Validation of RAPID3 using a Japanese version of Multidimensional Health Assessment Questionnaire with Japanese rheumatoid arthritis patients: characteristics of RAPID3 compared to DAS28 and CDAI.

OBJECTIVES: To validate Routine Assessment of Patient Index Data 3 (RAPID3) using a Japanese version of Multidimensional Health Assessment Questionnaire (MDHAQ) with Japanese rheumatoid arthritis (RA) patients and to describe the characteristics of RAPID3 by comparison with Disease Activity Score 28 (DAS28) and Clinical Disease Activity Index (CDAI). METHODS: The original MDHAQ was translated into Japanese with minor cultural modifications and was translated back in English. Test-retest reliability was evaluated in 50 Japanese RA patients and further validation was performed in 350 Japanese RA patients recruited by seven rheumatologists. RAPID3, CDAI, and DAS28 were assessed on two consecutive visits. RESULTS: The test-retest reliability and the internal reliability of RAPID3 were excellent. Spearman's correlation coefficients between RAPID3 score versus CDAI score and DAS28 score were 0.761and 0.555. However, the agreement measured by kappa (weighted) for RAPID3 category versus CDAI category and for RAPID3 category versus DA28 category were 0.225 (0.382) and 0.187 (0.336). The sensitivity and specificity of "RAPID3 ≤ 3 and swollen joint ≤ 1" for predicting Boolean remission were 90.0% and 93.4%, respectively. CONCLUSIONS: RAPID3 obtained by Japanese MDHAQ was validated with Japanese RA patients and the remission criteria were found to have excellent clinical utility in usual care.

Long-term heat exposure prevents hypoxia-induced apoptosis in mouse fibroblast cells.

Long-term continuous exposure to high ambient temperatures induces complete heat acclimation in humans and animals. However, to date, the effects of long-term exposure to heat stress on cells have not been fully evaluated. In this study, we investigated an adaptive physiological process induced in culture cells by continuous exposure to mild heat stress for 60 days. The results of this investigation provide evidence that after long-term heat acclimation in cells, (1) heat shock protein levels are increased, (2) hypoxia inducible factor-1α (HIF-1α) expression is upregulated, and (3) heat shock-induced and hypoxia-induced apoptoses are attenuated. These results suggest that the hypoxia response pathway is an intrinsic part of the heat acclimation repertoire and that the HIF-1 pathway following long-term heat acclimation induces cells with cross tolerance against hypoxia.

Upregulation of aquaporin expression in the salivary glands of heat-acclimated rats.

It is known that aquaporin (AQP) 5 expression in the apical membrane of acinar cells in salivary glands is important for the secretion of saliva in rodents and humans. Although heat acclimation enhances saliva secretion in rodents, the molecular mechanism of how heat induces saliva secretion has not been determined. Here, we found that heat acclimation enhanced the expression of AQP5 and AQP1 in rat submandibular glands concomitant with the promotion of the HIF-1α pathway, leading to VEGF induction and CD31-positive angiogenesis. The apical membrane distribution of AQP5 in serous acinar cells enhanced after heat acclimation, while AQP1 expression was restricted to the endothelial cells in the submandibular glands. A network of AQPs may be involved in heat-acclimated regulation in saliva secretion. Because AQPs probably plays a crucial role in saliva secretion in humans, these findings may lead to a novel strategy for treating saliva hyposecretion.

Japanese variant of multicentric castleman's disease associated with serositis and thrombocytopenia--a report of two cases: is TAFRO syndrome (Castleman- Kojima disease) a distinct clinicopathological entity?

Multicentric Castleman's disease (MCD) is a polyclonal lymphoproliferative disorder that manifests as marked hyper-γ-globulinemia, severe inflammation, anemia, and thrombocytosis. Recently, Takai et al. reported a new disease concept, TAFRO syndrome, named from thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly. Furthermore, Kojima et al. reported Japanese MCD cases with effusion and thrombocytopenia (Castleman-Kojima disease). Here, we report two cases of MCD associated with marked pleural effusion, ascites, and thrombocytopenia, and discuss the independence of the TAFRO syndrome (Castleman-Kojima disease). Case 1: A 57-year-old woman had fever, anemia, anasarca, and some small cervical lymphadenopathy. Although she had been administered steroid therapy, and full-coverage antibiotics, her general condition, including fever, systemic inflammation, and anasarca, deteriorated steadily. We administered chemotherapy [CHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisolone) regimen], but despite a transient improvement, she died due to septic shock. Case 2: A 73-year-old man with a history of aplastic anemia and remission presented with fever, severe inflammation, and anasarca. Prednisolone was administered (15 mg daily), and his hyperinflammation once improved. Nevertheless, his general condition, including pleural effusion and ascites, worsened, and C-reactive protein and interleukin-6 levels showed marked increases. The patient died due to multiorgan failure. Cases of TAFRO syndrome (Castleman-Kojima disease) are still rare. Therefore, it is necessary to conduct multicenter clinical surveys including similar cases, such as ours, to reach a consensus regarding diagnostic criteria, therapeutic strategy, and pathophysiological etiology for this syndrome.

Daily 500 mg valacyclovir is effective for prevention of Varicella zoster virus reactivation in patients with multiple myeloma treated with bortezomib.

BACKGROUND: In patients with multiple myeloma (MM), bortezomib is associated with a significant risk of Varicella zoster virus (VZV) reactivation. There are some reports that acyclovir reduces the risk of VZV reactivation. We assessed whether VZV reactivation could be reduced by using prophylactic valacyclovir at a dose of 500 mg daily. PATIENTS AND METHODS: We retrospectively evaluated 32 patients with MM who received bortezomib and valacyclovir prophylaxis at the Kanazawa Medical University Hospital. Patients received valacyclovir prophylaxis orally at a dose of 500 mg daily, without cessation during bortezomib treatment. RESULTS: The median age was 69 years (range=45-90 years). Fifteen patients were male and seventeen were female. The median bortezomib dose was 37.0 mg/m(2) (range=5.2-167.6 mg/m(2)). All patients also received corticosteroids. The median duration of valacyclovir prophylaxis was 301 days (range=24-1206 days) and the median valacyclovir dose was 150.5 g (range=12-603 g). VZV reactivation developed in only one patient during valacyclovir prophylaxis. VZV reactivation did not develop in three patients who had a past history of VZV reactivation without valacyclovir prophylaxis. Adverse events over grade 3 associated with valacyclovir were not observed. CONCLUSION: Valacyclovir at a dose of 500 mg daily appears to be effective at preventing VZV reactivation and was well-tolerated by patients with MM who received bortezomib.

Skewed production of IL-6 and TGFß by cultured salivary gland epithelial cells from patients with Sjögren's syndrome.

OBJECTIVE: To determine the cytokine production profile of cultured salivary gland epithelial (SGE) cells obtained from patients with Sjögren's syndrome (SS). METHODS: SGE cells obtained from 9 SS patients and 6 normal controls were cultured in the presence of exogenous IFNγ. Cell proliferation and apoptosis in response to IFNγ were determined by WST1 assay and by FACS analysis. The concentrations of IL-6 and TGFß secreted into culture supernatants were analyzed by ELISA. RESULTS: IFNγ did not significantly affect the proliferation or apoptosis of SGE cells. However, IL-6 concentrations were higher, and TGFß concentrations were lower, in culture supernatants of SGE cells from SS patients than from normal controls. CONCLUSION: Cytokine production by SGE cells from SS patients showed a skewed balance compared with normal controls, with increased IL-6 and decreased TGFß secretion. This imbalance may be critical in the regulation of Treg/Th17 cells and may foster a pathogenic milieu that may be causative and predictive in SS.

Cellular heat acclimation regulates cell growth, cell morphology, mitogen-activated protein kinase activation, and expression of aquaporins in mouse fibroblast cells.

The heat shock response has been extensively studied by a number of investigators to understand the molecular mechanism underlying the cellular response to severe heat stress (higher than 42°C). But, body or tissue temperature increases by only a few degrees Celsius during physiological events. Therefore, the physiological cellular response to mild heat stress rather than severe heat stress is likely to be more important. Repeated exposure to hyperthermia for consecutive 5 days induces heat acclimation which is an adaptive physiological process in humans and animals. However, thus far, the effect of continuous exposure to heat stress on cells has not been fully evaluated. In this study, we investigated an adaptive physiological process that is induced in culture cells by continuous exposure to mild heat stress for 5 days. Exposure to heat activated p38-mitogen-activated protein kinase; inhibited cell growth without apoptosis; and increased the levels of HSPs and HSF-1 in mouse fibroblast cells. Interestingly, exposure to heat regulated the expression of aquaporins and induced morphological change. In a physiological sense, these results suggested that continuous exposure to mild heat stress for 5 days, in which heat acclimation is attained in humans and animals, might induce molecular adaptation to heat in cells.

Cutoff Values of Serum IgG4 and Histopathological IgG4+ Plasma Cells for Diagnosis of Patients with IgG4-Related Disease.

IgG4-related disease is a new disease classification established in Japan in the 21st century. Patients with IgG4-related disease display hyper-IgG4-gammaglobulinemia, massive infiltration of IgG4+ plasma cells into tissue, and good response to glucocorticoids. Since IgG4 overexpression is also observed in other disorders, it is necessary to diagnose IgG4-related disease carefully and correctly. We therefore sought to determine cutoff values for serum IgG4 and IgG4/IgG and for IgG4+/IgG+ plasma cells in tissue diagnostic of IgG4-related disease. Patients and Methods. We retrospectively analyzed serum IgG4 concentrations and IgG4/IgG ratio and IgG4+/IgG+ plasma cell ratio in tissues of 132 patients with IgG4-related disease and 48 patients with other disorders. Result. Serum IgG4 >135 mg/dl demonstrated a sensitivity of 97.0% and a specificity of 79.6% in diagnosing IgG4-related disease, and serum IgG4/IgG ratios >8% had a sensitivity and specificity of 95.5% and 87.5%, respectively. IgG4+cell/IgG+ cell ratio in tissues >40% had a sensitivity and specificity of 94.4% and 85.7%, respectively. However, the number of IgG4+ cells was reduced in severely fibrotic parts of tissues. Conclusion. Although a recent unanimous consensus of all relevant researchers in Japan recently established the diagnostic criteria for IgG4-related disease, findings such as ours indicate that further discussion is needed.

[Once-weekly bortezomib plus dexamethasone therapy induced complete response, reducing severe gastrointestinal adverse events for a patient with relapsed multiple myeloma - a case report].

A 74-year-old female with relapsed multiple myeloma was treated with twice-weekly bortezomib plus dexamethasone (BD)therapy, but severe gastrointestinal adverse events(grade 3 paralytic ileus and constipation)developed. After changing to once-weekly BD therapy, ≥ grade 3 gastrointestinal adverse events did not develop, and she was able to continue BD therapy. A complete response and a treatment-free interval ≥ 2 years were obtained by 8 courses of BD therapy. This case report suggests that once-weekly BD therapy may reduce severe gastrointestinal adverse events without decreasing the clinical efficacy for multiple myeloma.

Low-dose cytarabine plus aclarubicin for patients with previously untreated acute myeloid leukemia or high-risk myelodysplastic syndrome ineligible for standard-dose cytarabine plus anthracycline.

BACKGROUND: In order to assess the role of the combination of low-dose cytarabine (Ara-C) plus aclarubicin (CA) in remission induction for patients with untreated acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS), we retrospectively analyzed the efficacy and safety of CA. PATIENTS AND METHODS: Data of twenty patients with untreated AML or high-risk MDS who were ineligible for standard-dose Ara-C plus anthracycline and received CA as remission-induction therapy were analyzed. CA consisted of low-dose Ara-C (10 mg/m(2), subcutaneous injection every 12 hours, for 14 days) and aclarubicin (14 mg/m(2) for patients <70 years old and 10 mg/m(2) for patients ≥70 years old in a one-hour infusion for 4 days). Granulocyte colony-stimulating factor (G-CSF) was used from day 1 of CA to white blood cell count (WBC) recovery, except for patients with initial WBC of more than 20.0×10(3)/mm(3). RESULTS: Eleven patients (55%) achieved complete remission. All four patients whose WBC were ≥20.0×10(3)/mm(3) and did not receive G-CSF were refractory to CA. The predicted 2-year overall survival rate and median survival duration of all 20 patients were 37.9% and 363 days, respectively. The predicted 1-year relapse-free survival (RFS) rate and median duration of RFS of 11 patients who achieved complete remission were 30.3% and 332 days, respectively. Only one patient died due to transfusion-related acute lung injury. No patients died due to severe infections. CONCLUSION: CA combination with G-CSF as remission-induction therapy is promising and well-tolerated in patients with previously untreated AML or high-risk MDS who are ineligible for standard-dose Ara-C plus anthracycline without leukocytosis. In order to improve RFS, intensive postremission chemotherapy or allogeneic hematopoietic stem cell transplantation should be introduced.

CD4+ T-cell dysfunctions through the impaired lipid rafts ameliorate concanavalin A-induced hepatitis in sphingomyelin synthase 1-knockout mice.

Membrane microdomains consisting of sphingomyelin (SM) and cholesterol appear to be important for signal transduction in T-cell activation. The present study was designed to elucidate the role of membrane SM in vivo and in vitro using sphingomyelin synthase 1 (SMS1) knock out (SMS1(-/-)) mice and Concanavalin A (ConA)-induced hepatitis. After establishing SMS1(-/-) mice, we investigated CD4+ T-cell functions including proliferation, cytokine production and signal transduction in vivo. We also examined severity of hepatitis, cytokine production in serum and liver after ConA injection at a dose of 20 mg kg(-1). CD4+ T cells from SMS1(-/-) mice showed severe deficiency of membrane SM and several profound defects compared with wild-type controls as follows: (i) cellular proliferation and production of IL-2 and IFN-γ by co-cross-linking of CD3 and CD4; (ii) tyrosine phosphorylation of LAT and its association with ZAP-70; (iii) clustering and co-localization of TCR with lipid rafts. Consistent with these impaired CD4+ T-cell functions in vitro, SMS1(-/-) mice showed decreased serum levels of IL-6 and IFN-γ by ConA injection, which renders SMS1(-/-) mice less sensitive to ConA-induced hepatitis. These results indicated that the deficiency of membrane SM caused the CD4+ T-cell dysfunction through impaired lipid raft function contributed to protection of ConA-induced liver injury, suggesting that the membrane SM is critical for full T-cell activation both in vitro and in vivo.

Prevention of fasting-mediated bone marrow atrophy by leptin administration.

Leptin is an adipokine that regulates body weight. In the current study, we demonstrate that continuous injection of leptin prevents the lymphocyte reduction observed in fasted mice, especially the immature B cell populations in the bone marrow. Although leptin administration reduced apoptotic cells in the bone marrow of fasted mice, it did not prevent glucocorticoid-mediated apoptosis in vitro. Bone marrow atrophy has also been shown in the leptin receptor-deficient db/db mice. In order to investigate the mechanisms underlying these processes, we transplanted bone marrow cells from db/db or control (+m/+m) mice into C.B-17/lcr-scid/scid mice. We found that the spleen and bone marrow B cell populations were completely reconstituted when db/db and +m/+m cells were transplanted into scid mice. Our findings suggest that direct interactions between leptin and bone marrow cells are not essential for the development of B cells in a metabologically normal environment.

Efficacy and safety of bortezomib plus dexamethasone therapy for refractory or relapsed multiple myeloma: once-weekly administration of bortezomib may reduce the incidence of gastrointestinal adverse events.

BACKGROUND: To establish the clinical use of bortezomib with fewer adverse events, we retrospectively analyzed the efficacy and safety of bortezomib plus dexamethasone (BD) therapy for relapsed or refractory multiple myeloma. PATIENTS AND METHODS: Patients received bortezomib (1.3 mg/m2) as an intravenous bolus on days 1, 4, 8 and 11 in a 3-week cycle (twice-weekly administration), or on days 1, 8, 15 and 22 in a 5-week cycle (once-weekly administration). Dexamethasone (20 mg) was given on the day of and day after bortezomib treatment. RESULTS: From January 2007 to July 2010, 22 patients began to receive BD therapy. Initially, bortezomib was administered twice-weekly, but some severe adverse events developed; therefore, from January 2008, bortezomib was administered twice-weekly for the first two courses, followed by once-weekly for the subsequent courses. Patients who were expected to have severe adverse events beforehand were treated initially with once-weekly administration. Of the 22 patients, 14 were treated with twice-weekly followed by once-weekly administration, five with only twice-weekly administration and three with only once-weekly administration. Seventeen patients (77.3%) achieved at least partial response, including three with complete response and seven with very good partial response. The median progression-free survival and the median overall survival of 22 patients were 512 days and not reached, respectively. The median progression-free survival and the median overall survival of 17 patients who received at least one course of once-weekly administration were 615 days and not reached, respectively. The most frequent ≥grade 3 adverse events with twice-weekly administration were gastrointestinal, especially paralytic ileus and constipation. Among seven patients who developed ≥grade 3 gastrointestinal adverse events with twice-weekly administration, all four patients changed the schedule to once-weekly were able to continue BD therapy. CONCLUSION: Once-weekly administration of bortezomib in BD therapy may reduce the incidence of gastrointestinal adverse events without reducing the clinical efficacy of this therapy for refractory or relapsed multiple myeloma.

Iron chelation therapy with deferasirox induced complete remission in a patient with chemotherapy-resistant acute monocytic leukemia.

BACKGROUND: A patient with chemotherapy-resistant acute monocytic leukemia who achieved complete remission (CR) after iron chelation therapy (ICT) with deferasirox is reported for the first time. A 73-year-old Japanese man with acute monocytic leukemia who was refractory to conventional remission induction chemotherapies achieved a partial response, with some improvement of his hemoglobin level and white blood cell count after gemtuzumab ozogamicin (GO) treatment. Seven months after GO treatment, the disease relapsed and the patient developed pancytopenia. He declined further chemotherapy, and started receiving 1,200-1,800 ml of packed red blood cell transfusion per month together with ICT with deferasirox (baseline serum ferritin level was 1,412 ng/ml). Twelve months after the initiation of deferasirox, the patient's serum ferritin level decreased to below 1,000 ng/ml and deferasirox was discontinued. Four months after discontinuation of deferasirox, the blood cell count normalized and the patient became transfusion-independent. Bone marrow aspiration and biopsy revealed hematological and cytogenetic CR. CONCLUSION: CR was achieved after ICT with deferasirox in a patient with acute myelogenous leukemia, suggesting that deferasirox may have an antileukemic effect in the clinical setting.

High-dose methotrexate with R-CHOP therapy for the treatment of patients with primary central nervous system lymphoma.

We describe MR-CHOP therapy, a novel treatment regimen consisting of high-dose methotrexate and R-CHOP that provides systemic anti-tumor activity with penetration of the blood-brain barrier in patients with newly diagnosed primary central nervous system lymphoma. The MR-CHOP regimen was administered with 2 g/m(2) of methotrexate and 375 mg/m(2) of rituximab on day 1, 750 mg/m(2) of cyclophosphamide on day 3, 50 mg/m(2) of doxorubicin on day 3, 1.4 mg/m(2) of vincristine on day 3 and 100 mg of prednisolone on days 1-5 in this pilot study of seven patients. Six cycles of MR-CHOP therapy were administered every 3 weeks, followed by high-dose chemotherapy with stem cell rescue in young patients, or an additional two cycles of 4 g/m(2) methotrexate and rituximab in older patients. The overall response rate was 100%, with 85.7% complete remission (CR). One patient showed partial response, relapsed and subsequently died. Another relapsed following CR, and was rescued by further salvage therapy. The others survive without relapse at a median observation period of 24 months. Hematological toxicity included grade 4 leukocytopenia in 4/7 and neutropenia in 5/7, which were transient and tolerated well. Non-hematological toxicities were tolerated well. The efficacy of this novel regimen as remission induction therapy was found to be promising in this pilot study, although the number of patients was small and follow-up short.

[Intravascular large B-cell lymphoma: an important cause of fever of unknown origin].

Intravascular large B-cell lymphoma (IVLBCL) is an important cause of fever of unknown origin (FUO) and multiple organ failure (MOF). Earlier, most IVLBCL cases were diagnosed only postmortem; however, now, it is possible to diagnose and treat these cases antemortem. Although hematogeneous dissemination of malignant tumor cells except lymphoma is beyond the scope of present treatment regimens, IVLBCL (hematogeneous dissemination of lymphoma) can be treated by chemotherapy so correct diagnosis is important. The onset and clinical course of IVLBCL is heterogeneous. Many IVLBCL cases show rapid deterioration, but some have a relatively indolent early period that transforms to rapid progression later. Leukemic appearance is not uncommon. It is difficult to distinguish between IVLBCL and lymphomas originating from extra-nodular organs with systemic dissemination into extra-nodular organs. Minimally invasive and highly sensitive procedures are required for its accurate diagnosis: bone marrow aspiration and biopsy, and random skin biopsy are recommended. If IVLBCL is suspected, to achieve the correct diagnosis, we should avoid glucocorticoid therapy before a biopsy is obtained, even in serious cases. IVLBCL shows remarkable response to treatment with rituximab-containing chemotherapy (R-CHOP). Delayed administration of rituximab and reduced dose of chemotherapy on the first course may be initially indicated in elderly, poor performance status or cases with high tumor burden. High-dose chemotherapy with autologous hematopoietic stem cell rescue should be considered, if possible. Aggressive combination therapy with high dose methotrexate is a recent idea because of central nervous system involvement, or relapse is common and there is poor prognosis.

Associations between salivary gland histopathologic diagnoses and phenotypic features of Sjögren's syndrome among 1,726 registry participants.

OBJECTIVE: To examine associations between labial salivary gland (LSG) histopathology and other phenotypic features of Sjögren's syndrome (SS). METHODS: The database of the Sjögren's International Collaborative Clinical Alliance (SICCA), a registry of patients with symptoms of possible SS as well as those with obvious disease, was used for the present study. LSG biopsy specimens from SICCA participants were subjected to protocol-directed histopathologic assessments. Among the 1,726 LSG specimens exhibiting any pattern of sialadenitis, we compared biopsy diagnoses against concurrent salivary, ocular, and serologic features. RESULTS: LSG specimens included 61% with focal lymphocytic sialadenitis (FLS; 69% of which had focus scores of ≥1 per 4 mm²) and 37% with nonspecific or sclerosing chronic sialadenitis (NS/SCS). Focus scores of ≥1 were strongly associated with serum anti-SSA/SSB positivity, rheumatoid factor, and the ocular component of SS, but not with symptoms of dry mouth or dry eyes. Those with positive anti-SSA/SSB were 9 times (95% confidence interval [95% CI] 7.4-11.9) more likely to have a focus score of ≥1 than were those without anti-SSA/SSB, and those with an unstimulated whole salivary flow rate of <0.1 ml/minute were 2 times (95% CI 1.7-2.8) more likely to have a focus score of ≥1 than were those with a higher flow rate, after controlling for other phenotypic features of SS. CONCLUSION: Distinguishing FLS from NS/SCS is essential in assessing LSG biopsies, before determining focus score. A diagnosis of FLS with a focus score of ≥1 per 4 mm², as compared to FLS with a focus score of <1 or NS/SCS, is strongly associated with the ocular and serologic components of SS and reflects SS autoimmunity.

Synergistic effects of topoisomerase I inhibitor, SN38, on Fas-mediated apoptosis.

Inhibitors of topoisomerase I, such as camptothecin, have proven to be among the most promising new classes of anti-neoplastic agents introduced into the clinical setting in recent years. Irinotecan (CPT-11) is one of the most widely used camptothecin analogs and is converted to form the active metabolite SN-38. The present study was designed to explore apoptosis induced by SN38 and anti-Fas antibody (CH11) in WR/Fas-SMS1 cells and its possible mechanisms. The results demonstrate that combination of SN38 and CH11 synergistically enhanced cell apoptosis in WR/Fas-SMS1 cells. Western blotting analysis showed that combination of SN38 and CH11 activated the ATM-Chk1-p53 pathway, increased protein expression of phospho-p53 and cleavaged caspase-3, but down-regulated expression of phospho-p21. Our data suggest that combination of SN38 and CH11 enhanced apoptosis through down-regulation of p21 phosphorylation. In conclusion, inhibition of p21 could be a new adjuvant approach in cancer therapy.

Complete response obtained by bortezomib plus dexamethasone in a patient with relapsed multiple myeloma with multiple plasmacytomas.

BACKGROUND: A case of relapsed multiple myeloma (MM) with multiple plasmacytomas of the parietal bone and the right orbit in which was achieved a complete response with bortezomib plus dexamethasone (BD) therapy is reported. A Japanese woman with Bench-Jones lambda-type MM who achieved a plateau phase with nine courses of melphalan plus prednisolone therapy complained of right exophthalmos and numbness around her mouth. Computed tomographic (CT) scan and T2-weighted magnetic resonance imaging showed tumours at the parietal bone and the right orbit. A tumour biopsy from the parietal bone revealed the histological morphology of a plasmacytoma. She was therefore diagnosed with relapsed MM with multiple plasmacytomas, and received BD therapy. A CT scan after the end of the second course of treatment revealed the disappearance of the plasmacytomas. At the end of the fifth course, no lambda light chain was detected by immunofixation of serum and urine, and the pathological plasma cells in bone marrow were fewer than 5%; therefore, she had achieved a complete response. The time to disease progression from the first course of BD therapy and the treatment-free interval were 400 days and 134 days, respectively. CONCLUSION: This case report indicates that bortezomib may be a promising agent for MM with multiple plasmacytomas.

DIP2 disco-interacting protein 2 homolog A (Drosophila) is a candidate receptor for follistatin-related protein/follistatin-like 1--analysis of their binding with TGF-ß superfamily proteins.

Follistatin-related protein (FRP)/follistatin-like 1 (FSTL1) is a member of the follistatin protein family, all of which share a characteristic structure unit found in follistatin, called the FS domain. Developmental studies have suggested that FRP regulates organ tissue formation in embryos. Immunological studies showed that FRP modifies joint inflammation in arthritic disease, and modulates allograft tolerance. However, the principle physiological function of FRP is currently unknown. To address this issue, we cloned four FRP-associated proteins using a two-hybrid cloning method: disco-interacting protein 2 homolog A from Drosophila (DIP2A), CD14, glypican 1 and titin. Only DIP2A was expected to be a membrane receptor protein with intracellular regions. Over-expression of FLAG epitope-tagged DIP2A augmented the suppressive effect of FRP on FBJ murine osteosarcoma viral oncogene homolog (FOS) expression, and the Fab fragment of IgG to FLAG blocked this effect. Knockdown of Dip2a leaded to Fos gene up-regulation, and this was not affected by exogenous FRP. These in vitro experiments confirmed that DIP2A could be a cell-surface receptor protein and mediate a FOS down-regulation signal of FRP. Moreover, molecular interaction analyses using Biacore demonstrated that FRP bound to DIP2A and CD14, and also with proteins of the TGF-ß superfamily, i.e. activin, TGF-ß, bone morphogenetic protein 2/4 (BMP-2/4), their receptors and follistatin. FRP binding to DIP2A was blocked by CD14, follistatin, activin and BMP-2. FRP blocked the ligand-receptor binding of activin and BMP-2, but integrated itself with that of BMP-4. This multi-specific binding may reflect the broad physiological activity of FRP.