Search

HBsAg loss with anti-HBs acquisition is considered a functional cure and ideal treatment goal for patients with CHB. Our group have reported the efficacy of therapeutic vaccine with HBsAg and HBcAg (NASVAC) by intranasal and subcutaneous injection. In this study, we investigated the safety and efficacy of newly developed CVP-NASVAC, which contained NASVAC with mucoadhesive carboxyl vinyl polymer (CVP) in the dedicated device.A single dose, open-label, phase IIa clinical trial of CVP-NASVAC was conducted. Patients with CHB treated with nucleoside/nucleotide analogs (NAs) and HBV carriers not undergoing anti-HBV treatment were enrolled. CVP-NASVAC was injected through the nose for, in total, 10 times. Participants were followed-up for 18 months, and their HBsAg reduction and anti-HBs induction assessed as endpoints.Among the patients with CHB treated with NAs (n = 27) and HBV carriers without NAs (n = 36), 74.1% and 75.0% exhibited reductions in their baseline HBsAg, and the mean reductions were -0.1454 logAnti-HBs induction and HBsAg reduction was observed after CVP-NASVAC treatment in some patients with CHB. The CVP-NASVAC is a safe treatment, which might expect to achieve functional cure for patients with CHB.

Background: Tokyo, the capital of Japan, is a densely populated city of >13 million people, so the population is at high risk of epidemic severe acute respiratory coronavirus 2 (SARS-CoV-2) infection. A serologic survey of anti–SARS-CoV-2 IgG would provide valuable data for assessing the city’s SARS-CoV-2 infection status. Therefore, this cross-sectional study estimated the anti–SARS-CoV-2 IgG seroprevalence in Tokyo. Methods: Leftover serum of 23,234 hospital visitors was tested for antibodies against SARS-CoV-2 using an iFlash 3000 chemiluminescence immunoassay analyzer (Shenzhen YHLO Biotech, Shenzhen, China) with an iFlash–SARS-CoV-2 IgG kit (YHLO) and iFlash–SARS-CoV-2 IgG-S1 kit (YHLO). Serum samples with a positive result (≥10 AU/mL) in either of these assays were considered seropositive for anti–SARS-CoV-2 IgG. Participants were randomly selected from patients visiting 14 Tokyo hospitals between September 1, 2020 and March 31, 2021. No participants were diagnosed with coronavirus disease 2019 (COVID-19), and none exhibited COVID-19-related symptoms at the time of blood collection. Results: The overall anti–SARS-CoV-2 IgG seroprevalence among all participants was 1.83% (95% confidence interval [CI], 1.66–2.01%). The seroprevalence in March 2021, the most recent month of this study, was 2.70% (95% CI, 2.16–3.34%). After adjusting for population age, sex, and region, the estimated seroprevalence in Tokyo was 3.40%, indicating that 470,778 individuals had a history of SARS-CoV-2 infection. Conclusions: The estimated number of individuals in Tokyo with a history of SARS-CoV-2 infection was 3.9-fold higher than the number of confirmed cases. Our study enhances understanding of the SARS-CoV-2 epidemic in Tokyo.

As long as the coronavirus disease-2019 (COVID-19) pandemic continues, new variants of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) with altered antigenicity will emerge. The development of vaccines that elicit robust, broad, and durable protection against SARS-CoV-2 variants is urgently required. We have developed a vaccine consisting of the attenuated vaccinia virus Dairen-I (DIs) strain platform carrying the SARS-CoV-2 S gene (rDIs-S). rDIs-S induced neutralizing antibody and T-lymphocyte responses in cynomolgus macaques and human angiotensin-converting enzyme 2 (hACE2) transgenic mice, and the mouse model showed broad protection against SARS-CoV-2 isolates ranging from the early-pandemic strain (WK-521) to the recent Omicron BA.1 variant (TY38-873). Using a tandem mass tag (TMT)-based quantitative proteomic analysis of lung homogenates from hACE2 transgenic mice, we found that, among mice subjected to challenge infection with WK-521, vaccination with rDIs-S prevented protein expression related to the severe pathogenic effects of SARS-CoV-2 infection (tissue destruction, inflammation, coagulation, fibrosis, and angiogenesis) and restored protein expression related to immune responses (antigen presentation and cellular response to stress). Furthermore, long-term studies in mice showed that vaccination with rDIs-S maintains S protein-specific antibody titers for at least 6 months after a first vaccination. Thus, rDIs-S appears to provide broad and durable protective immunity against SARS-CoV-2, including current variants such as Omicron BA.1 and possibly future variants.

Booster vaccinations against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are being promoted worldwide to counter the coronavirus disease 2019 (COVID-19) pandemic. In this study, we analyzed the longitudinal effect of the third BNT162b2 mRNA vaccination on antibody responses in healthcare workers. Additionally, antibody responses induced by the fourth vaccination were analyzed.The levels of anti-spike (S) IgG and neutralizing antibody against SARS-CoV-2 were measured at 7 months after the second vaccination (n = 1138), and at 4 (n = 701) and 7 (n = 417) months after the third vaccination using an iFlash 3000 chemiluminescence immunoassay analyzer. Among the 417 participants surveyed at 7 months after the third vaccination, 40 had received the fourth vaccination. A multiple linear regression analysis was performed to clarify which factors were associated with the anti-S IgG and neutralizing antibody. Variables assessed included sex, age, number of days after the second or third vaccination, diagnostic history of COVID-19, and anti-nucleocapsid (N) IgG level.At 7 months after the third vaccination, antibody responses were significantly higher than those at the same time after the second vaccination. Unlike the second vaccination, age had no effect on the antibody responses induced by the third vaccination. Furthermore, the fourth vaccination resulted in a further increase in antibody responses. The multiple linear regression analysis identified anti-N IgG level, presumably associated with infection, as a factor associated with antibody responses.Our findings showed that BNT162b2 booster vaccinations increased and sustained the antibody responses against SARS-CoV-2.

Purpose The current study aims to test the hypothesis that the ratio of T1-weighted image to T2-weighted image signal intensity (T1w/T2w-Ratio: rT1/T2), an imaging surrogate developed for myelin integrity, is predictive of histologically lower-grade glioma's IDH mutation status. Materials and Methods 25 histologically and molecularly confirmed lower-grade glioma patients with eight IDH-wildtype (IDHwt) and 17 IDH-mutant (IDHmt) tumors at Asahikawa Medical University Hospital (AMUH) were used as a test cohort. Twenty-nine patients (IDHwt: 13, IDHmt: 16) from Osaka International Cancer Institute (OICI) and 101 patients from the Cancer Imaging Archive (TCIA) / Cancer Genome Atlas (TCGA) dataset (IDHwt: 19, IDHmt: 82) were used as external cohorts. rT1/T2 images were calculated from T1- and T2-weighted images using a recommended signal correction. The relationship between the mean rT1/T2 (mrT1/T2) and the IDH mutation status was investigated. Moreover, t-Distributed Stochastic Neighbor Embedding (t-SNE) investigated the difference in MRI qualities and characteristics between the three cohorts. Results The test cohort at AMUH revealed that mrT1/T2 of IDHwt tumors was significantly higher than that of IDHmt tumors (p < 0.05) and that the optimal cut-off of mrT1/T2 for discriminating IDHmt was 0.666-0.677, (AUC = 0.75, p < 0.05), which finding was validated by the external domestic cohort at OICI (AUC = 0.75, p = 0.02). However, the external international cohort deriving from TCIA/TCGA could not validate this (AUC = 0.63, p = 0.08). t-SNE analysis revealed that the difference in image characteristics within the cohort was more diverse for the TCIA/TCGA than for the two domestic cohorts. Conclusion The current study revealed that mrT1/T2 was able to discriminate IDHwt and IDHmt tumors in two domestic cohorts significantly. This was not validated by the TCIA/TCGA cohort due to the wide variety in the original imaging characteristics of the TCIA/TCGA cohort.

Background AimsIn natural infections with hepatitis B virus (HBV), large amounts of hepatitis B surface-small antigen (HBs-S) subviral particles (SVPs), which do not contain viral nucleocapsid, are secreted into the blood. The function of excess amounts of SVPs remains largely unknown. In this study, we analyzed the function of HBs-S in HBV infection.MethodsThe effect of HBs-S in HBV infection was evaluated in a human hepatoma cell line, in primary human hepatocytes, and in chimeric mice with humanized livers. To analyze the involvement of glycosaminoglycan, HBs-S attachment to cells in the presence of heparin was evaluated by enzyme-linked immunosorbent assay (ELISA), and the enhancement of viral attachment was evaluated by measurement of viral DNA. Additionally, the interaction between HBs-S and viral particles was analyzed by immunoprecipitation.ResultsAttachment of the HBV DNA to cells inoculated with the combination of virus and HBs-S was significantly higher than that to cells inoculated with HBV only. Pretreatment of the cells with HBs-S also increased viral DNA levels significantly compared to that in untreated cells. In contrast, HBs-L did not enhance the viral attachment. Enhancement of viral attachment was associated with the attachment of HBs-S to the cells via heparan sulfate. HBs-S also interacted with the viral particle. Furthermore, in chimeric mice with humanized livers, HBs-S enhanced HBV infection.ConclusionsWe demonstrated that HBs-S enhances viral attachment in vitro and viral infection in vivo. HBs-S interacted with heparan sulfate on the cellular surface, and this interaction contributed to the enhancement of viral attachment. These data indicate that HBs-S enhances the viral infection, and may contribute to the high transmissibility of HBV.

Most anti-influenza drugs currently used, such as oseltamivir and zanamivir, inhibit the enzymatic activity of neuraminidase. However, neuraminidase inhibitor-resistant viruses have already been identified from various influenza virus isolates. Here, we report the development of a class of macrocyclic peptides that bind the influenza viral envelope protein hemagglutinin, named iHA. Of 28 iHAs examined, iHA-24 and iHA-100 have inhibitory effects on the in vitro replication of a wide range of Group 1 influenza viruses. In particular, iHA-100 bifunctionally inhibits hemagglutinin-mediated adsorption and membrane fusion through binding to the stalk domain of hemagglutinin. Moreover, iHA-100 shows powerful efficacy in inhibiting the growth of highly pathogenic influenza viruses and preventing severe pneumonia at later stages of infection in mouse and non-human primate cynomolgus macaque models. This study shows the potential for developing cyclic peptides that can be produced more efficiently than antibodies and have multiple functions as next-generation, mid-sized biomolecules.

To analyze the molecular pathogenesis of SARS-CoV-2, a small animal model such as mice is needed: human ACE2, the receptor of SARS-CoV-2, needs to be expressed in the respiratory tract of mice. We conferred SARS-CoV-2 susceptibility in mice by using an adenoviral vector expressing hACE2 driven by an EF1α promoter with a leftward orientation. In this model, severe pneumonia like human COVID-19 was observed in SARS-CoV-2-infected mice, which was confirmed by dramatic infiltration of inflammatory cells in the lung with efficient viral replication. An early circulating strain of SARS-CoV-2 caused the most severe weight loss when compared to SARS-CoV-2 variants of concern, although histopathological findings, viral replication, and cytokine expression characteristics were comparable. We found that a distinct proteome of an early circulating strain infected lung characterized by elevated complement activation and blood coagulation, which were mild in other variants, can contribute to disease severity. Unraveling the specificity of early circulating SARS-CoV-2 strains is important in elucidating the origin of the pandemic.

Only several cases of internal carotid artery (ICA) stenosis involving the persistent primitive hypoglossal artery (PPHA) have been treated with carotid endarterectomy (CEA) because of its extreme rarity. CEA was performed for an 87-year-old female with severe stenosis of the right ICA–PPHA bifurcation requiring shunting from CCA to both PPHA and ICA. We initially attempted to insert two intraluminal balloon shunts into the CCA, as previously reported. However, we found this procedure technically impossible to achieve. An improvised three-way junction tube was inserted distally into PPHA and ICA and proximally into CCA, securing blood flow during CEA. Unfortunately, the patient suffered post-operative ischemic brain lesions due to the prolonged ischemic time during our initial unsuccessful shunt attempt. A three-way junction shunting tube could be an effective shunt technique during an anatomically complicated CEA.

Models of animals that are susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can usefully evaluate the efficacy of vaccines and therapeutics. In this study, we demonstrate that infection with the SARS-CoV-2 B.1.351 variant (TY8-612 strain) induces bodyweight loss and inflammatory cytokine/chemokine production in wild-type laboratory mice (BALB/c and C57BL/6 J mice). Furthermore, compared to their counterparts, BALB/c mice had a higher viral load in their lungs and worse symptoms. Importantly, infecting aged BALB/c mice (older than 6 months) with the TY8-612 strain elicited a massive and sustained production of multiple pro-inflammatory cytokines/chemokines and led to universal mortality. These results indicated that the SARS-CoV-2 B.1.351 variant-infected mice exhibited symptoms ranging from mild to fatal depending on their strain and age. Our data provide insights into the pathogenesis of SARS-CoV-2 and may be useful in developing prophylactics and therapeutics.

Influenza virus HA-specific antibodies can be detected via the hemagglutination inhibition (HI) assay, the neutralization (NT) assay, and the enzyme-linked immunosorbent assay (ELISA). However, these assays have some drawbacks, including narrow dynamic range and the requirement for large amounts of sera., Antibody detection is crucial for monitoring host immune responses to specific pathogen antigens (Ags) and evaluating vaccine efficacies. The luciferase immunoprecipitation system (LIPS) was developed for sensitive detection of Ag-specific antibodies in sera from various species. In this study, we describe NanoLIPS, an improved LIPS assay based on NanoLuciferase (NLuc), and employ the assay for monitoring antibody responses following influenza virus infection or vaccination. We generated recombinant influenza virus hemagglutinin (HA) proteins tagged with N-terminal (N-NLuc-HA) or C-terminal (C-NLuc-HA) NLuc reporters. NLuc-HA yielded an at least 20-fold higher signal-to-noise ratio than did a LIPS assay employing a recombinant HA-Gaussia princeps luciferase (GLuc) fusion protein. NanoLIPS-based detection of anti-HA antibodies yielded highly reproducible results with a broad dynamic range. The levels of antibodies against C-NLuc-HA generated by mice vaccinated with recombinant vaccinia virus DIs strain expressing an influenza virus HA protein (rDIs-HA) was significantly correlated with the protective effect elicited by the rDIs-HA vaccine. C-NLuc-HA underwent glycosylation with native conformations and assembly to form a trimeric structure and was detected by monoclonal antibodies that detect conformational epitopes present on the globular head or stalk domain of HA. Therefore, NanoLIPS is applicable for evaluating vaccine efficacy. We also showed that C-NLuc-HA is applicable for detection of HA-specific antibodies in sera from various experimental species, including mouse, cynomolgus macaque, and tree shrew. Thus, NanoLIPS-based detection of HA offers a simple and high-sensitivity method that detects native conformational epitopes and can be used in various experimental animal models. IMPORTANCE Influenza virus HA-specific antibodies can be detected via the hemagglutination inhibition (HI) assay, the neutralization (NT) assay, and the enzyme-linked immunosorbent assay (ELISA). However, these assays have some drawbacks, including narrow dynamic range and the requirement for large amounts of sera. As an alternative to an ELISA-based method, luciferase immunoprecipitation system (LIPS) was developed. We focused on NanoLuciferase (NLuc), which has a small size, higher intensity, and longer stability. In this study, we developed a technically feasible and highly sensitive method for detecting influenza virus-specific antibodies using a NLuc-tagged recombinant HA protein produced in mammalian cells. HA with a C-terminal NLuc extension (C-NLuc-HA) was glycosylated and formed trimeric complexes when expressed in mammalian cells. Furthermore, C-NLuc-HA was recognized not only by monoclonal antibodies that bind to the globular head domain but also by those that bind to the stalk domain. We also demonstrated that the data obtained by this assay correlate with the protection of an experimental vaccine in animal models.

Isolated spontaneous common carotid artery (CCA) dissection is extremely rare. Moreover, only a few case reports for isolated spontaneous CCA dissection treated with carotid artery stenting (CAS) can be found so far. Here, the authors report a case where intravascular ultrasonography (IVUS) provided valuable information about lesion evaluation, stent selection and stent placement during CAS for isolated CCA dissection. A 69-year-old male was diagnosed with an isolated spontaneous left CCA dissection. CAS assisted with IVUS was performed to prevent further dissection and cerebral infarction recurrence. To the best of our knowledge, this is the first case report of an isolated spontaneous CCA dissection treated with CAS assisted by IVUS. CAS assisted by IVUS may be an effective treatment option to prevent intraoperative complications and further stroke recurrence for isolated spontaneous CCA dissection.

The northern tree shrew (Tupaia belangeri) possesses high potential as an animal model of human diseases and biology, given its genetic similarity to primates. Although genetic information on the tree shrew has already been published, some of the entire coding sequences (CDSs) of tree shrew genes remained incomplete, and the reliability of these CDSs remained difficult to determine. To improve the determination of tree shrew CDSs, we performed sequencing of the whole-genome, mRNA, and total RNA and integrated the resulting data. Additionally, we established criteria for the selection of reliable CDSs and annotated these sequences by comparison to the human transcriptome, resulting in the identification of complete CDSs for 12,612 tree shrew genes and yielding a more accurate tree shrew genome database (TupaiaBase: http://tupaiabase.org). Transcriptome profiles in hepatitis B virus infected tree shrew livers were analyzed for validation. Gene ontology analysis showed enriched transcriptional regulation at 1 day post-infection, namely in the “type I interferon signaling pathway”. Moreover, a negative regulator of type I interferon, SOCS3, was induced. This work, which provides a tree shrew CDS database based on genomic DNA and RNA sequencing, is expected to serve as a powerful tool for further development of the tree shrew model.

Avian-origin influenza viruses like H5N1 and H7N9 often cause severe symptoms with high mortality in humans. Animal models are useful for clarification of the mechanisms of pathogenicity of these infections. In this study, to expand the potential utility of the Northern tree shrew (Tupaia belangeri) for influenza virus infection, we assessed the pathogenicity of H5N1 and H7N9 avian influenza viruses in tupaia. Infectious virus was detected continuously from nasal, oral, tracheal, and conjunctival swab samples in the animals infected with these viruses. H5N1 influenza virus infection of tupaia caused severe diffuse pneumonia with fever and weight loss. In contrast, H7N9 influenza virus infection caused focal pneumonia. The severity of pneumonia was correlated with proinflammatory cytokine transcript levels. These results indicated that tupaia can be another suitable animal model for avian influenza virus research.

A 39-year-old woman visited our hospital with complaints of nausea, vomiting, and lower abdominal pain for 2 weeks. Abdominal CT revealed thickening of the transverse colonic wall, dilated bowel, and a metastatic ischemic tumor in the liver (S7). We diagnosed her with obstructive colon cancer, clinical Stage Ⅳa(T, type 2, cT3, N0, M1a[liver]). At first, we placed a self-expanding metallic stent(SEMS)to decompress bowel obstructions. We planned a surgical resection of the primary tumor followed by partial resection of the liver. We performed a laparoscopic right hemicolectomy(D3)24 days after the stenting. Pathologically, we diagnosed her with BRAF-mutated colon cancer, pStage Ⅳa(pT4a, N1b[2/43], M1a[liver]). On completion of 4 courses of mFOLFOXIRI and bevacizumab, we confirmed a reduction of the S7 tumor but found a new tumor in S6. Since the tumors were potentially resectable, we performed partial liver resection(S6, S7)1 month later. A month following the hepatectomy, CT revealed a new tumor in S4. The patient has been receiving general chemotherapy (CapeOX and bevacizumab)without disease progression for 6 months. We experienced a challenging case of BRAF- mutated obstructive colon cancer with liver metastases.

We report 2 cases of neuroendocrine carcinoma(NEC)of colon and rectum with distant metastasis. The treatment of NEC with distant metastasis is based on the treatment of small cell lung cancer, but that is controversial because NEC is relatively rare. Case 1: A 75-year-old man who was admitted for anal pain. Physical examination showed the anal tumor and swelling inguinal lymph nodes. CT showed rectum tumor and multiple lymph node metastases to the pelvis and inguinal region. Colonoscopy showed a Type 3 tumor in the rectum. He was diagnosed with NEC based on biopsy and immunostaining. Colostomy was performed for pain relief and etoposide/cisplatin(EP)therapy was introduced. After 6 courses of the chemotherapy, CT showed progression of the tumor, then we made the shift to palliative treatment. Case 2: A 69-year-old man who was admitted for abdominal pain and back pain. CT showed transverse colon tumor with multiple metastases to the liver, lung, and lymph nodes. Colonoscopy showed a circumferential tumor in the transverse colon. He was diagnosed with NEC based on biopsy and immunostaining. He refused chemotherapy and died 2 months later.

Background: Eagle’s syndrome is famous for one of the causes of internal carotid artery dissection. The treatment strategy for the illness, however, is not well established. Here, we report a case of internal carotid dissection due to an elongated styloid process successfully treated by carotid artery stenting (CAS). Case Description: A 72-year-old male with temporary dysarthria and consciousness disorder was diagnosed to suffer from multiple cerebral infarctions due to Eagle’s syndrome. A cerebral blood flow (CBF) study revealed decreased blood flow and a CAS was performed 15 days after admission to preserve antegrade blood flow, resulting in full recovery of the affected CBF. Conclusion: We reported a case of vascular Eagle’s syndrome in which the patient showed fluctuated neurological deficits successfully treated by CAS. Our experience suggests that cases of vascular Eagle’s syndrome due to hemodynamic stress can be treated by CAS.

The coronavirus disease 2019 (COVID‐19) pandemic witnessed several clusters of children with fever and multisystem inflammation resembling Kawasaki disease (KD). Due to the evidence of a preceding severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection in most of these patients, post‐viral immunological reactions were thought to play an important role in the pathogenesis.1,2 The condition, called “pediatric inflammatory multisystem syndrome temporally associated with SARS‐CoV‐2 infection (PIMS‐TS)”, has thus far been reported mainly from Europe and the United States,1,2 and no cases have been diagnosed in Asia. We herein analyzed the clinical data on patients in whom KD was diagnosed during a local COVID‐19 epidemic to investigate the relationship between KD and SARS‐CoV‐2 infections in Japan, which has the highest KD incidence in the world.

Mammary gland cancer is the most common cancer occurring in women globally. Incidences of this cancer in Japan are on the increase. Annually, more than 70,000 new cases are recorded in Japan and about 1.7 million in the world. Many cases are still difficult to cure completely, and animal models are required for the characterization of the biology, therapeutic strategy, and preventive measures for spontaneous mammary tumor. The mouse model used currently has some limitations owing to structural differences between mouse and human mammary glands. Tupaia belangeri (tree shrew), which belongs to the Tupaiidae family, shows relatively high genetic homology and structural similarity to human mammary glands. Here, we characterized the spontaneous mammary tumors in 61 female tree shrews of different ages. The incidence rate was 24.6% (15/61), and the rate of simultaneous or metachronous multiplex tumors was 60% (9/15). From the incidence pattern, some cases seemed to be of familial mammary gland tumor, as the offspring of female tree shrews No. 3 and 9 and male tree shrew No. 11 showed a high incidence rate, of 73.3% (11/15). Average incidence age for tumor development was 2 years and 3 months, and the earliest was 10 months. Histochemical analysis indicated that spontaneous mammary gland tumors in the tree shrew show the features of intraductal papillary adenomas (22 cases), except 2 tubulopapillary carcinoma cases (No. 75 and 131). All the cases were positive for the progesterone receptor, whereas 91.3% were positive for the estrogen receptor, and 4.3% were HER-2 positive. We have also confirmed the expression of nectin-4 in some mammary tumor cells. Additionally, we subjected tree shrews to cytodiagnosis or X-ray CT. Thus, the findings of this study highlight the potential of the tree shrew as a valuable new animal model for mammary gland tumor study.

A woman in her mid-50's presented to our hospital with jaundice, fatigue, and fever. Jaundice, elevated tumor markers, and lower bile duct stricture suggested malignancy, for which subtotal stomach-preserving pancreaticoduodenectomy was performed. The patient also had annular pancreas as the second part of the duodenum was surrounded by pancreatic parenchyma. The histopathological diagnosis was adenosquamous carcinoma of the duodenal papilla associated with annular pancreas. Adjuvant chemotherapy with TS-1 was administered for 1 year. Although para-aortic lymph node metastasis was detected radiographically 3 years 9 months after surgery, the recurrence remains under control and she is alive at 5 years 9 months after surgery due to multidisciplinary therapy.

One of the challenges in glioblastoma (GBM) imaging is to visualize non-enhancing tumor (NET) lesions. The ratio of T1- and T2-weighted images (rT1/T2) is reported as a helpful imaging surrogate of microstructures of the brain. This research study investigated the possibility of using rT1/T2 as a surrogate for the T1- and T2-relaxation time of GBM to visualize NET effectively. The data of thirty-four histologically confirmed GBM patients whose T1-, T2- and contrast-enhanced T1-weighted MRI and 11C-methionine positron emission tomography (Met-PET) were available were collected for analysis. Two of them also underwent MR relaxometry with rT1/T2 reconstructed for all cases. Met-PET was used as ground truth with T2-FLAIR hyperintense lesion, with >1.5 in tumor-to-normal tissue ratio being NET. rT1/T2 values were compared with MR relaxometry and Met-PET. rT1/T2 values significantly correlated with both T1- and T2-relaxation times in a logarithmic manner (p < 0.05 for both cases). The distributions of rT1/T2 from Met-PET high and low T2-FLAIR hyperintense lesions were different and a novel metric named Likeliness of Methionine PET high (LMPH) deriving from rT1/T2 was statistically significant for detecting Met-PET high T2-FLAIR hyperintense lesions (mean AUC = 0.556 ± 0.117; p = 0.01). In conclusion, this research study supported the hypothesis that rT1/T2 could be a promising imaging marker for NET identification.

Background: Tumor mass of glioblastoma is considered to exist beyond gadolinium-enhancing lesion into T2/FLAIR-high intensity lesions (T2/FL-HIL) on MRI. However, it is challenging to differentiate non-enhancing tumor region (NET) from pure brain edema for T2/FL-HIL. The T1/T2 ratio (rT1/T2) is an MRI metric considered to semi-quantify the tissue relaxation time on MRI. This research tested the hypothesis that rT1/T2 is useful for identifying NET within T2/FL-HIL by comparing it with 11C-methionine positron emission tomography (MET-PET). Method: Forty-six glioblastoma (GBM) patients at Osaka International Cancer Institute and Osaka University Hospital where T1-, T2- and contrast-enhanced T1-weighted MRI and MET-PET were available were included in this study. rT1/T2 maps were obtained after signal corrections were performed, as reported previously. Region-of-interests (ROIs) were defined within T2/FL-HILs beyond the gadolinium-enhanced lesion. MET-PET and rT1/T2 maps were co-registered to the same coordinate system, and the relationship between methionine uptake and rT1/T2 values was examined in a voxel-wise manner.ResultApproximately three million voxels were included for analysis. Lesions with methionine uptake higher than 5.0 on T/N showed 0.7 &lt rT1/T2 &lt 0.98. For those with methionine uptake higher than 3.0, rT1/T2 was between 0.70 and 1.04.DiscussionThis report suggested that rT1/T2 represents histological characteristics of the glioblastoma within T2/FL-HIL. It also indicated that rT1/T2 could be a useful biomarker for detecting NET within T2/FL-HIL for glioblastoma.

We experienced a successful case in which the patient was treated with a combination of operation and transcatheter arterial chemoembolization for a hypervascular tumor of unknown primary origin in the liver; we report this case with a literature review. A 76-year-old man noticed an upper abdominal tumor and he visited our department for detailed examination. Enhanced CT scan showed multiple hypervascular tumors scattered across both lobes of the liver, and the pattern of contrast effect implied that the tumors were primary neuroendocrine tumors or endocrine metastases. Gastroscopy and colonoscopy showed no tumor in the intestine. TACE was performed mainly for the tumors in the right lobe. One month later, we performed left lateral segmentectomy and partial hepatectomy for segment 6. Histopathological findings showed that the tumors in the left lateral segment had neuroendocrine properties, and the tumor in segment 6 was necrosed. One year has passed since the surgery without recurrence of neuroendocrine tumors in the liver or other organs.

A 62-year-old man presented with complaints of acute abdominal pain. Abdominal enhanced CT showed free air in the abdominal cavity, a thickened stomach wall accompanied by deep ulcer, and enlarged lymph nodes around the stomach. Emergent surgery was conducted, and a perforation in the upper part of the stomach was found. Total gastrectomy was performed. On pathological examination, a mucosa-associated lymphoid tissue lymphoma was diagnosed. Histologic examination revealed the absence of Helicobacter pylori in the gastric mucosa. After the operation, adjuvant chemotherapy was not administered. However, he has been well for 11 months without any recurrence. Gastric MALT lymphoma with spontaneous perforation is considered extremely rare. A brief review of the literature is presented.

We report 2 successful cases treated with trans-catheter arterial embolization(TAE)for hemorrhagic shock due to pseudoaneurysm rupture at the primary tumor site in advanced colorectal cancer. Case 1: A 73-year-old female underwent Hartmann surgery at another hospital for rectal perforation and peritonitis. Six months later, she had a massive bloody stool and was transferred to our hospital. She was diagnosed with bleeding from advanced rectal cancer that remained following the first surgery. Contrast computed tomography(CT)showed that a branch of the superior rectal artery(SRA)developed an aneurysm at the primary tumor site, and TAE was performed to stop bleeding on hospital day 3. Case 2: A 79-year-old male with type 2 sigmoid colon cancer and simultaneous multiple liver metastases developed copious blood in the stool before primary tumor resection and was transferred to our hospital. Contrast CT showed that a branch of the SRA developed an aneurysm at the primary tumor site, and TAE was immediately performed to stop bleeding.

A 60-year-old male undergoing pelvic evisceration with D3 lymph node dissection for pR0 in 2006f or carcinoma of the rectum was diagnosed pathologically with moderately differentiated adenocarcinoma, fStage ⅡA(UICC pT3, pN0, M0). Follow-up CT revealed hypovascular liver tumors with intrahepatic bile duct dilation in the right lobe 8 years after the pelvic evisceration. We conducted right lobe hepatectomy. The resected specimens showed that the tumor extended predominantly along the right intrahepatic bile duct. Histological findings and an immunohistochemical examination of CK7, CK20, and CDX2 revealed metastasis of the rectum cancer. We finally diagnosed him with intrahepatic bile duct metastasis from rectal adenocarcinoma.

Background & Aims Antiviral agents including entecavir (ETV) suppress the replication of the hepatitis B virus (HBV) genome in human hepatocytes, but they do not reduce the abundance of viral proteins. The present study focused on effectively reducing viral protein levels. Methods We designed siRNAs (HBV-siRNA) that target consensus sequences in HBV genomes. To prevent the emergence of escaped mutant virus, we mixed three HBV-siRNAs (HBV-siRNAmix); the mixture was encapsulated in a novel pH-sensitive multifunctional envelope-type nanodevice (MEND), a hepatocyte-specific drug delivery system. Coagulation factor 7 siRNA was used to assess delivery and knockdown efficiencies of MEND/siRNA treatments in mice. The potency of MEND/HBV-siRNAmix was evaluated in primary human hepatocytes and in chimeric mice with humanized liver persistently infected with HBV. Results Effective knockdown of targets, efficient delivery of siRNA, and liver-specific delivery were each observed with MEND. MEND/HBV-siRNA caused efficient reduction of HBsAg and HBeAg in vitro and in vivo . However, ETV treatment did not efficiently reduce HBsAg or HBeAg when compared with a single MEND/HBV-siRNAmix treatment. Furthermore, the suppressive effects of a single dose of MEND/HBV-siRNAmix persisted for 14days in vitro and in vivo . Conclusion We demonstrated that MEND/HBV-siRNA controlled HBV more efficiently than did ETV. Furthermore, the effect of a single dose of MEND/HBV-siRNA persisted for a long time. These results indicated that MEND/HBV-siRNA may be a promising novel HBV treatment that is more effective than reverse transcriptase inhibitors.

Previous neuroimaging studies have reported that the ventral temporal cortex (VTC) processes visual stimuli and thereby establish visual categories, which can be detected in electrophysiological signals such as electrocorticography (ECoG). However, most of the studies are based on visual stimulation through a computer. Thus, the degree to which those categories can be generalized is unclear under real-world conditions. This study extends the findings of a previous experiment, which aimed in real-time detection of visual perception, and investigated whether neural face and kanji categories obtained by computer stimuli can be confirmed in a real-world scenario. The real-time decoder accuracy and latency of two patients with epilepsy revealed that real-world faces and kanji can be detected with 79.9% and 28.4% accuracy, respectively, showing an average online detection latency of 447 ms with respect to presentation time. Hence, the VTC cortex elicits robust and similar responses to computer stimuli and real-world face, leading to a powerful brain-computer interface to track a person's attention in a real-world scenario.

We report a rare case of a extrarenal retroperitoneal angiomyolipoma. A 64-year-old female visited our hospital because of an abdominal mass in her lower right abdomen. Enhanced CT scan revealed a 67×52mm tumor in lower right retroperitoneal space. MRI revealed adipose component in the tumor on T1 weighted images and T2 weighted images. Our preoperative diagnosis was retroperitoneal liposarcoma, and we performed retroperitoneal tumor resection. At operation the tumor was on the fossa iliaca, which was covered with capsule. It did not invade surrounding tissues. The resected tumor measured 90× 60×45 mm, and tiny hemorrhage was seen in the tumor. Histopathological findings showed that the tumor was composed of a mixture of adipose tissue, vessels, and smooth muscle. Immunohistochemistry demonstrated the tumor was stained with asmooth muscle actin(aSMA). We diagnosed the tumor as extrarenal retroperitoneal angiomyolipoma.

Hepatitis C virus (HCV) is a leading cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma. To address the molecular basis of HCV pathogenesis using tupaias (Tupaia belangeri), we characterized host responses upon HCV infection. Adult tupaias were infected with HCV genotypes 1a, 1b, 2a, or 4a. Viral RNA, alanine aminotransferase, anti-HCV core and anti-nonstructural protein NS3 antibody titres, reactive oxygen species (ROS), and anti-3β-hydroxysterol-Δ24reductase (DHCR24) antibody levels were measured at 2-week intervals from 0 to 41 weeks postinfection. All HCV genotypes established infections and showed intermittent HCV propagation. Moreover, all tupaias produced anti-core and anti-NS3 antibodies. ROS levels in sera and livers were significantly increased, resulting in induction of DHCR24 antibody production. Similarly, lymphocytic infiltration, disturbance of hepatic cords, and initiation of fibrosis were observed in livers from HCV-infected tupaias. Intrahepatic levels of Toll-like receptors 3, 7, and 8 were significantly increased in all HCV-infected tupaias. However, interferon-β was only significantly upregulated in HCV1a- and HCV2a-infected tupaias, accompanied by downregulation of sodium taurocholate cotransporting polypeptide. Thus, our findings showed that humoral and innate immune responses to HCV infection, ROS induction, and subsequent increases in DHCR24 auto-antibody production occurred in our tupaia model, providing novel insights into understanding HCV pathogenesis.

We report a case where resection was performed for pancreatic metastasis from renal cell carcinoma 21 years after nephrectomy. A 72-year-old man had undergone total gastrectomy with distal pancreatomy and splenectomy for gastric cancer, and right nephrectomy for primary renal cell carcinoma in 1993. Incidentally, a CT scan performed in 2014 revealed a tumor in the head of the pancreas. Enhanced MRI suggested that the tumor contained some fat tissue. The tumor in the pancreatic body had sharp margins; therefore, we performed subtotal pancreatectomy. The tumor was considered pancreatic metastasis from renal cell carcinoma. Pathological findings indicated clear-cell type carcinoma(G1-G2), which is very similar to renal cell carcinoma. We diagnosed pancreatic metastasis from renal cell carcinoma. The patient has remained well, with no recurrence 20 months after the pancreatectomy.

We herein present a case of a 59-year-old man who had undergone pylorus preserving pancreaticoduodenectomy with regional lymph node dissection prior to episodes of melena. Series of conventional endoscopic investigations failed to identify the bleeding source. Enhanced computed tomography scan revealed complete obstruction of the main portal vein with numerous collateral veins running towards the hepatic hilus. Comprehensively, hemorrhage from the jejunal varices caused by postoperative portal hypertension was highly suspected. As the jejunal loop was out of reach, adult variable-stiffness colonoscope (AVSC) was utilized to solve the Roux-en-Y anatomy. Numerous telangiectasis and small varices at hepaticojejunostomy were observed and in the mean time, bleeding was noticed and endoclips were placed without any delay. Ectopic variceal bleeding in jejunal loop after pancreaticoduodenectomy is difficult to manage. We believe that AVSC is an alternative device when specialized jejunal endoscopy is not available.

To date, the chimpanzee has been used as the natural infection model for hepatitis B virus (HBV). However, as this model is very costly and difficult to use because of ethical and animal welfare issues, we aimed to establish the tupaia (Tupaia belangeri) as a new model for HBV infection and characterized its intrahepatic innate immune response upon HBV infection. First, we compared the propagation of HBV genotypes A2 and C in vivo in tupaia hepatocytes. At 8-10days post infection (dpi), the level of HBV-A2 propagation in the tupaia liver was found to be higher than that of HBV-C. Abnormal architecture of liver cell cords and mitotic figures were also observed at 8 dpi with HBV-A2. Moreover, we found that HBV-A2 established chronic infection in some tupaias. We then aimed to characterize the intrahepatic innate immune response in this model. First, we infected six tupaias with HBV-A2 (strains JP1 and JP4). At 28 dpi, intrahepatic HBV-DNA and serum hepatitis B surface antigens (HBsAg) were detected in all tupaias. The levels of interferon (IFN)-β were found to be significantly suppressed in the three tupaias infected with HBV A2_JP4, while no significant change was observed in the three infected with HBV A2_JP1. Expression of toll-like receptor (TLR) 1 was suppressed, while that of TLR3 and TLR9 were induced, in HBV A2_JP1-infected tupaias. Expression of TLR8 was induced in all tupaias. Next, we infected nine tupaias with HBV-A2 (JP1, JP2, and JP4), and characterized the infected animals after 31 weeks. Serum HBsAg levels were detected at 31 weeks post-infection (wpi) and IFN-β was found to be significantly suppressed in all tupaias. TLR3 was not induced, except in tupaia #93 and #96. Suppression of TLR9 was observed in all tupaias, except tupaia #93. Also, we investigated the expression levels of cyclic GMP-AMP synthase, which was found to be induced in all tupaias at 28 dpi and in four tupaias at 31 wpi. Additionally, we evaluated the expression levels of sodium-taurocholate cotransporting polypeptide, which was found to be suppressed during chronic HBV infection. Thus, the tupaia infection model of HBV clearly indicated the suppression of IFN-β at 31 wpi, which might have contributed to the establishment of chronic HBV infection.

The innate immune system is essential for controlling viral infection. Hepatitis B virus (HBV) persistently infects human hepatocytes and causes hepatocellular carcinoma. However, the innate immune response to HBV infection in vivo remains unclear. Using a tree shrew animal model, we showed that HBV infection induced hepatic interferon (IFN)-γ expression during early infection. Our in vitro study demonstrated that hepatic NK cells produced IFN-γ in response to HBV only in the presence of hepatic F4/80+ cells. Moreover, extracellular vesicles (EVs) released from HBV-infected hepatocytes contained viral nucleic acids and induced NKG2D ligand expression in macrophages by stimulating MyD88, TICAM-1, and MAVS-dependent pathways. In addition, depletion of exosomes from EVs markedly reduced NKG2D ligand expression, suggesting the importance of exosomes for NK cell activation. In contrast, infection of hepatocytes with HBV increased immunoregulatory microRNA levels in EVs and exosomes, which were transferred to macrophages, thereby suppressing IL-12p35 mRNA expression in macrophages to counteract the host innate immune response. IFN-γ increased the hepatic expression of DDX60 and augmented the DDX60-dependent degradation of cytoplasmic HBV RNA. Our results elucidated the crucial role of exosomes in antiviral innate immune response against HBV. Accession Number Accession number of RNA-seq data is DRA004164 (DRA in DDBJ).

We study transitions of hadronic matter (HM) to 3-flavor quark matter (3QM) locally, regarding the conversion processes as combustion and describing them hydrodynamically. Not only the jump condition on both sides of the conversion front but the structures inside the front are also considered by taking into account what happens during the conversion processes on the time scale of weak interactions as well as equations of state (EOS's) in the mixed phase. Under the assumption that HM is metastable with their free energies being larger than those of 3QM but smaller than those of 2-flavor quark matter (2QM), we consider the transition via 2QM triggered by a rapid density rise in a shock wave. Based on the results, we discuss which combustion modes (strong/weak detonation) may be realized. HM is described by an EOS based on the relativistic mean field theory and 2, 3QM's are approximated by the MIT bag model. We demonstrate for a wide range of bag constant and strong coupling constant in this combination of EOS's that the combustion may occur in the so-called endothermic regime, in which the Hugoniot curve for combustion runs below the one for the shock wave in P-V plane, and which has no terrestrial counter part. We find that strong detonation always occurs. Depending on the EOS of quark matter (QM) as well as the density of HM and the Mach number of the detonation front, deconfinement from HM to 2QM is either completed or not completed in the shock wave. In the latter case, which is more likely if the EOS of QM ensures that deconfinement occurs above the nuclear saturation density and that the maximum mass of cold quark stars is larger than two solar mass, the conversion continues further via the mixing state of HM and 3QM on the time scale of weak interactions., Comment: 44 pages, 18 figures, accepted for publication in PRD

We report a case of multiple brain metastases from pancreatic cancer, which had responded remarkably to FOLFIRINOX. A 47-year-old man had hypovascular tumors, 25 mm on the body and 23 mm on the uncus of the pancreas; multiple liver metastases; and skin metastasis. A diagnosis of unresectable pancreatic cancer, cT4N3M1 (HEP, LYM, PUL, SKI), cStage Ⅳb was made. We chose FOLFIRINOX for treatment because of his young age and good performance status. After 6 courses, he showed decreasing tumor marker levels, an almost complete disappearance of the primary lesion, and reduced liver metastases. After 8 courses, abnormal behaviors were noted and we performed a head contrast-enhanced MRI, which revealed diffuse enhancement of the cerebral and cerebellar hemisphere. Multiple brain metastases from pancreatic cancer were diagnosed. We made the shift to palliative treatment, but his general condition was worsening and he died a month later, 7 months after the first diagnosis.

In our recent epidemiological survey conducted in Mexico for hantavirus infection, we identified three distinct viruses circulating in Mexican wild rodents, namely Montano virus (MTNV), Huitzilac virus (HUIV), and Carrizal virus (CARV). To gain a detailed understanding of hantavirus epidemiology and its associated hosts, 410 rodents were captured at eight collecting points in Morelos and Guerrero, Mexico, and examined for hantavirus seroprevalence, the presence of viral RNA, and rodent host species identification using cytochrome b gene sequences. Of the 32 species captured, seven species were positive for hantavirus: Peromyscus beatae (31/127; 24.4%), Reithrodontomys sumichrasti (6/15; 40%), Reithrodontomys megalotis (2/25; 8%), Peromyscus aztecus evides (1/1; 100%), Peromyscus megalops (1/41; 2.4%), Megadontomys thomasi (1/9; 11.1%), and Neotoma picta (1/6; 16.7%), with an overall prevalence of 10.5%; virus genome persisted in the majority of seropositive rodents. Nucleotide sequence and phylogenetic analysis showed that the viruses belonged mainly to the three lineages previously identified. The data showed that MTNV and CARV were primarily carried by P. beatae and R. sumichrasti, respectively. In addition, the data revealed an apparent complex interaction between hantaviruses and their hosts, suggesting active transmission and/or spillover infections within sympatric rodent species.

Hemorrhagic fever with renal syndrome (HFRS) is a serious public health issue in Far East Russia. Two different hantaviruses were isolated from rodents captured in the Khabarovsk region: Amur virus (AMRV; Khekhtsir/ AP209/2005 strain from Apodemus peninsulae) and Hantaan virus (HTNV; Galkino/AA57/2002 strain from A. agrarius). Genetic analysis of the new isolates revealed that the M and L segments were apparently different between AMRV and HTNV, but S segments of the two viruses were closer. The antigenicities of AMRV, HTNV, and Seoul virus (SEOV) were differentiated by cross-neutralization. Serological differential diagnoses of 67 HFRS patients in the Prymorsky and Khabarovsk regions of Far East Russia were conducted using a neutralization test. The results revealed that the major cause of HFRS varied with location in Far East Russia: SEOV for Vladivostok city in the Prymorsky region, AMRV in rural areas of the Primorsky region, and probably HTNV for the Khabarovsk region.

A variety of hantaviruses are harbored by rodents in North and South America, some of which can cause hantavirus pulmonary syndrome. To obtain greater evolutionary insight into hantaviruses in the Americas, a total of 211 rodents were captured in the Mexican states of Guerrero and Morelos in 2006. Anti-hantavirus antibodies were detected in 27 of 211 serum samples (12.8%) by ELISA. The distribution of seropositive rodents was: 17 Peromyscus beatae, 1 Megadontomys thomasi, 1 Neotoma picta, 6 Reithrodontomys sumichrasti, and 2 Reithrodontomys megalotis. The hantavirus small (S), medium (M), and large (L) genome segments from P. beatae, R. sumichrasti, and R. megalotis were amplified and the sequences covering the open reading frames were determined. The hantaviruses from P. beatae, R. sumichrasti, and R. megalotis were provisionally designated Montano (MTN), Carrizal (CAR), and Huitzilac (HUI), respectively. The M segment amino acid identities among the Mexican hantaviruses were 80.8–93.0%. When these M segments were compared to those of known hantaviruses, MTN virus was most closely related to Limestone Canyon (LSC) virus (88.9% amino acid identity), while the CAR and HUI viruses were most closely related to El Moro Canyon (ELMC) virus (90–91% identity). Phylogenetic analysis revealed that the MTN, CAR, and HUI viruses occupy a monophyletic clade with the LSC, ELMC, and Rio Segundo viruses, which are harbored by Peromyscus boylii, R. megalotis, and Reithrodontomys mexicanus, respectively. The data obtained in this study provide important information for understanding the evolution of hantaviruses in the Americas.

The mechanism of hantavirus persistent infection in natural hosts is poorly understood due to a lack of laboratory animal models. Herein, we report that Syrian hamsters (Mesocricetus auratus) infected with Puumala virus (PUUV) at 4 weeks old show persistent infection without clinical symptoms for more than 2 months. IgG and IgM antibodies against the viral nucleocapsid protein and neutralizing antibody were first detectable at 14 days postinoculation (dpi) and maintained through 70 dpi. Viral RNA was first detected from 3 dpi in lungs and blood clots, and was detected in all tissues tested at 7 dpi. The viral RNA persisted for at least 70 days in the lungs, kidney, spleen, heart, and brain. The highest level of RNA copies was observed at 14 dpi in the lungs. Slight inflammatory reactions were observed in the lungs, adrenal glands, and brain. Immunohistochemical analysis revealed that PUUV antigen persisted until 56 dpi in the kidneys and adrenal glands. Infected hamsters showed no body weight loss or clinical signs. These results indicate that PUUV infection in hamsters is quite similar to the hantavirus infection of natural host rodents.

We study transitions of hadronic matter (HM) to 3-flavor quark matter (3QM), regarding the conversion processes as combustion and describing them hydrodynamically. Under the assumption that HM is metastable with their free energies being larger than those of 3QM but smaller than those of 2-flavor quark matter (2QM), we consider in this paper the conversion induced by diffusions of seed 3QM. This is a sequel to our previous paper, in which the shock-induced conversion was studied in the same frame work. We not only pay attention to the jump condition on both sides of the conversion front but the structures inside the front are also considered by taking into account what happens during the conversion processes on the time scale of weak interactions. We employ for HM the Shen's EOS, which is based on the relativistic mean field theory, and the bag model-based EOS for QM just as in the previous paper. We demonstrated in that paper that in this combination of EOS's the combustion will occur for a wide range of the bag constant and strong coupling constant in the so-called endothermic regime, in which the Hugoniot curve for combustion runs below the initial state. We find that weak deflagration nearly always occurs and that weak detonation is possible only when the diffusion constant is (unrealistically) large and the critical strange fraction is small. The velocities of the conversion front are ~ $10^3-10^7$ cm/s depending on the initial temperature and density as well as the parameters in the QM EOS and become particularly small when the final state is in the mixed phase. Finally we study linear stability of the laminar weak-deflagration front and find that it is unstable in the exothermic regime (Darrius-Landau instability) but stable in the endothermic regime, which is quite contrary to the ordinary combustions., Comment: 36 pages, 21 figures, accepted for publication in PRD

症例は63歳の女性で, 2004年8月胆管癌に対して胆管切除, 胆管空腸吻合術が施行された. 同年11月に発熱がつづいたため入院となった. 入院時の腹部CTにて肝S7を中心に直径8cm大の低吸収域を認め, 胆道再建後の胆管炎に起因する肝膿瘍と診断し, 経皮経肝的ドレナージおよび抗生剤による治療を開始した. 血液および膿汁の培養からKlebsiella pneumoniae が検出された. 入院2日目ごろより頭痛, 意識障害, 項部硬直などの症状が出現し, 髄液の細胞数が増加しており, 細菌性髄膜炎と診断された. 髄液の培養でもK. pneumoniae が検出され, 肝膿瘍からの感染の転移による細菌性髄膜炎と考えられた. 肝膿瘍ドレナージおよび約8週間の抗生剤投与, さらには続発性の水頭症に対する脳室腹腔シャント術により軽快した. 胆管癌術後に発生した細菌性肝膿瘍から遠隔臓器に感染が波及した1典型例として報告する.

To better understand the pathogenesis of biliary tract carcinoma (BTC) and to increase the accuracy of predicting outcomes for patients with this disease, we performed molecular cytogenetic analyses of BTC cell lines and tumors to identify non-random amplification(s) and target gene(s) within the amplicons. Among several non random chromosomal aberrations detected in BTC cell lines by comparative genomic hybridization, gain/ampli-fication of DNA at 5p was the most frequently observed alteration. We assessed the copy number and expression status of the possible target gene SKP2 for 5p amplification in cell lines and 33 primary stage II or III tumors of BTC. SKP2 was amplified, and subsequently overexpressed in both cell lines and primary tumors of BTC. However, levels of Skp2 and p27Kip1 proteins were not correlated inversely. Heightened expression of Skp2 and reduced expression of p27Kip1 were both associated with a shorter disease-free and/or overall survival in univariate analyses. In multivariate regression analyses, Skp2 and p27Kip1 were independent predictive factors. Those results suggest that (a) overexpression of Skp2 through an amplification mechanism may contribute to the progression of BTC, (b) not only each molecule, but also the combination of Skp2 and p27Kip1, might be a useful predictor of the prognosis of BTC, and (c) molecular targets of Skp2 other than p27Kip1 may also be important factors in the pathogenesis of this disease.