Clinical role of serum programmed death ligand 1 in patients with hepatocellular carcinoma: Where does it come from?

Programmed death ligand 1 (PD-L1) is a key target for the treatment of several malignancies. The present study was conducted to clarify the role of serum PD-L1 in hepatocellular carcinoma (HCC). Serum PD-L1 (sPD-L1) was examined by an enzyme-linked immunosorbent assay in 153 patients with HCC who underwent curative hepatectomy at Kumamoto University in 2011–2016. The expression of PD-L1 in tissue (tPD-L1) was investigated by immunohistochemistry. The clinical roles of the PD-L1 expression in both serum and tissue were examined. The sPD-L1 was significantly elevated in HCC patients compared to patients without any malignant or inflammatory disease (234 vs. 93 pg/mL, p < 0.0001). The percentage of the tPD-L1-positive area (%tPD-L1) in the background liver was significantly higher than in the tumor (1.52% vs. 0.48%, p < 0.0001). The %tPD-L1 in the background liver but not in the tumor was significantly correlated with the sPD-L1 level (p = 0.0079). The sPD-L1, %tPD-L1 in the tumor, and %tPD-L1 in the background liver were not correlated with the overall survival after surgery. PD-L1-expressing cells in the background liver, but not in the tumor tissue, appeared to contribute to the sPD-L1 level. The sPD-L1 level may thus not indicate the tumor burden in patients with HCC.     

Impact of Diesel Exhaust Particles on Th2 Response in the Lung in Asthmatic Mice

Although it has been accepted that pulmonary exposure to diesel exhaust particles (DEP), representative constituents in particulate matter of mass median aerodynamic diameter < or 2.5 µm (PM_2.5), exacerbates murine allergic asthma, the in vivo effects of DEP on their cellular events in the context of allergen-specific Th response have never been examined. The aim of this study is to elucidate whether in vivo repetitive exposure to DEP combined with allergen (ovalbumin) facilitate allergen-specific Th response in the lung using a simple ex vivo assay system. As a result, repetitive pulmonary exposure to DEP in vivo, if combined with allergen, amplifies ex vivo allergen-specific Th2 response in the lung compared to that to allergen alone, characterized by high levels of interleukin (IL)-4 and IL-5. The result suggests that in asthmatic subjects, DEP promote Th2-prone milieu in the lung, which additively/synergistically augment asthma pathophysiology in vivo.     

Metabolism and physiologically based pharmacokinetic modeling of flumioxazin in pregnant animals

A physiologically based pharmacokinetic (PBPK) model was developed to predict the concentration of flumioxazin, in the blood and fetus of pregnant humans during a theoretical accidental intake (1000 mg/kg). The data on flumioxazin concentration in pregnant rats (30 mg/kg po) was used to develop the PBPK model in pregnant rats using physiological parameters and chemical specific parameters. The rat PBPK model developed was extrapolated to a human model. Liver microsomes of female rats and a mixed gender of humans were used for the in vitro metabolism study. To determine the % of flumioxazin absorbed after administration at a dose of 1000 mg/kg assuming maximum accidental intake, the biliary excretion study of [phenyl-U-¹⁴C]flumioxazin was conducted in bile duct-cannulated female rats (Crl:CD (SD)) to collect and analyze the bile, urine, feces, gastrointestinal tract, and residual carcass. The % of flumioxazin absorbed at a dose of 1000 mg/kg in rats was low (12.3%) by summing up ¹⁴C of the urine, bile, and residual carcass. The pregnant human model that was developed demonstrated that the maximum flumioxazin concentration in the blood and fetus of a pregnant human at a dose of 1000 mg/kg po was 0.86 μg/mL and 0.68 μg/mL, respectively, which is much lower than K_m (202.4 μg/mL). Because the metabolism was not saturated and the absorption rate was low at a dose of 1000 mg/kg, the calculated flumioxazin concentration in pregnant humans was thought to be relatively low, considering the flumioxazin concentration in pregnant rats at a dose of 30 mg/kg. For the safety assessment of flumioxazin, these results would be useful for further in vitro toxicology experiments.     

Effects of Asian sand dust particles on the respiratory and immune system

Epidemiologic studies have reported that Asian sand dust (ASD) particles can affect respiratory health; however, the mechanisms remain unclear. We investigated the effects of ASD on airway epithelial cells and immune cells, and their contributing factors to the effects. Human airway epithelial cells were exposed to ASD collected on 1–3 May (ASD1) and on 12–14 May (ASD2) 2011 in Japan and heat‐treated ASD1 for excluding heat‐sensitive substances (H‐ASD) at a concentration of 0, 3, 30 or 90 µg ml^–1 for 4 or 24 h. Furthermore, bone marrow‐derived dendritic cells (BMDC) from atopic prone mice were differentiated by culture with granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) then these BMDC were exposed to the ASD for 24 h. Also splenocytes as mixture of immune cells were exposed to the ASD for 72 h. All ASD dose dependently reduced viability of airway epithelial cells. Non‐heated ASD showed a dose‐dependent increase in the protein release of interleukin (IL)‐6 and IL‐8. The raises induced by ASD1 were higher than those by ASD2. ASD1 and ASD2 also elevated ICAM‐1 at the levels of mRNA, cell surface protein and soluble protein in culture medium. In contrast, H‐ASD did not change most of these biomarkers. Non‐heated ASD showed enhancement in the protein expression of DEC205 on BMDC and in the proliferation of splenocytes, whereas H‐ASD did not. These results suggest that ASD affect airway epithelial cells and immune cells such as BMDC and splenocytes. Moreover, the difference in ASD events and components adhered to ASD can contribute to the health effects. Copyright © 2013 John Wiley & Sons, Ltd.     

Femoral arterial cannulation remains a safe and reliable option for aortic dissection repair

BackgroundThe optimal cannulation site for repair of type A aortic dissection remains controversial. The concern for Malperfusion syndrome has initiated a national trend away from femoral cannulation to axillary artery and direct ascending aortic cannulation. The purpose of this study was to report a single center experience with femoral artery cannulation for the repair of a type A dissection.MethodsA retrospective study was performed on 52 patients who underwent surgical repair for a type A dissection between January 1^st, 2012 and June 30^th, 2019 at a single institution. Of the 52 patients analyzed, 35 (67.3%) underwent femoral artery, 11 (21.2%) direct ascending aortic, and 6 (11%) axillary artery cannulation for arterial access. Deep hypothermic circulatory arrest was used in all the patients. Rates of postoperative complication and mortality were reported.ResultsThe mortality and bleeding rates for all the patients undergoing repair of the type A dissection repairs were 27% (14/52) and 19% (10/52), respectively. Cardiopulmonary bypass was established in 100% of the patients that had femoral arterial cannulation. There were no complications specifically related to femoral arterial cannulation nor the axillary or direct aortic approach. Specifically, there was no episodes of malperfusion syndrome, bleeding, or injury with femoral artery cannulation. Bleeding rates were higher in cases that proceeded with a femoral (13%) versus alternate (6%) approach however; neither of the bleeding was related to the cannulation site. None of the mortalities identified were directly attributable to the cannulation approach in each case.ConclusionsDespite the recent shift away from femoral cannulation, the results of the study show that femoral artery cannulation is safe and produces excellent results for establishing cardiopulmonary bypass. The concerns for malperfusion syndrome related to femoral cannulation were not seen.     

Successful treatment of invasive pulmonary aspergillosis caused by Aspergillus felis,a cryptic species within the Aspergillus section Fumigati: A case report

Aspergillus species are a major cause of life-threatening infections in immunocompromised hosts, and the most common pathogen of invasive aspergillosis is Aspergillus fumigatus. Recently, the development of molecular identification has revealed cryptic Aspergillus species, and A. felis is one such species within the Aspergillus section Fumigati reported in 2013.We describe a case of invasive pulmonary aspergillosis caused by A. felis in a 41-year-old Japanese woman diagnosed with myelodysplastic syndrome. She presented with fever 19 days after undergoing autologous peripheral blood stem cell transplantation and was clinically diagnosed with invasive pulmonary aspergillosis. Bronchoscopy and bronchoalveolar lavage were performed for definitive diagnosis. The β-tubulin genes of the mold isolated from the bronchoalveolar lavage fluid, and sequenced directly from the PCR products using a primer pair were found to have 100% homology with A. felis. We successfully treated the patient with echinocandin following careful susceptibility testing.To the best of our knowledge, this is the first published case reporting the clinical course for diagnosis and successful treatment of invasive aspergillosis by A. felis.     

Asymptomatic colorectal cancer detected by screening

PURPOSE: Colorectal cancer screening has become prevalent. To discuss the efficacy of screening, we studied the characteristics of asymptomatic Colorectal cancer detected by screening. METHODS: This is a retrospective review of patients with colorectal cancer treated at our institution. During the past 20 years, 96 of 1,046 cases of colorectal cancer were asymptomatic and detected by screening. Sixty-one of these cases were detected in the recent five years. The initial screening procedures were fecal occult blood test in 51 cases, sigmoidoscopy or colonoscopy in 18, barium enema in 9, and other tests in 18. RESULTS: Thirteen lesions (14 percent) were smaller than 1.0 cm and 32 (33 percent) were 1–2 cm in size. There were 34 Tis, 21 T1, and 8 T2 tumors. Of the 55 Tis or T1 lesions, 14 showed nonpolypoid growth (5 flat-elevated, 7 flat-elevated with depression, 1 flat, 1 depressed), and 12 of these were detected on endoscopy. Thirty-four cases were TNM Stage 0, 25 were Stage I, 16 were Stage II, 12 were Stage III, and 9 were Stage IV. Sixty-one percent of those detected by screening were in either Stage 0 or Stage I compared with 16 percent in the symptomatic group. Cumulative five-year disease-free survival rates were 100 percent for both Stage 0 and Stage I, 94 percent for Stage II, and 52 percent for Stage III. Overall cumulative five-year survival rate was 87 percent for those detected by screening, compared with 57 percent in symptomatic patients. CONCLUSIONS: Asymptomatic cancers detected by screening were at a less advanced stage. In particular, many nonpolypoid early cancers were detected by endoscopic screening.Poster presentation at the meeting of The American Society of Colon and Rectal Surgeons, Montreal, Quebec, Canada, May 7 to 12, 1995.     

Beta-catenin expression in hepatocellular carcinoma: a possible participation of beta-catenin in the dedifferentiation process

BACKGROUND: beta-Catenin is known as a multifunctional protein acting as a regulator of the cadherin-mediated cell-cell adhesion system and in the Wingless/Wnt signal transduction pathway. Recent studies reported mutation of the beta-catenin gene in some tissues of hepatocellular carcinoma (HCC). METHODS: 'Nodule-in-nodule' appearance is a feature of well-differentiated HCC containing a distinct nodule of less-differentiated cancer tissue inside, and it is presumed to be a morphological expression of the dedifferentiation process. The present study immunohistochemically investigated the beta-catenin expression according to the dedifferentiation process of HCC, that is, in small well-differentiated HCC with indistinct margins, HCC with a 'nodule-in-nodule' appearance, moderately differentiated HCC, which does not have a 'nodule-in-nodule' appearance, and sarcomatous HCC. RESULTS: The expression of beta-catenin was observed in approximately 70% of small well-differentiated HCC with indistinct margins. In HCC with a 'nodule-in-nodule' appearance, membranous expression of beta-catenin was higher in the well-differentiated cancer tissues than in the less-differentiated cancer tissues (P < 0.01), cytoplasmic expression was higher in the less-differentiated cancer tissues (P < 0.01), and nuclear expression was higher in the less-differentiated cancer tissues (P < 0.001). In moderately differentiated HCC, tumors with membranous expression of beta-catenin had more frequent intrahepatic metastasis than those without having the expression (P < 0.001). CONCLUSIONS: Accumulation of beta-catenin was already present in the early stage of HCC, and in less-differentiated cancer tissue the membranous expression of beta-catenin could be related to intrahepatic metastasis.