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Mogamulizumab (KW-0761) is a humanized anti-CCR4 monoclonal antibody with a defucosylated Fc region (Potelligent® Technology), which markedly enhances antibody-dependent cellular cytotoxicity by increasing its binding affinity to the Fcγ receptor expressed on effector cells. It is an effective agent for patients with CCR4-positive adult T-cell leukemia and peripheral T-cell lymphoma, for which no standard therapy exists, and it has an acceptable toxicity profile. In addition, because CCR4 is expressed on CD45RA-FOXP3highCD4+ effector regulatory T (Treg) cells, it is an even more attractive target, because Treg cells involved in the tumor escape from host immunity in the tumor microenvironment. Based on this concept, we conducted a clinical study of mogamulizumab for the treatment of CCR4-negative advanced or recurrent solid cancer, with the aim of depleting effector Treg cells and thus boosting anti-cancer immune responses. In this study, mogamulizumab infusion at doses ranging from 0.1 to 1.0 mg/kg was safe and well tolerated. Four of 10 patients showed stable disease during treatment and showed long-term survival. Mogamulizumab efficiently depleted effector Treg cells even at the lowest dose of 0.1 mg/kg, and an augmentation or induction of specific immune responses to cancer/testis antigens was observed in some patients. In the near future, a novel immunotherapy targeting Treg cells with mogamulizumab will be offered to patients with different types of cancer. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Examines noise characteristics of a high precision digital multimeter HP3457A or HP3458A by presenting a conceptual but useful model for generation of zero voltage error under short-circuited input terminals. Test of two setting states, auto-zero on and auto-zero off; Extensive potential of auto-zero off.

To realize a general-purpose magnetic field sensor having a detection sensitivity of the order of 10-12 T/&radicHz; at room temperature, a problem of removing the effect of the Earth's magnetism from the sensor must be solved because its magnitude is 4.5 × 104 times Larger than that in the range to be detectable. For this purpose, a well- known approach of exciting the sensor in the opposite direction to the Earth's magnetism to cancel out the value has been adopted. This paper aims at realizing a magnetic field sensor free from the Earth's magnetism by introducing a method called "zero magnetic field. In practice, such a sensor was developed and the tested results confirmed that the detection performance was maintained without losing the high sensitivity. [ABSTRACT FROM AUTHOR]

The article proposes an inverter-fed induction motor and describes its stability analysis and stabilizing control. The voltage frequency constant control system which is important to drive a three-phase induction motor by means of a voltage-source inverted, is applied widely in the semiconductor industry.

Regulatory T cells (Tregs) play an important role in creating an immunosuppressive microenvironment in cancer tissues. However, the mechanisms by which Tregs are activated and suppress cancer immunity remain unclear. To elucidate these mechanisms, we performed a T cell receptor (TCR) repertoire analysis of Tregs and conventional T cells in peripheral blood, draining lymph nodes (DLNs), and cancer tissues of patients with head and neck squamous cell cancer (HNSCC). We found that the TCR repertoire was skewed in cancer tissue and metastatic DLNs (M‐DLNs) compared with non‐metastatic DLNs, and TCR repertoire similarities in Tregs and CD8+ T cells between M‐DLNs and cancer tissue were high compared with those at other sites. These results suggest that Tregs and CD8+ T cells are activated in M‐DLNs and cancer tissues by cancer antigens, such as neoantigens, and shared antigens and Tregs suppress CD8+ T cell function in a cancer antigen‐specific manner in M‐DLNs and cancer tissue. Moreover, M‐DLNs might be a source of Tregs and CD8+ T cells recruited into the cancer tissue. Therefore, targeting Tregs in M‐DLNs in an antigen‐specific manner is expected to be a novel immunotherapeutic strategy for HNSCCs. [ABSTRACT FROM AUTHOR]

Introduction: Regulatory T cells (Tregs) have attracted attention as a novel therapeutic target to augment the clinical efficacy of immunotherapy. We conducted phase Ia and Ib trials to examine the safety and efficacy of the anti-CCR4 antibody, KW-0761 (mogamulizumab), which may eliminate effector Tregs (eTregs). We herein overviewed the results of these trials, presented cases with a durable clinical response, and investigated factors associated with the clinical effects of KW-0761. Methods: Forty-nine patients with CCR4-negative solid cancers were enrolled in the phase Ia and Ib trials on KW-0761. An integral analysis of safety, clinical responses, prognosis, blood laboratory data, and cancer testis antigen-specific immune responses was performed. Results: Grade 3–4 treatment-related adverse events were reported in 21 (42.9%) out of 49 patients, all of which were manageable. A partial response and stable disease were observed in 1 and 9 patients, respectively. A durable clinical response was noted in 2 esophageal and 2 lung cancer patients. eTreg depletion in peripheral blood was confirmed in most patients, and eTreg depletion was sustained during the KW-0761 treatment. High lymphocyte levels at baseline and 2 weeks after the initiation of KW-0761 were associated with a favorable clinical outcome. Conclusions: A durable clinical response was noted in some patients, and high lymphocyte levels before treatment initiation may be a biomarker for the efficacy of KW-0761. The synergistic effect of KW-0761 for depleting Tregs and other immunotherapies is expected in the future. [ABSTRACT FROM AUTHOR]

Neck dissection for cervical lymph node metastasis is an established procedure for head and neck cancer (HNC). However, with the advent of immunotherapy, head and neck surgical oncologists need to rethink removing all lymph nodes, including those with immune function. We investigated the anti-cancer immune response of the cervical lymph nodes in four patients with human papillomavirus type 16 (HPV16)-positive head and neck squamous cell carcinoma. Using lymphocytes extracted from local, metastatic, and non-metastatic lymph nodes and peripheral blood from these patients, we performed an intracellular flow cytometric cytokine assay using anti-IFNγ and anti-TNF-α monoclonal antibodies to detect HPV16 E6- and E7-specific T cells. HPV status and p16 immunostaining were determined by in situ detection using the HPV RNAscope method and immunohistochemistry. In one case, E6-specific and E7-specific CD8+ T cells were detected in proximal metastatic nodes and distal non-metastatic nodes. This finding suggests that non-metastatic nodes should be preserved for their immune function during neck dissection and that the immune function of non-metastatic lymph nodes is important when administering immunotherapy. In this context, head and neck surgical oncologists treating HNC should consider the place of immunotherapy and neck dissection in the treatment of HNC. [ABSTRACT FROM AUTHOR]

Patients with advanced/recurrent mucoepidermoid carcinoma (MEC) have a poor prognosis. This study aimed to establish and characterize human mucoepidermoid carcinoma cell lines from the initial surgical specimen and biopsy specimen upon recurrence from the same patient to provide a resource for MEC research. MEC specimens from the initial surgical procedure and biopsy upon recurrence were used to establish cell lines. The established cell lines were cytogenetically characterized using multi-color fluorescence in situ hybridization and detection, and the sequence of the CRTC1-MAML2 chimeric gene was determined. Furthermore, the susceptibility of head and neck mucoepidermoid carcinoma to standard treatment drugs such as cisplatin, 5-fluorouracil, and cetuximab was investigated. We successfully established unique MEC cell lines, AMU-MEC1, from an initial surgical specimen and AMU-MEC1-R1 and AMU-MEC1-R2 from the recurrent biopsy specimen in the same patient. These cell lines exhibited epithelial morphology and developed in vitro-like cobblestones. They shared eight chromosomal abnormalities, including der(19)ins(19;11)(p13;?), which resulted in a chimeric CRTC1-MAML2 gene, indicating the same origin of the cell lines. The susceptibility of all cell lines to cisplatin and 5-fluorouracil was low. Interestingly, EGFR dependency for cell growth decreased in AMU-MEC-R1 and AMU-MEC-R2 but was retained in AMU-MEC1. These cytogenetic and biochemical findings suggest that the established cell lines can be used to investigate the disease progression mechanisms and develop novel therapeutics for MEC. [ABSTRACT FROM AUTHOR]

The expression of programmed death ligand-1 (PD-L1) is controlled by complex mechanisms. The elucidation of the molecular mechanisms of PD-L1 expression is important for the exploration of new insights into PD-1 blockade therapy. Detailed mechanisms of the in situ expression of PD-L1 in tissues of oral squamous cell carcinomas (OSCCs) have not yet been clarified. We examined the mechanisms of PD-L1 expression focusing on the phosphorylation of downstream molecules of epidermal growth factor (EGF) and interferon gamma (IFN-γ) signaling in vitro and in vivo by immunoblotting and multi-fluorescence immunohistochemistry (MF-IHC), respectively. The in vitro experiments demonstrated that PD-L1 expression in OSCC cell lines is upregulated by EGF via the EGF receptor (EGFR)/PI3K/AKT pathway, the EGFR/STAT1 pathway, and the EGFR/MEK/ERK pathway, and by IFN-γ via the JAK2/STAT1 pathway. MF-IHC demonstrated that STAT1 and EGFR phosphorylation was frequently shown in PD-L1-positive cases and STAT1 phosphorylation was correlated with lymphocyte infiltration and EGFR phosphorylation. Moreover, the phosphorylation pattern of the related molecules in PD-L1-positive cells differed among the cases investigated. These findings indicate that PD-L1 expression mechanisms differ depending on the tissue environment and suggest that the examination of the tissue environment and molecular alterations of cancer cells affecting PD-L1 expression make it necessary for each patient to choose the appropriate combination drugs for PD-1 blockade cancer treatment. [ABSTRACT FROM AUTHOR]

Reactivation of hepatitis B virus (HBV) has been reported as a fatal complication following systemic chemotherapy or other immunosuppressive therapy. The risk of HBV reactivation differs according to both the patient's HBV infection status prior to systemic chemotherapy and the degree of immunosuppression due to chemotherapy. For establishing an optimal strategy for hepatitis prevention and treatment, it is necessary to understand the characteristics, the clinical course and the risk factors for HBV reactivation and to recognize the difference between hepatitis B surface antigen (HBsAg)-positive and -negative patients with HBV reactivation. Among the important viral risk factors, HBV-DNA level and HBV-related serum markers have been reported to be associated with HBV reactivation in addition to cccDNA, genotypes and gene mutations. Rituximab-plus-steroid combination chemotherapy has recently been identified as a host risk factor for HBV reactivation in hepatitis B core antibody (anti-HBc)-positive and/or hepatitis B surface antibody (anti-HBs) positive-but nonetheless HBsAg-negative-lymphoma patients. For these patients with resolved hepatitis B, preemptive therapy guided by serial HBV-DNA monitoring is a reasonable strategy to enable early diagnosis of HBV reactivation and initiation of antiviral therapy. In this review, we summarize the characteristics of HBV reactivation following rituximab-plus-steroid combination chemotherapy, mainly in HBsAg-negative lymphoma patients, and propose a strategy for managing HBV reactivation. [ABSTRACT FROM AUTHOR]

Multiple myelomas often occur in elderly people with age-related complications as they age further. A 54-year-old man was first admitted with cerebral infarction and multiple myeloma (IgG kappa, stage IIIA) in November 1989. There was partial remission following chemotherapy. The karyotype of the marrow cells was 46, XY, and no p53 gene mutations were detected by polymerase chain reaction and single-strand conformation polymorphism analysis. In February 1999, chemotherapy (melphalan, vindesine, ranimustine, prednisolone) was administered as a result of aggravation of the myeloma. Later, after daily subcutaneous injection of 50 µg of nartograstim for 6 days to treat febrile neutropenia, the soft tissues around the right eye swelled gradually, but without redness accompanied by an elevation of the serum creatine-kinase concentration. When nartograstim was discontinued, however, the swelling disappeared and the creatine-kinase level normalized. Then in July, on the sixth day of daily subcutaneous injections of 75 µg of filgrastim following the same chemotherapy regimen, similar swelling of the soft tissues occurred around the left eye, and was again reversed by withdrawal of the drug. In July 2000, infusion of dexamethasone was conducted, and following daily subcutaneous-injection of 75 µg of filgrastim for 5 days, the right subclavicular soft tissue became swollen. The patient later died of myocardial infarction and an autopsy revealed an infiltration of myeloma cells into the right subclavicular muscle and bone marrow that was packed with myeloma cells. This case suggests that exposure to granulocyte-colony stimulating factors enables myeloma cells to proliferate and infiltrate into soft tissues. [ABSTRACT FROM AUTHOR]

Presents information on a study which analyzed various mutant clones of the juxtamembrane domain in regard to autophosphorylation and signal transduction in leukemia Insight on class III receptor tyrosine kinases; Materials and methodology of the study; Results and discussion.

Summary: Adult T‐cell leukaemia/lymphoma (ATL) patients have a poor prognosis. Here, we investigated the impact of TP53 gene mutations on prognosis of ATL treated in different ways. Among 177 patients, we identified 47 single nucleotide variants or insertion‐deletions (SNVs/indels) of the TP53 gene in 37 individuals. TP53 copy number variations (CNVs) were observed in 38 patients. Altogether, 67 of 177 patients harboured TP53 SNVs/indels or TP53 CNVs, and were categorized as having TP53 mutations. In the entire cohort, median survival of patients with and without TP53 mutations was 1·0 and 6·7 years respectively (P < 0·001). After allogeneic haematopoietic stem cell transplantation (HSCT), median survival of patients with (n = 16) and without (n = 29) TP53 mutations was 0·4 years and not reached respectively (P = 0·001). For patients receiving mogamulizumab without allogeneic HSCT, the median survival from the first dose of antibody in patients with TP53 mutations (n = 27) was only 0·9 years, but 5·1 years in those without (n = 42; P < 0·001). Thus, TP53 mutations are associated with unfavourable prognosis of ATL, regardless of treatment strategy. The establishment of alternative modalities to overcome the adverse impact of TP53 mutations in patients with ATL is required. [ABSTRACT FROM AUTHOR]

Summary: Multiple oncogenic events are involved in the development of adult T‐cell leukaemia/lymphoma (ATL). Because CD28 plays a pivotal role in T‐cell activation, we focused on alterations of the CD28 gene in ATL. We found multiple genetic abnormalities related to CD28 among the 144 patients enrolled in the present study. These involved gene fusions with the cytotoxic T‐lymphocyte‐associated antigen 4 or the inducible T‐cell co‐stimulator in 14 patients (10%), CD28‐activating mutations in 3 (2%), and CD28 copy number variations in 34 (24%). Patients with such CD28 gene alterations were significantly younger than those without. In patients not receiving allogeneic haematopoietic stem cell transplantation, those with CD28 gene alterations tended to have a worse prognosis than those without. Finally, patients with chronic or smouldering ATL subtypes with CD28 gene alterations had a significantly worse prognosis than those without. These findings indicate that ATL, especially chronic or smouldering subtypes, have a more aggressive clinical course and are more refractory to conventional chemotherapies or mogamulizumab if they harbour CD28 gene alterations, likely because of continuous, prolonged, and enhanced CD28 activatory signalling. Novel treatment strategies to overcome the effects of these CD28 gene alterations are warranted. [ABSTRACT FROM AUTHOR]

Macrophages play an indispensable role in both innate and acquired immunity, while the persistence of activated macrophages can sometimes be harmful to the host, resulting in multi-organ damage. Macrophages develop from monocytes in the circulation. However, little is known about the organ affinity of macrophages in the normal state. Using in vivo imaging with XenoLight DiR®, we observed that macrophages showed strong affinity for the liver, spleen and lung, and weak affinity for the gut and bone marrow, but little or no affinity for the kidney and skin. We also found that administered macrophages were still alive 168 hours after injection. On the other hand, treatment with clodronate liposomes, which are readily taken up by macrophages via phagocytosis, strongly reduced the number of macrophages in the liver, spleen and lung. [ABSTRACT FROM AUTHOR]

To clarify the prognostic impact of tumor-infiltrating effector regulatory T cells (eTregs) in non-small cell lung cancer (NSCLC), eTregs were evaluated by immunohistochemical detection of CCR4 and Foxp3 in 108 consecutive surgical NSCLC tumors. Multivariate analysis showed that a high ratio of CCR4+ eTregs to total Tregs (≥40%) was the only independent risk factor for relapse-free survival (odds ratio [OR]: 6.54, 95% confidence interval: 1.67-25.7, p = .007) and overall survival (OR: 3.76, p = .037) in lung squamous cell carcinoma (SqCC). These results highlight the prognostic importance of the balance of tumor-infiltrating Tregs in resected lung SqCC. [ABSTRACT FROM AUTHOR]

Methotrexate (MTX) is currently used as first‐line anchor drug for rheumatoid arthritis (RA). Therefore, the number of MTX‐associated lymphoproliferative disorders, including Epstein–Barr virus‐positive mucocutaneous ulcer (EBVMCU), has increased. Some aspects of MTX‐associated EBVMCU (MTX‐EBVMCU), particularly clinical behavior and treatment for RA after MTX cessation, have not been well described. Herein, we report nine cases of MTX‐EBVMCU with clinical information regarding RA. Seven of nine patients showed spontaneous regression (SR) after immunosuppressive (IS) cessation. The other two required cytotoxic chemotherapy. Eventually, all achieved complete remission. No patients experienced EBVMCU relapse. Eight patients had RA flare after IS cessation. To control the RA activity, rituximab was administered to three patients. The remaining patients were treated by other agents. Regarding the RA activity, all were in the status of low disease activity or clinical remission. In conclusion, MTX‐associated EBVMCU has an indolent clinical course and SR after IS cessation can be expected. After the withdrawal of MTX, the majority of patients experience RA flare and required treatment. In our series, RA was well controlled without reinitiating MTX. Therefore, to prevent the EBVMCU relapse, it might be advisable to avoid MTX reintroduction, and rituximab might be the more preferable agent for RA treatment. [ABSTRACT FROM AUTHOR]

Peripheral T cell lymphomas are an aggressive group of non-Hodgkin lymphomas with poor outcomes for most subtypes and no accepted standard of care for relapsed patients. This study evaluated the efficacy and safety of forodesine, a novel purine nucleoside phosphorylase inhibitor, in patients with relapsed peripheral T cell lymphomas. Patients with histologically confirmed disease, progression after ≥ 1 prior treatment, and an objective response to last treatment received oral forodesine 300 mg twice-daily. The primary endpoint was objective response rate (ORR). Secondary endpoints included duration of response, progression-free survival (PFS), overall survival (OS), and safety. Forty-eight patients (median age, 69.5 years; median of 2 prior treatments) received forodesine. In phase 1 (n = 3 evaluable), no dose-limiting toxicity was observed during the first 28 days of forodesine treatment. In phase 2 (n = 41 evaluable), the ORR for the primary and final analyses was 22% (90% CI 12-35%) and 25% (90% CI 14-38%), respectively, including four complete responses (10%). Median PFS and OS were 1.9 and 15.6 months, respectively. The most common grade 3/4 adverse events were lymphopenia (96%), leukopenia (42%), and neutropenia (35%). Dose reduction and discontinuation due to adverse events were uncommon. Secondary B cell lymphoma developed in five patients, of whom four were positive for Epstein-Barr virus. In conclusion, forodesine has single-agent activity within the range of approved therapies in relapsed peripheral T cell lymphomas, with a manageable safety profile, and may represent a viable treatment option for this difficult-to-treat population. [ABSTRACT FROM AUTHOR]

The recent development of immune checkpoint inhibitors for many types of cancers has prompted us to identify markers that predict patients with clinical benefits. Several trials on nivolumab for the treatment of esophageal squamous cell carcinoma (ESCC) have been performed worldwide, and the identification of markers specific to ESCC is urgently needed. We conducted a clinical trial on nivolumab for advanced ESCC (JapicCTI-No.142422) and investigated markers using peripheral blood collected from 20 patients enrolled in our institute, including 1 with a complete response (CR), 5 with a partial response (PR), 6 with a stable disease (SD), and 8 with a progressive disease (PD) as clinical responses. The expression of surface molecules and cytokine production by T cells were analyzed using flow cytometry, and clinicopathological factors and general blood parameters were examined. Albumin, neutrophils, %Tim3, %OX40, %CD103, %CD45RA−CD27−, and IL-1b after the first cycle of nivolumab treatment, but not at baseline, distinguished CR/PR from SD/PD patients. When markers to distinguish longer survivors with nivolumab therapy were analyzed, changes in these levels between baseline and after the first cycle of nivolumab treatment, but not levels at each period, were indicative, similar to the tumor burden. Among them, elevations in %Tim-3+CD4 had a marked impact on survival rates. In conclusion, dynamic elevations in %Tim-3 in T cells in the early period of nivolumab therapy have potential as a marker for the clinical responses and prognosis of advanced ESCC patients. [ABSTRACT FROM AUTHOR]

We report an adult T-cell leukemia--lymphoma (ATL) patient suffering from fatal reactivation of hepatitis B virus (HBV) infection after treatment with the anti-CC chemokine receptor 4 (CCR4) monoclonal antibody, mogamulizumab. HBV reactivation occurred without liver damage in this hepatitis B surface antigen (HBsAg) negative patient, who was seropositive for antibodies against the viral core and surface antigens at baseline, after two cycles of CHOP regimen (cyclophosphamide, doxorubicin, vincristine and prednisolone) followed by six cycles of THP-COP regimen (cyclophosphamide, pirarubicin, vincristine and prednisolone). Unexpectedly, mogamulizumab monotherapy for relapsed CCR4 positive ATL induced sudden and fatal liver failure due to HBV reactivation, despite antiviral prophylaxis with entecavir. This clinical course may not only offer important suggestions to prevent critical HBV reactivation in HBsAg positive cancer patients who receive immune-enhancing drugs such as anti-CCR4 antibody, but also provide a clue to understanding the pathogenesis of HBV reactivation following systemic chemotherapy. [ABSTRACT FROM AUTHOR]

Macrophage infiltration of skin GVHD lesions correlates directly with disease severity, but the mechanisms underlying this relationship remain unclear and GVHD with many macrophages is a therapeutic challenge. Here, we characterize the macrophages involved in GVHD and report that dexamethasone palmitate (DP), a liposteroid, can ameliorate such GVHD by inhibiting macrophage functions. We found that host-derived macrophages could exacerbate GVHD in a mouse model through expression of higher levels of pro-inflammatory TNF-α and IFN-γ, and lower levels of anti-inflammatory IL-10 than resident macrophages in mice without GVHD. DP significantly decreased the viability and migration capacity of primary mouse macrophages compared to conventional dexamethasone in vitro. DP treatment on day 7 and day 14 decreased macrophage number, and attenuated GVHD score and subsequent mortality in a murine model. This is the first study to provide evidence that therapy for GVHD should be changed on the basis of infiltrating cell type. [ABSTRACT FROM AUTHOR]

The introduction of molecularly targeted drugs has increased the risk of reactivation of hepatitis B virus ( HBV), which is a potentially fatal complication following anticancer chemotherapy even in patients who have previously resolved their HBV infection. CC chemokine receptor 4 ( CCR4) has been identified as a novel molecular target in antibody therapy for patients with adult T-cell leukemia-lymphoma ( ATL) and peripheral T-cell lymphoma, and the humanized anti- CCR4 monoclonal antibody mogamulizumab has been developed. We reported HBV reactivation of an ATL patient with previously resolved HBV infection after mogamulizumab treatment in a dose-finding study for this antibody. Our retrospective analysis using preserved samples also revealed the detailed kinetics of HBV DNA levels before and just after HBV reactivation. [ABSTRACT FROM AUTHOR]

Objective The objective of this study was to evaluate the therapeutic potential of bevacizumab with or without systemic chemotherapy for adult T-cell leukemia/lymphoma ( ATL) and clarify the significance of angiogenesis for ATL pathogenesis. Methods NOD/ Shi- scid, IL-2 Rγnull ( NOG) mice were used as recipients of tumor cells from a patient with ATL, which engraft and proliferate in a microenvironment-dependent manner. The ATL cells could be serially transplanted in NOG mice, but could not be maintained in in vitro cultures. Results Injection of bevacizumab alone significantly increased necrosis and decreased vascularization in the tumor tissue. Levels of human soluble interleukin two receptor in the serum (reflecting the ATL tumor burden) of bevacizumab-treated mice were significantly lower than in untreated mice. Although bevacizumab monotherapy showed these clear anti-angiogenesis effects, it did not prolong survival. In contrast, injection of bevacizumab together with cyclophosphamide, doxorubicin, vincristine, prednisolone ( CHOP) led to a significant prolongation of survival of the ATL mice relative to CHOP alone. Conclusions This is the first report to evaluate the efficacy of bevacizumab for ATL in a tumor microenvironment-dependent model. Bevacizumab therapy combined with chemotherapy could be a valuable treatment strategy for that subgroup of ATL probably depending to a large extent on angiogenesis via vascular endothelial growth factor. [ABSTRACT FROM AUTHOR]

Abstract: We established an angioimmunoblastic T-cell lymphoma (AITL) mouse model using NOD/Shi-scid, IL-2Rγnull mice as recipients. The immunohistological findings of the AITL mice were almost identical to those of patients with AITL. In addition, substantial amounts of human immunoglobulin G/A/M were detected in the sera of the AITL mice. This result indicates that AITL tumor cells helped antibody production by B cells or plasma cells. This is the first report of reconstituting follicular helper T (TFH) function in AITL cells in an experimental model, and this is consistent with the theory that TFH cell is the cell of origin of AITL tumor cells. [Copyright &y& Elsevier]

The role of dacarbazine in ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) therapy in Hodgkin lymphoma (HL) remains unclear. This phase II study assessed the efficacy and safety of ABV therapy with an increased doxorubicin dose (30 mg/m2) in advanced-stage HL. The primary endpoint was complete response rate (%CR). Patients received six or eight cycles of ABV every 4 weeks followed by involved-field radiation therapy (IFRT) in residual disease and initial bulky mass. Seventy-two patients were enrolled. An interim analysis in 46 assessable patients showed that %CR had exceeded the stopping criteria.However, the 2-year progression-free survival (%PFS) rate of 49.4% (95% confidence interval [CI] 32.2-66.6) was markedly lower than the 79.2% PFS (95% CI 70.6-87.7) seen in our previously reported study (JCOG9305) of ABVd with two-thirds the dose of dacarbazine of the original ABVD. Therefore, the study was closed early. The %CR in the 70 eligible patients after ABV was 31.4% (95% CI 20.9-43.6) and was increased to 70.0% (95% CI 57.9-80.4) after the addition of IFRT. ABV was inferior to ABVd for PFS in patients with advanced HL, suggesting that dacarbazine is indispensable in ABVD/ABVd. [ABSTRACT FROM AUTHOR]

To find HDAC8-selective inhibitors, we designed a libraryof HDAC inhibitor candidates, each containing a zinc-binding groupthat coordinates with the active-site zinc ion, linked via a triazolemoiety to a capping structure that interacts with residues on therim of the active site. These compounds were synthesized by usingclick chemistry. Screening identified HDAC8-selective inhibitors including C149(IC50= 0.070 μM), which was more potentthan PCI-34058 (6) (IC50= 0.31 μM),a known HDAC8 inhibitor. Molecular modeling suggested that the phenylthiomethylgroup of C149binds to a unique hydrophobic pocket ofHDAC8, and the orientation of the phenylthiomethyl and hydroxamatemoieties (fixed by the triazole moiety) is important for the potencyand selectivity. The inhibitors caused selective acetylation of cohesinin cells and exerted growth-inhibitory effects on T-cell lymphomaand neuroblastoma cells (GI50= 3–80 μM).These findings suggest that HDAC8-selective inhibitors have potentialas anticancer agents. [ABSTRACT FROM AUTHOR]

Adult T-cell leukemia/lymphoma (ATLL) is an intractable hematologic malignancy caused by human T-lymphotropic virus type 1 (HTLV-1), which infects approximately 20 million people worldwide. Here, we have explored the possible expression of cancer/testis (CT) antigens by ATLL cells, as CT antigens are widely recognized as ideal targets of cancer immunotherapy against solid tumors. A high percentage (87.7%) of ATLL cases (n = 57) expressed CT antigens at the mRNA level: NY-ESO-1 (61.4%), MAGE-A3 (31.6%), and MAGE-A4 (61.4%). CT antigen expression was confirmed by immunohistochemis-try. This contrasts with other types of lymphoma or leukemia, which scarcely express these CT antigens. Humoral immune responses, particularly against NY-ESO-1, were detected in 11.6% (5 of 43) and NY-ESO-1-specific CD8+ T-cell responses were observed in 55.6% (5 of 9) of ATLL patients. NY-ESO-1-specific CD8+ T cells recognized autologous ATLL cells and produced effector cytokines. Thus, ATLL cells characteristically express CT antigens and therefore vaccination with CT antigens can be an effective immunotherapy of ATLL. [ABSTRACT FROM AUTHOR]

Psoriatic arthritis (PsA) is a chronic inflammatory skin disease that causes enthesitis and destructive arthritis and significantly lowers patient quality of life. Recognition of the two target organs (the skin and joints) involved in the immunopathophysiology of PsA helped in elucidating the pathology of various systemic autoimmune diseases targeting multiple organs. Recent advances in immunology and genetics have made it clear that acquired immunity, especially that mediated by the Th17/IL-23 axis, plays an important role in the inflammatory pathology observed in psoriasis and PsA. Additionally, involvement of natural immunity has also been suggested. Microbial infection has been known to trigger psoriasis and PsA. Recent clinical studies using biopharmaceuticals, such as tumor-necrosis-factor- (TNF-) α inhibitors and IL-12/23 p40 antibodies, indicate that studies need not be based only on the immunological phenomena observed in PsA pathology since disease pathology can now be verified using human-based science. Considering this aspect, this paper discusses the immunopathology of PsA compared to psoriasis (cutaneous) and rheumatoid arthritis in humans and immunopathology of PsA with respect to the Th17/IL-23 axis and microbial infection. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) has many pulmonary manifestations, including bronchial abnormalities that can develop into Mycobacterium avium-complex (MAC) pulmonary disease (PD). MAC-PD can be lethal in patients receiving tumor necrosis factor-alpha blockers despite administration of antibiotics. Diagnosis of MAC-PD is often difficult, because MAC is an environmental organism. In this study, we investigated the usefulness of serodiagnosis of MAC-PD in RA patients by using an enzyme immunoassay (EIA) kit that detects anti-glycopeptidolipid (GPL) core antigen IgA antibodies. Antibody levels were measured in 63 patients with RA: 14 with MAC-PD plus 3 cultured nontuberculous mycobacteria (NTM) other than MAC, 16 with pulmonary abnormalities characterizing NTM but undetected in sputum culture, and 30 control subjects. RA patients with MAC-PD showed significantly higher antibody levels than controls ( p = 0.02). The cutoff point was set at 0.7 IU/l, making the sensitivity and specificity of the antibody in MAC-PD and control patients 43% and 100%, respectively. The EIA kit is useful for diagnosis of MAC-PD in RA patients because of its high specificity. This test is an easier and less invasive form of examination and could therefore replace bronchoscopy as the main diagnostic procedure for RA patients with MAC-PD. [ABSTRACT FROM AUTHOR]

Engineering the Fc region of monoclonal antibodies (mAb) in order to enhance effector functions such as antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity (CDC) is likely to a be promising approach for next-generation mAb therapy. Here, we report on such an antibody, 113F, a novel CDC-enhancing variant of rituximab, and determine the tumor-associated factors influencing susceptibility to 113F-induced CDC. The latter included the quantity of complement inhibitors present, such as CD55 and CD59. We report that compared to rituximab, 113F mediated highly enhanced CDC against primary CD20-expressing lymphoma cells in vitro. Currently, a major problem in the field of immunotherapy research is the lack of suitable small animal models to evaluate human CDC in vivo. Therefore, we established a novel human tumor-bearing NOD/Shi- scid, IL-2Rγ mouse model, in which human complement functions as the CDC mediator. We demonstrated that rituximab exerted significant antitumor effects via human CDC in this humanized mouse. The finding of specific localization of human C1q on CD20-expressing tumor cell membranes was consistent with the observation that human CDC indeed contributed to the antitumor effect in this model. Moreover, 113F exerted significantly more potent antitumor effects than rituximab in this in vivo model. The detection of more abundant dense signals from C1q using 113F compared to rituximab was consistent with the concept that this reagent represented a CDC-enhancing mAb. In the near future, the efficacy of this type of CDC-enhancing antibody will be determined in clinical trials in humans. [ABSTRACT FROM AUTHOR]

Clostridium difficile is a major cause of antibiotic-associated diarrhea and frequently results in healthcare-associated infections. The epidemiology of C. difficile infection (CDI), including the prevalent polymerase chain reaction (PCR) ribotypes and the clinical characteristics of the patients, is not well known in Japan, compared to the situation in the United States and Europe. We performed PCR ribotyping of C. difficile isolates from 71 consecutive patients with CDI at a University Hospital over a 3-year period and investigated the clinical features of those patients. CDI was diagnosed when a patient with diarrhea or colitis was found to have toxin B-positive C. difficile with no other enteropathogenic microorganisms. Toxin A-positive, toxin B-positive, binary toxin-positive (ABCDT) strains; toxin A-positive, toxin B-positive, binary toxin-negative (ABCDT) strains; and toxin A-negative, toxin B-positive, binary toxin-negative (ABCDT) strains were isolated from 4, 58, and 9 patients, respectively, indicating that infections with binary toxin-positive strains were uncommon (5.6%). PCR ribotyping of the isolates demonstrated that among the 71 strains, 20 different PCR ribotypes were identified and that types smz, yok, and hr were predominant (19, 14, and 13 isolates, respectively), all of which were ABCDT. No specific time periods or wards were found to be associated with the three types; PCR ribotyping analysis clearly showed that the three types spread almost evenly in all wards for the 3 years studied. Comparative analysis of the clinical characteristics of patients harboring the three C. difficile types indicated that the duration of CDI was longer in the yok group than in the hr group. PCR ribotyping, which is easy to perform, appears to give us useful information to trace CDI cases in clinical settings. Further, the analysis of a large number of CDI cases may allow evaluation of the possible relationship between specific C. difficile types and the clinical features of patients. [ABSTRACT FROM AUTHOR]

We aimed to determine the sensitivity and specificity of QuantiFERON-TB Gold (QFT-G) in Japanese rheumatoid arthritis (RA) patients with a past history of tuberculosis (TB). We assessed whether it is possible to decrease the cutoff using receiver operating characteristic (ROC) analysis. We evaluated chest computed tomography (CT) findings, prior history of treatment, and contact with active TB in 370 RA patients. Forty-nine patients before initiation of treatment with tumor necrosis factor (TNF) inhibitors were divided into two groups: 22 with a past history of TB and 27 without. We estimated the efficacy of QFT-G compared with the tuberculin skin test and antituberculosis (anti-TB) glycolipid antigen antibody. QFT-G was positive (≥0.35 IU/ml) in 13.6% with a past history of TB, increasing to 27.3% at the intermediate range cutoff of 0.1 IU/ml. The sensitivity and specificity of QFT-G was 0.27 and 1.00, respectively, at 0.1 IU/ml. Using ROC analysis, the area under the curve (AUC) of QFT-G but not for the other two tests was significantly large. QFT-G is a useful diagnostic method due to its superior specificity, but the use of a cutoff value of 0.35 IU/ml will likely result in an underestimate. We propose that a lower interferon-γ (IFN-γ) titer of 0.1 IU/ml be adopted when deciding to administer anti-TB drugs before initiation of TNF inhibitors. [ABSTRACT FROM AUTHOR]

Abstract: A series of 2-anilinobenzamide derivatives were designed, synthesized and evaluated for their SIRT1-inhibitory activity. Among these, compounds 3 and 5 inhibited SIRT1 activity in enzyme assays and suppressed the growth of Daudi and HCT116 cells. [Copyright &y& Elsevier]

There are no suitable small animal models to evaluate human antibody-dependent cellular cytotoxicity (ADCC) in vivo, due to species incompatibilities. Thus, the first aim of this study was to establish a human tumor-bearing mouse model in which human immune cells can engraft and mediate ADCC, but where the endogenous mouse immune cells cannot mediate ADCC. The second aim was to evaluate ADCC mediated in these humanized mice by the defucosylated anti-CC chemokine receptor 4 (CCR4) monoclonal antibody (mAb) which we have developed and which is now in phase I clinical trials. NOD/Shi- scid, IL-2Rγnull (NOG) mice were the recipients of human immune cells, and CCR4-expressing Hodgkin lymphoma (HL) and cutaneous T-cell lymphoma (CTCL) cell lines were used as target tumors. Humanized mice have been established using NOG mice. The chimeric defucosylated anti-CCR4 mAb KM2760 showed potent antitumor activity mediated by robust ADCC in these humanized mice bearing the HL or CTCL cell lines. KM2760 significantly increased the number of tumor-infiltrating CD56-positive NK cells which mediate ADCC, and reduced the number of tumor-infiltrating FOXP3-positive regulatory T (Treg) cells in HL-bearing humanized mice. Anti-CCR4 mAb could be an ideal treatment modality for many different cancers, not only to directly kill CCR4-expressing tumor cells, but also to overcome the suppressive effect of Treg cells on the host immune response to tumor cells. In addition, using our humanized mice, we can perform the appropriate preclinical evaluation of many types of antibody based immunotherapy. [ABSTRACT FROM AUTHOR]

Abstract   Clostridium difficile is a nosocomial pathogen that is transmissible between patients via hospital staff and via contaminated environmental surfaces. Recently, a typing system based on the slpA sequence for C. difficile was developed. To elucidate the validity and efficacy of the system in the setting of a local hospital, we carried out typing of C. difficile from patients in our hospital using the system. Twenty-eight stool samples obtained from 17 patients with C. difficile-associated diarrhea were investigated. Twenty-two of the 28 samples were positive for C. difficile by stool culture, and they were able to be classified by slpA sequence typing. The smz-1 and smz-2 strains were revealed to be the predominant types in our hospital, accounting for 73% of all strains. The yok-1, yok-2, t25-1, hr-1, and hj2-2 strains were identified in 1 patient each. The smz-1 strain was identified in all wards except for ward D, while smz-2 was identified in 3 of 4 patients in ward D and was restricted to this ward. Nosocomial infection of smz-1 and smz-2 in our hospital was demonstrated. Distinguishing smz-1 from smz-2 by slpA sequence typing clarified the transmission of C. difficile among patients. In conclusion, slpA sequence typing was useful in the setting of a local hospital and may be a powerful tool for the epidemiological study of C. difficile infection. [ABSTRACT FROM AUTHOR]

Background: A variety of complementary and alternative medicine (CAM) treatments are provided to the elderly. We investigated the efficacy and safety of CAM substances that are available to patients with osteoarthritis (OA) and rheumatoid arthritis (RA), both in Japan and overseas. Methods: Information on CAM products was collected from the World Wide Web, using the keywords “arthritis” and “supplement” in five languages (Japanese, English, French, Italian and German) using a popular search engine for each of the languages. References to published work on the products were researched using PubMed with the keywords of “arthritis”, “anti-inflammatory” and “analgesics”. Such published work was classified according to the evidence levels established by the Cochrane Library. Results: Two-hundred and sixty CAM products for OA or RA were available in Japan, of which 41 CAM products had been tested in randomized controlled trials (RCT); there was no scientific evidence for the remaining 219 CAM products. Most of the previous RCT suggested that CAM was effective in OA or RA. Herein, we confirmed the significant OA relieving effects of chondroitin sulfate through a meta-analysis. Effectiveness was assessed using subjective scores, not disease-specific immunological or serological markers for assessment. Toxicological investigations had only been performed for a few CAM products. Conclusion: Some CAM products that are effective against RA may be used together with biological therapy. However, some of the CAM products available in Japan should be tested using objective markers. Some CAM products for OA could be used for the relief of pain. [ABSTRACT FROM AUTHOR]

Scleroderma and eosinophilia often occur together, though the pathogenesis is unclear. We investigated the effect of olopatadine hydrochloride in a series of cases of limited scleroderma (LS). Ten patients with LS and positive eosinophil counts (LSE) were enrolled (average age, 85 years; six men and four women). Serum concentrations of the anti-Scl-70 antibody were positive. Olopatadine hydrochloride was prescribed at 10 mg/day for 3 weeks. Serum concentrations of the anti-Scl-70 antibody significantly decreased, but changes in eosinophil numbers and percentages in peripheral blood were not significant. Factor analysis suggested a correlation between serum concentrations of the anti-Scl-70 antibody and complement C4. Olopatadine could be effective in reducing anti-Scl-70 antibodies in the elderly with LSE. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to identify factors that predict treatment outcome in patients with metastatic pancreatic cancer treated with gemcitabine, and then to use these factors to develop a practical prognostic index. Methods: A retrospective study was performed on 66 consecutive patients with histologically confirmed pancreatic adenocarcinoma who were treated with gemcitabine. Factors that predicted treatment outcome were identified by univariate and multivariate analyses using the Cox proportional hazards model. Results: Multivariate analysis identified Eastern Cooperative Oncology Group performance status, primary tumor location, and C-reactive protein as important independent predictive factors. Prognostic score was calculated using the following formula: score = (1 if performance status is 0 or 1; 2 if performance status is 2; and 5 if performance status is 3) + (1 if primary site is body or tail, 3 if primary site is head) + (1 if C-reactive protein is <1 mg/dL, 3 if C-reactive protein is 1–3 mg/dL, 6 if C-reactive protein is >3 mg/dL). Patients were accordingly divided into three groups: good (prognostic index = 3 or 4), fair (prognostic index = 5–7), and poor (prognostic index = 8). Median survival was 265, 155, and 65 days for each group, respectively ( P < 0.0001). The internally validated c-index (receiver operating characteristics area under the curve) of this model was 0.711. Applied to another data set, the externally validated c-index was 0.692. Prognosis was favorable in the good prognosis group, patients in the fair prognosis group were likely to benefit from gemcitabine, and those in the poor prognosis group were unlikely to benefit. Conclusion: This index improved predictive ability in patients with metastatic pancreatic cancer treated with gemcitabine, which may be helpful in counseling patients and making first treatment decisions. [ABSTRACT FROM AUTHOR]

Primary mucosa-associated lymphoid tissue (MALT) lymphoma of the prostate is rare, and only five cases have been reported. Reported herein is a new case that has involved a 9 year follow up. A 79-year-old man was treated with transurethral resection (TUR) for a mass of the right prostatic lobe, and followed up under a diagnosis of benign prostatic hyperplasia with atypical lymphoid infiltration. Seven years later TUR was again performed for a right lobe mass. The lesion was diagnosed as a relapsed MALT lymphoma after detailed histological and immunoglobulin heavy chain gene analyses of the initial and relapsed lesions. Interestingly, lymphoepithelial lesions were observed only infrequently in this tumor. The API2-MALT1 fusion, a gene alteration specific to MALT lymphoma, was absent. The patient had stage IA disease at the time of tumor relapse, and has been alive and well for the 2 years after the second TUR. The present case suggests that despite tumor recurrence, prostatic MALT lymphoma is indolent, and function-preserving therapy is warranted. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented that discusses the augmentation of antitumour activity of defucosylated chimeric anti-CCR4 monoclonal antibody in severe-combined immunodeficient mouse model of adult T-cell leukaemia/lymphoma using granulocyte colony-stimulating factor.

Aim: The aim of the present study was to examine DNA methylation and histone modification changes in hepatocellular carcinomas (HCC). Methods: DNA methylation in the P16, RASSF1a, progesterone receptor ( PGR) and estrogen receptor α ( ERα) promoters was determined by quantitative bisulfite-pyrosequencing technique in HCC patients. Histone H3-lysine (K) 4, H3-K9 and H3-K27 modifications in all these four genes were examined by chromatin immunoprecipitation (ChIP) assay in HCC cell lines. Expression of two DNA methyltransferases (DNMT1 and DNMT3b) and three histone methyltransferases (SUV39H1, G9a and EZH2) in HCC patients was measured by real-time polymerase chain reaction. Results: Aberrant DNA methylation was detected in all the HCC. Patients with DNA methylation in the RASSF1a, PGR and ERα promoters in cancers also had substantial DNA methylation in their non-cancerous liver tissues, whereas DNA methylation in the P16 promoter was cancer specific. Epigenetic states in HCC cell lines showed that silencing of P16 and RASSF1a depended on DNA methylation and histone H3-K9 methylation. However, silencing of the PGR and ERα genes was more closely related to H3-K27 methylation rather than DNA methylation. Consistent with the alteration of histone status, higher expression of G9a and EZH2 was found in HCC than in non-cancerous liver tissues ( P < 0.01). Conclusion: These data suggest that multiple epigenetic silencing mechanisms are inappropriately active in HCC cells. [ABSTRACT FROM AUTHOR]

Abstract: We report here the development of a polyclonal antibody for human equilibrative nucleoside transporter 1 (hENT1) and assess the expression of hENT1 in non-small cell lung cancer (NSCLC) patients who were treated with gemcitabine-containing chemotherapy. hENT1 expression was analyzed by immunohistochemical staining in 24 NSCLC biopsy samples of formalin-fixed, paraffin-embedded tissues. The hENT1-positive staining in NSCLC samples was significantly associated with response to gemcitabine-containing chemotherapy. Responses to gemcitabine-containing chemotherapy were evident in none of the seven patients with no hENT1 expression. These results indicate that the absence of hENT1 expression may be useful to predict NSCLC patients who will not respond to gemcitabine-containing chemotherapy. [Copyright &y& Elsevier]

Background: Drug-induced hypersensitivity syndrome (DIHS) is characterized by a severe multiorgan hypersensitivity reaction that usually appears after prolonged exposure to certain drugs and may be related to reactivation of herpes viruses. There have been few reports regarding the clinical association of DIHS with pathogens other than herpes viruses. Case Summary: We report a case of scleroderma with DIHS associated with paramyxovirus infection. A 61- year-old man with early diffuse cutaneous scleroderma with myositis and progressive interstitial pneumonia developed generalized erythema with high fever 3 weeks after taking sulfamethoxazole/trimethoprim. The diagnosis of DIHS was made based on the patient's history of using an offending drug, clinical manifestations and laboratory data showing peripheral eosinophilia with the presence of atypical lymphocytes. Virological tests showed significant increases of antibody titers against mumps virus and parainfluenza virus type 2, which strongly suggested that paramyxovirus infection occurred during the clinical course of DIHS. Discussion: These findings suggest that paramyxovirus infection had contributed to the development of DIHS in this patient and that there is a need to seek evidence of other viral infections in some cases of DIHS, especially those without herpes virus reactivation/infection. [ABSTRACT FROM AUTHOR]

There is substantial evidence that the decreased risk of lung cancer with high intake of vegetables and fruits is linked to folate as a specific nutrient. Functional polymorphisms in genes encoding one-carbon metabolism enzymes, methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), methionine synthase (MTR A2756G), methionine synthase reductase (MTRR A66G) and thymidylate synthase, influence folate metabolism and thus might be suspected of impacting on lung cancer risk. We therefore conducted a case–control study with 515 lung cancer cases newly and histologically diagnosed and 1030 age- and sex-matched non-cancer controls to clarify associations with these five polymorphisms according to lung cancer subtype. Gene–environment interactions with smoking and drinking habit and folate consumption were also evaluated by logistic regression analysis. None of the polymorphisms showed any significant impact on lung cancer overall risk by genotype alone, but on histology-based analysis increase in MTHFR 677T and 1298C alleles was associated with reduced risk of squamous/small cell carcinoma (P = 0.029), especially among heavy smokers (P = 0.035), whereas the MTHFR 677TT genotype was linked to decreased risk for these subtypes among heavy drinkers (odds ratio = 0.17, 95% confidence interval: 0.03–0.98). In addition, we found interactions between the MTRR A66G polymorphism and smoking (P = 0.015) and the MTHFR A1298C polymorphism and alcohol consumption (P = 0.025) for risk of lung cancer overall. In conclusion, the results suggest that MTHFR polymorphisms contribute to risk of squamous/small cell carcinomas of the lung, along with possible interactions among folate metabolism-related polymorphisms and smoking/drinking habits. Further evaluation is warranted. [ABSTRACT FROM PUBLISHER]

Abstract: We investigated the clinical significance of a blood eosinophilia in a cohort of 158 consecutive patients with adult T-cell leukemia/lymphoma (ATLL), and multivariate analysis revealed that a blood eosinophilia was an independent and a significant unfavorable prognostic factor. Interestingly, a blood eosinophilia was independent of serum LDH level, which might reflect the tumor burden. The present study shows that measurement of the blood eosinophil count is useful for predicting the prognosis and for determining a suitable treatment strategy for ATLL patients. [Copyright &y& Elsevier]

The article provides information on a study which assessed familial cancer risk for common sites in Japan. The authors of the research conducted a large-scale, case-control study with a further emphasis on interactions with smoking and other confounding environmental factors. The study reviewed a total of 18,836 cancer cases and enrolled 28,125 age-matched and sex-matched controls, confirmed as being free of cancer. Results of the study revealed a genetic susceptibility to cancers in family members.

In Japan, approximately 10% of hepatocellular carcinoma (HCC) patients are negative for both hepatitis B surface antigen (HBsAg) and antibodies to hepatitis C virus (anti-HCV), i.e., they constitute the so-called category of non-B non-C (NBNC) HCC. Little is known about the characteristics of NBNC-HCC. Potential risk factors for carcinogenesis (including occult HBV infection [HBsAg is negative but HBV DNA is positive by polymerase chain reaction (PCR)], obesity, and diabetes) were assessed in 233 HCC patients grouped according to hepatitis virus serological status (152 with HCV-HCC, 36 with HBV-HCC, and 45 with NBNC-HCC). The prevalence of patients with obesity or diabetes was significantly higher in the NBNC-HCC group than in the HBV-HCC group. The same trend was observed even when patients with massive alcohol intake were excluded from the analysis. Only 8 patients (18%) in the NBNC-HCC group had detectable serum HBV DNA, and this was at very low levels (HBV/Ce/C2 and HBV/D were determined in 7 and 1 patients, respectively). In the NBNC-HCC group, the determined nucleotide sequences of the enhancer II/core promoter/precore/core region did not contain any HCC-associated mutations, whereas 25 of 30 patients in the HBV-HCC group carried strains with C1653T, T1753V, and/or A1762T/G1764A mutations. A weak association between occult HBV infection and HCC development was observed in the NBNC patients. This study indicates that nonalcoholic steato-hepatitis should be further investigated to assess its contribution to HCC development in this category of patients. [ABSTRACT FROM AUTHOR]

Aim: Peptide-based therapeutic vaccines are being developed. The aim of this study was to determine the feasibility of immunotherapy to hepatitis C virus (HCV)-positive hepatocellular carcinoma (HCC) by assessing the inductivity of peptide-specific cytotoxic T lymphocyte (CTL) by dendritic cells. Methods: The inductivity of CTL was characterized in six patients with HCV-positive HCC, and compared to seven healthy volunteers and six patients with chronic HCV hepatitis (control). Results: Peptide-specific CTL was comparably induced in controls, but not induced in any patients with HCC. To characterize this, the cytokine profile and the expression of surface molecules interacting between dendritic and T cells were evaluated. Among the cytokines, production of interferon (IFN)-γ was found to be impaired and closely related to the results of CTL assays, while the expression of surface molecules showed no significant changes. Conclusions: In HCV-positive HCC patients, CTL inductivity by dendritic cells is impaired. This may be related to the impaired production of IFN-γ. [ABSTRACT FROM AUTHOR]

We describe three cases of acute renal failure with diffuse alveolar hemorrhage, which is designated pulmonary-renal syndrome (PRS), in systemic sclerosis (SSc) and review the literature to better define this rare but severe complication of SSc. The clinical course of three SSc patients with acute renal failure and concomitant diffuse alveolar hemorrhage are reported, and the literature published between 1967 and 2005 is reviewed following a PubMed search. Including our cases, a total of 19 SSc patients with acute renal failure and concomitant diffuse alveolar hemorrhage have been reported. Pulmonary-renal syndrome developing in SSc patients can be categorized clinicopathologically into three entities: PRS with thrombotic microangiopathy, PRS with small vessel vasculitides accompanied with SSc, and d-penicillamine-induced Goodpasture-like syndrome. Patients with scleroderma PRS with thrombotic microangiopathy, to which group our all patients belong, often developed diffuse alveolar hemorrhage after receiving high-dose corticosteroid therapy. Pulmonary-renal syndrome is a fatal complication of SSc and results from different pathogenic processes. Prompt differential diagnosis between the subsets is critical, because therapeutic strategy may differ in the use of high-dose corticosteroid and plasma exchange between the subsets of PRS. Clinical courses of the patients with PRS with thrombotic microangiopathy suggest that high-dose corticosteroid therapy is a trigger of diffuse alveolar hemorrhage in patients with diffuse SSc with signs of thrombotic microangiopathy. [ABSTRACT FROM AUTHOR]