Randomized study of orally administered fluorinated pyrimidines (capecitabine versus S-1) in women with metastatic or recurrent breast cancer: Japan Breast Cancer Research Network 05 Trial.

PURPOSE: Capecitabine and S-1 are orally administered fluorinated pyrimidines with high-level activity against metastatic breast cancer (MBC). This randomized, multicenter, phase II study compared the activities and safeties of the oral fluoropyrimidines, capecitabine and S-1, in breast cancer patients. METHODS: Patients with MBC were randomly assigned to receive capecitabine 825 g/m(2) twice daily on days 1-21 every 4 weeks or S-1 40-60 mg twice daily, according to body surface area, on days 1-28 every 6 weeks. The primary endpoint was progression-free survival (PFS). RESULTS: A total of 142 patients were enrolled and randomized to either capecitabine (N = 73) or S-1 (N = 69). Median PFS (progression-free survival) was 1.2 years for capecitabine and 1.3 years for S-1, with a hazard ratio (S-1/capecitabine) of 0.85 (95 % confidence interval [CI] 0.52-1.38) (P = 0.48 by log-rank). The confirmed objective response rates were 24.0 % for capecitabine and 23.1 % for S-1 (P = 0.938). The most common treatment-related adverse events were grade 1-2 in intensity. Thrombocytopenia (S-1: 9.2 %, capecitabine: 1.4 %; P = 0.040) and nausea (S-1: 26.2 %, capecitabine: 14.1 %; P = 0.079) were more frequent in the S-1 group, while hand-foot syndrome occurred more often in the capecitabine group (S-1: 10.8 %, capecitabine: 25.4 %; P = 0.029). CONCLUSIONS: The results of the current study demonstrate that both S-1 and capecitabine are effective and well-tolerated treatments in patients with MBC, while their adverse events were different. They are both convenient, orally administered drugs, making them attractive agents for use in outpatient treatment.

Phase II trial of preoperative chemotherapy for breast cancer: Japan Breast Cancer Research Network (JBCRN)-02 trial.

BACKGROUND: Neoadjuvant chemotherapy (NAC) is one of the main strategies for patients with locally advanced breast cancer. In our previous study, biological markers such as estrogen receptor (ER), progesterone receptor (PgR), and HER2 were essential predictors of the effectiveness of NAC to help individualize treatment. This study examined the effect of NAC on the disease-free survival (DFS) of breast cancer patients. Furthermore, the study was expanded by adding Ki-67 as a biological marker, and examined the correlation between Ki-67 and the prognosis. PATIENTS AND METHODS: Between September 2005 and September 2007, 43 patients with breast cancer received NAC and surgery. Four cycles of DC (doxorubicin: 60 mg/m(2) and cyclophosphamide: 500 mg/m(2)) were administered intravenously (i.v.) on day 1 every 21 days, followed by 12 cycles of paclitaxel i.v. (80 mg/m(2)) every 7 days, prior to surgery. The primary endpoint was the pathological complete response (pCR) rate and the secondary endpoint was DFS; the pCR rate was estimated for each groups stratified by the presence or absence of different factors (PcR, ER/PgR, and Ki-67). RESULTS: The clinical response (cCR+cPR) rate was 81.0%, and the pCR rate was 25.6%. The pCR rate was 75, 50, 9 and 0% in HER2(+)/ER(-), HER2(+)/ER(+), HER2(-)/ER(-), and HER2(-)/ER(+) patients, respectively. The 4-year DFS rate was estimated at 78% for all patients. The HER2 status was an independent predictor of pathological complete response (pCR). The DFS rate of patients with lower Ki-67 values (<15%) was higher than that of patients with higher Ki-67 values (≥15%). The treatment-related adverse events were manageable: the majority were mild, but five patients experienced grade 3 (neutropenia and sensory neuropathy) adverse events. CONCLUSION: DC followed by weekly paclitaxel is an active and manageable preoperative regimen for breast cancer patients. HER2 overexpression may be a good predictive marker of pCR, and the Ki-67 value after NAC may be a prognostic factor for DFS.

Efficacy of S-1 in patients with capecitabine-resistant breast cancer-Japan Breast Cancer Research Network (JBCRN) 04-1 trial.

BACKGROUND: S-1 is an orally administered fluorinated pyrimidine with high activity in metastatic breast carcinoma (MBC) and in chemotherapy-pretreated metastatic breast carcinoma. PATIENTS AND METHODS: Forty patients with MBC who did not respond to capecitabine-based chemo-therapy and then received S-1 were identified from our data base of records between 2006 and 2008. The clinico-pathological data and outcomes of these patients were then reviewed. RESULTS: The overall response rate was 27.8%. The median survival was 19.2 months, and the median time to disease progression was 6.2 months. The most common treatment-related adverse events (all grades) were hand-foot syndrome (15%), nausea (15%), vomiting (7.5%), disorder of taste (7.5%), and diarrhea (5%). However, the majority were mild to moderate in intensity, and only one patient experienced grade 3 (according to the National Cancer Institute of Canada Common Toxicity criteria) adverse events. Myelosuppression and alopecia were rare, and there were no reported treatment-related deaths. CONCLUSION: The results of the current study demonstrate that S-1 is an effective and well-tolerated treatment in patients with capecitabine-resistant MBC. In addition, it is a convenient, orally administered drug, which makes it an attractive agent for use in outpatient treatment.

Inter-rater reliability of proxy simple symptom assessment scale between physician and nurse: a hospital-based palliative care team setting.

Symptom management in palliative care requires reliable symptom assessment. We assessed the inter-rater reliability of a simple proxy symptom-assessment scale using the Japanese version of the Support Team Assessment Schedule (STAS-J) in a hospital-based palliative care team (HPCT) setting. By doing this, we assessed symptoms in a series of consecutive patients at two university hospitals with certified HPCTs within 2 days of referral and 7 days after. A physician and nurse assessed 20 symptoms. In total, 120 patients were assessed within 2 days of referral and 92 patients at 7 days after referral. As a result, we find that the intra-class correlation coefficients were 0.02-0.89 at referral and 0.20-0.92 at 7 days after. The perfect concordance rates were 37-89% at referral and 53-96% at 7 days after. The perfect or +/-1 concordance rates were 71-97% at referral and 73-100% at 7 days after. In conclusion, the symptom item of the STAS-J had high inter-rater reliability.

Nonresectable hepatocellular carcinoma: improved percutaneous ethanol injection therapy guided by CO(2)-enhanced sonography.

OBJECTIVE: The purpose of our study was to evaluate the usefulness of percutaneous ethanol installation using CO(2)-enhanced sonography for patients with nonresectable hepatocellular carcinoma (HCC). SUBJECTS AND METHODS: Forty-six patients with 65 HCC lesions were examined with contrast-enhanced sonography with direct injection of CO(2) into the proper hepatic artery during arteriography. We performed percutaneous ethanol injection guided by CO(2)-enhanced sonography for the treatment of hypervascular HCC lesions that could not be treated with conventional percutaneous ethanol injection or with transcatheter arterial embolization. RESULTS: CO(2)-enhanced sonography detected five additional small HCC lesions before treatment (p<0.05) and 14 new lesions during follow-up (p<0.01), than conventional sonography detected. CO(2)-enhanced sonography showed positive enhancement of residual lesions after initial treatment (n = 3) and incomplete local treatment (n = 5) that were not detected on conventional sonography. These 27 lesions were successfully treated with percutaneous ethanol injection using a mixture of iodized oil and ethanol and guided by CO(2)-enhanced sonography. CONCLUSION: CO(2)-enhanced sonography is a sensitive method for detecting residual viable lesions and small new HCC lesions that cannot be detected with conventional sonography. Percutaneous ethanol injection guided by CO(2)-enhanced sonography can treat hypervascular HCC lesions that cannot be treated with conventional percutaneous ethanol injection or transcatheter arterial embolization.

[Nontuberculous atypical mycobacterial infection with progressive pancytopenia in a patient with myelodysplastic syndrome].

We describe a patient with myelodysplastic syndrome (MDS) who developed disseminated infection due to nontuberculous mycobacteria (NTM). A 64-year-old man was admitted because of persistent fever that had been unresponsive to antibiotics. Bone marrow aspiration specimens showed myelodysplasia (RA), but the origin of the fever was unclear. Cytopenia worsened to a level that required transfusion of red blood cells and platelets. Repeated bone marrow examination revealed hypoplasia with hemophagocytosis. Several weeks later, photochromogenic NTM was isolated from bone marrow specimens, sputum and broncho-alveolar lavage (BAL) fluid which had been obtained on admission. Antituberculosis treatment with clarithromycin markedly improved the patient's general condition and hematological abnormalities. Three months after resolution of the NTM infection, the peripheral blood monocyte count increased, the fever recurred, and the patient suddenly died of myocardial infarction. Disseminated infection with NTM has gained attention as a frequent complication of AIDS, and NTM can also be one of the pathogens causing disseminated infection in patients with MDS. In the present case, infection with mycobacteria that normally would have been digested by macrophages and would not have caused disseminated infection in a healthy individual, was probably related to the clinical features including high fever, severe pancytopenia and hemophagocytosis.

Intestinal perforation due to metastasis of breast carcinoma, with special reference to chemotherapy: a case report.

We report a case of small-bowel perforation due to metastatic carcinoma of the breast during chemotherapy. Partial resection of the small intestine and primary anastomosis were performed. Although the patient made a good recovery from panperitonitis, she died of the disease on the 55th postoperative day. Since perforation during chemotherapy results in an extremely poor prognosis, special caution during chemotherapy is needed for patients with possible gastrointestinal involvement with tumor.

MEK and p38MAPK inhibitors potentiate TNF-alpha induced apoptosis in U937 cells.

BACKGROUND: TNF-alpha is one of the key inflammatory cytokines and it modulates various events through several pathways. U937 myelomonocytic leukemia cells are sensitive to TNF-alpha and about 20% of these cells undergo apoptosis within 6 hours after treatment. Co-treatment of these cells with actinomycin D or cycloheximide enhances TNF-alpha induced apoptosis, suggesting that some TNF-alpha-derived signals can augment apoptosis. We investigated whether mitosis-activating protein kinases (MAPKs) had an influence on TNF-alpha induced apoptosis. MATERIALS AND METHODS: U937 cells were treated by TNF-alpha with or without MEK or p38MAPK inhibitors. Apoptosis was assessed morphologically by fluorescence microscopy and caspase-3 was studied by immunoblotting. Expression of apoptosis-inhibitory proteins was studied by RT-PCR whilst the activation of JNKs was investigated by detecting their phosphorylation. RESULTS: TNF-alpha treatment induced apoptosis in about 23% of the cells, while pretreatment with a MEK inhibitor (PD98059) caused 69% of the cells to undergo apoptosis. The inhibition of p38MAPK by SB203580 scarcely enhanced apoptosis, although another p38MAPK inhibitor (PD169316) induced apoptosis in 37% of the cells. Simultaneous pretreatment of cells with PD98059 and PD169316 resulted in the highest level of TNF-alpha induced apoptosis and 90% of the cells underwent apoptosis after 6 hours. In cells pretreated with PD98059 plus PD169316, caspase-3 was completely cleaved at 6 hours and early induction of c-IAP2/HIAP 1 mRNA was not observed. JNKs showed rapid and extensive phosphorylation in these cells. CONCLUSION: TNF-alpha induced apoptosis was potentiated by the inhibition of either MEK alone, or MEK plus p38MAPK, suggesting that the MAPK pathway may be a promising target for cancer therapy.

Contrast-enhanced, wide-band harmonic gray scale imaging of hepatocellular carcinoma: correlation with helical computed tomographic findings.

We evaluated the usefulness of contrast-enhanced, wide-band harmonic gray scale imaging for the diagnosis of hepatocellular carcinoma and compared it with helical computed tomography. Forty-eight patients with 61 hepatocellular carcinoma lesions were scanned by contrast-enhanced, wide-band harmonic gray scale imaging after an intravenous bolus injection of the contrast agent Levovist. Fifty-seven of the 61 hepatocellular carcinoma lesions showed hypervascular enhancement, and intratumoral vessels could be observed in 40 of the 57 lesions. Helical computed tomography revealed a high-attenuation area in 54 of the 61 lesions, whereas the other lesions showed an equivocal-attenuation area. Contrast-enhanced, wide-band harmonic gray scale imaging is a useful method for diagnosing the vascularity of hepatocellular carcinoma.

Concentration-dependent variable effects of etoposide on the cell cycle of CML cells.

BACKGROUND: Etoposide, a DNA-topoisomerase II inhibitor, is used for a broad spectrum of cancers with various therapeutic strategies. But the molecular mechanisms of its concentration-dependent effects are not clearly defined. MATERIALS AND METHODS: Chronic myelogenous leukemia K562 cells were treated with low (5 microM) or high (100 microM) concentrations of this drug and the changes of cell cycle progression, expression of cell cycle regulating genes and cyclin B1-dependent histone H1 kinase activity were studied. RESULTS: In the presence of 5 microM etoposide, K562 cells continued to synthesize DNA and most cells showed progress into G2 phase until 24 hours. In contrast, 100 microM etoposide rapidly inhibited DNA synthesis by around 6 hours and most cells remained in their initial phase, while the incorporation of bromodeoxyuridine was partially resumed from 12 hours. The histone H1 kinase activity was only down-regulated in the early phase of 100 microM treated cells. Among the cell cycle controlling genes, c-Myc and P21Cip1/WAF1 showed impressive responses to the two etoposide concentrations. At 100 microM, c-Myc protein rapidly vanished at 3 hours, while p21Cip1/WAF1 was inversely induced from 3 hours. These changes were also observed at 5 microM, but they occurred slowly and weakly. CONCLUSION: The present findings indicate that two concentrations of etoposide functioned as an anticancer agent through modulating the genes related in cell cycle progression. Differing responses of c-Myc and p21Cip1/WAF1 at two concentrations may govern the antiproliferative effects of etoposide.

Lineage-specific regulation of cell cycle control gene expression during haematopoietic cell differentiation.

To maintain the fidelity and integrity of blood formation, the cell cycle is under strict regulation during haematopoietic cell differentiation. To elucidate the molecular mechanisms of cell cycle regulation during haematopoiesis, we examined cell cycle control gene expression during lineage-specific differentiation from CD34+ progenitor cells. Expression of cyclin-dependent kinases (cdks) and cyclins, except cdk4, was generally suppressed in CD34+ cells freshly isolated from the bone marrow of healthy volunteers. Among four major cdk inhibitors, p16 was expressed more highly in CD34+ cells than in CD34-negative bone marrow mononuclear cells, whereas the amounts of p21 and p27 transcripts increased in the CD34- population. The behaviour of cell cycle control genes during haematopoietic differentiation was classified into four patterns: (i) universal upregulation (cdc2, cdk2, cyclin A, cyclin B and p21); (ii) upregulation in specific lineages (cyclin D1, cyclin D3 and p15); (iii) no induction or stable expression (cdk4, cyclin D2, cyclin E and p27); and (iv) universal downregulation (p16). Lineage-specific changes included the sustained elevation of cdc2 and cyclin A during erythroid differentiation, cyclin D1 and p15 induction in myeloid lineage and selective upregulation of cyclin D3 in megakaryocytes. Blocking induction of cyclin D3 resulted in the inhibition of megakaryocytic differentiation. These results suggest that the expression of cell cycle control genes is distinctively regulated in a lineage-dependent manner, reflecting the cell cycle characteristics of each lineage. Some of these genes play an essential role in the process of differentiation itself.

Comparison of anti-tumor responses against TL positive lymphoma induced by skin grafting and dendritic cell immunization.

When the skin of Tg.Con.3-1 transgenic mice expressing the TL (thymus leukemia) antigen in most tissues is grafted on syngeneic C3H mice, it is rejected, and a cytotoxic T cell (CTL) response against the TL antigen is induced. In this study, we first demonstrated that growth of TL positive lymphoma is suppressed in mice immunized by skin grafting. Immunization with bone marrow derived dendritic cells (DCs) from Tg.Con.3-1, was also found to be associated with an anti-tumor response, but less potent than skin grafting. Relative CTL precursor frequency with DC immunization was also approximately only one third that of skin grafting. The numbers of IFN-gamma producing cells in responder CD8 and CD4 T cell populations were higher with DC immunization than with skin grafting. However, DC immunization seems to induce non-specific immune responses, as re-stimulation with TL negative C3H spleen cells resulted in induction of almost half the number observed with TL positive cells. Thus, the actual number of IFN-gamma producing cells in specific responses to TL is not necessarily larger than with skin grafting immunization. The present results altogether suggest that DC immunization is capable of inducing an anti-tumor reaction, but also possibly unwanted immune responses. In vitro monitoring of specific and non-specific responses in the immune system, thus, is of particular importance for future development of cancer immunotherapy.

The epitope detected by cytotoxic T lymphocytes against thymus leukemia (TL) antigen is TAP independent.

Thymus leukemia (TL) antigens belong to the family of MHC class Ib antigens. We have shown in our previous studies that they serve as transplantation antigens, and can be recognized by both TCR alpha beta and TCR gamma delta cytotoxic T lymphocytes (CTL) with TL but not H-2 restriction. Although TL are known to be expressed TAP independently, it is unclear whether peptide loading on TL molecules is necessary for the formation of CTL epitopes. In the present study, we first showed that TL expression is beta(2)-microglobulin (beta(2)m)-dependent but TAP1 independent by flow cytometric analysis of thymocytes from beta(2)m- or TAP1-deficient mice crossed with TL transgenic mice expressing Tla(a)-3-TL on their thymocytes. Subsequently, we investigated the epitope recognized by CTL derived from C3H mice immunized with skin from a transgenic mouse expressing T3(b)-TL ubiquitously. Bulk CTL lines against TL from primary mixed lymphocyte cultures showed comparable cytotoxicity against T3(b)-TL transfectants of TAP2-deficient murine RMA-S grown at 37 degrees C to that against those grown at 25 degrees C. Furthermore, TCR alpha beta and TCR gamma delta CTL clones against TL recognized TL expressed on T3(b)-TL transfectants of RMA-S and Drosophila melanogaster cells having broad defects in peptide loading of MHC, and lysed these target cells. These results together indicate that TL-specific CTL populations primarily recognize epitopes expressed TAP independently.

Murine Delta homologue, mDelta1, expressed on feeder cells controls cellular differentiation.

The Delta/Serrate-Notch pathway is involved in intercellular signaling that controls cell fate during the development of invertebrates and vertebrates. Delta is a prototype of Notch ligands and has been studied extensively in Drosophila. In higher vertebrates, four Delta/Serrate homologues and four Notch homologues have been identified. Recent studies showed that the murine Delta homologue, mDelta1, is essential in early embryogenesis. The biological activity of mammalian Delta and its roles in cellular differentiation, however, have remained unclear. In this study, we first surveyed expression of mDelta1 in the adult mouse and found it to be present in a wide range of tissues. For testing biological activity of mDelta1, we expressed a mDelta1 full-length cDNA in L cells using a eukaryotic expression vector. Effects of mDelta1 on cellular differentiation were examined in two independent systems, featuring C2C12 myogenic differentiation and multipotent murine bone marrow cell differentiation. Inhibition of the former was observed with mDelta1 expression on L cells, associated with suppression of myogenin, a myogenic transcription factor. Expression of mDelta1 in conjunction with GM-CSF promoted differentiation of bone marrow cells to myeloid dendritic cells at the expense of other lineages. Although the effects of mDelta1 on two differentiation systems appeared opposing, as inhibition occurring in one and induction in the other, this can be understood by the unifying concept of generation of diverse cell types from equivalent progenitors. Thus, the present study provided evidence that mammalian Delta participates in intercellular signaling, determining the cell fate in a wide variety of tissues.

Phosphorylation of Bcl-2 protein by CDC2 kinase during G2/M phases and its role in cell cycle regulation.

Although it has been reported that Bcl-2 phosphorylation is associated with certain types of apoptosis, there is much controversy over the functional significance of and the kinases responsible for the phosphorylation. In this study, we examined whether Bcl-2 is phosphorylated by CDC2 kinase, a master regulator of G(2)/M transition in the eukaryotic cell cycle. When CDC2 was activated by okadaic acid in HL-60 cells, Bcl-2 phosphorylation was readily induced. The phosphorylation was correlated with the accumulation of cells in G(2)/M phases, but was not proportional to the level of apoptosis. Furthermore, we found that Bcl-2 was phosphorylated during G(2)/M phases of normal cell cycle. The ability of CDC2 to phosphorylate Bcl-2 was confirmed by in vitro kinase assay with a highly purified CDC2-cyclin B complex. Using synthetic peptides and mutant cell lines, we identified threonine 56, one of two consensus sites for CDC2 within the Bcl-2 sequence, as a residue phosphorylated by CDC2. Mutation at threonine 56 abrogated the cell cycle inhibitory effect of Bcl-2 without affecting anti-apoptotic function. These results suggest that two distinct functions of Bcl-2 (anti-apoptosis and cell cycle inhibition) are differentially regulated by post-translational mechanisms such as phosphorylation. CDC2-mediated phosphorylation of Bcl-2 may play some physiological roles in the negative regulatory events during mitosis.

[Disseminated MALT lymphoma associated with macroglobulinemia].

We report a case of disseminated MALT lymphoma with macroglobulinemia in an 80-year-old man who presented with a persistent fever. A radiograph of the chest showed infiltration of the left lung and pleural effusion of the right lung. The fluid contained numerous atypical lymphoid cells, which were positive for CD19, CD20, and HLA-DR, and negative for CD5 and CD10. Analysis of a pleural biopsy sample demonstrated no abnormality. A CT scan of the abdomen showed extensive thickening of the wall of the stomach adjacent to a peritoneal mass. Endoscopic examination disclosed antral ulceration. Histopathological examination of gastric samples revealed infiltration by centrocyte-like cells and lymphoepithelial lesions. Serum electrophoresis detected a macroglobulin peak at 34.5 g/l, and immunoelectrophoresis revealed an IgM kappa component. A bone marrow aspirate showed infiltration by the same lymphoid cells as those in the pleural fluid. A chromosome study of the lymphoid cells from both the bone marrow and pleural fluid showed a normal karyotype. The final diagnosis was MALT lymphoma involving the stomach, lungs and bone marrow. The patient did not consent to chemotherapy, and instead was given oral prednisolone. He died of respiratory distress one year and four months after diagnosis. Autopsy revealed wide dissemination of the tumor cells.

Interferon-alpha repressed telomerase along with G1-accumulation of Daudi cells.

The implications of telomerase on senescence and human carcinogenesis are widely accepted, but the changes of telomerase activity along with cell cycle modulation by anticancer treatment still remain obscure. In this paper, we issued whether the telomerase activity fluctuated along with cell cycle of cultured cancer cells using the antiproliferative effect of interferon-alpha (IFN-alpha). Daudi Burkitt lymphoma cells, treated with IFN-alpha, showed proliferation inhibition and cell cycle arrest at G1. The telomerase activity at 72 h was repressed to about 20% of control cells. Furthermore, after 72 h IFN-alpha treatment, the cells in G1 phase showed the marked decrease of telomerase activity, while cells in S and G2/M still possessed it. Among expressions of telomerase-related genes, only the catalytic subunit of telomerase (hTERT) decreased from 48 h, while the template RNA component (hTERC) and telomerase-associated protein 1 (TEP-1) were not affected. The downregulation of c-Myc preceded the change of hTERT. Moreover, the analysis of cells treated with IFN-alpha for 24 h revealed that cells in G1-to-S transition mainly expressed high hTERT, while S and G2/M cells had higher level of telomerase activity than that of G1 cells. These results indicate that (i) the expression of hTERT precedes the telomerase activity which is higher in S and G2/M phases than G1 phase, (ii) IFN-alpha repressed the telomerase activity in a cell cycle-dependent manner with the downregulation of hTERT.

Transcriptional repression of the E2F-1 gene by interferon-alpha is mediated through induction of E2F-4/pRB and E2F-4/p130 complexes.

E2F is a heterodimeric transcription factor composed of one of five E2F subunits (E2F-1 to E2F-5) and a DP subunit. E2F regulates the expression of several growth-promoting genes, and thus, can be a target of antiproliferative action of interferons (IFNs). In this study, we investigated the mechanisms whereby IFN-alpha suppresses transcription of the E2F-1 gene. Transfection studies revealed that E2F-1 promoter was functionally divided into two parts: upstream activation sequences (UAS) and a downstream negative-regulatory element (E2F-binding sites). When cells were proliferating, transcription of the E2F-1 gene was primarily driven by the UAS, while E2F sites were not involved in activation. IFN-alpha markedly reduced E2F-1 promoter activity, but introduction of non-binding mutation at the E2F sites completely abrogated the inhibition. Free E2F4 was found to be the predominant species bound to the E2F sites in proliferating cells. IFN-alpha induced upregulation of E2F-4 along with dephosphorylation of pRB and p130, which resulted in the formation of E2F-4/pRB and E2F-4/p130 complexes on the E2F-1 promoter. These complexes function as transcriptional repressors to inhibit E2F-1 mRNA expression. Our findings indicate that E2F-4 is a critical regulator of E2F-1, which offer an excellent paradigm for understanding functional diversity within the E2F family.

[A case of aggressive myeloma with abnormal plasmocytes in pleural effusion and cerebrospinal fluid].

Extramedullary involvement of myelomas is common but invasion of myeloma cells into the pleural cavity and cerebrospinal fluid (CSF) is rare. We report an aggressive case of multiple myelomas (Bence Jones lambda type) with pleural and meningeal infiltration. A 66-year-old man was referred to our hospital because of anemia, thrombocytopenia, and dyspnea. His peripheral blood contained 2% bizarre plasma cells. Bone marrow biopsy specimens and immunoelectrophoresis confirmed the diagnosis. A chest radiograph disclosed pleural effusion in both lungs containing M-protein and numerous abnormal cells. The patient also suffered from disorientation, speech disorder, and muscle weakness. A lumbar puncture revealed atypical plasma cells in CSF. Four courses of chemotherapy (cyclophosphamide, doxorubicin, and prednisolone) and the intrathecal administration of methotrexate and cytarabine at 3-week intervals were effective in decreasing the pleural effusions and eliminating plasma cells from CSF. Nonetheless a chest wall tumor, pelvic mass, and pneumonia developed, and the patient died 5 months after initial presentation. Pleural infiltration of myeloma cells and multiple lesions with plasma cell involvement were discovered at autopsy.