Regulatory function of interferon-inducible 44-like for hepatitis B virus covalently closed circular DNA in primary human hepatocytes.

AIM: Curing hepatitis B virus (HBV) infection requires elimination of covalently closed circular DNA (cccDNA). Interferon (IFN)-γ has noncytolytic antiviral potential; however, elimination of cccDNA could not be achieved. To enhance the regulatory effect, we comprehensively analyzed the host factors associated with cccDNA amplification and IFN-γ and IFN-α effects using an in vitro HBV infection system showing various transcription levels. METHODS: Primary human hepatocytes were infected with HBV using genomic plasmids carrying the basic core promoter mutation A1762T/G1764A and/or the precore mutation G1896A and treated with IFN-γ and IFN-α. Comprehensive and functional studies involving microarray and small interfering RNA analysis revealed the host factors related to cccDNA regulation. RESULTS: The HBV infection system reproduced the HBV life cycle and showed various propagation levels. Microarray analysis revealed 53 genes correlated with the cccDNA levels. Of the 53 genes, expression of IFN-induced protein 44-like (IFI44L) was significantly upregulated by IFN-γ and IFN-α. The anti-HBV effect of IFI44L is exerted regardless of IFN-γ or IFN-α by inhibiting the activation of nuclear factor-κB and signal transducer and activator of transcription 1 pathways. CONCLUSIONS: Using the in vitro HBV infection system, an IFN-inducible molecule, IFI44L, associated with cccDNA amplification, was identified. These results suggest an innovative molecular strategy for the regulation of HBV cccDNA by controlling a novel host factor, IFI44L.

Bipolar-current needle-knife with a water jet function (Jet B-knife) shortens the procedure time of endoscopic submucosal dissection for colorectal tumors.

BACKGROUND: Endoscopic submucosal dissection (ESD) is a technically difficult and time-consuming procedure for the treatment of large colorectal tumors. In Japan, the ball-tip bipolar-current needle-knife (BB-knife) has been used in ESD as a safe device that minimizes the damage to deeper tissues of colorectal neoplasms. In May 2012, a BB-knife combined with a water jet function (Jet B-knife) was newly developed. METHODS: This retrospective study was aimed at examining the effectiveness and safety of the Jet B-knife. The BB-knife was used in 276 lesions (BB-knife group), while the Jet B-knife was used in 245 lesions (Jet B-knife group). We evaluated tumor characteristics and the results of the ESD procedures, including the size of the resected tumor, histological diagnosis, time required for resection, frequency of using other electrical devices, en bloc resection rate, and incidence rate of associated complications. Then, the data obtained were compared between the two groups. RESULTS: The histological evaluation of the resected tumors revealed that the incidence of cancer was not significantly different between the two groups. The median time required for resection was 103 min (45-255) in the BB-knife group and 51 min (28-210) in the Jet B-knife group. The difference was statistically significant (p < 0.05). Furthermore, the median tumor diameters were 23.1 mm (18-50) and 26.2 mm (20-60) in the BB-knife and Jet B-knife groups, respectively, demonstrating a statistically significant difference (p < 0.05). Multivariate logistic regression analysis revealed that short resection time (p < 0.001) and reduced use of hemostatic devices (p < 0.01) were independent favorable features of Jet B-knife. The en bloc resection rate and the perforation rate were not statistically significant between the two groups. CONCLUSIONS: Use of the Jet B-knife may contribute to the development of a time-saving, cost-effective, and safe procedure for ESD of colorectal tumors.

Molecular signature of hepatitis B virus regulation by interferon-γ in primary human hepatocytes.

AIM: A complete cure for chronic hepatitis B virus (HBV) infection requires elimination of covalently closed circular DNA; however, this remains to be clinically achieved. Interferon (IFN)-γ, a type II IFN, is produced by intrahepatic cytotoxic T lymphocytes and has non-cytolytic antiviral potential. However, the mechanism by which IFN-γ regulates HBV infection has not been fully elucidated. Thus, we developed an in vitro HBV infection assay system and analyzed the molecular signature of HBV regulation by IFN-γ. METHODS: The in vitro HBV infection assay system was established in primary human hepatocytes infected with HBV derived from the plasmid containing 1.3-mer HBV genome, and treated with IFN-γ. The antiviral effects and signaling pathways of IFN-γ were examined using microarray, and assessed by siRNA knockdown experiments of the related genes. RESULTS: IFN-γ treatment suppressed both HBV propagation and transcription as efficiently as IFN-α. Microarray analysis showed that IFN-γ stimulation induced the activation of both IFN-γ and IFN-α signaling, regulating HBV covalently closed circular DNA. HBV production was decreased by IFN-γ through Janus kinase/signal transducer and activator of transcription signaling and interferon-stimulated genes, such as 2'-5'-oligoadenylate synthase 2 and apolipoprotein B mRNA editing enzyme catalytic subunit 3G. CONCLUSIONS: IFN-γ can suppress HBV propagation and transcription in hepatocytes by activating specific intracellular signaling pathways in hepatocytes, and suggests the future application of these particular signaling pathways or genes for the complete elimination of HBV.

Genetic polymorphism and decreased expression of HLA class II DP genes are associated with HBV reactivation in patients treated with immunomodulatory agents.

Hepatitis B virus (HBV) reactivation can be triggered by immunosuppressive chemotherapy. HLA class II molecules may play a role in HBV reactivation. Genetic polymorphism and mRNA expression of HLA class II were examined in patients with latent HBV infection treated with immunosuppressive therapies. Subjects with resolved HBV infection who had undergone treatment with immunosuppressive chemotherapies were retrospectively enrolled (n = 42) and divided into reactivated (n = 9) and non-reactivated groups (n = 33). Patients were genotyped for 17 single nucleotide polymorphisms (SNPs) within HLA class II DPA1, and DPB1, and mRNA expression levels of HLA class II genes were assessed. The frequency of the AA genotype of rs872956, a SNP in HLA-DPB1, was significantly higher in the reactivated group than in the non-reactivated group (55.6% vs 12.1%, P < 0.05). The frequencies of the T allele and non-AA genotypes (AT/TT) of rs3116996 (located in DPB1) were significantly higher in the reactivated group (T allele frequency: 16.7% vs 0.0% [P < 0.01], non-AA genotype frequency: 22.2% vs 0.0% [P < 0.05]). Multivariate logistic regression identified the AA genotype of rs872956 as an independent protective factor against HBV reactivation (odds ratio [OR] = 18.1, 95% confidence interval [CI] = 2.6-126.7, P < 0.01). mRNA expression of HLA-DPB1 was lower in the HBV reactivated group than in the non-reactivated group (median 276.1 ± 165.6/ß-actin vs 371.4 ± 407.5/ß-actin [P < 0.05]). These results suggest the involvement of HLA class II molecules in HBV reactivation after treatment with immunomodulatory agents.

Identification of novel variants in HLA class II region related to HLA DPB1 expression and disease progression in patients with chronic hepatitis C.

Recent genome-wide studies have demonstrated that HLA class II gene may play an important role in viral hepatitis. We studied genetic polymorphism and RNA expression of HLA class II genes in HCV-related liver diseases. The study was performed in groups consisting of 24 patients with HCV-related liver disease (12 of persistent normal ALT: PNALT group and 12 of advanced liver disease: ALD group) and 26 patients without HCV infection (control group). In PBMC samples, RNA expression of HLA class II genes (HLA-DPA1, DPB1, DQA1, DQB1, and DRB1) was analyzed by real-time RT-PCR. Furthermore, 22 single nucleotide polymorphisms (SNPs) in HLA class II gene and two SNPs in IL28B gene were genotyped by genetic analyzer (GENECUBE®). In expression analysis, only DPB1 level was significantly different. Mean expression level of DPB1gene in control group was 160.0, PNALT group 233.8, and ALD group 465.0 (P < 0.01). Of 24 SNPs, allele frequencies were statistically different in two SNPs (rs2071025 and rs3116996) between PNALT groups and ALD group (P < 0.01). In rs2071025, TT genotype was frequently detected in ALD group and expression level was significantly higher than the other genotypes (449.2 vs 312.9, P < 0.01). In rs3116996, TA or TT (non AA) genotype was frequently detected in ALD group and expression level was significantly higher than genotype AA (457.1 vs 220.9, P < 0.01). Genotyping and expression analysis in HLA class II gene revealed that two SNPs of HLA-DPB1 (rs2071025 and rs3116996) were significantly correlated to RNA expression and progression of HCV-related liver diseases.

[The Usefulness of Strain Elastography for Determining Liver Fibrosis Stage in Chronic Viral Hepatitis: An Analysis Using Tissue Doppler Imaging with Manual Compression].

BACKGROUND/AIM: Accurate determination of the stage of liver fibrosis is an essential component in choice of treatment and assessment of cancer risk in patients with chronic viral hepatitis. The aim of this study was to evaluate the usefulness of strain elastography based on tissue Doppler imaging for liver fibrosis in chronic viral hepatitis. METHODS: A total of 37 patients with chronic viral hepatitis and 8 healthy volunteers were enrolled. Strain value was measured by using a conventional ultrasound machine that included strain imaging technolo- gy. Strain elastography was performed at the right subcostal area with manual compression. Liver fibrosis stages were assessed by using liver biopsy and compared with strain values. Diagnostic performance of the strain value for fibrosis stage 4, cirrhosis, was determined by performing a receiver-operating characteristics (ROC) curve analysis. RESULTS: Twenty-seven patients were positive for HCV RNA, 9 were positive for HBs antigen, and 1 was positive for both (Fibrosis stage F1, n=11; F2, n=7; F3, n=15; F4, n=4). The strain value of F3 and F4 was 0.066±0.02 and 0.042±0.011, respectively. These strain Values were significantly lower compared to those of healthy volunteers (0.112 ±0.018) (P< 0.05). Using a cutoff value of 0.042, the area under ROC curve was 0.88 for the diagnosis of F4. The sensitivity, specificity, positive predictive value, and negative predictive value were 75%, 92%, 50%, and 94%, respectively. CONCLUSIONS: Strain elastography based on tissue Doppler imaging with manual compression appears to be a useful tool to diagnose cirrhosis in patients with chronic viral hepatitis. [Original].

Pituitary metastasis of hepatocellular carcinoma presenting with panhypopituitarism: a case report.

BACKGROUND: Metastasis to the pituitary gland is extremely rare and is often detected incidentally by symptoms associated with endocrine dysfunction. Breast and lung cancer are the most common primary metastasizing to pituitary gland. Metastasis from hepatocellular carcinoma to the pituitary gland is extremely rare, with only 10 cases having been previously reported. We present here the first case of pituitary metastasis of hepatocellular carcinoma presenting with panhypopituitarism diagnosed by magnetic resonance imaging. CASE PRESENTATION: We report the case of an 80-year-old Japanese woman who presented with the sudden onset of hypotension and bradycardia after having previously been diagnosed with hepatocellular carcinoma. Based on low levels of pituitary hormones, she was diagnosed with panhypopituitarism caused by metastasis of the hepatocellular carcinoma to the pituitary gland. Magnetic resonance imaging with arterial spin-labeling was effective in the differential diagnosis of the intrasellar tumor. The patient died despite hormone replacement therapy because of hypovolemic shock. CONCLUSION: Metastasis to the pituitary gland causes various non-specific symptoms, so it is difficult to diagnose. The present case emphasizes the importance of diagnostic imaging in identifying these metastases. Clinicians should consider the possibility of pituitary metastasis in patients with malignant tumors who demonstrate hypopituitarism.

Ruptured hepatic metastases of cutaneous melanoma during treatment with vemurafenib: an autopsy case report.

BACKGROUND: The spontaneous rupture of hepatic metastases is rare compared to that of primary hepatic tumors. In addition, vemurafenib, a selective inhibitor of the mutant BRAF protein or gene product, has been reported to be extremely effective in patients with metastatic melanoma who harbor a BRAF V600E mutation. CASE PRESENTATION: A 44-year-old female had previously undergone surgery for resection of a malignant melanoma in the lower right leg. Four years later, hepatic metastases became apparent, and transcatheter arterial embolization (TAE) was performed. Then she underwent treatment with vemurafenib. The size of the hepatic metastases markedly decreased. Two months later, they enlarged rapidly and ruptured, requiring emergency TAE. However, the patient developed hemorrhagic shock and died of renewed intra-abdominal bleeding on the 26th postoperative day. CONCLUSIONS: This is a rare case of ruptured hepatic metastases of malignant melanoma during treatment with vemurafenib. Postmortem examination and immunohistochemical analysis indicated reactivation of the mitogen-activated protein kinase pathway in the metastatic tumor, suggesting secondary resistance to vemurafenib as the possible underlying mechanism.

[A case of hepatic sarcoidosis presenting with cirrhotic symptoms].

A man in 40s with skin sarcoidosis presented with signs and symptoms of liver injury and thrombocytopenia. Enhanced computed tomography and magnetic resonance imaging revealed cholecystolithiasis, hepatic deformation, and giant splenomegaly. Gastrointestinal endoscopy showed esophageal varices. Cholecystectomy, splenectomy, and wedge biopsy of the liver were performed. Histopathology of the liver revealed many granulomas and severe periportal fibrosis without lobular reconstruction. These findings were compatible with hepatic sarcoidosis, but not liver cirrhosis. Here we report a rare case of hepatic sarcoidosis presenting with cirrhotic symptoms.

[A case of superficial esophageal basaloid squamous cell carcinoma resected by endoscopic submucosal dissection].

A woman in her 70s visited our hospital to undergo endoscopy. Esophagogastroduodenoscopy showed a white submucosal tumor-like lesion in the upper esophagus. Analysis of a biopsy specimen revealed that the tumor was a basaloid squamous cell carcinoma. A superficial squamous cell carcinoma was also revealed near the basaloid squamous cell carcinoma before endoscopic submucosal dissection. Curative en bloc resection was successfully performed. Histopathological examination revealed that the basaloid and superficial squamous cell carcinomas had invaded the lamina propria (pT1a-LPM) and epithelium (pT1a-EP), respectively. In addition, the basaloid squamous cell carcinoma had two different components in terms of malignancy and differentiation. Here we report a rare case of esophageal basaloid squamous cell carcinoma resected by endoscopic submucosal dissection.

Isolation of mucosa-associated microbiota dysbiosis in the ascending colon in hepatitis C virus post-sustained virologic response cirrhotic patients.

Background: Achieving sustained virologic response (SVR) in patients infected with hepatitis C virus (HCV) reduces all-cause mortality. However, the mechanisms and risk factors for liver fibrosis and portal hypertension post-SVR remain incompletely understood. In the gut-liver axis, mucosa-associated microbiota (MAM) substantially influence immune and metabolic functions, displaying spatial heterogeneity at the anatomical intestinal site. We analyzed MAM composition and function to isolate the locoregional MAM involved in chronic liver disease progression in HCV post-SVR patients. Methods: We collected MAM samples from three intestinal sites (terminal ileum, ascending colon, and sigmoid colon) via brushing during colonoscopy in 23 HCV post-SVR patients and 25 individuals without liver disease (controls). The 16S rRNA of bacterial DNA in specimens collected with a brush and in feces was sequenced. The molecular expression of intestinal tissues and hepatic tissues were evaluated by quantitative real-time PCR. Results: In the post-SVR group, the microbial ß-diversity of MAM, especially in the ascending colon, differed from the control group and was associated with liver fibrosis progression. In PICRUSt analysis, MAM in the ascending colon in the liver cirrhosis (LC) group showed compromised functions associated with the intestinal barrier and bile acid production, and FGF19 expression was markedly decreased in the terminal ileum biopsy tissue in the LC group. At the genus level, six short-chain fatty acid (SCFA)-producing bacterial genera, Blautia, Alistipes, Roseburia, Agathobaculum, Dorea, and Pseudoflavonifractor were reduced in the ascending colon of post-SVR LC patients. Conclusion: In patients of HCV post-SVR, we identified the association between the degree of liver fibrosis and dysbiosis of mucosa-associated SCFA-producing bacterial genera that may be related to intestinal barrier and bile acid production in the ascending colon.

Histology and cytokine levels in hepatic injury accompanying a case of non-severe COVID-19.

The pathogenesis of liver dysfunction that complicates coronavirus disease 2019 (COVID-19) remains unclear, especially in mild to moderate severity cases. In this case, a novel coronavirus infection was detected by polymerase chain reaction (PCR) in a 76-year-old woman hospitalized after presenting with fever. No other abnormal physical findings were observed, and oxygen administration was not required. Chest computed tomography (CT) showed a ground-glass-like and an infiltrative shadow in the right lung, and moderate COVID-19 was diagnosed. Initially, the fever resolved, and PCR turned negative; however, the fever reappeared on hospitalization day 14, and CT showed pneumonia exacerbation accompanied by new onset of fatty liver. Biochemical testing revealed marked liver dysfunction, accompanied by elevated serum interleukin (IL)-6, IL-10, and tumor necrosis factor-α levels. Physical findings and all laboratory parameters improved after conservative treatment, and she was discharged on day 22. A liver biopsy performed 44 days post-discharge showed T-cell-dominant inflammatory cell infiltration, mainly in the portal region. Some hepatocytes showed fatty degeneration.We report a case of moderate COVID-19 in which histological hepatitis persisted after a substantial period had passed since the initial infection had cleared and associated transaminase elevations had resolved, with a comparison of serum cytokine dynamics.

Hepatocellular carcinoma progression promoted by 5-lipoxygenase activity in CD163(+) tumor-associated macrophages.

Arachidonic acid 5-lipoxygenase (5-LOX), an enzyme that synthesizes leukotrienes (LTs), is involved in cancer development including proliferation, invasion, metastasis and drug resistance. However, the functional role of 5-LOX in hepatocellular carcinoma (HCC) remains to be elucidated. In this study, we analyzed the contribution of 5-LOX in HCC progression and investigated the potential of targeted therapy. Analysis of 86 resected HCC specimens and the clinical data of 362 cases of liver cancer from The Cancer Genome Atlas Liver Hepatocellular Carcinoma dataset, showed that 5-LOX expression was associated with postoperative survival. The cancer proliferative and stem cell potential were correlated with the levels of 5-LOX in CD163(+) tumor-associated macrophages (TAMs). In an HCC mouse model, CD163(+) TAMs expressed 5-LOX and produced LTB4 and LTC/D/E4; the 5-LOX inhibitor, zileuton, suppressed HCC progression. LTB4 and LTC/D/E4 promoted cancer proliferation and stem cell capacity via phosphorylation of extracellular signal-regulated kinase 1/2 and stem cell-associated genes. Taken together, we identified a novel mechanism of HCC progression in which CD163(+) TAMs express 5-LOX and produce LTB4 and LTC/D/E4, thereby enhancing the proliferative and stem cell potential of HCC cells. Furthermore, inhibition of 5-LOX activity regulates HCC progression, suggesting it has potential as a new therapeutic target.

[A case of hepatocellular carcinoma showed the usefulness of endoscopic ultrasound-guided fine needle aspiration cytology using the cell block technique for differential diagnosis of gastric submucosal tumor].

A mass lesion presenting difficulty in differential diagnosis between a tumor in the lateral segment of the liver and a gastric submucosal tumor (SMT) was found in a 59-year-old man with chronic hepatitis B. For differential diagnosis between the 2 lesions, endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) was performed. EUS showed a tumor exhibiting a mosaic pattern with a halo derived from the lateral segment of the hepatic left lobe in contact with the stomach. FNA using the cell block technique revealed findings consistent with HCC. No examination-associated complications developed. In patients with HCC that is in contact with the stomach and shows extrahepatically protruding growth, which is difficult to differentiate from gastric SMT, EUS-FNA is a method worthy of trying.

Elderly onset congenital hepatic fibrosis with portal hypertension diagnosed after recurrent cholangitis: a case report.

Congenital hepatic fibrosis is a rare autosomal recessive disorder caused by ductal plate malformation that can manifest as hepatic fibrosis alone or as a component in various fibropolycystic diseases including renal involvement. It is often diagnosed early in life, presenting with ascites and esophageal variceal bleeding due to non-cirrhotic portal hypertension. Here, we report a rare case of congenital hepatic fibrosis with portal hypertension diagnosed at an advanced age. A 78-year-old woman with a 6 history of recurrent cholangitis experienced abdominal distension. Imaging revealed ascites and esophageal varices. Histopathologic analysis of the liver revealed the fibrous expansion of portal tracts accompanying increased bile ducts with irregular contours in the portal area. These characteristic findings are consistent with the diagnosis of congenital hepatic fibrosis. The present case showed an extremely unique clinical course, because she did not develop any associated renal abnormalities or any disease-related symptoms until old age. Because of the variability of this disease, the slowly progressive type may be difficult to diagnose and cause non-cirrhotic portal hypertension even in the elderly. Although an unusual clinical course may suggest the presence of the disease, timely histologic assessment is crucial for the definitive diagnosis of congenital hepatic fibrosis.

Cholesterol crystal embolism in multiple organs after transarterial chemoembolization for hepatocellular carcinoma: An autopsy case report.

RATIONALE: Transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) rarely causes cholesterol crystal embolism (CCE). In our case, the histological findings suggested that the onset of CCE occurred at different time points in different organs. PATIENT CONCERNS: A 72-year-old Japanese woman with HCC underwent TACE. After TACE, serum creatinine level and eosinophil count gradually increased. Three months later, she was admitted to our department with a fever and back pain. DIAGNOSIS: Laboratory examinations showed sepsis with disseminated intravascular coagulation. She was treated with antimicrobial agents and anticoagulants, but died of multiple organ failure. INTERVENTIONS: An autopsy was performed to examine the cause of multiple organ failure after 3 months of TACE. OUTCOMES: A mixture of both chronic phase emboli with intimal thickening and fibrosis and acute phase emboli with inflammatory cell infiltration were observed in the small intestine. Moreover, multiple intravascular cholesterol fissures were observed in the kidney, stomach, duodenum, colon, pancreas, and spleen, which were the vascular dominant organs of the celiac artery and superior mesenteric artery. These histological findings suggested that cholesterol crystals were continuously disseminated after TACE. LESSONS: TACE for HCC may cause progressive CCE and damage in multiple organs. When progressive renal dysfunction, eosinophilia, or multiple organ dysfunction is observed after TACE, the CCE should be suspected.

Successful early diagnosis of monomorphic epitheliotropic intestinal T-cell lymphoma manifesting as chronic diarrhea and hypokalemia using video capsule endoscopy and double-balloon enteroscopy.

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), formerly known as enteropathy-associated T-cell lymphoma (EATL) type II, is a rare disease with a poor prognosis that is often diagnosed when patients present with intestinal perforation or obstruction. Our patient, a man in his 60 s, had a 5-month history of persistent watery diarrhea. Upper and lower gastrointestinal endoscopy, abdominal computed tomography (CT), and stool culture results were unremarkable. He was admitted to our hospital 8 months later with a weight loss of 20 kg, general fatigue, and hypokalemia. Contrast-enhanced CT of the abdomen revealed mild thickening and contrast enhancement of the small intestinal wall. Video capsule endoscopy and double-balloon enteroscopy were performed to reveal a broad ulcer in the jejunum and multiple erosions throughout the small intestine. Examination of the biopsy specimens showed infiltration of atypical lymphocytes with pale cytoplasm in the glandular epithelium. The atypical lymphocytes were positive for CD3, CD8, CD56, granzyme B, and T-cell intracellular antigen-1 by immunostaining. Early diagnosis of MEITL was made, and the patient survived for 21 months with continuous chemotherapy. Aggressive examination of the small intestine is effective for the early diagnosis of serious diseases, such as MEITL, in patients with chronic diarrhea of unknown origin.

A rare case of eosinophilic gastritis induced by nivolumab therapy for metastatic melanoma.

Cancer immunotherapy using immune checkpoint inhibitors can cause immune reactions at various sites as a side effect called immune-related adverse events (irAEs). The gastrointestinal tract is susceptible to irAEs, however, the degree and presentation vary considerably from case to case. A 76-year-old woman was diagnosed with anal mucosal melanoma. She underwent radical surgery and received postoperative adjuvant therapy. However, because new metastases were also found in bilateral inguinal lymph nodes, immunotherapy with nivolumab was performed. Approximately 10 months after the initiation of nivolumab administration, she presented with epigastric discomfort and nausea, and her laboratory data showed severe eosinophilia (1938/mm3). Computed tomography demonstrated a diffuse thickening of the gastric wall. Esophagogastroduodenoscopy and endoscopic ultrasonography showed mucosal thickening due to edema, and histologic examination revealed severe invasion of eosinophils in the lamina propria. Subsequently, she was diagnosed with eosinophilic gastritis due to irAEs induced by nivolumab. Oral administration of prednisolone rapidly normalized her endoscopic and histologic findings, dramatically reducing her symptoms. This is a very rare and important case report of nivolumab-induced severe eosinophilic gastritis. Although gastric lesions as IrAEs is rare, it is necessary to differentiate eosinophilic gastritis if unexplained nausea occurred during the administration of immune checkpoint inhibitors.

Advanced primary adenosquamous carcinoma of the liver with a small cell carcinoma component: an autopsy case report.

Primary adenosquamous carcinoma (ASC) of the liver is a rare subtype of cholangiocarcinoma that comprises both adenocarcinoma and squamous cell carcinoma components. We report a 48-year-old woman with advanced primary ASC and small cell carcinoma of the liver who had extrahepatic metastasis and received multiple chemotherapy regimens. After first presenting with upper abdominal pain, imaging revealed a 10.2 × 9.5 cm mass in the right lobe of the liver with lymph node and lung metastases. A liver tumor biopsy revealed adenocarcinoma and squamous cell carcinoma components, leading to a diagnosis of advanced primary ASC of the liver. The tumor shrank with gemcitabine/cisplatin therapy; however, neuron-specific enolase (NSE) and CYFRA levels were increased and the tumor grew. Next, hepatic arterial infusion chemotherapy using 5-fluorouracil and cisplatin decreased NSE and CYFRA levels and suppressed tumor growth. However, due to tumor growth, she died 14 months post-initial diagnosis. Post-autopsy pathology revealed a mixture of CD56- and synaptophysin-positive small cell carcinoma component in addition to ASC. We report a rare advanced primary ASC with small cell carcinoma of the liver diagnosed at autopsy.

Pembrolizumab-induced autoimmune side effects of colon and pancreas in a patient with lung cancer.

Immune checkpoint inhibitors have been shown to be effective for treating many carcinomas. However, the activated immune response may lead to the development of multiple immune-related adverse events, including rare immune-mediated inflammation due to autoimmune mechanisms. An 82-year-old man was diagnosed with large cell lung cancer (T1aN3M1 stage IVB) and was treated with inhibitors of the programmed cell death receptor-1, pembrolizumab. Diarrhea and melena occurred after six doses of pembrolizumab, and colonoscopy revealed mucosal inflammation of the rectum and sigmoid colon in a continuous manner, resembling the typical endoscopic findings of ulcerative colitis. Subsequently, fever and hyperamylasemia appeared, and the patient was diagnosed with pancreatitis resembling type 2 autoimmune pancreatitis on imaging tests and cytological examination, which showed infiltration of inflammatory cells, mainly neutrophils. Steroid therapy was administered and both, colitis and pancreatitis markedly improved. Here, we present a patient who developed colitis and pancreatitis after ICI treatment for advanced lung cancer. Both are thought to be due to autoimmune side effects of pembrolizumab. Although pancreatitis is a rare irAE, clinicians should be aware of the development of pancreatitis, especially in the case of irAE colitis resembling ulcerative colitis.