Comparison of the accuracy and characteristics of the prognostic prediction of survival of identical terminally ill cancer patients by oncologists and palliative care physicians.

Most terminally ill cancer patients in our hospice ward are referred from hospitals for anticancer treatment. For identical terminally ill cancer patients referred from other hospitals, differences in the accuracy and characteristics of the prognostic prediction of survival by oncologists and palliative care physicians were examined. We investigated 101 patients and compared the prognostic value between the clinical prediction of survival with oncologists and prognostic tool-conducted prediction by palliative care physicians with the actual survival times; the results were then classified as accurate, pessimistic and optimistic. Prognostic prediction by palliative care physicians was closer to the actual survival time. The number of accurately predicted cases by palliative care physicians was more than that by oncologists, and the number of optimistically predicted cases by oncologists was more than that by palliative care physicians. The palliative care physicians' prediction was more accurate, while the oncologists' prediction was more optimistic.

CCAR1/CoCoA pair-mediated recruitment of the Mediator defines a novel pathway for GATA1 function.

The MED1 subunit of the Mediator transcriptional coregulator complex coactivates GATA1 and induces erythropoiesis. Here, we show the dual mechanism of GATA1- and MED1-mediated transcription. MED1 expression levels in K562 erythroleukemia cells paralleled the levels of GATA1-targeted gene transcription and erythroid differentiation. An N-terminal fragment of MED1, MED1(1-602), which is incapable of interacting with GATA1, enhanced GATA1-targeted gene transcription and erythroid differentiation, and introduction of MED1(1-602) into Med1(-/-) mouse embryonic fibroblasts (MEFs) partially rescued GATA1-mediated transcription. The C-terminal zinc-finger domain of GATA1 interacts with the MED1(1-602)-interacting coactivator CCAR1, CoCoA and MED1(681-715). CCAR1 and CoCoA synergistically enhanced GATA1-mediated transcription from the γ-globin promoter in MEFs. Recombinant GATA1, CCAR1, CoCoA and MED1(1-602) formed a complex in vitro, and GATA1, CCAR1, CoCoA and MED1 were recruited to the γ-globin promoter in K562 cells during erythroid differentiation. Therefore, in addition to the direct interaction between GATA1 and MED1, CoCoA and CCAR1 appear to relay the GATA1 signal to MED1, and multiple modes of the GATA1-MED1 axis may help to fine-tune GATA1 function during GATA1-mediated homeostasis events.

Mediator subunit MED1 is a T3-dependent and T3-independent coactivator on the thyrotropin ß gene promoter.

The MED1 subunit of the Mediator transcriptional coregulator complex is a nuclear receptor-specific coactivator. A negative feedback mechanism of thyroid-stimulating hormone (TSH, or thyrotropin) expression in the thyrotroph in the presence of triiodothyronine (T3) is employed by liganded thyroid hormone receptor ß (TRß) on the TSHß gene promoter, where conventional histone-modifying coactivators act as corepressors. We now provide evidence that MED1 is a ligand-dependent positive cofactor on this promoter. TSHß gene transcription was attenuated in MED1 mutant mice in which the nuclear receptor-binding ability of MED1 was specifically disrupted. MED1 stimulated GATA2- and Pit1-mediated TSHß gene promoter activity in a ligand-independent manner in cultured cells. MED1 also stimulated transcription from the TSHß gene promoter in a T3-dependent manner. The transcription was further enhanced when the T3-dependent corepressors SRC1, SRC2, and HDAC2 were downregulated. Hence, MED1 is a T3-dependent and -independent coactivator on the TSHß gene promoter.

A der(13)t(7;13)(p13;q14) with monoallelic loss of RB1 and D13S319 in myelodysplastic syndrome.

Deletions or translocations of chromosome band 13q14, the locus of the retinoblastoma gene (RB1), have been observed in a variety of hematological malignancies including myelodysplastic syndrome (MDS). We describe here a novel unbalanced translocation der(13)t(7;13)(p13;q14) involving 13q14 in a patient with MDS. A 66-year-old woman was diagnosed as having MDS, refractory anemia with excess of blasts (RAEB-1) because of 7.4% blasts and trilineage dysplasia in the bone marrow cells. G-banding and spectral karyotyping analyses showed complex karyotypes as follows: 46,XX,der(6)t(6;7)(q11;?),der(7)del(7)(?p13)t(6;7)(q?;q11)t(6;13)(q?;q?),der(13)t(7;13)(p13;q14). Fluorescence in situ hybridization (FISH) analyses demonstrated that one allele of the RB1 gene and the microsatellite locus D13S319, located at 13q14 and telomeric to the RB1 gene, was deleted. Considering other reported cases, our results indicate that submicroscopic deletions accompanying 13q14 translocations are recurrent cytogenetic aberrations in MDS. The RB1 gene or another tumor suppressor gene in the vicinity of D13S319, or both, may be involved in the pathogenesis of MDS with 13q14 translocations by monoallelic deletion.

Feasibility of acute physiology and chronic health evaluation (APACHE) II and III score-based screening in patients receiving allogeneic hematopoietic stem-cell transplantation.

Patients who require management in the intensive care unit (ICU) for complications after allogeneic hematopoietic stem-cell transplantation (HSCT) generally have a poor outcome. We retrospectively studied whether the risk-prediction stratification systems commonly used for patients admitted to the ICU, that is, the Acute Physiology and Chronic Health Evaluation (APACHE) II and APACHE III systems, could be useful for identifying patients who should receive intensive care earlier. We reviewed the medical records of 210 patients who underwent allogeneic HSCT and found that 18 (8.6%) had been admitted to the ICU for acute respiratory failure (n=9), acute renal failure (n=7), and septic shock (n=2). The median APACHE II and III scores were, respectively, 16 (10-27) and 55 (22-87) at the onset of complications and 26 (15-43) and 101 (65-157) upon admission to the ICU. Thus, both the APACHE II and APACHE III scores at ICU admission were higher than those at the onset of complications (P <0.0001). Seventeen patients (94%) subsequently died, with a median ICU stay of 7.5 days (1-51 days), as a result of multiorgan failure (n=14), respiratory failure (n=2), and septic shock (n=1). The APACHE II and III scores of the sole surviving patient were, respectively, 21 and 71 at the onset and 24 and 86 upon transfer to the ICU. Thus, the APACHE scores in this study were lower than those reported for other surgical or medical patients treated in the ICU, despite their uniform poor prognosis. Although nine patients had developed grade III to IV acute graft-versus-host disease, which is the most common cause of morbidity and mortality after allogeneic HSCT, this was not fully evaluated in the current scoring systems. Application of these systems to HSCT will require adequate modification, with particular attention to organ dysfunction secondary to graft-versus-host disease.

Morphologic, flow cytometric and cytogenetic evaluation of bone marrow involvement in B-cell lymphoma.

BACKGROUND AND OBJECTIVES: Flow cytometric immunophenotypic analysis (FC) and cytogenetic analysis are essential techniques for the diagnosis and classification of many hematologic disorders. The roles of these analyses in B-cell lymphoma to detect bone marrow (BM) involvement in clinical staging and to evaluate the effectiveness of treatments have not yet been determined. The aim of this study was to evaluate the usefulness of FC and cytogenetic analysis in the assessment of BM involvement in B-cell lymphoma. DESIGN AND METHODS: We retrospectively analyzed the usefulness of three-color FC and cytogenetic analysis in detecting BM involvement by examining 104 BM specimens from patients with B-cell lymphoma. RESULTS: By morphologic evaluation of BM biopsy (BMB), the BM was involved in 11 specimens (10.6%), not involved in 92 specimens (88.5%) and involvement could not be determined in 1 specimen (0.9%). FC identified a monoclonal B-cell population in 24 samples (23.1%). FC detected BM involvement in all but one BMB positive sample, and showed negative results in a BMB undetermined sample. Conclusively, FC found a monoclonal B-cell population in 14 of 92 BMB negative samples (15.2%). In particular, FC detected smaller amounts of BM involvement than did morphologic evaluation. Cytogenetic analysis revealed clonal abnormalities in only 9 of 104 samples (8.7%). However, 2 of these 9 samples were from patients with aggressive lymphoma with complex structural chromosomal abnormalities detectable only by cytogenetic analysis. INTERPRETATION AND CONCLUSIONS: Although morphologic evaluation of adequate amounts of BMB specimens remains essential for the evaluation of BM involvement, three-color FC is more sensitive in detecting BM disease than morphologic or cytogenetic analysis. Cytogenetic analysis seems to have low sensitivity and specificity, but this method may improve the detection of BM involvement in a small number of aggressive lymphomas that have many mitotic cells.

Unbalanced translocation der(11)t(11;12)(q23;q13): a new recurrent cytogenetic aberration in myelodysplastic syndrome with a complex karyotype.

Cytogenetic abnormalities are observed in approximately one half of cases of myelodysplastic syndrome (MDS). Partial or complete chromosome losses and chromosome gains are frequently found, but there is a relatively high incidence of unbalanced translocations in MDS. We describe here two cases of MDS with an unbalanced translocation, der(11)t(11;12)(q23;q13). Both patients were 69 years of age and diagnosed with refractory anemia with excess of blasts in transformation (RAEB-t) according to the high percentage of blasts in the peripheral blood. Cytoplasmic hypogranulation of neutrophils was evident as a dysplastic change. The blasts were positive for CD4 and CD41a as well as CD13, CD33, CD34 and HLA-DR in both cases. Chromosome analysis showed complex karyotypes including a der(11)t(1;11)(q11;p15)t(11;12)(q23;q13) in case 1 and der(11)t(11;12)(q23;q13) in case 2 plus several marker chromosomes. Spectral karyotyping confirmed the der(11)t(11; 12)(q23;q13) and clarified the origin of marker chromosomes, resulting in del(5q) and del(7q). Fluorescence in situ hybridization (FISH) analyses with a probe for the MLL gene demonstrated that the breakpoints at 11q23 were telomeric to the MLL gene in both cases. FISH also showed that the breakpoint at 11p15 of the case 1 was telomeric to the NUP98 gene. Considering another reported case, our results indicate that the der(11)t(11;12)(q23;q13) is a recurrent cytogenetic abnormality and may be involved in the pathogenesis of advanced-stage MDS.

A novel t(2;6)(p12;q23) appearing during transformation of follicular lymphoma with t(18;22)(q21;q11) to diffuse large cell lymphoma.

Follicular lymphoma is characterized genetically by t(14;18)(q32;q21), whereas t(18;22)(q21;q11), a rare variant form of t(14;18), has been preferentially observed in chronic lymphocytic leukemia (CLL). We describe here an unusual case of follicular lymphoma with a t(18;22)(q21;q11), that progressed to diffuse large cell lymphoma with a novel t(2;6)(p12;q23). Spectral karyotyping revealed that add(2)(p12) and add(6)(q23) were derived from a t(2;6)(p12;q23). Fluorescence in situ hybridization analysis confirmed rearrangements of the BCL2 gene at 18q21 and the BCL6 gene at 3q27. Our results indicate that a reciprocal translocation involving 6q23 could be implicated in the progression of follicular lymphoma and that t(18;22) may have a specific role in the pathogenesis of follicular lymphoma as well as CLL.

Effective anti-viral therapy for hemophagocytic syndrome associated with B-cell lymphoma.

A rheumatoid arthritis (RA) patient treated with low-dose methotrexate (MTX) therapy suffered from hemophagocytic syndrome (HPS) associated with B-cell lymphoma (B-LAHS). Administration of acyclovir and intravenous immunoglobulin promptly resolved laboratory test abnormalities accompanied with HPS. Moreover, hemophagocytic histiocytes and lymphoma cells in the bone marrow disappeared without anti-cancer therapy. Two months after reintroduction of MTX for RA flare, lymphoma re-grew rapidly without bone marrow involvement and HPS. Two cycles of combination chemotherapy induced the lymphoma to a complete remission/unconfirmed (CRu), but then the chemotherapy was discontinued due to severe side effects. In this case, on the basis of RA and MTX induced immunosuppressive state, Epstein-Barr virus (EBV) infection was associated with the development of HPS and lymphoma. Anti-viral therapy alone was effective against HPS and lymphoma at initial presentation and improved her general condition. This case indicates that anti-cancer therapy should be preceded by anti-viral therapy and withdrawal of immunosuppressive therapy in patients under immunosuppressive therapy, as long as the clinical situation permits.

Mediator subunits MED1 and MED24 cooperatively contribute to pubertal mammary gland development and growth of breast carcinoma cells.

The Mediator subunit MED1 is essential for mammary gland development and lactation, whose contribution through direct interaction with estrogen receptors (ERs) is restricted to involvement in pubertal mammary gland development and luminal cell differentiation. Here, we provide evidence that the MED24-containing submodule of Mediator functionally communicates specifically with MED1 in pubertal mammary gland development. Mammary glands from MED1/MED24 double heterozygous knockout mice showed profound retardation in ductal branching during puberty, while single haploinsufficient glands developed normally. DNA synthesis of both luminal and basal cells were impaired in double mutant mice, and the expression of ER-targeted genes encoding E2F1 and cyclin D1, which promote progression through the G(1)/S phase of the cell cycle, was attenuated. Luciferase reporter assays employing double mutant mouse embryonic fibroblasts showed selective impairment in ER functions. Various breast carcinoma cell lines expressed abundant amounts of MED1, MED24, and MED30, and attenuated expression of MED1 and MED24 in breast carcinoma cells led to attenuated DNA synthesis and growth. These results indicate functional communications between the MED1 subunit and the MED24-containing submodule that mediate estrogen receptor functions and growth of both normal mammary epithelial cells and breast carcinoma cells.

The transcriptional mediator subunit MED1/TRAP220 in stromal cells is involved in hematopoietic stem/progenitor cell support through osteopontin expression.

MED1/TRAP220, a subunit of the transcriptional Mediator/TRAP complex, is crucial for various biological events through its interaction with distinct activators, such as nuclear receptors and GATA family activators. In hematopoiesis, MED1 plays a pivotal role in optimal nuclear receptor-mediated myelomonopoiesis and GATA-1-induced erythropoiesis. In this study, we present evidence that MED1 in stromal cells is involved in supporting hematopoietic stem and/or progenitor cells (HSPCs) through osteopontin (OPN) expression. We found that the proliferation of bone marrow (BM) cells cocultured with MED1 knockout (Med1(-/-)) mouse embryonic fibroblasts (MEFs) was significantly suppressed compared to the control. Furthermore, the number of long-term culture-initiating cells (LTC-ICs) was attenuated for BM cells cocultured with Med1(-/-) MEFs. The vitamin D receptor (VDR)- and Runx2-mediated expression of OPN, as well as Mediator recruitment to the Opn promoter, was specifically attenuated in the Med1(-/-) MEFs. Addition of OPN to these MEFs restored the growth of cocultured BM cells and the number of LTC-ICs, both of which were attenuated by the addition of the anti-OPN antibody to Med1(+/+) MEFs and to BM stromal cells. Consequently, MED1 in niche appears to play an important role in supporting HSPCs by upregulating VDR- and Runx2-mediated transcription on the Opn promoter.

Smoking and small, dense low-density lipoprotein particles: cross-sectional study.

All forms of tobacco cause cardiovascular disease, and tobacco-related disease is a leading cause of death worldwide. Smoking oxidizes low-density lipoprotein (LDL) particles, and oxidized LDL particles are thought to play an early and critical role in atherosclerogenesis. Hyper-low-density lipoproteinemia is one of the risk factors for cardiovascular disease, but small, dense LDL particles have been associated with an increased risk for cardiovascular disease. Small, dense LDL correlates with some cardiovascular risk factors such as diabetes mellitus, hypertriglyceridemia, hypo-high-density lipoproteinemia, and hypertension. Although smoking is also a major risk factor for cardiovascular disease, the relationship between smoking and small, dense LDL particles has not been described previously. Our cross-sectional study examined this relationship in a population of 18 healthy young adult men (9 smokers and 9 never-smokers, aged 21-24 years) from the same college. Concentrations of blood lipids and the LDL migration index (LDL-MI) were examined. Although concentrations of blood lipids did not differ between smokers and never-smokers, the LDL-MI had a strong tendency to be lower in smokers. The LDL-MI is larger in the presence of a greater proportion of small, dense LDL particles. These results indicate that tobacco smoking is associated with a decrease in the proportion of small, dense LDL particles. Regardless of these surprising results, we do not recommend smoking, given that it is a major cause of cardiovascular disease.

The role of transcriptional coactivator TRAP220 in myelomonocytic differentiation.

The TRAP220 subunit of the thyroid hormone receptor-associated polypeptide transcription coactivator complex (TRAP/Mediator complex), mammalian counterpart of the yeast Mediator complex, is proposed to act on a variety of major and specific biological events through physical interactions with nuclear receptors. The vitamin D receptor (VDR) and retinoic acid receptor (RAR), coupled with retinoid X receptor (RXR), are nuclear receptors which have important roles for monopoiesis and granulopoiesis, respectively. In this study, we present the functional role of TRAP220 in nuclear receptor-mediated monopoiesis and granulopoiesis. The mouse Trap220(-/-) yolk sac hematopoietic progenitor cells were resistant to 1,25-dihydroxyvitamin D(3)-stimulated differentiation into monocytes/macrophages. Furthermore, flow cytometric analyses showed that HL-60 cells, human promyelocytic leukemia cell line, wherein TRAP220 was down-regulated, did not differentiate efficiently into monocytes and granulocytes by stimulation with 1,25-dihydroxyvitamin D(3) and all-trans retinoic acid, correspondingly. The expression of direct target genes of VDR or RAR, as well as the differentiation marker genes, was low in the knockdown cells. These results indicated a crucial role of TRAP220 in the optimal VDR- and RAR-mediated myelomonocytic differentiation processes in mammalian hematopoiesis.

TRALI after the infusion of marrow cells in a patient with acute lymphoblastic leukemia.

BACKGROUND: TRALI is one of the most serious, life-threatening complications after blood transfusion. Antibodies against neutrophils or HLA molecules from the donor are thought to be the primary causative agents. Rarely, antibodies in the recipient may react with transfused neutrophils and initiate the same events, which raises the possibility that TRALI may also occur in an allogeneic PBPC transplantation setting. CASE REPORT: A 30-year-old Japanese man with acute lymphoblastic leukemia developed TRALI immediately after the infusion of marrow cells from an unrelated donor. The infusion was suspended, and he gradually improved after receiving steroids and oxygen support. The next day, the remaining cells, which were separated to MNCs, were infused with no reactions. He then recovered over 5 days without the use of mechanical ventilation. RESULTS: Laboratory evaluation disclosed the presence of antibodies to neutrophils in his sera sampled after transplantation, but not in the donor's marrow graft. Hence, antibodies to neutrophils in the recipient may have reacted with neutrophils in the graft and contributed to the development of TRALI. CONCLUSION: This is the first reported case of TRALI after allogeneic BMT. TRALI should be recognized as a rare but serious complication in allogeneic hematopoietic stem cell transplantation.

Involvement of casein kinase Iepsilon in cytokine-induced granulocytic differentiation.

Two closely related casein kinase I (CKI) isoforms, CKIdelta and CKIepsilon, are ubiquitously expressed in many human tissues, but their specific biologic function remains to be clarified. Here, we provide the first evidence that CKIepsilon is involved in hematopoietic cell differentiation. CKIepsilon, but not CKIdelta, was down-regulated along with human granulocytic differentiation. The specific down-regulation was observed in granulocyte colony-stimulating factor (G-CSF)-induced cell differentiation of murine interleukin-3 (IL-3)-dependent myeloid progenitor 32D cells. Introduction of wild-type (WT)-CKIepsilon into 32D cells inhibited the G-CSF-induced cell differentiation, whereas kinase-negative (KN)-CKIepsilon promoted the differentiation. Neither WT- nor KN-CKIepsilon affected IL-3-dependent cell growth. Moreover, introduction of WT- or KN-CKIdelta did not affect the cytokine-induced cell growth and differentiation. While G-CSF-induced activation of signal transducers and activators of transcription 3 (STAT3) was sustained by KN-CKIepsilon, STAT3 activation was attenuated by WT-CKIepsilon. This may be explained by the fact that the suppressor of cytokine signaling 3 (SOCS3) was stabilized by its physical association with CKIepsilon. Such stabilization by CKIepsilon was also seen in IL-3-induced beta-catenin. The stabilization of downstream components of cytokine and Wnt signaling by CKIepsilon might be critical for integration of several intracellular signaling pathways to a cell-specific biologic response in hematopoietic cell self-renewal.

Impact of stem cell source and conditioning regimen on erythrocyte recovery kinetics after allogeneic haematopoietic stem cell transplantation from an ABO-incompatible donor.

We evaluated erythrocyte recovery in 121 allogeneic haematopoietic stem cell transplantation (HSCT) recipients. There were 35 major and minor ABO-incompatible transplants, respectively, including 10 bi-directionally ABO-incompatible transplants. The use of peripheral blood stem cells facilitated erythrocyte recovery, regardless of the presence or absence of major ABO-incompatibility, and was associated with a frequent detection of anti-host isohaemagglutin early after minor ABO-incompatible transplantation, which was not associated with clinically relevant haemolysis. The use of a reduced-intensity regimen combining a purine analogue and busulphan did not delay erythrocyte recovery after major ABO-incompatible transplantation, suggesting this regimen had a strong activity against host plasma cell.