Detection Rates of Non-Cavitary Epithelioid Cell Granuloma by Gastrointestinal Biopsy in Patients with Treatment-Naïve Crohn's Disease.

Introduction: Detecting non-cavitary epithelioid cell granuloma by gastrointestinal biopsy is important in the initial diagnosis of Crohn's disease (CD). In the present study, we aimed to determine the rate of granuloma detection by gastrointestinal biopsy according to the number of biopsies performed. Methods: The present study included patients newly diagnosed with CD at our hospital between April 2017 and March 2023. During endoscopic examinations, biopsy specimens were taken from affected lesions. Initially, one section per biopsy was examined to detect granuloma. In cases where no granulomas were detected, step sections were additionally prepared and examined. The rate of granuloma detection by gastrointestinal biopsy was retrospectively examined. Results: A total of 30 patients with a new diagnosis of CD were included in this study. In total, 284 gastrointestinal biopsies were performed in 29 cases. The rate of granuloma detection by gastrointestinal biopsy per case was 58.6% (17 out of 29 cases). The rate of granuloma detection by gastrointestinal biopsy per biopsy was 6.0% (17 out of 284 biopsies) on initial histological examination and 11.6% (33 out of 284 biopsies) following examination of step sections. The rate of granuloma detection was significantly improved by performing histological examination of step sections compared with initial examinations (p < 0.05). Conclusion: The rate of granuloma detection per biopsy was 11.6%, even after histological examination of step sections. These results indicate that performing multiple intestinal biopsies and assessing for the presence of granuloma using multiple section examinations are required in the initial diagnosis of CD.

Diffuse pancreatic parenchymal atrophy, an imaging finding predictive of the development of pancreatic ductal adenocarcinoma: A case-control study.

Background and Aim: Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer, partly because its early detection is difficult. This study aimed to identify computed tomography (CT) findings associated with PDAC prior to diagnosis. Methods: Past CT images were retrospectively collected from the PDAC group (n = 54) and the control group (n = 90). The following imaging findings were compared: pancreatic mass, main pancreatic duct (MPD) dilatation with or without cutoff, cyst, chronic pancreatitis with calcification, partial parenchymal atrophy (PPA), and diffuse parenchymal atrophy (DPA). In the PDAC group, CT findings were examined during the pre-diagnostic period and 6-36 months and 36-60 months before diagnosis. Multivariate analyses were performed using logistic regression. Results: MPD dilatation with cutoff (P < 0.0001) and PPA (P = 0.023) were identified as significant imaging findings 6-36 months before diagnosis. DPA was identified as a novel imaging finding at 6-36 months (P = 0.003) and 36-60 months (P = 0.009) before diagnosis. Conclusion: DPA, MPD dilatation with cutoff, and PPA were identified as imaging findings associated with pre-diagnostic PDAC.

BEX2 is poor prognostic factor and required for cancer stemness in gastric cancer.

Gastric cancer is the fifth most common malignancy worldwide. However, targeted therapy for advanced gastric cancer is still limited. Here, we report BEX2 (Brain expressed X-linked 2) as a poor prognostic factor in two gastric cancer cohorts. BEX2 expression was increased in spheroid cells, and its knockdown decreased aldefluor activity and cisplatin resistance. BEX2 was found to upregulate CHRNB2 (Cholinergic Receptor Nicotinic Beta 2 Subunit) expression, a cancer stemness-related gene, in a transcriptional manner, and the knockdown of which also decreases aldefluor activity. Collectively, these data are suggestive of the role of BEX2 in the malignant process of gastric cancer, and as a promising therapeutic target.

Direct peroral cholangioscopy with red dichromatic imaging 3 detected the perihilar margin of superficial papillary extension in a patient with intraductal papillary neoplasm of the bile duct.

Intraductal papillary neoplasms of the bile duct (IPNB) are a tumor derived from bile duct epithelium that tends to spread laterally and non-invasively. Surgery is the first-choice treatment for IPNB. It is extremely important to accurately diagnose the extent of lateral tumor extension. Although peroral cholangioscopy (POCS) is a potentially useful modality for detecting tumor range with direct observation, poor image quality is a limitation of POCS. Recently, a new-generation endoscopy system (EVIS X1) was equipped with functions such as red dichromatic imaging to improve image quality. A 75-year-old man with cholangitis was referred to our department. Various imaging studies showed a mass in the middle to lower bile duct and dilatation of the common bile duct and the intrahepatic bile duct. Endoscopic retrograde cholangiopancreatography was performed. A biopsy of the main tumor in the lower common bile duct revealed IPNB. It was difficult to determine the extent of superficial tumor extension with modalities such as contrast-enhanced computed tomography, magnetic resonance imaging, and endoscopic ultrasonography but the detailed evaluation was possible using POCS with red dichromatic imaging 3. The patient underwent hepatopancreatoduodenectomy. This case suggests the usefulness of direct observation using POCS with red dichromatic imaging 3 to determine the range of IPNB.

Treatment strategy after noncurative endoscopic resection for early gastric cancers in patients aged ≥ 85 years: a multicenter retrospective study in a highly aged area of Japan.

BACKGROUND: The guidelines recommend additional gastrectomy after noncurative endoscopic resection for early gastric cancers (EGCs). However, no additional treatment might be acceptable in some patients aged ≥ 85 years. We aimed to identify this patient group using the data in a highly aged area. METHODS: We enrolled patients aged ≥ 85 years after noncurative endoscopic resection for EGCs at 30 institutions of the Tohoku district in Japan between 2002 and 2017. Treatment selection and prognosis after noncurative endoscopic resection were investigated. Fourteen candidates were evaluated using the Cox model to identify risk factors for poor overall survival (OS) in patients with no additional treatment. RESULTS: Of 1065 patients aged ≥ 85 years, 143 underwent noncurative endoscopic resection. Despite the guidelines' recommendation, 88.8% of them underwent no additional treatment. The 5-year OS rates in those with additional gastrectomy and those with no additional treatment were 63.1 and 65.2%, respectively. Multivariate analysis showed independent risk factors for poor OS in patients with no additional treatment were the high-risk category in the eCura system (hazard ratio [HR], 2.91), Charlson comorbidity index (CCI) ≥ 3 (HR, 2.78), and male (HR, 2.04). In patients with no additional treatment, nongastric cancer-specific survival was low (69.0% in 5 years), whereas disease-specific survival rates were very high in the low- and intermediate-risk categories of the eCura system (100.0 and 97.1%, respectively, in 5 years). CONCLUSIONS: No additional treatment may be acceptable in the low- and intermediate-risk categories of the eCura system in patients aged ≥ 85 years with noncurative endoscopic resection for EGCs.

Prediction model of 3-year survival after endoscopic submucosal dissection for early gastric cancer in elderly patients aged ≥ 85 years: EGC-2 model.

PURPOSE: Little is known about the prognostic factors for survival after endoscopic submucosal dissection (ESD) in elderly patients with early gastric cancer (EGC). The aim of this study is to determine prognostic factors and a prediction model of 3-year survival after ESD for EGC in patients aged ≥ 85 years. METHODS: We retrospectively evaluated the clinical outcomes of 740 patients with EGC aged ≥ 85 years, who were treated by ESD at 30 institutions in Japan. Overall survival (OS) and disease-specific survival (DSS) were calculated with the Kaplan-Meier method. Prediction models for 3-year OS after ESD were estimated using the Cox proportional hazards model based on Uno's C-statistics. RESULTS: During the follow-up period, 309 patients died of any cause and 10 patients died of gastric cancer. OS and DSS after 3 years were 82.7% and 99.2%, respectively. No significant differences in OS were found among curability categories. The Cox proportional hazards model revealed the geriatric nutritional risk index (GNRI) and the Charlson comorbidity index (CCI) to be predictors of 3-year survival. We established a final model (EGC-2 model) expressed by GNRI - (2.2×CCI) with a cutoff value of 96. The overall survival rate was significantly lower in the model value < 96 group than in the model value ≥ 96 group (P < 0.001). CONCLUSIONS: The prediction model using GNRI and CCI will be useful to support decision-making for the treatment of EGC in elderly patients aged ≥ 85 years.

RELA is required for CD271 expression and stem-like characteristics in hypopharyngeal cancer.

CD271 (also referred to as nerve growth factor receptor or p75NTR) is expressed on cancer stem cells in hypopharyngeal cancer (HPC) and regulates cell proliferation. Because elevated expression of CD271 increases cancer malignancy and correlates with poor prognosis, CD271 could be a promising therapeutic target; however, little is known about the induction of CD271 expression and especially its promoter activity. In this study, we screened transcription factors and found that RELA (p65), a subunit of nuclear factor kappaB (NF-κB), is critical for CD271 transcription in cancer cells. Specifically, we found that RELA promoted CD271 transcription in squamous cell carcinoma cell lines but not in normal epithelium and neuroblastoma cell lines. Within the CD271 promoter sequence, region + 957 to + 1138 was important for RELA binding, and cells harboring deletions in proximity to the + 1045 region decreased CD271 expression and sphere-formation activity. Additionally, we found that clinical tissue samples showing elevated CD271 expression were enriched in RELA-binding sites and that HPC tissues showed elevated levels of both CD271 and phosphorylated RELA. These data suggested that RELA increases CD271 expression and that inhibition of RELA binding to the CD271 promoter could be an effective therapeutic target.

Self-expandable metal stents have longer patency and less cholangitis than inside stents in malignant perihilar biliary obstruction.

Background and Aim: Outcomes of an inside stent (IS, a plastic stent placed above the sphincter of Oddi) versusa self-expandable metal stent (SEMS) for the drainage of malignant perihilar biliary obstruction has not been fully studied. The drainage strategy for perihilar biliary obstruction is difficult and should be clarified. Methods: Clinical data of patients who underwent biliary drainage for malignant perihilar biliary obstruction with IS or SEMS between April 2016 and September 2021 at our institution were retrospectively examined. Outcomes, including the time to recurrent biliary obstruction (TRBO), survival, and incidence of recurrent biliary obstruction with concomitant cholangitis (RBOC), were retrospectively evaluated. Results: Median TRBO was 280 (95% confidence interval [CI], 110-not available) days in the SEMS group (n = 24) and 113 (95% CI, 74-192) days in the IS group (n = 25) (P = 0.043). Among the patients with perihilar cholangiocarcinoma, the median survival of the two groups was comparable, namely 330 days in the SEMS group and 359 days in the IS group (P = 0.46). The incidence of RBOC at re-intervention was significantly higher in patients with ISs (83.9%) than in those with SEMSs (0%) (P = 0.00004). Conclusions: TRBO was significantly longer in the SEMS group. Regardless of whether SEMSs or ISs were placed during the first intervention, patient survival was similar. Using easily removable ISs first might be a reasonable option because TRBO with SEMSs was shorter than patient survival. Cholangitis is a problem associated with the placement of IS.

Neutrophil Infiltration and Acinar-ductal Metaplasia Are the Main Pathological Findings in Pembrolizumab-induced Pancreatitis.

The histopathological findings of immune checkpoint inhibitor (ICI)-induced pancreatitis have rarely been reported. A 56-year-old man with squamous cell carcinoma of the lung with bone metastasis was being treated with pembrolizumab, an anti-programmed cell death protein-1 antibody. After 13 doses, he was referred to our department due to pancreatitis. Despite characteristic symptoms of acute pancreatitis, imaging findings were similar to those of autoimmune pancreatitis. However, a histological examination showed neutrophil-based inflammatory cell infiltration and acinar-ductal metaplasia. Immunostaining showed CD8-positive T lymphocyte infiltration. This case revealed the characteristic histopathology of pembrolizumab-induced pancreatitis, which was previously poorly understood.

PP6 deficiency in mice with KRAS mutation and Trp53 loss promotes early death by PDAC with cachexia-like features.

To examine effects of PP6 gene (Ppp6c) deficiency on pancreatic tumor development, we developed pancreas-specific, tamoxifen-inducible Cre-mediated KP (KRAS(G12D) plus Trp53-deficient) mice (cKP mice) and crossed them with Ppp6cflox / flox mice. cKP mice with the homozygous Ppp6c deletion developed pancreatic tumors, became emaciated and required euthanasia within 150 days of mutation induction, phenotypes that were not seen in heterozygous or wild-type (WT) mice. At 30 days, a comparative analysis of genes commonly altered in homozygous versus WT Ppp6c cKP mice revealed enhanced activation of Erk and NFκB pathways in homozygotes. By 80 days, the number and size of tumors and number of precancerous lesions had significantly increased in the pancreas of Ppp6c homozygous relative to heterozygous or WT cKP mice. Ppp6c-/- tumors were pathologically diagnosed as pancreatic ductal adenocarcinoma (PDAC) undergoing the epithelial-mesenchymal transition (EMT), and cancer cells had invaded surrounding tissues in three out of six cases. Transcriptome and metabolome analyses indicated an enhanced cancer-specific glycolytic metabolism in Ppp6c-deficient cKP mice and the increased expression of inflammatory cytokines. Individual Ppp6c-/- cKP mice showed weight loss, decreased skeletal muscle and adipose tissue, and increased circulating tumor necrosis factor (TNF)-α and IL-6 levels, suggestive of systemic inflammation. Overall, Ppp6c deficiency in the presence of K-ras mutations and Trp53 gene deficiency promoted pancreatic tumorigenesis with generalized cachexia and early death. This study provided the first evidence that Ppp6c suppresses mouse pancreatic carcinogenesis and supports the use of Ppp6c-deficient cKP mice as a model for developing treatments for cachexia associated with pancreatic cancer.

Establishment of a monoclonal antibody against glycosylated CD271 specific for cancer cells in immunohistochemistry.

Various proteins are highly expressed in cancer (e.g., epidermal growth factor receptor); however, the majority are also expressed in normal cells, although they may differ in expression intensity. Recently, we reported that CD271 (nerve growth factor receptor), a glycosylated protein, increases malignant behavior of cancer, particularly stemlike phenotypes in squamous cell carcinoma (SCC). CD271 is expressed in SCC and in normal epithelial basal cells. Glycosylation alterations generally occur in cancer cells; therefore, we attempted to establish a cancer-specific anti-glycosylated CD271 antibody. We purified recombinant glycosylated CD271 protein, immunized mice with the protein, and screened hybridomas using an ELISA assay with cancer cell lines. We established a clone G4B1 against CD271 which is glycosylated with O-glycan and sialic acid. The G4B1 antibody reacted with the CD271 protein expressed in esophageal cancer, but not in normal esophageal basal cells. This specificity was confirmed in hypopharyngeal and cervical cancers. G4B1 antibody recognized the fetal esophageal epithelium and Barrett's esophagus, which possess stem cell-like characteristics. In conclusion, G4B1 antibody could be useful for precise identification of dysplasia and cancer cells in SCC.

Hypereosinophilia with Hepatic Nodule Formation Caused by Ganoderma lucidum.

A 61-year-old man who underwent surgery for rectal adenocarcinoma developed multiple hepatic nodules. The nodules were 1-3 cm without a capsular structure or contrast enhancement on computed tomography/magnetic resonance imaging, findings that were atypical for adenocarcinoma metastases. A biopsy showed the aggregation of eosinophils without larval bodies, ova, or granulomas. Laboratory tests showed a marked increase in eosinophils and a slight liver enzyme elevation. He had been taking the commercial herbal medicine Ganoderma lucidum for his liver function. After discontinuing G. lucidum, the eosinophil counts and liver enzyme levels rapidly resolved, and the nodules disappeared completely. This is a rare case of hypereosinophilia with hepatic nodules reactive to herbal medicine rather than a parasitic infection.

A Gas-forming Liver Abscess with Massive Bleeding into the Abscess Cavity Due to a Ruptured Inferior Phrenic Artery.

An 88-year-old woman developed a huge abscess, forming an air-fluid level in the right lobe of the liver. A pigtail catheter was placed and drained thick pus with putrid odor from the abscess cavity. Gram-positive rods were detected in the pus, which were subsequently determined to be Clostridium perfringens by culture. She developed hemorrhaging in the abscess cavity when the right inferior phrenic artery was damaged by inflammation that had spread from the abscess. Emergency transarterial embolization with gelatin sponges was performed, and the bleeding ceased. We herein report a rare case of liver abscess that caused inferior phrenic artery injury, resulting in bleeding.

Nasopancreatic Drainage for 4 Patients during the Early Phase of Acute Pancreatitis.

We encountered 4 patients with acute pancreatitis (AP) of various etiologies and coexisting acute cholangitis who underwent endoscopic biliary stenting (EBS) and nasopancreatic drainage (NPD) via endoscopic retrograde cholangiopancreatography (ERCP) during the early phase of AP. ERCP is performed to treat acute cholangitis even in the context of AP. However, in difficult cases, accidental contrast media injection or guidewire insertion into the pancreatic duct can happen during ERCP for the purpose of EBS. It is concerned that cannulation injury and increased pancreatic duct pressure can exacerbate existing AP. Because pancreatic guidewire-associated techniques were required for all of them due to difficult biliary cannulation, we performed a NPD catheter placement using the pancreatic guidewire to decompress the pancreatic duct to prevent further exacerbating AP. Surprisingly, all patients dramatically improved without systemic or local complications. NPD could be performed without any adverse events and did not worsen the course of AP. Early decompression of a pancreatic duct using NPD may rather improve AP that had already developed. Further prospective research is needed to confirm our observations.

Immunoglobulin G4-Related Hepatic Inflammatory Pseudotumor Diagnosed with Endoscopic Ultrasound-Guided Fine-Needle Biopsy.

A 71-year-old man with obstructive jaundice was referred to our department. He underwent cholangiojejunostomy 15 years ago for palliative drainage. At that time, he had obstructive jaundice caused by an unresectable pancreatic head tumor. Contrast-enhanced computed tomography (CE-CT) now revealed a mass with low enhancement in the hepatic hilum that occluded the hilar bile duct and infiltrated extensively along the portal vein and hepatic artery. CE-CT also showed marked atrophy of the left hepatic lobe. No swelling or tumors were observed in the pancreas. Serum immunoglobulin G4 (IgG4) levels were as high as 465 mg/dL. Endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) was performed targeting the hepatic hilar lesion. Immunohistological results of the biopsy specimens suggested that the lesion was an IgG4-related hepatic inflammatory pseudotumor (IPT) with no atypical cells. Steroid treatment resulted in rapid clinical improvement. This case suggested the usefulness of EUS-FNB for diagnosing IgG4-related hepatic hilar IPT.

BEX2 is required for maintaining dormant cancer stem cell in hepatocellular carcinoma.

Cancer stem cells (CSCs) are responsible for therapy resistance and share several properties with normal stem cells. Here, we show that brain-expressed X-linked gene 2 (BEX2), which is essential for dormant CSCs in cholangiocarcinoma, is highly expressed in human hepatocellular carcinoma (HCC) lesions compared with the adjacent normal lesions and that in 41 HCC cases the BEX2high expression group is correlated with a poor prognosis. BEX2 localizes to Ki67-negative (nonproliferative) cancer cells in HCC tissues and is highly expressed in the dormant fraction of HCC cell lines. Knockdown of BEX2 attenuates CSC phenotypes, including sphere formation ability and aldefluor activity, and BEX2 overexpression enhances these phenotypes. Moreover, BEX2 knockdown increases cisplatin sensitivity, and BEX2 expression is induced by cisplatin treatment. Taken together, these data suggest that BEX2 induces dormant CSC properties and affects the prognosis of patients with HCC.

Suggestive Diagnostic Process in a Case of Multiple Myeloma with Gastrointestinal Immunoglobulin Light-Chain Amyloidosis Accompanied by Protein-Losing Enteropathy.

Multiple myeloma is a type of plasma cell neoplasm that produces monoclonal immunoglobulin. Multiple myeloma is known to cause immunoglobulin light-chain (AL) amyloidosis, which frequently involves the kidney and heart. Bone pain or fractures caused by osteolytic lesions and physical disorders related to renal or cardiac AL amyloidosis are major initial symptoms in multiple myeloma. Multiple myeloma diagnosed from the gastrointestinal symptoms is rare. We report a case of an 80-year-old man with multiple myeloma accompanied by gastrointestinal AL amyloidosis and secondary protein-losing enteropathy. The diagnostic process was suggestive, in that diarrhea and refractory leg edema related to protein-losing enteropathy were the primary symptoms and the trigger for making a sequential diagnosis of gastrointestinal AL amyloidosis and underlying multiple myeloma. This case is highly suggestive, in that multiple myeloma with gastrointestinal AL amyloidosis should be considered one of the background diseases of protein-losing enteropathy.

Molecular Approaches Using Body Fluid for the Early Detection of Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is the most malignant form of gastrointestinal tumor and is the fourth leading cause of deaths due to cancer in Japan. This cancer shows a poor outcome due to the difficulty of its early diagnosis and its rapid growth. Once this disease becomes clinically evident, it is frequently accompanied by distant metastasis at the time of diagnosis. A recent multicenter study in Japan revealed that patients with the early stage of this disease (stage 0 and I) showed favorable prognosis after surgical resection, indicating the importance of early detection for improvement of PDAC prognosis. PDAC develops through a stepwise progression from the precursor lesion, and over the last few decades molecular analyses have shown the detailed genetic alterations that occur in this process. Since advances in molecular technologies have enabled the detection of genetic changes from a very small quantity of samples, a large number of non-invasive molecular approaches have been utilized in an attempt to find precursor or non-invasive carcinoma lesions. In this review, the current efforts in terms of the molecular approaches applied for the early detection of PDAC-especially using body fluids such as pancreatic juice, blood, and saliva-are summarized.

Discovery of a chemical compound that suppresses expression of BEX2, a dormant cancer stem cell-related protein.

Cancer stem cells (CSCs) are believed to cause cancer metastasis and recurrence. BEX2 (brain expressed X-linked gene 2) is a CSC-related gene that is expressed in dormant CSCs in cholangiocarcinoma and induces resistance against chemotherapy. The aim of the present study was to identify small compounds that have activity to inhibit BEX2 expression and result in the attenuation of CSC-related phenotypes. We screened 9600 small chemical compounds in high-throughput screening using cholangiocarcinoma cell line HuCCT1 expressing BEX2 protein fused with NanoLuc, and identified a compound, BMPP (1, 3-Benzenediol, [4-(4-methoxyphenyl)-1H-pyrazol-3-yl]). BMPP was found to exert decreasing effects on BEX2 protein expression and G0 phase population of the tumor cells, and increasing effects on ATP levels and chemotherapeutic sensitivity of the cells. These findings indicate that BMPP is a valuable chemical compound for reducing dormant CSC-related phenotypes. Thus, the identification of BMPP as a potential CSC suppressor provides scope for the development of novel therapeutic modalities for the treatment of cancers with BEX2 overexpressing CSCs.