Usefulness of pancreatic volume quantitative analysis as a predictor of development and severity of post-endoscopic retrograde cholangiopancreatography pancreatitis.

BACKGROUND: Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) is one of the most common and serious adverse events associated with ERCP. Thus, we aimed to investigate the usefulness of pre-ERCP pancreatic volume, which is deeply involved in exocrine pancreatic function, as a predictor of PEP development and severity. METHODS: In total, 1107 patients who underwent their first ERCP were recruited from January 2012 to December 2022 for this retrospective study. Pancreatic volume was measured by cross-sectional analysis using pre-ERCP computed tomography images. The potential risk factors for PEP were analyzed using multivariate logistic regression. RESULTS: Of the 745 patients included in the study, 34 (4.6 %) developed PEP: severe, moderate, or mild PEP in 1, 7, and 26 cases, respectively. Multivariate analysis revealed that only a large pancreatic volume (>70 cm3) was an independent risk factor for the development of PEP (odds ratio, 7.98; 95 % confidence interval, 11.80-67.50; P < 0.001). Additionally, the incidence of PEP was significantly higher in patients with a pancreatic volume >70 cm3 than in those with a pancreatic volume ≤70 cm3 (18.5 % [31/168] vs. 0.5 % [3/577]; P < 0.001). Also, the association between the pre-ERCP pancreatic volume and PEP severity was positively correlated (r = 0.625, P < 0.005), with a larger pancreatic volume corresponding to increased PEP severity. CONCLUSIONS: A large pancreatic volume before ERCP may be a novel risk factor for PEP incidence and severity. This finding suggests that quantitative analysis of the pre-ERCP pancreatic volume could be a useful predictor of PEP.

High correlation of hepatic shear wave velocity with esophageal varices complication rate in patients with chronic liver diseases.

BACKGROUND: Histological evaluation by liver biopsy is considered the gold standard for assessing liver disease; however, it is highly invasive. Non-invasive liver stiffness measurement by shear wave elastography (SWE) is effective for evaluating the hepatic fibrosis stage and related diseases. In this study, we investigated the correlations of liver stiffness with hepatic inflammation/fibrosis, functional hepatic reserve, and related diseases in patients with chronic liver disease (CLD). METHODS: Shear wave velocity (Vs) values were measured using point SWE in 71 patients with liver disease from 2017 to 2019. Liver biopsy specimens and serum biomarkers were collected at the same time, and splenic volume was measured using computed tomography images with the software Ziostation2. Esophageal varices (EV) were evaluated by upper gastrointestinal endoscopy. RESULTS: Among CLD-related function and complications, Vs values were highly correlated with liver fibrosis and EV complication rates. The median Vs values for liver fibrosis grades F0, F1, F2, F3, and F4 were 1.18, 1.34, 1.39, 1.80, and 2.12 m/s, respectively. Comparison of receiver operating characteristic (ROC) curves to predict cirrhosis showed that area under the ROC (AUROC) curve for Vs values was 0.902, which was not significantly different from the AUROCs for the FIB-4 index, platelet count, hyaluronic acid, or type IV collagen 7S, while it was significantly different from the AUROC for mac-2 binding protein glycosylation isomer (M2BPGi) (P < 0.01). Comparison of ROC curves to predict EV showed that the AUROC for Vs values was 0.901, which was significantly higher than the AUROCs for FIB-4 index (P < 0.05), platelet count (P < 0.05), M2BPGi (P < 0.01), hyaluronic acid (P < 0.05), and splenic volume (P < 0.05). In patients with advanced liver fibrosis (F3 + F4), there was no difference in blood markers and splenic volume, while Vs value was significantly higher in patients with EV (P < 0.01). CONCLUSIONS: Hepatic shear wave velocity was highly correlated with EV complication rates in chronic liver diseases as compared to blood markers and splenic volume. In advanced CLD patients, Vs values of SWE are suggested to be effective in predicting the appearance of EV noninvasively.

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.

[Efficacy of TS-1 as a Late-Line Treatment for Metastatic Breast Cancer].

We report 4 female patients with metastatic breast cancer who were administered TS-1 as a late-line treatment and showed favorable outcomes. Their average age was 66.3. The patients, all of whom had undergone prior treatment with both anthracyclines and taxanes, showed intrinsic Luminal A or B subtypes. After administration of TS-1 in the lines of 2 to 9 in metastatic settings, all patients showed a long progression-free survival with a favorable quality of life.

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.

Factors responsible for long-term survival in metastatic breast cancer.

BACKGROUND: Although survival of patients with metastatic breast cancer (MBC) has been significantly prolonged over the past decade due to improvement of anti-cancer therapeutics, only a few patients survive for more than 10 years. It has not been determined which patients can have long-term survival with treatment. METHODS: To determine prognostic factors responsible for long-term survival, we retrospectively compared clinicopathologic factors of patients with MBC who survived for 50 months or more after diagnosis with patients who did not. Of 70 patients with MBC who received chemotherapy between November 2005 and September 2011, 23 patients who survived for 50 months or more after diagnosis and 28 patients who died within 50 months after diagnosis were assessed for their clinicopathologic factors and outcomes. RESULTS: The proportion of patients with hormone receptor-positive (HR+) tumors was significantly higher and the proportion of patients with triple negative tumors (TN) was lower in long-term survivors than in non-long-term survivors (HR+: 87% versus 28.6%, P=0.000037; TN: 13.1% versus 53.6%, P=0.0028). Metastatic site, number of disease sites, prior chemotherapeutic regimens and human epidermal growth factor receptor-2 (HER2) status did not differ between the two groups. The proportion of patients who received metronomic regimens was significantly higher in long-term survivors than in non-long-term survivors (65.2% versus 35.7%, P=0.034) when the most effective regimen among regimens that were received in metastatic settings was compared between the two groups. Overall response rate was significantly higher (82.6% versus 17.9%, P<0.00001) and time to treatment failure after receiving the most effective regimen was longer in long-term survivors than in non-long-term survivors (26 versus 5 months, P=0.0001). The number of chemotherapeutic regimens for breast cancer and that for MBC did not differ between the two groups. CONCLUSIONS: Patients with luminal-type MBC who benefit at least once from chemotherapy including metronomic regimens, or patients who continued to receive the most effective regimen for more than two years can be expected to have long-term survival after diagnosis of MBC, regardless of the number of chemotherapeutic regimens they had received.

[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.

Changes of circulating tumor cells expressing CD90 and EpCAM in early-phase of atezolizumab and bevacizumab for hepatocellular carcinoma.

Circulating tumor cells (CTCs) are noninvasive biomarkers that can indicate the therapeutic response and prognosis. The study aimed to investigate the cellular characteristics of CTCs focusing on monitoring during atezolizumab and bevacizumab (Atezo-Bev) therapy in patients with hepatocellular carcinoma (HCC). Peripheral blood samples were collected from 10 healthy controls and 40 patients with HCC. CTCs enriched using RosetteSep™ Human CD45 depletion cocktail were analyzed by multiparametric flow cytometry. CTC isolation was based on PanCK(+)CD45(-) cells, and CTCs exhibiting markers CD90, CD133, EpCAM, or vimentin. The total number of CTCs and the number of CTCs expressing CD90, CD133, EpCAM, and vimentin were correlated with the BCLC stage of HCC. The change in total CTC count accurately reflected the initial response to Atezo-Bev therapy. The numbers and mean fluorescence intensity of the CTC subsets expressing CD90 and EpCAM molecules decreased in patients with partial response/stable disease, and increased in patients with progressive disease and were markedly correlated with overall survival. CD90(+) and EpCAM(+) CTCs may be candidate biomarkers for the early prediction of the treatment response and the overall survival of patients with HCC receiving Atezo-Bev therapy.

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.

Serial Changes of Circulating Tumor Cells in Patients with Hepatocellular Carcinoma Treated with Atezolizumab Plus Bevacizumab.

Immune checkpoint inhibitors have promising outcomes in patients with hepatocellular carcinoma (HCC); however, there is no reliable biomarker for predicting disease progression. Circulating tumor cells (CTCs) derived from peripheral blood have attracted attention in monitoring therapeutic efficacy. In this study, CTCs were serially collected from HCC patients undergoing atezolizumab plus bevacizumab (Atezo+Bev), and changes in molecular expression and CTC numbers were analyzed to identify effective biomarkers. Changes in CTC numbers during Atezo+Bev reflected the tumor volume. Targeted RNA sequencing with next-generation sequencing (NGS) revealed that patients with elevated transforming growth factor (TGF)-ß signaling molecules had a poorer response, whereas those with elevated apoptosis signaling molecules had a favorable response. In addition, compared with changes in CTC counts, changes in TGF-ß signaling molecule expression in CTCs accurately and promptly predicted treatment response. Overall, NGS analysis of CTC-derived RNA showed that changes in TGF-ß signaling molecules predict treatment response earlier than changes in CTC counts. These findings suggest that changes in the expression of TGF-ß molecules in CTCs could serve as novel biomarkers for the early prediction of therapeutic response in patients with unresectable HCC undergoing Atezo+Bev.

Programmed Death Ligand 1 Expression in Circulating Tumor Cells as a Predictor and Monitor of Response to Atezolizumab plus Bevacizumab Treatment in Patients with Hepatocellular Carcinoma.

There remains no reliable biomarker of therapeutic efficacy in hepatocellular carcinoma (HCC) for the PD-L1 inhibitor atezolizumab and bevacizumab (Atezo/Bev). Circulating tumor cells (CTCs) enable the serial collection of living tumor cells. Pre-treatment and serial CTC gene expression changes and tumor histology were evaluated to identify predictors of response to Atezo/Bev. Peripheral blood from 22 patients with HCC treated with Atezo/Bev and 24 patients treated with lenvatinib was serially collected. The RNA expression in CTCs was analyzed using qRT-PCR. Higher PD-L1 expression in pre-treatment CTCs was associated with response and improved prognosis with Atezo/Bev treatment, but not with lenvatinib. There was no correlation between PD-L1 expression in CTCs and that in liver tumor biopsy specimens scored using imaging software. Furthermore, PD-L1 RNA expression in CTCs was dynamically altered by Atezo/Bev, decreasing during effective response and increasing upon progression. CTC-derived RNA collected during Atezo/Bev indicates that patients with higher PD-L1 expression in CTCs at baseline were 3.9 times more responsive to treatment. Therefore, PD-L1 RNA levels in CTCs are an accurate response predictor and may be a monitorable biomarker that changes dynamically to reflect the response during Atezo/Bev treatment.

S-1-propenyl-L-cysteine suppresses lipopolysaccharide-induced expression of matrix metalloproteinase-1 through inhibition of tumor necrosis factor-α converting enzyme-epidermal growth factor receptor axis in human gingival fibroblasts.

Periodontal disease is the most common dental health problem characterized by the destruction of connective tissue and the resorption of alveolar bone resulting from a chronic infection associated with pathogenic bacteria in the gingiva. Aged garlic extract has been reported to improve gingival bleeding index and probing pocket depth score in patients with mild to moderate periodontitis. Although our previous study found that aged garlic extract and its constituents suppressed the tumor necrosis factor-α-induced inflammatory responses in a human gingival epithelial cell line, the mechanism underlying the effect of aged garlic extract on the destruction of the gingiva remains unclear. The present study investigated the effect of S-1-propenyl-L-cysteine, one of the major sulfur bioactive compounds in aged garlic extract, on the lipopolysaccharide-induced expression of matrix metalloproteinases in human gingival fibroblasts HGF-1 cells. Matrix metalloproteinases are well known to be closely related to the destruction of the gingiva. We found that S-1-propenyl-L-cysteine suppressed the lipopolysaccharide-induced expression and secretion of matrix metalloproteinase-1 in HGF-1 cells. In addition, S-1-propenyl-L-cysteine inhibited the lipopolysaccharide-induced phosphorylation of epidermal growth factor receptor and expression of the active form of tumor necrosis factor-α converting enzyme. Furthermore, the inhibitors of epidermal growth factor receptor tyrosine kinase and tumor necrosis factor-α converting enzyme, AG-1478 and TAPI-1, respectively, reduced the lipopolysaccharide-induced protein level of matrix metalloproteinase-1, as did S-1-propenyl-L-cysteine. Taken together, these results suggested that S-1-propenyl-L-cysteine suppresses the lipopolysaccharide-induced expression of matrix metalloproteinase-1 through the blockade of the tumor necrosis factor-α converting enzyme-epidermal growth factor receptor axis in gingival fibroblasts.

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.

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.