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.

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 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.

A case of idiopathic portal hypertension accompanying multiple hepatic nodular regenerative hyperplasia in a patient with systemic sclerosis.

Idiopathic portal hypertension (IPH) is one of the background diseases causing nodular regenerative hyperplasia (NRH). Furthermore, IPH patients accompanied with autoimmune diseases, such as systemic lupus erythematosus (SLE) and systemic sclerosis (SSc), are more likely to form NRH in the liver. A 76-year-old woman had been aware of the Raynaud's phenomenon and scleroderma for the past 30 years. In this case, she presented with abdominal fullness, and her imaging analysis revealed ascites and multiple liver nodules. On Gd-EOB-DTPA enhanced magnetic resonance imaging (EOB-MRI), donut-like uptake was observed in the nodules in the hepatobiliary phase. Liver biopsy of a nodule demonstrated that it was composed of hyperplastic hepatocytes without fibrous septa, and dilated sinusoids were observed beside the nodule. Conversely, background liver showed that peripheral portal veins appeared stenotic with dense fibrosis in the portal area. The final diagnosis was that multiple NRH of the liver developed in SSc patient accompanying IPH. This case suggests that NRH may be unexpectedly diagnosed in patients with autoimmune diseases accompanying IPH.

Reactivation of intraabdominal tuberculous lymphadenopathy after drug-eluting beads transcatheter arterial chemoembolization in a patient with hepatocellular carcinoma.

Owing to effective treatments and sanitary improvements, the incidence of latent tuberculosis infection (LTBI) has decreased. However, approximately one-quarter of the world's population is thought to have LTBI, and the reactivation of tuberculosis (TB) sometimes occurs in immunocompromised hosts. A 54-year-old man presented with a fever. The patient had past histories of alcoholic and hepatitis C virus-related cirrhosis and hepatocellular carcinoma (HCC). He was treated with drug-eluting beads transarterial chemoembolization (DEB-TACE) for HCC three times, beginning 10 months before his current visit. A computed tomography scan showed enlarged intraabdominal lymph nodes with calcification, and the interferon-gamma release assay for TB infection was positive. The patient was diagnosed with tuberculous reactivation. Anti-TB therapy was administered to the patient, after which we restarted TACE and the TB infection remains controlled. In this case, we presumed that DEB-TACE is associated with the reactivation of TB infection and that anthracycline increases the risk of reactivating TB infection. In summary, we experienced a case of TB reactivation during the clinical course of a patient with HCC who was treated with DEB-TACE. When patients with HCC are treated with TACE, their symptoms, laboratory data, and imaging results should be monitored when latent TB infections are suspected.

The prevalence of endoscopic gastric mucosal damage in patients with rheumatoid arthritis.

OBJECTIVES: Rheumatoid arthritis (RA) patients often take non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids as supportive drugs. In this study, we investigated the prevalence of endoscopic gastric damage and their prescribed medications under an actual clinical condition. METHODS: We collected the data of 1704 RA patients who underwent upper gastrointestinal fiberscopy. Gastric mucosal erosion and ulcer were classified using modified LANZA score. We analyzed these data with a multiple regression analysis. RESULTS: The prevalence of endoscopic gastric mucosal damage in these RA patients was 16.7% (285 cases). A multiple regression analysis indicated that prednisolone (PSL), NSAIDs and proton pump inhibitors (PPIs) were independent risk factors associated with the modified LANZA score. PSL and NSAIDs were positively correlated with the score, while the administration of PPIs was inversely correlated with the score. The modified LANZA score in RA patients treated with both PSL and NSAIDs was significantly higher than that in those treated with PSL alone (no NSAIDs use). CONCLUSIONS: Our findings suggest that PSL and NSAIDs were exacerbating factors for gastric mucosal damage, while PPIs usage was a protective factor. And, the combined usage of corticosteroids and NSAIDs may induce the development of gastric ulcers.

Duplication cyst of the ileum presenting with severe anemia detected by double-balloon endoscopy.

Background and study aims Duplication cysts of the ileum are rare and present with non-specific clinical manifestations such as abdominal pain, vomiting, melena, and intussusception. Therefore, preoperative diagnosis is difficult. Here, we report a case of duplication cyst of the small intestine that was diagnosed preoperatively using double-balloon enteroscopy. A 19-year-old man presented with severe iron deficiency anemia, abdominal pain, and exertional dyspnea. Gastroscopy and colonoscopy revealed no remarkable findings. Abdominal computed tomography revealed a cystic structure in the ileum. Therefore, we performed double-balloon enteroscopy via the anal route. The intestinal tract was bifurcated, with one segment ending in a blind sac containing normal villi and an ulceration. Tc-99 m pertechnetate scintigraphy showed no accumulation in the lesion. Accordingly, we diagnosed a duplication cyst and suspected that this was the cause of severe anemia. Following small bowel resection with cyst excision and anastomosis, the anemia and presenting symptoms resolved. This report highlights the usefulness of double-balloon enteroscopy of the small intestine for preoperative diagnosis of the obscure gastrointestinal bleeding, including duplication cysts .

Tocilizumab induced acquired factor XIII deficiency in patients with rheumatoid arthritis.

Factor XIII is one of the twelve coagulation factors and also known as a fibrin-stabilizing factor. In 2012, we encountered a male RA patient with hemorrhagic factor XIII deficiency who had been treated with tocilizumab for two years. There are few reports regarding the relationship between tocilizumab (a humanized monoclonal antibody against the interleukin-6 receptor (IL-6R)) and factor XIII. We measured the factor XIII activity levels in the plasma of 40 RA patients (10 patients treated without biologics, 30 patients treated with biologics (15 patients treated with necrosis factor inhibitors and 15 patients treated with tocilizumab)) and 19 healthy controls. Consequently, the tocilizumab group exhibited lower levels than the other three groups according to the Steel-Dwass test (P<0.01). Furthermore, we compared the plasma factor XIII activity levels and the plasma factor XIII concentrations in the RA patients treated with biologics. Pearson's correlation test was used to assess the relationship between the factor XIII activity levels and the plasma factor XIII concentrations (r=0.449, P=0.019). According to the multiple regression analysis, the treatment with tocilizumab is an independent risk factor for plasma factor XIII reduction in RA patients. In conclusion, RA patients treated with tocilizumab, an IL-6R blocker, are at risk of developing acquired factor XIII deficiency. The mechanisms underlying the reduced factor XIII activity observed in RA patients treated with tocilizumab may result from the quantitative reduction in the plasma. These data imply that IL-6 plays an important role in maintaining the factor XIII activity level.

Value of the 13C-urea breath test for detection of gastric Helicobacter spp. infection in dogs undergoing endoscopic examination.

Urea breath test (UBT) using an infrared spectral analyzer is widely used for non-invasive and rapid detection of gastric Helicobacter spp. in human, but not veterinary medicine. The main purposes of this study were to determine the reference range of the UBT in dogs and to evaluate its clinical usefulness. To address the first aim, 6 healthy laboratory beagles were subjected to UBT and upper gastrointestinal endoscopy. Gastric endoscopic biopsy samples from the antrum, corpus and fundus were examined for Helicobacter spp. by polymerase chain reaction (PCR) testing, rapid urease test (RUT), histology and cytology. Amoxicillin, metronidazole and omeprazole were given to infected dogs for 14 days, and dogs that became Helicobacter-negative were used to determine the reference range for UBT. To address the second aim, 32 canine patients underwent UBT before upper gastrointestinal endoscopy, and the sensitivity and specificity of UBT were calculated based on our newly determined reference range using PCR as the gold standard for detection of Helicobacter spp. Initially, all 6 laboratory beagles were infected in all gastric regions and became uninfected after eradication. The mean ± 2 SD UBT value after eradication was 0.6 ± 1.8‰, and the reference range for UBT was determined to be less than 2.5‰. UBT was completed successfully in 27 patients. Using our reference range, UBT displayed 89% (16/18) sensitivity and 89% (8/9) specificity, indicating that UBT was quite useful for the detection of gastric Helicobacter spp. infection in dogs.

A familial case of autoimmune hepatitis.

Autoimmune hepatitis is a chronic liver disease, and both genetic background and environmental factors are related to its pathogenesis. Here, we report that out of five members of a family with similar human leukocyte antigen haplotypes, two developed autoimmune hepatitis, one was positive for antinuclear antibody, and the remaining two had no features of autoimmunity. The two patients with autoimmune hepatitis had a history of medication use, whereas the other family members did not. Our familial study suggests that in addition to genetic background, medication use and other environmental factors may be related to the onset of autoimmune hepatitis.

Recurrence of autoimmune hepatitis after liver transplantation without elevation of alanine aminotransferase.

It is controversial whether steroid therapy should be continued to prevent the recurrence of autoimmune hepatitis (AIH) in patients who have undergone liver transplantation (LTx) due to AIH. We report a case of recurrent autoimmune hepatitis after LTx despite a persistently normal range of alanine aminotransferase (ALT). A 50-year-old woman was admitted to our hospital because of jaundice and severe liver dysfunction, where she was diagnosed with liver failure due to AIH. Steroid therapy was not effective enough and the patient received living-donor LTx in 1999. Following the operation, the level of ALT was maintained within a normal range and anti-nuclear antibody (ANA) became negative, however, the serum level of IgG gradually elevated and ANA became positive, while platelets decreased. A liver biopsy performed 6 years after LTx showed histological findings of AIH and she was diagnosed with recurrent AIH. A recurrence of AIH may occur after LTx even if the level of ALT remains within a normal range. We consider that a protocol liver biopsy should be performed in patients who undergo LTx due to AIH to decide the indication for steroid therapy.

Clinical features of symptomatic primary biliary cirrhosis initially complicated with esophageal varices.

BACKGROUND: Esophageal varices (EV), one feature of portal hypertension, have been regarded as a late complication of liver diseases. However, accumulating evidence indicates that EV sometimes develop early during the course of primary biliary cirrhosis (PBC). The prognosis is usually poorer for patients with symptomatic PBC than for those with asymptomatic PBC. Nevertheless, the clinical features and prognosis of patients with PBC whose initial symptoms are EV have not been clarified. METHODS: The clinical features and the prognosis of patients who initially developed EV without other symptoms (v-PBC) were retrospectively investigated in 54 patients with symptomatic PBC. RESULTS: The leukocyte and platelet counts were lower in patients with v-PBC than in those with PBC accompanied by other symptoms (s-PBC). Liver function tests, autoantibodies, and histological stage did not differ between patients with v-PBC and those with s-PBC. Although the prognosis did not differ, the incidence of hepatocellular carcinoma was significantly higher in v-PBC than in s-PBC (P = 0.0037). CONCLUSIONS: These data indicate that v-PBC is a hypercarcinogenic state and constitutes a new subgroup of PBC.

[Zafirlukast (Accolate): a review of its pharmacological and clinical profile].

Today, bronchial asthma is considered as a chronic inflammatory disease of the airway. It has been revealed that various chemical mediators are involved in the onset of bronchial asthma. Among them, particularly, the peptide leukotrienes, LTC4, LTD4 and LTE4, have been known to play a pathophysiological important role in asthma. Zafirlukast binds to the CysLT1 receptors competitively with these peptide leukotrienes and inhibited peptide leukotriene-induced constriction of isolated guinea pig trachea and lung parenchyma and isolated human bronchi. Zafirlukast also demonstrated dose-dependent inhibition of LTD4-induced dyspnea in guinea pigs in vivo. Zafirlukast demonstrated preventive and alleviating effects on LTD4- and ovalbumin-induced decrease in the lung function. Zafirlukast also displayed inhibitory effects on LTD4-induced eosinophil infiltration into airway tissues and bronchial edema. In sheep naturally allergic to Ascaris suum antigen, zafirlukast exhibited inhibitory effects on Ascaris suum antigen-induced immediate and late type airway constriction and increase in airway hypersensitivity. In clinical pharmacology studies, zafirlukast inhibited LTD4- or allergen-induced airway constriction and exercise-induced reduction of the pulmonary function. It also prevented onset of methacholine-induced airway hyperresponsiveness. Furthermore, good efficacy of zafirlukast was confirmed in clinical trials in adult bronchial asthma patients. As above, zafirlukast is effective for treatment of bronchial asthma, which is attributed to its peptide leukotriene antagonistic action.