Hepatitis C virus（HCV）infection can cause chronic liver disease; it has also been associated with lymphoproliferative disorders（LPDs）, such as cryoglobulinemia and B-cell non-Hodgkin’s lymphoma. Our previous studies suggested that cryoglobulinemia, high titer of rheumatoid factor（RF）, and hypocomplementemia are immunological markers of LPDs. In addition, recent therapies with direct-acting antivirals（DAAs）have achieved high rates of sustained virological response（SVR）in patients with chronic hepatitis C（CH-C）. This study analyzed the efficacy of DAA therapy in CH-C patients with cryoglobulinemia, and the association of biochemical and other immune markers for LPDs with persistence of cryoglobulinemia in patients after DAA therapy. Of 226 patients tested, 31（13.7％）had cryoglobulinemia prior to receiving DAAs, and these individuals showed lower complement 4 levels, decreased complement hemolytic activity, and higher IgM than patients without cryoglobulinemia. Of the 24 cryoglobulinemia-positive patients（83％）who could be followed for 24 weeks, 20 became cryoglobulinemia negative after the therapy. The remaining four patients retained the abnormal LPD markers, indicating the possibility of long-term LPD persistence even following successful eradication of HCV in CH-C patients. Thus, long-term follow-up is recommended to avoid exacerbation of extrahepatic manifestations as well as new events.
Hepatocellular carcinoma（HCC）is the sixth most commonly diagnosed cancer worldwide. Sorafenib is an oral multikinase inhibitor used in the palliative treatment of advanced HCC. However, there were no reported cases of complete response（CR）from two previous large phaseⅢ clinical trials. Here, we report a case of CR in a patient with advanced HCC with multiple lymph node and bone metastases, treated with sorafenib monotherapy for 8 months. To our knowledge, this is the first evidence showing CR following sorafenib monotherapy for HCC with bone metastasis.
<div>Abstract<p>The development of effective immunotherapeutic strategies for central nervous system (CNS) tumors requires a firm understanding of factors regulating the trafficking of tumor antigen–specific CTLs into CNS tumor lesions. Using C57BL/6 mice bearing intracranial (i.c.) ovalbumin-transfected melanoma (M05), we evaluated the efficacy and tumor homing of i.v. transferred type 1 or 2 CTLs (Tc1 or Tc2, respectively) prepared from ovalbumin-specific T-cell receptor–transgenic OT-1 mice. We also tested our hypothesis that intratumoral (i.t.) delivery of dendritic cells that had been transduced with <i>IFN-α</i> cDNA (DC-IFN-α) would enhance the tumor-homing and antitumor effectiveness of adoptively transferred Tc1 via induction of an IFN-γ-inducible protein 10 (IP-10). <i>In vitro</i>, DC-IFN-α induced IP-10 production by M05 and enhanced the cytolytic activity of Tc1. <i>In vivo</i>, i.v. transferred Tc1 trafficked efficiently into i.c. M05 and mediated antitumor responses more effectively than Tc2, and their effect was IP-10 dependent. I.t. injections of DC-IFN-α remarkably enhanced the tumor homing, therapeutic efficacy, and <i>in situ</i> IFN-γ production of i.v. delivered Tc1, resulting in the long-term survival and persistence of systemic ovalbumin-specific immunity. These data suggest that Tc1-based adoptive transfer therapy may represent an effective modality for CNS tumors, particularly when combined with strategies that promote a type 1 polarized tumor microenvironment. (Cancer Res 2006; 66(8): 4478-87)</p></div>
<div>Abstract<p>The development of effective immunotherapeutic strategies for central nervous system (CNS) tumors requires a firm understanding of factors regulating the trafficking of tumor antigen–specific CTLs into CNS tumor lesions. Using C57BL/6 mice bearing intracranial (i.c.) ovalbumin-transfected melanoma (M05), we evaluated the efficacy and tumor homing of i.v. transferred type 1 or 2 CTLs (Tc1 or Tc2, respectively) prepared from ovalbumin-specific T-cell receptor–transgenic OT-1 mice. We also tested our hypothesis that intratumoral (i.t.) delivery of dendritic cells that had been transduced with <i>IFN-α</i> cDNA (DC-IFN-α) would enhance the tumor-homing and antitumor effectiveness of adoptively transferred Tc1 via induction of an IFN-γ-inducible protein 10 (IP-10). <i>In vitro</i>, DC-IFN-α induced IP-10 production by M05 and enhanced the cytolytic activity of Tc1. <i>In vivo</i>, i.v. transferred Tc1 trafficked efficiently into i.c. M05 and mediated antitumor responses more effectively than Tc2, and their effect was IP-10 dependent. I.t. injections of DC-IFN-α remarkably enhanced the tumor homing, therapeutic efficacy, and <i>in situ</i> IFN-γ production of i.v. delivered Tc1, resulting in the long-term survival and persistence of systemic ovalbumin-specific immunity. These data suggest that Tc1-based adoptive transfer therapy may represent an effective modality for CNS tumors, particularly when combined with strategies that promote a type 1 polarized tumor microenvironment. (Cancer Res 2006; 66(8): 4478-87)</p></div>
Abstract Background Toll-like receptor (TLR)3 ligands serve as natural inducers of pro-inflammatory cytokines capable of promoting Type-1 adaptive immunity, and TLR3 is abundantly expressed by cells within the central nervous system (CNS). To improve the efficacy of vaccine strategies directed against CNS tumors, we evaluated whether administration of a TLR3 ligand, polyinosinic-polycytidylic (poly-IC) stabilized with poly-lysine and carboxymethylcellulose (poly-ICLC) would enhance the anti-CNS tumor effectiveness of tumor peptide-based vaccinations. Methods C57BL/6 mice bearing syngeneic CNS GL261 glioma or M05 melanoma received subcutaneous (s.c.) vaccinations with synthetic peptides encoding CTL epitopes- mEphA2 (671–679), hgp100 (25–33) and mTRP-2 (180–188) for GL261, or ovalbumin (OVA: 257–264) for M05. The mice also received intramuscular (i.m.) injections with poly-ICLC. Results The combination of subcutaneous (s.c.) peptide-based vaccination and i.m. poly-ICLC administration promoted systemic induction of antigen (Ag)-specific Type-1 CTLs expressing very late activation antigen (VLA)-4, which confers efficient CNS-tumor homing of vaccine-induced CTLs based on experiments with monoclonal antibody (mAb)-mediated blockade of VLA-4. In addition, the combination treatment allowed expression of IFN-γ by CNS tumor-infiltrating CTLs, and improved the survival of tumor bearing mice in the absence of detectable autoimmunity. Conclusion These data suggest that poly-ICLC, which has been previously evaluated in clinical trials, can be effectively combined with tumor Ag-specific vaccine strategies, thereby providing a greater index of therapeutic efficacy.
Appropriate sedative and analgesic selection is essential to reduce patient discomfort and body movement to safely conduct endoscopic ultrasonography (EUS). However, few cases have examined sedation with propofol in EUS, and few studies the need for combined analgesia. In this study, we retrospectively evaluated the usefulness and safety of propofol without analgesics for sedation in biliopancreatic observational EUS.
To investigate the roles of NF-kappa B and I-kappa B in chondrocytes in the cartilage destruction of mouse collagen-induced arthritis.DBA/1 mice were immunized with bovine type II collagen (C II) emulsified with Freund's incomplete adjuvant. Histological abnormalities in the mouse knees were evaluated in sections stained with hematoxylin and eosin, or toluidine blue. Immunostaining using anti-NF-kappa B and anti-I-kappa B antibodies was performed to observe the expression and nuclear shift of NF-kappa B and I-kappa B in articular chondrocytes.Loss of metachromasia of perichondrial cartilage was found in 8 out of 10 knees of the mice at 5 weeks, and in all 10 knees at 7 weeks after C II-immunization. The mean percentage of NF-kappa B-positive chondrocytes at 3, 5 and 7 weeks and in the control was 33.6 +/- 7.6, 54.9 +/- 2.7, 75.9 +/- 1.0 and 27.9 +/- 3.8%, respectively. The mean percentage of NF-kappa B-positive nuclei was 9.1 +/- 0.7, 19.5 +/- 3.7, 47.5 +/- 3.0 and 8.6 +/- 0.1%, respectively. NF-kappa B-positive chondrocytes significantly increased from 3 to 7 weeks in a time-dependent manner (p < 0.0001). The percentage of I-kappa B-positive chondrocytes at 3, 5 and 7 weeks and in the control was 15.5 +/- 1.7, 41.1 +/- 2.5, 51.2 +/- 5.7 and 12.1 +/- 2.1%, respectively. I-kappa B-positive chondrocytes significantly increased from 3 to 5 weeks (p < 0.005).These findings suggest that nuclear shift of NF-kappa B localization causes cartilage destruction in the early stage of arthritis in DBA/1 mice immunized with C II.
