Ki67 and p53. RESULTS: Of the SNs, 91.5% were diagnosed as adenoma and 8.5% were diagnosed as carcinoma (Tis carcinoma, 3.5%; T1 carcinoma, 5.0%). 61.0% of the SNs were located in the right colon, 31.2% were located in the left colon, and 7.8% were located in the rectum. When classified based on the site of the lesion, 70.9% of SNs occurred outside and 29.1% within the affected area. Of all SNs included, 95.7% were endoscopically resected and 4.3% were surgically resected. Among the 59 patients included, synchronous SNs occurred in 23.7% and metachronous multiple SNs occurred in 40.7% during surveillance. The 5-year cumulative incidence of metachronous multiple SNs was higher in patients with synchronous multiple SNs (54.2%) than in those without synchronous multiple SNs (46.4%). CONCLUSION: Patients with UC with synchronous multiple SNs are at a higher risk of developing metachronous multiple SNs and may require a closer follow-up by total colonoscopy than patients without synchronous SNs.

Encapsulating Peritoneal Sclerosis 43 Years after Distal Gastrectomy for Early Gastric Cancer.

We herein report a case of encapsulating peritoneal sclerosis (EPS) in a patient without chronic kidney disease after gastrectomy. A 69-year-old man underwent distal gastrectomy for early gastric cancer at 25 years old. After 43 years, he developed bowel obstruction and underwent enterolysis of the encapsulated small intestine. A pathological examination of the capsular membranes revealed inflammation, foam, and giant cells that destroyed foreign substances. The patient was discharged 1.5 months later. Foreign body reactions to surgical instruments used in gastrectomy are considered a cause of EPS. EPS due to foreign body reactions to surgical instruments should also be considered in such cases.

Investigating the Role of Tumor-Infiltrating Lymphocytes as Predictors of Lymph Node Metastasis in Deep Submucosal Invasive Colorectal Cancer: A Retrospective Cross-Sectional Study.

The role of tumor-infiltrating T cells (TILs) in colorectal cancer (CRC) and their significance in early-stage CRC remain unknown. We investigated the role of TILs in early-stage CRC, particularly in deep submucosal invasive (T1b) CRC. Sixty patients with CRC (20 each with intramucosal [IM group], submucosal invasive [SM group], and advanced cancer [AD group]) were randomly selected. We examined changes in TILs with tumor invasion and the relationship between TILs and LN metastasis risk. Eighty-four patients with T1b CRC who underwent initial surgical resection with LN dissection or additional surgical resection with LN dissection after endoscopic resection were then selected. TIL phenotype and number were evaluated using triple immunofluorescence for CD4, CD8, and Foxp3. All subtypes were more numerous according to the degree of CRC invasion and more abundant at the invasive front of the tumor (IF) than in the center of the tumor (CT) in the SM and AD groups. The increased Foxp3 cells at the IF and high ratios of Foxp3/CD4 and Foxp3/CD8 positively correlated with LN metastasis. In conclusion, tumor invasion positively correlated with the number of TILs in CRC. The number and ratio of Foxp3 cells at the IF may predict LN metastasis in T1b CRC.

Disease surveillance evaluation of primary small-bowel follicular lymphoma using capsule endoscopy images based on a deep convolutional neural network (with video).

BACKGROUND AND AIMS: Capsule endoscopy (CE) is useful in evaluating disease surveillance for primary small-bowel follicular lymphoma (FL), but some cases are difficult to evaluate objectively. This study evaluated the usefulness of a deep convolutional neural network (CNN) system using CE images for disease surveillance of primary small-bowel FL. METHODS: We enrolled 26 consecutive patients with primary small-bowel FL diagnosed between January 2011 and January 2021 who underwent CE before and after a watch-and-wait strategy or chemotherapy. Disease surveillance by the CNN system was evaluated by the percentage of FL-detected images among all CE images of the small-bowel mucosa. RESULTS: Eighteen cases (69%) were managed with a watch-and-wait approach, and 8 cases (31%) were treated with chemotherapy. Among the 18 cases managed with the watch-and-wait approach, the outcome of lesion evaluation by the CNN system was almost the same in 13 cases (72%), aggravation in 4 (22%), and improvement in 1 (6%). Among the 8 cases treated with chemotherapy, the outcome of lesion evaluation by the CNN system was improvement in 5 cases (63%), almost the same in 2 (25%), and aggravation in 1 (12%). The physician and CNN system reported similar results regarding disease surveillance evaluation in 23 of 26 cases (88%), whereas a discrepancy between the 2 was found in the remaining 3 cases (12%), attributed to poor small-bowel cleansing level. CONCLUSIONS: Disease surveillance evaluation of primary small-bowel FL using CE images by the developed CNN system was useful under the condition of excellent small-bowel cleansing level.

Low-Dose Alcohol-Induced Inhibition of Mouse Orthotopically Transplanted Tumors Is Associated with T-Cell Response.

INTRODUCTION: The effects of low-dose alcohol consumption on colorectal cancer development are not well understood. Epidemiological studies have reported that people who consume small amounts of alcohol have lower mortality rates than both nondrinkers and heavy drinkers. This phenomenon has been labeled the "J-curve effect" of alcohol. This study examined the effects of low-dose alcohol (0.5%, 1%, and 2%) on tumor growth in a transplant colon cancer model. METHODS: BALB/c and BALB/c nude mice were used to analyze T-cell immunity. Syngeneic CT26 murine colon cancer cells were implanted into the cecal wall, and the resulting T-cell immune effects were monitored. RESULTS: The growth of orthotopic tumors was markedly inhibited upon ingestion of low-dose (0.5%) alcohol compared with that in the control mice. In contrast, cells from the same line were injected into the cecal wall of nude mice, and tumor growth inhibition was not observed. Histopathological and RNA sequence analyses were performed to elucidate the mechanisms underlying tumor growth inhibition. An increase in tumor CD8+ T lymphocytes and changes in cytokine levels were observed. Microbiome analysis using 16S rRNA gene sequencing of cecal contents was performed and revealed Mucispirillum schaedleri and Clostridium cocleatum showed decreased and increased abundance, respectively, in the alcohol group. DISCUSSION/CONCLUSION: Ingesting a threshold amount of alcohol results in the infiltration of T lymphocytes, which may enhance immune responsiveness in mouse colorectal cancer models.

Acute necrotic disorder of the small intestine post-coronavirus disease-2019 vaccination.

The Pfizer-BioNTech coronavirus disease 2019 (COVID-19) vaccine is extensively used worldwide, and its safety has been proven. Herein, we report a case of an acute necrotic disorder in the small intestine post-COVID-19 vaccination. The patient developed severe abdominal pain the day after the first vaccination. Contrast-enhanced computed tomography showed extensive ileum wall thickening and ascites. Colonoscopy revealed a ring-shaped ulcer and stricture in the terminal ileum. Ileocecal resection was performed, and the patient did not have further episodes of a necrotic disorder in the small intestine. Although it is unknown if this event is associated with vaccination, and this occurrence also does not outweigh the efficacy and safety of the Pfizer-BioNTech COVID-19 vaccine, gastroenterologists need to be aware of this rare case, given its noteworthy timing.

Two cases of ulcerative colitis that developed while using abatacept.

Abatacept (ABT) is a recombinant fusion protein consisting of the Fc domain fragment of human IgG1 and the extracellular domain of human cytotoxic T lymphocyte antigen-4 (CTLA-4). The function of ABT is similar to that of CTLA-4, which selectively regulates T-cell activation by inhibiting the co-stimulation of CD80/CD86 on antigen-presenting cells and CD28 on T lymphocytes. ABT is used for the treatment of rheumatoid arthritis (RA) and juvenile idiopathic arthritis. We report two cases of ulcerative colitis (UC) that developed while using ABT. Case 1 is of a 58-year-old man who developed diarrhea and hematochezia 2 months after starting ABT therapy for RA. Case 2 is of a 66-year-old man who experienced hematochezia 15 months after starting ABT therapy for RA. In both cases, no obvious gastrointestinal symptoms were observed before ABT therapy was initiated. Colonoscopy after disease onset showed UC findings in both cases. The patients' condition improved following ABT withdrawal and treatment for UC. Several cases of UC development during ABT therapy have been reported. The complication of UC should be considered when diarrhea and hematochezia are observed in patients with RA being treated with CTLA-4Ig agents.

Vertical tumor margin of endoscopic resection for T1 colorectal carcinoma affects the prognosis of patients undergoing additional surgery.

BACKGROUND: Vertical tumor margin-negative T1 colorectal carcinoma (CRC) is an absolute curative condition following complete endoscopic resection (ER). However, the influence on prognosis in relation to vertical tumor margin is unclear. Therefore, we evaluated the influence of the distance from vertical tumor margin to resected specimen edge (vertical margin distance) of ER for T1b (submucosal invasion depth > 1000 µm) CRC on the prognosis of patients undergoing additional surgery after ER. METHODS: In total, 215 consecutive patients with T1b CRC who underwent additional surgery after ER at Hiroshima University Hospital between February 1992 and June 2019 were enrolled. We assessed 191 patients without lymph node metastases at the additional surgery. The specimens resected by ER were classified into three groups based on the vertical margin distance: patients with a vertical margin distance of ≥ 500 µm (Group A); patients with a vertical margin distance of < 500 µm (Group B); and patients with a positive vertical tumor margin (Group C). Subsequently, we evaluated the prognosis of the patients in relation to the clinicopathological characteristics among the three groups. RESULTS: There were no significant differences in clinicopathological characteristics among the three groups. Group A had a significantly higher recurrence-free 5-year survival rate than Groups B and C (100%, 84.5%, and 81.8%, respectively). Similarly, Group A had a significantly higher disease-specific 5-year survival rate than Group C (100% vs. 95.5%). CONCLUSIONS: Complete en bloc resection with sufficient submucosal layer from the invasive front (vertical margin distance > 500 µm) by ER for T1 CRC reduces the risk of metastatic recurrence after additional surgery.

Role of tumor-associated macrophages at the invasive front in human colorectal cancer progression.

Macrophages are an essential component of antitumor activity; however, the role of tumor-associated macrophages (TAMs) in colorectal cancer (CRC) remains controversial. Here, we elucidated the role of TAMs in CRC progression, especially at the early stage. We assessed the TAM number, phenotype, and distribution in 53 patients with colorectal neoplasia, including intramucosal neoplasia, submucosal invasive colorectal cancer (SM-CRC), and advanced cancer, using double immunofluorescence for CD68 and CD163. Next, we focused on the invasive front in SM-CRC and association between TAMs and clinicopathological features including lymph node metastasis, which were evaluated in 87 SM-CRC clinical specimens. The number of M2 macrophages increased with tumor progression and dynamic changes were observed with respect to the number and phenotype of TAMs at the invasive front, especially at the stage of submucosal invasion. A high M2 macrophage count at the invasive front was correlated with lymphovascular invasion, low histological differentiation, and lymph node metastasis; a low M1 macrophage count at the invasive front was correlated with lymph node metastasis. Furthermore, receiver operating characteristic curve analysis revealed that the M2/M1 ratio was a better predictor of the risk of lymph node metastasis than the pan-, M1, or M2 macrophage counts at the invasive front. These results suggested that TAMs at the invasive front might play a role in CRC progression, especially at the early stages. Therefore, evaluating the TAM phenotype, number, and distribution may be a potential predictor of metastasis, including lymph node metastasis, and TAMs may be a potential CRC therapeutic target.

Clinical usefulness of linked color imaging for evaluation of endoscopic activity and prediction of relapse in ulcerative colitis.

PURPOSE: In the treatment of ulcerative colitis (UC), accurate evaluation of UC activity is important to achieve mucosal healing. We sought to investigate the clinical utility of linked color imaging (LCI) for the evaluation of endoscopic activity and prediction of relapse in UC patients. METHODS: We enrolled 72 consecutive UC patients in remission who underwent colonoscopy at our institution between September 2016 and October 2018. The relationship between the presence of redness in white light imaging (WLI) and LCI and histopathological inflammation (Geboes score: GS) at 238 biopsy sites was examined. We also assessed the presence or absence of planar redness in the entire rectum as ± and classified the patients into three groups according to the combination of WLI/LCI: A: WLI-/LCI-, B: WLI-/LCI+, and C: WLI+/LCI+. The relationship between WLI/LCI classification and relapse in 64 patients followed up for more than 12 months from initial colonoscopy was assessed and compared to the Mayo endoscopic subscore (MES). RESULTS: A GS of 0 or 1 accounted for 89% of WLI/LCI non-redness sites, while a GS of 2 or 3 accounted for 42% of WLI non-redness/LCI redness sites. LCI findings were significantly correlated with GS. During follow-up, 10 patients in group C and four patients in group B relapsed, but none in group A. Non-relapse rates were significantly correlated with WLI/LCI classification, but not with MES. CONCLUSION: LCI is a useful modality for accurate assessment of endoscopic activity and prediction of relapse in UC by detecting mild inflammation unrecognizable by WLI.

Preceding endoscopic submucosal dissection in submucosal invasive gastric cancer patients does not impact clinical outcomes.

Submucosal deep invasion of gastric cancer (T1b2; depth of submucosal invasion ≥ 500 µm) is a risk factor for lymph node metastasis and, thus, is one of the criteria for curative treatment. Our aim was to evaluate the specific influence of endoscopic submucosal dissection (ESD) on the prognosis of patients with T1b2 gastric cancer. This was a retrospective analysis of 248 consecutive patients, with 252 pT1b2 gastric cancer lesions, who underwent ESD prior to additional surgery (Group A, n = 101) or surgery only (Group B, n = 147). After propensity score-matching (for sex, age, tumor diameter and gross type), we compared pathological characteristics between the 2 groups and the prognosis over a follow-up period ≥ 60 months. Compared to Group B, patients in Group A were older, with a higher proportion of men. The proportion of depressed and undifferentiated type tumors was greater in Group B than A, with larger tumor size and depth of submucosal invasion as well. There was no incidence of local recurrence, but distant metastasis was identified in 5% of cases in Group A and 3% in Group B. After propensity score-matching, there were no difference in the 5-year overall survival rate between Group A and B (87.5% vs. 91.2%, respectively), nor in the 5-year disease-specific survival rate (96.3% vs. 96.4%, respectively). ESD prior to surgery for T1b2 gastric cancer did not adversely affect clinical outcomes after additional surgery.

Long-Term Outcomes after Endoscopic Submucosal Dissection for Ulcerative Colitis-Associated Dysplasia.

INTRODUCTION: The Surveillance for Colorectal Endoscopic Neoplasia Detection and Management in Inflammatory Bowel Disease Patients: International Consensus Recommendations guidelines recommend surveillance colonoscopy instead of colectomy after the complete removal of "endoscopically resectable" dysplastic lesions in ulcerative colitis (UC). There are no studies on long-term outcomes of endoscopic submucosal dissection (ESD) for UC-associated neoplasia (UCAN). We aimed to evaluate the clinical outcomes of ESD for UC-associated dysplasia (UCAD) during long-term follow-up. METHODS: We retrospectively enrolled 17 consecutive UC patients with 22 UCADs, who underwent initial ESD or total proctocolectomy at the Hiroshima University Hospital. The clinicopathological features of the patients and neoplasias and clinical outcomes of ESD were evaluated and compared with those of total proctocolectomy. RESULTS: UCAD in the ESD and total proctocolectomy groups was mostly noted on the left side of the colon, and most lesions were superficial macroscopic lesions. In the ESD group, en bloc resection and histological complete resection rates were 83 and 67%, respectively. One patient died of malignant melanoma; however, none of the patients died of UC-associated carcinoma in both groups. Metachronous neoplasias developed in 5 of the 7 patients in the ESD group. Among the 5 patients with metachronous UCAN, 4 finally underwent total proctocolectomy and 1 underwent additional ESD. CONCLUSIONS: ESD for UCAD is a useful method for total excisional biopsy. UC patients with UCAD resected by ESD have a high risk of developing metachronous UCAN during the follow-up period.

Clinical significance of immunohistochemical lymphovascular evaluation to determine additional surgery after endoscopic submucosal dissection for colorectal T1 carcinoma.

PURPOSE: The Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines indicate lymphovascular invasion-evaluated by hematoxylin and eosin (HE) staining-as a surgical requirement after endoscopic submucosal dissection (ESD) in T1 colorectal carcinoma (CRC) patients; however, immunohistochemical evaluation may be superior. This study aimed to clarify the significance of immunohistochemical lymphovascular evaluation as an indicator for additional surgery of T1 CRC after ESD, and assessed the guidelines' adequacy, even when evaluating through immunostaining. METHODS: Patients with T1 CRC who underwent ESD were enrolled across three institutions between January 2012 and December 2017. Immunohistochemical lymphovascular evaluation was performed. Clinicopathological features, pathological evaluations, and surgery indications were recorded. Univariate and multivariate logistic regression identified risk factors for lymph node (LN) metastasis of T1 CRC after ESD. RESULTS: Among 370 patients with T1 CRC, recurrence, 5-year overall survival, and 5-year disease specific survival rates were 1.6%, 94.6%, and 99.5%, respectively. Six patients (1.6%) experienced recurrence, five of whom underwent additional surgery. Those with no risk factors did not exhibit recurrence. A total of 215 (58.1%) patients underwent additional surgery after ESD, 21 (9.7%) of whom exhibited LN metastasis. Among 16 patients who underwent additional surgery due to lymphovascular invasion, three (18.8%) had LN metastasis. Multivariate logistic regression analysis identified lymphatic invasion as a significant risk factor for LN metastasis (odds ratio 3.9, 95% confidence interval 1.0-14.6, P = 0.0421). CONCLUSIONS: The JSCCR guidelines have clinical validity, and immunohistochemical lymphatic evaluation findings potentially predict LN metastasis for T1 CRC after ESD.

Genomic Landscape of Early-stage Colorectal Neoplasia Developing From the Ulcerative Colitis Mucosa in the Japanese Population.

BACKGROUNDS: Colorectal neoplasias (CRN)s developing from the ulcerative colitis (UC) mucosa include both colitic and sporadic neoplasias. Although several genomic analyses of advanced colitis-associated cancer are available, such studies do not distinguish between colitic and sporadic cases, and the early-stage genomic alterations involved in the onset of colitic cancer remain unclear. To address this, we performed a genomic analysis of early-stage CRN developing from the UC mucosa (CRNUC). METHODS: We extracted DNA from 36 early-stage CRNUCs (T1 cancer, 10; dysplasia, 26) from 32 UC patients and performed targeted sequencing of 43 genes commonly associated with colitis-associated cancer and compared the results with sequencing data from the Japanese invasive colitis-associated cancer. RESULTS: The most frequently mutated gene in the CRNUC cohort was APC (mutated in 47.2% of the cases), followed by TP53 (44.4%), KRAS (27.8%), and PRKDC (27.8%). None of the TP53 mutations occurred at any of the hotspot codons. Although the TP53 mutations in The Cancer Genome Atlas of Colorectal Cancer were dispersed throughout the gene, those detected here in CRNUC cases were concentrated in the amino terminal part of the DNA-binding domain. Interestingly, the mutations in KRAS and TP53 were mutually exclusive in CRNUC, and CRNUCs with KRAS mutations had histologically serrated lesions in the gland duct. Mayo endoscopic subscore was higher in TP53-mutated CRNUCs and lower in KRAS-mutated CRNUCs. CONCLUSIONS: Our findings suggest that early-stage CRNUC can be classified into 2 groups: those developing through the carcinogenic pathway via TP53 mutations and those developing through the carcinogenic pathway via KRAS mutations.

PARP6 suppresses the proliferation and metastasis of hepatocellular carcinoma by degrading XRCC6 to regulate the Wnt/ß-catenin pathway.

PARP6 belongs to the mono-ADP-ribosyltransferase family and has been shown to be involved in the genesis and development of some tumours. However, the role of PARP6 in hepatocellular carcinoma (HCC) development remains to be fully elucidated. In the current study, we demonstrated that PARP6 was expressed at a low level in HCC cells and was negatively related to the degree of tumour differentiation. Additionally, silencing PARP6 led to an increase in the proliferation, invasion and migration ability of HCC cells in both in vitro and in vivo assays. Conversely, an elevation in the PARP6 expression level had the opposite effect. Through gene chip analysis combined with experimental verification, we confirmed that PARP6 can inhibit the expression of XRCC6 by inducing degradation and thus affect the Wnt/ß-Catenin signalling pathway, which contributes to the suppression of HCC. Further mechanistic investigation demonstrated that the ubiquitin ligase HDM2 can interact with PARP6 and XRCC6, and mediated the regulatory effect of PARP6 on XRCC6 degradation. Taking together, PARP6 appears to inhibit HCC progression through the XRCC6/Wnt/ß-catenin signal axis and could be used as a biomarker for the clinical monitoring of HCC development.

Neoplastic meningitis due to colorectal cancer.

Herein, we describe a rare case of neoplastic meningitis in a 54-year-old male with a history of colorectal cancer. He first noticed a loss of sensation in his left thigh along with back pain. Magnetic resonance imaging showed a tumor lesion in the cauda equina. The tumor was surgically resected and pathologically diagnosed as a metastatic tumor of the descending colon cancer for which he had undergone resection a year earlier. The patient was treated with chemotherapy using capecitabine, oxaliplatin, and cetuximab. During chemotherapy, his tumor markers decreased and magnetic resonance imaging showed tumor shrinkage, but he became aware of neurological symptoms such as hearing loss, tinnitus, and headache. The patient's condition suddenly worsened during the 5th course of chemotherapy and he died 5 months after the diagnosis. Neoplastic meningitis occurs in 4-15% of patients with solid tumors, but it is rarely seen in colorectal cancer. It should be considered when a patient with a history of cancer has back pain or neurological symptoms. The progression of neoplastic meningitis is fast and it has a poor prognosis. Diagnosis in the early stages is important to prevent progression of neurological symptoms and to provide the most effective treatment.

m6A demethylase ALKBH5 inhibits pancreatic cancer tumorigenesis by decreasing WIF-1 RNA methylation and mediating Wnt signaling.

BACKGROUND: Pancreatic cancer is one of the most lethal types of cancer with extremely poor diagnosis and prognosis, and chemo-resistance remains a major challenge. The dynamic and reversible N6-methyladenosine (m6A) RNA modification has emerged as a new layer of epigenetic gene regulation. METHODS: qRT-PCR and IHC were applied to examine ALKBH5 levels in normal and pancreatic cancer tissues. Cancer cell proliferation and chemo-resistance were evaluated by clonogenic formation, chemosensitivity detection, and Western blotting assays. m6A-seq was performed to identify target genes. We evaluated the inhibitory effect of ALKBH5 in both in vivo and in vitro models. RESULTS: Here, we show that m6A demethylase ALKBH5 is downregulated in gemcitabine-treated patient-derived xenograft (PDX) model and its overexpression sensitized pancreatic ductal adenocarcinoma (PDAC) cells to chemotherapy. Decreased ALKBH5 levels predicts poor clinical outcome in PDAC and multiple other cancers. Furthermore, silencing ALKBH5 remarkably increases PDAC cell proliferation, migration, and invasion both in vitro and in vivo, whereas its overexpression causes the opposite effects. Global m6A profile revealed altered expression of certain ALKBH5 target genes, including Wnt inhibitory factor 1 (WIF-1), which is correlated with WIF-1 transactivation and mediation of the Wnt pathway. CONCLUSIONS: Our work uncovers the tumor suppressive and chemo-sensitizing function for ALKBH5, which provides insight into critical roles of m6A methylation in PDAC.