Synchronous Primary Lung Adenocarcinoma and Hepatocellular Carcinoma Successfully Treated with a Combination of Atezolizumab, Bevacizumab, Carboplatin, and Paclitaxel.

Chemotherapy for multiple primary malignancies is challenging. We herein report a case of synchronous primary lung adenocarcinoma and hepatocellular carcinoma (HCC). A 72-year-old man was admitted for the evaluation of an abnormal shadow on his lung. Computed tomography revealed a lung nodule in the right upper lobe and multiple liver masses. He was diagnosed with synchronous primary lung adenocarcinoma and HCC. Atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP) chemotherapy was efficacious for both tumors. ABCP chemotherapy may be a potential treatment option for synchronous primary lung adenocarcinoma and HCC.

[Pulmonary tuberculosis following anti-tumor necrosis factor-α therapy in Crohn's disease:a case report].

Anti-tumor necrosis factor-α (TNF-α) is a principal treatment for Crohn's disease (CD). However, it increases the susceptibility to tuberculosis (TB) infection, and therefore, screening examination prior to treatment initiation is crucial. Here, we report the case of a patient with CD who developed pulmonary TB following anti-TNF-α therapy, despite negative screening. A 19-year-old female who had no history of TB or had traveled to TB-endemic regions was diagnosed with CD. After negative TB screening with chest X-ray and interferon-gamma release assay, the patient was initiated on oral prednisolone and pH-dependent mesalazine. The treatment was changed to infliximab (IFX) because of the inadequate response observed to prednisolone;however, she developed pulmonary TB only 10 weeks after the initiation of IFX. The standard short-course anti-TB regimen was initiated to treat pulmonary TB, whereas IFX was discontinued and replaced with budesonide. Our case suggests that the risk of developing TB should not be excluded, despite the initial negative TB screening, particularly when a patient develops respiratory symptoms during anti-TNF-α therapy.

Clinical significance of human intestinal spirochetosis: a retrospective study.

The clinical and pathological features of human intestinal spirochetosis (HIS) are not well known. Here we report 55 patients with HIS who were diagnosed at our institution during the past 5 years. Seven patients presented with symptoms such as abdominal pain or diarrhea, while the others were incidentally diagnosed during screening colonoscopy. Most patients had non-specific endoscopic findings, including intestinal edema or erosion. The diagnosis of HIS was histologically confirmed via hematoxylin and eosin staining, periodic acid-Schiff staining, and/or immunohistochemistry using anti-Treponema pallidum antibody. Among the 55 patients, five were diagnosed with diseases other than HIS (amoebic colitis, three;ulcerative colitis, one). Sixteen patients were treated with either amoxicillin or metronidazole;only metronidazole proved to be effective. The clinical significance of asymptomatic HIS remains unknown. Some case reports suggest a risk for increased severity in patients with immunodeficiency and/or sexually transmitted diseases. Therefore, aggressive treatment for HIS should be considered, particularly in high-risk patients.

[Hepatocyte nuclear factor 1α-inactivated hepatocellular adenomatosis in a patient with maturity-onset diabetes of the young type 3: case report and literature review].

A 19-year-old Japanese woman had been diagnosed with diabetes at the age of 9 years. She had a strong family history of diabetes, and genetic screening showed she had maturity-onset diabetes of the young type 3 (MODY3). Ultrasonography of the liver and magnetic resonance imaging showed multiple nodules consistent with hepatocellular adenoma (HA). Biopsy of the liver tumors revealed hepatocyte nuclear factor (HNF) 1α-inactivated HA. HA is known as a MODY3-related disease due to mutations in HNF1α. We present the first report of HA associated with MODY3 in Japan.

Safety and efficacy of faldaprevir with pegylated interferon alfa-2a and ribavirin in Japanese patients with chronic genotype-1 hepatitis C infection.

BACKGROUND & AIMS: Faldaprevir (BI 201335) is a potent once-daily (QD) NS3/4A protease inhibitor for the treatment of patients with genotype-1 (GT-1) hepatitis C virus (HCV). The aim of this study was to evaluate the safety, pharmacokinetics and efficacy of faldaprevir plus pegylated interferon alfa-2a (PegIFN) and ribavirin (RBV) in Japanese patients infected with chronic GT-1 HCV. METHODS: Part 1 of this phase II study was a randomized, double-blind, placebo-controlled, dose-ascending study. Treatment-naïve patients received faldaprevir 120 or 240 mg QD, or placebo, plus PegIFN/RBV for 4 weeks, then PegIFN/RBV alone for 44 weeks. In Part 2 (open label), treatment-experienced patients received faldaprevir 240 mg QD plus PegIFN/RBV for 4 weeks, then PegIFN/RBV alone for 44 weeks. Efficacy was assessed using sustained virological response (SVR) 24 weeks after treatment completion. The pharmacokinetics, safety and tolerability of faldaprevir were also assessed. RESULTS: SVR was achieved by 4/6 (67%) treatment-naïve patients treated with faldaprevir 120 mg QD, 5/6 (83%) patients treated with faldaprevir 240 mg QD and 2/4 (50%) patients who received placebo. Of the treatment-experienced patients, 3/6 (50%) achieved SVR. Faldaprevir was well tolerated. There was one serious adverse event, which was not considered to be treatment related. Rash and hyperbilirubinaemia were more frequently reported with faldaprevir than with placebo in treatment-naïve patients, but no cases were severe or serious and none led to discontinuation. Steady-state plasma concentrations of faldaprevir were reached within 7 days of QD dosing. CONCLUSIONS: Faldaprevir with PegIFN/RBV was efficacious and well tolerated, supporting further evaluation of this combination in Japanese patients.

[A case of small intestine type steroid-naïve Crohn disease in which osteomalacia was diagnosed by fractures on the transcervical bone].

We present a 35-year-old Japanese man with Crohn disease. He underwent ileocolectomy for ileum perforation when he was 28 years old, Crohn ileitis was diagnosed and medical treatment was commenced. When he was 35 years old, he complained of severe pain of the right upper torso and the left leg with no apparent trigger. A full check-up revealed that he had multiple fractures including a transcervical fracture of the left femur, ribs on both sides, and fracture of the sacroiliac joint. He had no history of prior use of steroids, and the fractures were thought to have been caused by vitamin D deficiency. This case suggests that clinicians should be aware of the possibility of osteomalacia caused by malabsorption of fat-soluble vitamin D when examining patients with ileocolic Crohn disease.

[Campylobacter].

Campylobacter bacterial infection is the second most cause of food poisoning in Japan. Patients are often found in outpatient clinic with symptom of severe diarrhea. The common risk factor of Campylobacter infection is reported to be half-backed chicken intake. Because incubation period is reported to be 2-7 days, it is often difficult to identify the causative food. Macrolide is the first choice of medicine when the patient has severe symptom. Some patients develop Guillain-Barré syndrome(G-B syndrome) 2-3 weeks after Campylobacter infection. It is said that 30% of G-B syndrome patients have Campylobacter infection before they develop G-B syndrome.

[Natural toxin poisoning].

Natural toxin poisoning often occurs when amateur who has no expert knowledge of food collects and cooks the wrong material. In many cases, the symptoms of natural toxin poisoning are mild and the patients recover from illness within a day. However, if the patients have respiratory or neurological symptoms after several hours of intake, the patients must go to hospital immediately. Mushroom poisoning is often reported and puffer fish poisoning is sometimes reported in Japan.

Disadvantages of peginterferon and ribavirin treatment in older patients with chronic hepatitis C: an analysis using the propensity score.

PURPOSE: Peginterferon (PEG-IFN) and ribavirin (RBV) combination treatment for patients with chronic hepatitis C (CHC), infected by genotype-1 hepatitis C virus with high viral loads, results in a sustained viral response (SVR) in ~50%. However, a trend of decreasing SVR in the older patients has been reported. In the present study, we verified this trend of treatment efficacy in older patients using the propensity score (PS). METHODS: We conducted a survey of 327 patients with CHC (genotype 1 and high viral loads) who were treated with PEG-IFN and RBV for 48 weeks. The SVR rate was compared between patients =60 and <60 years of age. Because backgrounds of these patients differed considerably, we verified this efficacy between the older (n = 102) and younger (n = 102) patients matched for gender, body weight, platelets (PLT), and red blood cell (RBC) counts using PS. RESULTS: The total SVR rate was 42.9% (161/327); this rate decreased with increasing age and was lower in the older patients (≥60 years: 41.5%, <60 years: 54.3%, P = 0.0245). Moreover, younger age was a significant factor for SVR. After correction by PS, the SVR in older patients remained significantly lower (≥60 years: 43.1%, <60 years: 57.8%, P = 0.0497). In addition, RBC counts and hemoglobin (Hgb) concentrations, as well as RBV adherence in the older patients, decreased with this treatment, although there were no significant differences in pretreatment RBC and Hgb levels. CONCLUSIONS: The analysis using PS indicated that RBV adherence in the older patients decreased even if they did not have lower pretreatment RBC and Hgb levels.

[A case of pneumatosis cystoides intestinalis induced by steroid pulse therapy for severe acute hepatitis B].

A 26-year-old Japanese woman was admitted to the hospital because of fever and general fatigue. A diagnosis of acute hepatitis B was given because of high levels of transaminase and positivity for HBs-Ag, HBe-Ag and HBc-IgM. On the 2nd day progression to fulminant hepatitis was suspected, and steroid pulse therapy, cyclosporin, entecavir, and interferon-ß were started. Her laboratory data improved until transaminase showed an increase on 18th day, and steroid was once again administered. Abdominal CT scan and plain abdominal X-ray showed pneumatosis cystoides intestinalis (PCI) mainly along the ascending colon without any symptoms. After discontinuation of steroid therapy, abnormal gas gradually disappeared. This is a very rare case of PCI, which may have been caused by short-term steroid pulse therapy.

Optimal erythrocyte ribavirin level to reduce the risk of anemia and obtain an early virological response in patients with chronic hepatitis C caused by genotype 1b infection.

Aims. To determine whether the erythrocyte phosphorylated ribavirin (RBV) level might be a useful index of EVR and risk of anemia and to determine the optimal dose of RBV in 24 patients with hepatitis C with pegylated interferon and RBV. Methodology. The RBV level was measured by a high-performance liquid chromatography. Results and Conclusion. In patients aged 50 years or over, a negative correlation (r = -0.548, P < .05) was observed between the RBV level at week 2 and rate of Hb reduction (ΔHb) at week 4. The ΔHb at week 4 was significantly greater in patients with RBV levels of ≥800 µM (-25.5 ± 10.1%) than in patients with RBV levels <800 µM (-15.6 ± 7.7%). None of the patients with RBV levels <600 µM at week 2 achieved EVR and SVR. Thus the optimal levels of erythrocyte phosphorylated RBV at week 2 of therapy in order to achieve EVR without anemia seemed to be 600-800 µM.

Pentoxifylline prevents pig serum-induced rat liver fibrosis by inhibiting interleukin-6 production.

BACKGROUND/AIM: Pig serum-induced rat liver fibrosis is a model of liver fibrosis in the absence of obvious hepatocyte injury. Penoxifylline (PTX), a xanthine derivative, which is a well-known suppressor of tumor necrosis factor-alpha (TNF-alpha) production from inflammatory cells, has also been shown to inhibit the growth of hepatic stellate cells and to inhibit collagen synthesis in these cells in vitro. We investigated the effect of PTX on pig serum-induced liver fibrosis in vivo, and assessed the mechanisms of prevention of fibrogenesis by this drug. METHODS: Male Wistar rats were given intraperitoneal injections of 0.5 ml normal pig serum twice a week for 10 weeks with or without concomitant oral administration of PTX (20 mg/kg). RESULTS: Rats that received pig serum showed significant liver fibrosis, and their serum interleukin-6 (IL-6) and hyaluronic acid levels were significantly increased. The serum levels of IL-6 were well correlated with the serum levels of hyaluronic acid, and increased as the liver fibrosis progressed. Penoxifylline prevented the development of fibrosis in this animal model and reduced the serum levels of IL-6 in a dose-dependent manner. In vitro, by the addition of PTX to the culture medium of the rat hepatic stellate cells (HSCs), the proliferation of the HSCs was significantly inhibited and IL-6 in the culture supernatant was also reduced significantly. Exogenous addition of IL-6 partially restored the proliferation. CONCLUSION: Penoxifylline prevents pig serum-induced rat liver fibrosis by inhibiting the proliferation of HSCs and by inhibiting the production of IL-6 from HSCs.

Polaprezinc attenuates liver fibrosis in a mouse model of non-alcoholic steatohepatitis.

BACKGROUND AND AIM: The effect of polaprezinc, a zinc-carnosine chelate compound, on the development of non-alcoholic steatohepatitis (NASH) was investigated in dietary methionine and choline deficient (MCD) mice. METHODS: Mice were fed the MCD diet with or without polaprezinc (2.2 g/kg diet) for 10 weeks. Liver histopathology, triglyceride and lipid peroxide levels, and the expression of genes linked to fibrosis were then assessed. RESULTS: MCD mice developed steatohepatitis accompanied by mild fibrosis with an increase in lipid peroxidation, hepatic stellate cell (HSC) activation, and the augmented mRNA expression of tumor necrosis factor-alpha, transforming growth factor-beta1 and procollagen alpha1(I). The mRNA expression levels of matrix metalloproteinase (MMP)-2 and tissue inhibitors of metalloproteinase (TIMP)-1 and TIMP-2 were also enhanced. Histopathologically, polaprezinc supplementation did not influence the development of steatosis but it apparently attenuated fibrosis. Polaprezinc slightly reduced lipid peroxidation and suppressed HSC activation as well as the mRNA expression of pro-inflammatory cytokines. Polaprezinc affected the MCD diet-enhanced expression of TIMP-1 even when administered relatively late. CONCLUSION: These results suggest that polaprezinc attenuates fibrosis in NASH by reducing inflammation and lipid peroxidation and, during a later phase, promoting fibrolysis via the inhibition of TIMP expression in the liver. Further investigation is required to clarify the clinical efficacy of polaprezinc in patients with NASH.

Clinical application of the leukocyte migration test and new diagnostic criteria for identifying causative agents in patients with drug-induced liver injury.

BACKGROUND/AIMS: We examined the usefulness of the leukocyte migration test (LMT) in the identification of agents causing drug-induced liver injury (DILI). METHODOLOGY: In 14 patients who were tentatively diagnosed as having DILI in Kitasato Institute Hospital, pharmacists collected and evaluated drug information and patients' medication histories to identify causative agents. Simultaneously, LMT and drug lymphocyte stimulation test (DLST) were performed. Furthermore, scoring was performed according to the diagnostic criteria established by the International Consensus Meeting (ICM) and the Digestive Disease Week-Japan 2004 (DDW-J). RESULTS: LMT-positive agents showed a higher ICM score compared to DLST-positive agents. The rate of LMT-positive agents was examined with respect to ICM assessment, and 0%, 25%, 33%, and 100% of agents regarded as unrelated/unlikely, possible, probable, and highly probable showed positive reactions on LMT, respectively; the rate of LMT-positive agents increased with the degree of the agent's involvement. When the results of LMT were applied to the DDW-J criteria, there was a correlation with the ICM criteria in comparison to scoring based on the results of DLST. CONCLUSIONS: LMT may be useful for identifying agents causing DILI. Furthermore, the collection and evaluation of drug and patient information and in vitro testing in the identification of causative agents may support more reliable diagnosis.

Rho/Rho kinase is a key enzyme system involved in the angiotensin II signaling pathway of liver fibrosis and steatosis.

BACKGROUND AND AIM: The molecular mechanisms underlying the involvement of the renin-angiotensin system in hepatic fibrosis are unclear. Recently, it was reported that a Rho kinase inhibitor prevented fibrosis of various tissues and that the Rho/Rho kinase pathway was involved in the renin-angiotensin system of vascular smooth muscle cells. In this study, the involvement of the Rho/Rho kinase pathway on angiotensin II signaling in liver fibrogenesis and generation of steatosis was investigated. METHODS: Rats were fed a choline-deficient/L-amino acid-defined (CDAA) diet continuously and treated with a Rho kinase inhibitor, Y-27632, and an angiotensin II receptor blocker, TCV-116. Liver histology and hepatic stellate cell activation were analyzed. Free radical production was detected by 4-hydroxynonenal and 8-hydroxy-2'-deoxyguanosine immunostaining and the expression of tumor necrosis factor-alpha was examined. Isolated hepatic stellate cells were pretreated with a Rho kinase inhibitor, Y-27632, or an angiotensin II receptor blocker, CV-11974, and stimulated with angiotensin II, and mRNA expression of transforming growth factor-beta and alpha-smooth muscle actin was analyzed. RESULTS: Both the angiotensin II receptor blocker and the Rho kinase inhibitor improved fibrosis and steatosis of the liver in CDAA-fed rats. The increase in the number of hepatocytes positive for 4-hydroxynonenal and 8-hydroxy-2'-deoxyguanosine in CDAA-fed rats was significantly prevented by the angiotensin II receptor blocker and the Rho kinase inhibitor. The levels of tumor necrosis factor-alpha mRNA in the liver of CDAA-fed rats were significantly increased and this increase was significantly inhibited by treatment with the angiotensin II receptor blocker and the Rho kinase inhibitor. mRNA expression of transforming growth factor-beta and alpha-smooth muscle actin stimulated by angiotensin II was also significantly suppressed by these two drugs. CONCLUSION: These results suggest that the Rho/Rho kinase pathway is at least partly involved in the renin-angiotensin system and plays an important role in hepatic fibrosis and steatosis.

Down-regulation of matrix-invasive potential of human liver cancer cells by type I interferon and a histone deacetylase inhibitor sodium butyrate.

We have demonstrated anti-proliferation and anti-metastasis effects of both interferon-alpha and a histone deacetylase inhibitor, sodium butyrate, on human liver cancer cell lines. In this study, invasive ability of human liver cancer cell lines through the matrix-coated membrane was examined and inhibitory effect of interferon-alpha and sodium butyrate was investigated. Among six human liver cancer cell lines, HLE and HLF showed high invasive ability using the Matrigel invasion assay. This invasion ability was significantly inhibited by pretreatment of the cells with 1000 IU/ml of interferon-alpha or 2 mM of sodium butyrate. Gelatin zymography and the matrix metalloproteinase-2 and -9 activity assay showed that these two cell lines produce active- and pro-matrix metalloproteinase-2 and -9, and their activity was significantly reduced by pretreatment with both agents. Real-time quantitative reverse transcription-polymerase chain reaction showed decrease in matrix metalloproteinase-1 mRNA levels by pretreatment with both agents, but mRNA levels of tissue inhibitor of matrix metalloproteinase-1 and -2 were differently modulated by interferon-alpha and sodium butyrate. These results suggest that interferon-alpha and sodium butyrate reduce a chance of invasion and metastasis of human liver cancer cells by inhibiting matrix metalloproteinase activity, although its inhibitor is differently regulated.

Clinical usefulness of edaravone for acute liver injury.

BACKGROUND: Edaravone, a newly synthesized radical scavenger, has shown an excellent effect on treating stroke patients. The effect of edaravone on carbon tetrachloride (CCl4)-induced acute liver injury was examined. METHODS: Six rats were injected with CCl4 alone and six rats were intravenously injected with edaravone immediately after and 3 h after injection of CCl4. Another six rats were injected with olive oil alone. The animals were killed at 24 h after the CCl4 injection. RESULTS: Injection of CCl4 was followed by a marked increase in serum alanine aminotranferase (ALT) level (CCl4, 1630.6 +/- 606.8 IU/L; olive oil, 21.0 +/- 2.6 IU/L; P < 0.001), lactate dehydrogenase (LDH) level (CCl4, 5068.0 +/- 2956.4 IU/L; olive oil, 203.6 +/- 30.5 IU/L; P < 0.005), and total bilirubin (TB) level (CCl4, 0.88 +/- 0.48 mg/dL; olive oil, 0.37 +/- 0.05 mg/dL; P < 0.01), whereas in the edaravone-treated rats, the ALT (119.4 +/- 113.5 IU/L, P < 0.001), LDH (369.7 +/- 288.2 IU/L, P < 0.005), and TB values (0.29 +/- 0.16 mg/dL, P < 0.01) were significantly decreased. Histological examination of the liver by hematoxylin and eosin and oil red O staining showed a marked reduction of steatosis in the CCl4 and edaravone-treated rats compared with the CCl4-injected rats. Significant inhibition of hepatocytic apoptosis was demonstrated by the terminal deoxynucleotidyl transferase-mediated UTP nick-end labeling (TUNEL) method in the edaravone-treated rats. CONCLUSIONS: These results suggest that edaravone has a marked preventive effect on oxidative stress-induced acute liver injury.

Essential role of the adhesion receptor LFA-1 for T cell-dependent fulminant hepatitis.

Viral hepatitis affects more than 2 billion people worldwide. In particular, no effective treatment exists to abrogate death and liver damage in fulminant hepatitis. Activation of T cells is an initial and critical event in the pathogenesis of liver damage in autoimmune and viral hepatitis. The precise molecular mechanisms that induce T cell-mediated hepatocyte injury remain largely unclear. In mice, T cell-dependent hepatitis and acute liver damage can be modeled using ConA. In this study, we examined the role of the adhesion receptor LFA-1 in ConA-induced acute hepatic damage using LFA-1(-/-) (CD11a) mice. Massive liver cell apoptosis and metabolic liver damage were observed in LFA-1(+/+) mice following ConA injection. By contrast, LFA-1(-/-) mice were completely resistant to ConA-induced hepatitis and none of the LFA-1(-/-) mice showed any hepatic damage. Whereas activated hepatic T cells remained in the liver in LFA-1(+/+) mice, activated T cells were rapidly cleared from the livers of LFA-1(-/-) mice. Mechanistically, T cells from LFA-1(-/-) mice showed markedly reduced cytotoxicity toward liver cells as a result of impaired, activation-dependent adhesion. Importantly, adoptive transfer of hepatic T cells from LFA-1(+/+) mice, but not from LFA-1(-/-) mice, sensitized LFA-1(-/-) mice to ConA-induced hepatitis. Thus, LFA-1 expression on T cells is necessary and sufficient for T cell-mediated liver damage in vivo. These results provide the first genetic evidence on an adhesion receptor, LFA-1, that has a crucial role in fulminant hepatitis. These genetic data identify LFA-1 as a potential key target for the treatment of T cell-mediated hepatitis and the prevention of liver damage.

Helicobacter pylori prevalence in dentists in Japan: a seroepidemiological study.

BACKGROUND: The infection mode of Helicobacter pylori is not well known. In order to prove that frequent exposure to saliva and dental plaque does not constitute a risk for acquiring H. pylori infection, we tested the hypothesis that the prevalence of H. pylori in dentists in Japan is the same as that in controls. We also studied factors associated with H. pylori prevalence by multivariate analysis. METHODS: We examined serum anti-H. pylori-IgG in 232 Japanese subjects (116 dentists and 116 age- and sex-matched nonclinical controls). Participants were given a questionnaire that included demographic data, life style, past history, and gastrointestinal symptoms, and dental practice. RESULTS: We analyzed the results for 111 dentists and 111 controls after exclusion of those who had an equivocal titer. The seroprevalence of H. pylori was 42.3% in dentists and 40.0% in controls. With multiple logistic regression, age was selected as the only independent variable correlated with seroprevalence (P = 0.0002; coefficient of determination 0.11). Factors associated with dental practice were not significant. CONCLUSIONS: We conclude that dental practice in Japan does not increase the risk of H. pylori infection for dentists.