bluuebunny/crossref_metadata_2025 huggingface dataset:
Improved outcome in high-risk childhood acute lymphoblastic leukemia defined by prednisone-poor response treated with double Berlin-Frankfurt-Muenster protocol II
Authors: Aricò Maurizio , Valsecchi Maria Grazia , Conter Valentino , Rizzari Carmelo , Pession Andrea , Messina Chiara , Barisone Elena , Poggi Vincenzo , De Rossi Giulio , Locatelli Franco , Micalizzi Maria Concetta , Basso Giuseppe , Masera Giuseppe
Published: October 2002

One hundred ninety-eight children and adolescents were entered in the Associazione Italiana di Ematologia ed Oncologia Pediatrica (AIEOP)-ALL95 study for high-risk acute lymphoblastic leukemia (ALL). Inclusion criteria were poor response to initial prednisone/intrathecal methotrexate (prednisone-poor response [PPR]), resistance to induction therapy, translocation t(9;22), infants with the t(4;11), or CD10− ALL. The event-free survival (EFS) rate at 4 years was 56.5% (SE, 3.9%) for the entire group. The overall EFS rate in the current study was significantly better (P = .002) than that obtained in a comparable group of patients treated in the early 1990s in the AIEOP-ALL91 study. In particular, patients with PPR had a 4-year EFS of 61.1% (SE, 4.4%) versus 42.8% (SE, 5.4%) in the ALL 91 study (P = .008). Among PPR patients, those who were PPR-only (60.1%)—that is, they achieved CR and were negative for t(9;22) and t(4;11) translocations—had the best outcomes with this intensive treatment, even when additional adverse features (hyperleukocytosis, T phenotype) were present (4-year EFS, 70.1%; SE, 4.7%). We attribute this improvement to the replacement of 6 alternating blocks of non–cross-resistant drugs with an 8-drug reinduction regimen (Berlin-Frankfurt-Muenster [BFM] protocol II), repeated twice, in the context of a standard BFM-type intensive chemotherapy for high-risk ALL. This modified therapy may lead to high cure rates for patients defined as at high risk for intrinsic resistance to corticosteroids only.
Presence of chromogranin-derived antimicrobial peptides in plasma during coronary artery bypass surgery and evidence of an immune origin of these peptides
Authors: Tasiemski Aurélie , Hammad Hamida , Vandenbulcke Franck , Breton Christophe , Bilfinger Thomas J. , Pestel Joel , Salzet Michel
Published: October 2002

Chromogranin A (CGA) and chromogranin B (CGB) are acidic proteins stored in secretory organelles of endocrine cells and neurons. In addition to their roles as helper proteins in the packaging of peptides, they may serve as prohormones to generate biologically active peptides such as vasostatin-1 and secretolytin. These molecules derived from CGA and CGB, respectively, possess antimicrobial properties. The present study demonstrates that plasmatic levels of both vasostatin-1 and secretolytin increase during surgery in patients undergoing cardiopulmonary bypass (CPB). Vasostatin-1 and secretolytin, initially present in plasma at low levels, are released just after skin incision. Consequently, they can be added to enkelytin, an antibacterial peptide derived from proenkephalin A, for the panoply of components acting as a first protective barrier against hypothetical invasion of pathogens, which may occur during surgery. CGA and CGB, more commonly viewed as markers for endocrine and neuronal cells, were also found to have an immune origin. RNA messengers coding for CGB were amplified by reverse transcription–polymerase chain reaction in human monocytes, and immunocytochemical analysis by confocal microscopy revealed the presence of CGA or CGB or both in monocytes and neutrophils. A combination of techniques including confocal microscopic analysis, mass spectrometry measurement, and antibacterial tests allowed for the identification of the positive role of interleukin 6 (IL-6) in the secretolytin release from monocytes in vitro. Because IL-6 release is known to be strongly enhanced during CPB, we suggest a possible relationship between IL-6 and the increased level of secretolytin in patients undergoing CPB.
Novel “hybrid” iron chelators derived from aroylhydrazones and thiosemicarbazones demonstrate selective antiproliferative activity against tumor cells
Authors: Lovejoy David B. , Richardson Des R.
Published: October 2002

We previously demonstrated that 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311) and other aroylhydrazone chelators possess potent antineoplastic activity because of their ability to bind iron (Fe). From these studies, we identified structural components of the hydrazones that provide antineoplastic activity, namely the salicylaldehyde and 2-hydroxy-1-naphthylaldehyde moieties. A related group of chelators known as the thiosemicarbazones also show pronounced antitumor activity because of their ability to inhibit ribonucleotide reductase. Considering this, we designed a new series of “hybrid ligands” by condensation of the aldehydes described above with a range of thiosemicarbazides. The parent compound of these ligands is 2-hydroxy-1-naphthylaldehyde thiosemicarbazone (NT). Of 8 NT analogues, 3 chelators, namely NT, N4mT (2-hydroxy-1-naphthylaldehyde-4-methyl-3-thiosemicarbazone), and N44mT (2-hydroxy-1-naphthylaldehyde-4,4-dimethyl-3-thiosemicarbazone), showed high antiproliferative activity against SK-N-MC neuroepithelioma cells (50% inhibitory concentration [IC50] = 0.5-1.5 μM). Indeed, their activity was significantly (P < .0001) greater than that of desferrioxamine (DFO) (IC50 = 22 μM). We demonstrate that 311, a 311 analogue (311m), and several NT-series chelators have significantly (P < .001) greater antiproliferative activity against tumor cells than against a range of normal cell types. For example, the IC50 values of NT and N4mT in SK-N-MC neuroepithelioma cells were 0.5 μM, whereas for fibroblasts the IC50 values were greater than 25 μM. Further, the effect of one of the most potent chelators (311m) on preventing the growth of bone marrow stem cell cultures was far less than that of doxorubicin and similar to that of cisplatin. These studies support the further development of these chelators as antiproliferative agents.
Imatinib mesylate (STI571) therapy for Philadelphia chromosome–positive chronic myelogenous leukemia in blast phase
Authors: Kantarjian Hagop M. , Cortes Jorge , O'Brien Susan , Giles Francis J. , Albitar Maher , Rios Mary Beth , Shan Jianqin , Faderl Stefan , Garcia-Manero Guillermo , Thomas Deborah A. , Resta Debra , Talpaz Moshe
Published: October 2002

Molecular abnormalities caused by the hybrid Bcr-Abl gene are causally associated with the development and progression of Philadelphia chromosome–positive (Ph+) chronic myelogenous leukemia (CML). Imatinib mesylate (STI571), a specific Bcr-Abl tyrosine-kinase signal-transduction inhibitor, has shown encouraging activity in phase I and II studies of CML. Here, we describe the use of imatinib mesylate to treat 75 patients in blast-phase CML (median age, 53 years; 65 with nonlymphoid and 10 with lymphoid blasts), and compare the results with those of a historical control group treated with standard cytarabine-based therapy. Imatinib mesylate was given as oral doses at 300 to 1000 mg per day and was the first salvage therapy for 47 patients. The objective response rate was 52% (39 of 75 patients: 16 had complete and 3 had partial hematologic response; 12 had hematologic improvement; 7 returned to second chronic phase; and 1 had a complete response in extramedullary blastic disease). Response rates were not different between nonlymphoid and lymphoid groups. The cytogenetic response rate was 16% (12 patients: 5 complete, 3 partial [Ph+ below 35%], and 4 minor [Ph+, 34% to 90%]). The estimated median overall survival was 6.5 months; the estimated 1-year survival was 22%. Response to therapy (landmark analysis at 8 weeks) was associated with survival prolongation. Compared with standard cytarabine combinations, imatinib mesylate therapy was less toxic and produced a higher response rate (55% versus 29%, P = .001), longer median survival (7 versus 4 months, P = .04), and lower 4-week induction mortality (4% versus 15%, P = .07). Imatinib mesylate is currently being tested in combination with other drugs to improve the prognosis for blast-phase CML.
Defective expression and function of natural killer cell–triggering receptors in patients with acute myeloid leukemia
Authors: Costello Régis T. , Sivori Simona , Marcenaro Emanuela , Lafage-Pochitaloff Marina , Mozziconacci Marie-Joelle , Reviron Denis , Gastaut Jean-Albert , Pende Daniela , Olive Daniel , Moretta Alessandro
Published: October 2002

The cytolytic function of natural killer (NK) cells is induced by the engagement of a series of activating receptors and coreceptors some of which have recently been identified and collectively termed natural cytotoxicity receptors (NCRs). Here, we analyzed the cytolytic function of NK cells obtained from patients with acute myeloid leukemia (AML). In sharp contrast with healthy donors, in most (16 of 18) patients with AML the majority of NK cells displayed low NCR surface density (NCRdull). This phenotype correlated with a weak cytolytic activity against autologous leukemic cells that could not be reversed by the monoclonal antibody-mediated disruption of HLA class I/killer immunoglobulinlike receptor interaction. The remaining 2 patients were characterized by NK cells having an NCRbright phenotype. Surprisingly, although displaying NCR-mediated cytolytic activity, these NCRbright NK cells were unable to kill autologous leukemic blasts. Importantly, the leukemic blasts from these 2 patients were also resistant to lysis mediated by normal NCRbrightallogeneic NK cells. Our study suggests that in most instances the inability of NK cells to kill autologous leukemic blasts is consequent to low NCR surface expression. In few cases, however, this failure appears to involve a mechanism of tumor escape based on down-regulation of ligands relevant for NCR-mediated target cell recognition.
Human platelets express heat shock protein receptors and regulate dendritic cell maturation
Authors: Hilf Norbert , Singh-Jasuja Harpreet , Schwarzmaier Petra , Gouttefangeas Cécile , Rammensee Hans-Georg , Schild Hansjörg
Published: October 2002

Immunizations using the endoplasmic reticulum–resident heat shock protein Gp96 induce specific immune responses. Specificity is based on the major histocompatibility complex class I–restricted cross-presentation of Gp96-associated peptides derived from endogenous proteins. Initiation of the immune response depends on the ability of Gp96 to induce the production of proinflammatory cytokines by macrophages and dendritic cells (DCs) and of their maturation in a fashion presumably independent of associated peptide. Both events are mediated by Gp96 receptors on antigen-presenting cells. It is known that Gp96 is released from cells at necrosis induced, for example, by virus infection. Although this event supports the efficient induction of immune responses, it might also interfere with processes that are susceptible to chronic inflammation, such as wound healing after tissue damage. Therefore, Gp96-mediated stimulation of the immune system requires tight regulation. Here we show that human thrombocytes specifically interact with Gp96 and that binding of Gp96 to platelets is enhanced more than 10-fold on activation by thrombin. Gp96 interferes with neither thrombin-induced platelet activation nor platelet aggregation. However, the presence of platelets during Gp96-mediated DC activation reduces the secretion of proinflammatory cytokines and the activation of DCs. This effect is independent of soluble platelet factors and cell-to-cell contact between DCs and thrombocytes. Thus, we provide evidence for a regulatory mechanism that neutralizes Gp96 molecules systemically, especially in the blood. This effect might be of significance in wounds in which chronic inflammation and immune responses against autoantigens have to be prevented.
Mixed chimerism induces donor-specific T-cell tolerance across a highly disparate xenogeneic barrier
Authors: Abe Masahiro , Qi Jin , Sykes Megan , Yang Yong-Guang
Published: October 2002

Induction of tolerance is likely to be essential for successful xenotransplantation because immune responses across xenogeneic barriers are vigorous. Although mixed hematopoietic chimerism leads to stable donor-specific tolerance in allogeneic and closely related xenogeneic (eg, rat-to-mouse) combinations, the ability of this approach to induce tolerance across a highly disparate xenogeneic barrier has not yet been demonstrated. In this study, we investigated the immune responses of murine T cells that developed in mice with pre-established porcine hematopoietic chimerism. Our results show for the first time that induction of porcine hematopoietic chimerism can eliminate the development of antiporcine donor responses in a highly disparate xenogeneic species. Porcine hematopoietic chimeras showed donor-specific nonresponsiveness in the mixed lymphocyte reaction, lack of antidonor IgG antibody production, and acceptance of donor skin grafts. Thus, mixed chimerism is capable of inducing tolerance in a highly disparate xenogeneic combination and may have clinical potential to prevent xenograft rejection.
Unlike AML1, CBFβ gene is not deregulated by point mutations in acute myeloid leukemia and in myelodysplastic syndromes
Authors: Leroy Hugues , Roumier Christophe , Grardel-Duflos Nathalie , Macintyre Elizabeth , Lepelley Pascale , Fenaux Pierre , Preudhomme Claude
Published: October 2002

The core-binding factor (CBF) complex is a heterodimeric transcription factor composed of 2 subunits, CBFα and CBFβ, that play a major role in hematopoiesis. Both members of the CBF complex are frequently altered in acute myeloid leukemia (AML) by translocation, most commonly t(8;21), t(12;21), and t(3;21) for CBFα, located in 21q22, and inv16(p13;q22) for CBFβ, located on 16q22. Recently, a new mechanism of alteration of CBFα, by point mutation, has been reported in myeloid malignancies, particularly in M0 AML. In the present study, we found no point mutation of theCBFβ gene in 30 myelodysplastic syndromes and 100 AMLs, suggesting a limited role, if any, of CBFβ point mutations in those disorders.
Antithrombin III inhibits nuclear factor κB activation in human monocytes and vascular endothelial cells
Authors: Oelschläger Christian , Römisch Jürgen , Staubitz Anne , Stauss Harald , Leithäuser Boris , Tillmanns Harald , Hölschermann Hans
Published: October 2002

The serpin antithrombin III (AT III), the most important natural inhibitor of thrombin activity, has been shown to exert marked anti-inflammatory properties and proven to be efficacious in experimental models of sepsis, septic shock, and disseminated intravascular coagulation. Moreover, clinical observations suggest a possible therapeutic role for AT III in septic disorders. The molecular mechanism, however, by which AT III attenuates inflammatory events is not yet entirely understood. We show here that AT III potently blocks the activation of nuclear factor κB (NF-κB), a transcription factor involved in immediate early gene activation during inflammation. AT III inhibited agonist-induced DNA binding of NF-κB in cultured human monocytes and endothelial cells in a dose-dependent manner, suggesting that AT III interferes with signal transduction leading to NF-κB activation. This idea was supported by demonstrating that AT III prevents the phosphorylation and proteolytic degradation of the inhibitor protein IκBα. In parallel to reducing NF-κB activity, AT III inhibited the expression of interleukin-6, tumor necrosis factor-α, and tissue factor, genes known to be under the control of NF-κB. The observation that chemically modified AT III that lacks heparin-binding capacity had no effect on NF-κB activation supports the current understanding that the inhibitory potency of AT III depends on the interaction of AT III with heparinlike cell surface glycosaminoglycans. This hypothesis was underscored by the finding that the AT III β-isoform, known to have higher affinity for glycosaminoglycans, is more effective in preventing NF-κB transactivation than α–AT III. These data indicate that AT III can alter inflammatory processes via inhibition of NF-κB activation.
Insulinlike growth factor–I signaling in multiple myeloma: downstream elements, functional correlates, and pathway cross-talk
Authors: Qiang Ya-Wei , Kopantzev Eugene , Rudikoff Stuart
Published: October 2002

In multiple myeloma cells, insulinlike growth factor–I (IGF-I) activates 2 distinct signaling pathways, mitogen-activated protein kinase (MAPK) and phosphoinositol 3-kinase (PI-3K), leading to both proliferative and antiapoptotic effects. However, it is unclear through which of these cascades IGF-I regulates these different responses. The present studies identify a series of downstream targets in the PI-3K pathway, including glycogen synthase kinase–3β, p70S6 kinase, and the 3 members of the Forkhead family of transcription factors. The contribution of the MAPK and PI-3K pathways and, where possible, individual elements to proliferation and apoptosis was evaluated by means of a series of specific kinase inhibitors. Both processes were regulated almost exclusively by the PI-3K pathway, with only minor contributions associated with the MAPK cascade. Within the PI-3K cascade, inhibition of p70S6 kinase led to significant decreases in proliferation and protection from apoptosis. Activation of p70S6 kinase could also be prevented by MAPK inhibitors, indicating regulation by both pathways. The Forkhead transcription factor FKHRL1 was observed to provide a dual effect in that phosphorylation upon IGF-I treatment resulted in a loss of ability to inhibit proliferation and induce apoptosis. The PI-3K pathway was additionally shown to exhibit cross-talk and to regulate the MAPK cascade, as inhibition of PI-3K prevented activation of Mek1/2 and other downstream MAPK elements. These results define important elements in IGF-I regulation of myeloma cell growth and provide biological correlates critical to an understanding of growth-factor modulation of proliferation and apoptosis.
Low incidence of second neoplasms among children diagnosed with acute lymphoblastic leukemia after 1983
Authors: Bhatia Smita , Sather Harland N. , Pabustan Olga B. , Trigg Michael E. , Gaynon Paul S. , Robison Leslie L.
Published: October 2002

Second malignant neoplasms are a serious complication after successful treatment of childhood acute lymphoblastic leukemia (ALL). With improvement in survival, it is important to assess the impact of contemporary risk-based therapies on second neoplasms in ALL survivors. A cohort of 8831 children diagnosed with ALL and enrolled on Children's Cancer Group therapeutic protocols between 1983 and 1995 were observed to determine the incidence of second neoplasms and associated risk factors. The median age at diagnosis of ALL was 4.7 years. The cohort had accrued 54 883 person-years of follow-up. Sixty-three patients developed second neoplasms, including solid, nonhematopoietic tumors (n = 39: brain tumors n = 19, other solid tumors n = 20), myeloid leukemia or myelodysplasia (n = 16), and lymphoma (n = 8). The cumulative incidence of any second neoplasm was 1.18% at 10 years (95% confidence interval, 0.8%-1.5%), representing a 7.2-fold increased risk compared with the general population. The risk was increased significantly for acute myeloid leukemia (standardized incidence ratio [SIR] 52.3), non-Hodgkin lymphoma (SIR 8.3), parotid gland tumors (SIR 33.4), thyroid cancer (SIR 13.3), brain tumors (SIR 10.1), and soft tissue sarcoma (SIR 9.1). Multivariate analysis revealed female sex (relative risk [RR] 1.8), radiation to the craniospinal axis (RR 1.6), and relapse of primary disease (RR 3.5) to be independently associated with increased risk of all second neoplasms. Risk of second neoplasms increased with radiation dose (1800 cGy RR 1.5; 2400 cGy RR 3.9). Actuarial survival at 10 years from diagnosis of second neoplasms was 39%. Follow-up of this large cohort that was treated with contemporary risk-based therapy showed that the incidence of second neoplasms remains low after diagnosis of childhood ALL.
Lck is required for stromal cell–derived factor 1α (CXCL12)–induced lymphoid cell chemotaxis
Authors: Inngjerdingen Marit , Torgersen Knut Martin , Maghazachi Azzam A.
Published: October 2002

Stromal cell–derived factor 1α (CXCL12) induces chemotaxis of lymphocytes through its receptor CXCR4. We examined the role of nonreceptor tyrosine kinases in CXCL12-induced chemotaxis of T cells and natural killer (NK) cells. Damnacanthal, a specific Lck inhibitor, but not the Syk inhibitor piceatannol, inhibited CXCL12-induced chemotaxis of both lymphocyte subsets. Similarly, damnacanthal was shown to inhibit CXCL12-induced chemotaxis of the Jurkat T-cell line. Stimulating T and NK cells with CXCL12 increased both the tyrosine phosphorylation and the kinase activity of Lck. A direct involvement of Lck in CXCL12-induced chemotaxis was demonstrated in the Lck-deficient Jurkat-derived cell line JCaM1.6. Although JCaM1.6 cells express CXCR4, no significant migration was detected after CXCL12 stimulation. Reconstitution with wild-type Lck restored both CXCL12-induced chemotaxis and Lck activation. Furthermore, cotransfection of wild-type Lck with C-terminal Src kinase (Csk) into JCaM1.6 failed to restore the chemotactic response induced by CXCL12. Finally, by targeting critical residues in the Src homology–2 (SH2) or SH3 domains of Lck, we observed that the SH3 domain is important for the function of Lck in CXCL12-mediated chemotaxis. Together, these results suggest a role for Lck in CXCL12-induced signaling pathways leading to lymphocyte chemotaxis.
Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis
Authors: Thiede Christian , Steudel Christine , Mohr Brigitte , Schaich Markus , Schäkel Ulrike , Platzbecker Uwe , Wermke Martin , Bornhäuser Martin , Ritter Markus , Neubauer Andreas , Ehninger Gerhard , Illmer Thomas
Published: October 2002

Constitutive activation of the FLT3 receptor tyrosine kinase, either by internal tandem duplication (ITD) of the juxtamembrane region or by point mutations in the second tyrosine kinase domain (TKD), has been described in patients with acute myelogenous leukemia (AML). We analyzed the prevalence and the potential prognostic impact of FLT3 mutations in 979 AML patients. Results were correlated with cytogenetic data and the clinical response. FLT3-ITD mutations were found in 20.4% and FLT3-TKD mutations in 7.7% of the patients. Each mutation was associated with similar clinical characteristics and was more prevalent in patients with normal karyotype. Significantly more FLT3 aberrations were found in patients with FAB M5, and fewer were found in patients with FAB M2 and M6. Although less frequent in patients with cytogenetic aberrations, FLT3-ITDs were found in 13 of 42 patients with t(15;17) and in 9 of 10 patients with t(6;9). The prevalence of the ITD allele on the DNA level was heterogeneous, ranging from faint mutant bands in some patients to predominant mutant bands in others. Based on quantitative analysis, the mutant–wild-type (wt) ratio ranged from 0.03 to 32.56 (median, 0.78). Patients with a high mutant/wt ratio (ie, greater than 0.78) had significantly shorter overall and disease-free survival, whereas survival in patients with ratios below 0.78 did not differ from those without FLT3 aberrations. Multivariate analysis confirmed a high mutant/wt ratio to be a strong independent prognostic factor. Taken together, these data confirm that FLT mutations represent a common alteration in adult AML. Constitutive activation may be associated with monocytoid differentiation. A high mutant/wt ratio in ITD-positive patients appears to have a major impact on the prognostic relevance.
Immunologic effects of prophylactic donor lymphocyte infusion after allogeneic marrow transplantation for multiple myeloma
Authors: Bellucci Roberto , Alyea Edwin P. , Weller Edie , Chillemi Antoinette , Hochberg Ephraim , Wu Catherine J. , Canning Christine , Schlossman Robert , Soiffer Robert J. , Anderson Kenneth C. , Ritz Jerome
Published: October 2002

Reconstitution of T-cell immunity after bone marrow transplantation (BMT) is often delayed, resulting in a prolonged period of immunodeficiency. Donor lymphocyte infusion (DLI) has been used to enhance graft-versus-leukemia activity after BMT, but the effects of DLI on immune reconstitution have not been established. We studied 9 patients with multiple myeloma who received myeloablative therapy and T-cell–depleted allogeneic BMT followed 6 months later by infusion of lymphocytes from the same donor. DLI consisted of 3 × 107 CD4+ donor T cells per kilogram obtained after in vitro depletion of CD8+ cells. Cell surface phenotype of peripheral lymphocytes, T-cell receptor (TCR) Vβ repertoire, TCR rearrangement excision circles (TRECs), and hematopoietic chimerism were studied in the first 6 months after BMT and for 1 year after DLI. These studies were also performed in 7 patients who received similar myeloablative therapy and BMT but without DLI. Phenotypic reconstitution of T and natural killer cells was similar in both groups, but patients who received CD4+ DLI developed increased numbers of CD20+ B cells. TCR Vβ repertoire complexity was decreased at 3 and 6 months after BMT but improved more rapidly in patients who received DLI (P = .01). CD4+ DLI was also associated with increased numbers of TRECs in CD3+ T cells (P < .001) and with conversion to complete donor hematopoiesis (P = .05). These results provide evidence that prophylactic infusion of CD4+ donor lymphocytes 6 months after BMT enhances reconstitution of donor T cells and conversion to donor hematopoiesis as well as promoting antitumor immunity.
Myeloid cell factor–1 is a critical survival factor for multiple myeloma
Authors: Zhang Bin , Gojo Ivana , Fenton Robert G.
Published: October 2002

Multiple myeloma (MM) is characterized by the accumulation of malignant plasma cells in the bone marrow caused primarily by failure of normal homeostatic mechanisms to prevent the expansion of postgerminal center plasma cells. We have examined the molecular mechanisms that promote the survival of MM cells and have identified a key role for myeloid cell factor–1 (Mcl-1), an antiapoptotic member of the Bcl-2 family. These experiments were initiated by the observation that MM cells were exquisitely sensitive to culture in the presence of actinomycin D: caspase activation occurred within 3 hours of treatment and cells were not protected by interleukin-6, the main MM cell growth and survival factor. Actinomycin D–induced apoptosis was blocked by proteasome inhibitors, suggesting that a labile protein was required for MM cell survival. Further analysis demonstrated that Mcl-1 was likely to be the labile factor governing MM cell survival. Mcl-1 protein levels decreased rapidly after culture in the presence of actinomycin D in concordance with effector caspase activation, but addition of proteasome inhibitors reversed the loss of Mcl-1 and maintained cell viability. The levels of other antiapoptotic proteins, including Bcl-2 and members of the inhibitors-of-apoptosis family, were unaffected by these interventions. Furthermore, Mcl-1 antisense oligonucleotides caused a rapid down-regulation of Mcl-1 protein levels and the coincident induction of apoptosis, whereas overexpression of Mcl-1 delayed actinomycin D–induced apoptosis with kinetics that correlated with expression levels of Mcl-1. These data indicate that Mcl-1 expression is required for the survival of MM cells and may represent an important target for future therapeutics.
Unrelated donor marrow transplantation for myelodysplastic syndromes: outcome analysis in 510 transplants facilitated by the National Marrow Donor Program
Authors: Castro-Malaspina Hugo , Harris Richard E. , Gajewski James , Ramsay Norma , Collins Robert , Dharan Bernie , King Roberta , Deeg H. Joachim
Published: October 2002

Between April 1988 and July 1998, 510 patients with myelodysplastic syndromes (MDS) underwent unrelated donor bone marrow transplantation (BMT) facilitated by the National Marrow Donor Program. Median age was 38 years (range, <1-62 years). Several conditioning regimens and graft-versus-host disease (GVHD) prophylaxis methods were used, and T-cell depletion was used in 121 patients. Donors were serologically matched for HLA-A, -B, and -DRB1 antigens for 74% of patients. Of 437 patients evaluable for engraftment, 24 (5% cumulative incidence, with 95% confidence interval [CI] of 3%-7%) failed to engraft, and an additional 33 (8% cumulative incidence; 95% CI, 6%-10%) had late graft failure. Grades II to IV GVHD developed in 47% of patients (95% CI, 43%-49%), and limited and extensive chronic GVHD developed at 2 years in 27% (95% CI, 24%-30%). The incidence of relapse at 2 years was 14% (95% CI, 11%-17%). Greater relapse was independently associated with advanced MDS subtype and no acute GVHD. The estimated probability of disease-free survival (DFS) at 2 years was 29% (95% CI, 25%-33%). Improved DFS was independently associated with less advanced MDS subtype, higher cell dose, recipient cytomegalovirus (CMV) seronegativity, shorter interval from diagnosis to transplantation, and transplantation in recent years. Common causes of death were treatment-related complications accounting for 82% of fatalities. The 2-year cumulative incidence of treatment-related mortality (TRM) was 54% (95% CI, 53%-61%). Sixty-nine percent of TRM occurred within the first 100 days, and 93% occurred within the first year of transplantation. Higher TRM was independently associated with older recipient and donor age, HLA mismatch, and recipient CMV seropositivity. This study demonstrates that unrelated donor BMT cures a significant proportion of patients with MDS. TRM is the major problem limiting the success of unrelated donor BMT in MDS. The observations made in this study should facilitate the design of prospective trials aimed at improving the results of unrelated donor stem cell transplantation for MDS.
An examination of procedures for predicting heat losses from underground structures
Authors: Mughal M P , Chattha J A
Published: October 2002

Numerical predictions for heat losses from two-dimensional underground structures of variable geometry are presented. The calculations include the effects of wind velocity, surface radiation, and deep soil temperature, none of which have been previously explored. Results are compared with calculations made using ASHRAE procedures for predicting such losses. It is demonstrated that the present study results differ from the ASHRAE procedures by 20% depending upon geometry, wind conditions, and deep soil temperature. A limited number of results for the transient heat losses are presented to guide the designer with regard to peak losses and time lags. A new calculation procedure is developed and presented based upon the numerical result. This procedure is simple yet more flexible and allows for the inclusion of variations in wind velocity, surface radiation, soil thermal conductivity, soil temperature at depth in addition to structure geometry.
Perfusion: a view from the British Heart Foundation
Authors: George Charles
Published: October 2002

The British Heart Foundation was established 40 years ago with the aim of playing a major role in the fight against cardiovascular disease. Despite spectacular advances in the surgical treatment of congenital and ischaemic heart disease, there is a continued need for research into the causes, diagnosis, prevention and treatment. The Foundation will continue to support professors, training fellowships and individual project and programme grants to meet these needs.
Spouses of first-ever stroke patients: their view of the future during the first phase after stroke
Authors: Forsberg-Wärleby Gunilla , Möller Anders , Blomstrand Christian
Published: October 2002

Background: A partner’s stroke can be perceived as a critical event by a spouse. Previous studies have focused primarily on the impact of stroke on spouses’ psychosocial well-being over the long term. However, the experience of spouses in the ”rst phase after stroke is not well known.

Aim: To investigate spouses’ perception of their future daily life after stroke and the association between this perception and the objective characteristics of the stroke.

Method: Eighty-three consecutively enrolled spouses of ”rst-ever stroke patients <75 years admitted to Sahlgrenska University Hospital in Göteborg, Sweden participated. The mean age of the spouses was 57 years. Sixty-two of the spouses were women and 21 men. Interviews about their experiences 10 days after onset were generally made at the hospital. The interviews were analysed, categorized and combined with statistical analyses of variables such as ages and sex of the spouses, type of lesion and presence of neurological impairments in the stroke patient.

Results: Four different categories of the concept ‘view of the future’ were developed on the basis of the interviews. Of the different characteristics of the stroke, the severity of the sensorimotor impairment seemed to have the greatest impact on the spouses’ view of the future. The spouses of stroke patients with pure sensorimotor impairment were more likely to have an optimistic view of the future than when the sensorimotor impairment was combined with cognitive de”cits. There was a broad distribution of the different characteristics of stroke between the four categories.

Conclusions: Although the perception of future daily life varied, it was possible to categorize the spouses’ cognitive image of future life according to degree of optimism. While the severity of stroke was of importance, the individual perception of the disease, impact on future activities and the spouses’ own coping capacity was of great signi”cance for the perception of future daily life.
A study to compare the reliability of composite finger flexion with goniometry for measurement of range of motion in the hand
Authors: Ellis Bridget , Bruton Anne
Published: October 2002

Objective: To establish the intra and inter-rater reliability of composite finger flexion (CFF), and to compare this with goniometry.

Design: Fifty-one physiotherapists and occupational therapists took part in the study. The hand of a normal subject was splinted in three different positions. Using a goniometer and a ruler alternately, each therapist measured both the proximal interphalangeal joint and CFF of three digits, following a standardized protocol. This process was repeated three times.

Setting: Eighteen NHS hospital sites in the UK.

Results: The two measurement methods produced different ranges and standard deviations for each digit. The repeatability coef”cient shows that repeated intra-rater goniometric measures fall within 4–5 degrees of each other 95% of the time. Inter-rater goniometric measures fall within 7–9 degrees. Repeated intra-rater CFF measures fall within 5–6 mm of each other, whereas inter-rater fall within 7–9 mm. The in‘uence of occupation, experience in hand therapy, years of practice and routine use were found to have no effect on reliability. Scaling of the two methods of measurement allowed comparison between them to be made. CFF and goniometry are equally reliable when comparing inter-rater reliability, but goniometry displays less variability than composite ”nger ‘exion for intra-rater measurements.

Conclusion: In this study involving a subject with normal joints, goniometry is more reliable than CFF when only one measurer is involved. However, CFF may be a useful alternative where multiple joint measures are required, or when goniometry is impracticable.
Factors associated with cardiac rehabilitation attendance: a systematic review of the literature
Authors: Cooper A F , Jackson G , Weinman J , Horne R
Published: October 2002

Background: Many eligible patients fail to attend cardiac rehabilitation courses.

Objective: To undertake a systematic literature review of studies that have investigated factors associated with cardiac rehabilitation attendance.

Methods: Literature published between 1978 and 2001 was searched using the MEDLINE, PSYCINFO and CINAHL computerized databases. Studies were sought that examined course attendance in eligible patient samples. Studies had to include at least one baseline predictor variable.

Results: Fifteen studies were identified and predictor variables were usually categorized as sociodemographic, medical and psychological. Nonattenders are more likely to be older, to have lower income/greater deprivation, to deny the severity of their illness; they are less likely to believe they can influence its outcome or to perceive that their physician recommends cardiac rehabilitation. Job status, gender and health concerns play an indirect role in attendance behaviour. Comparison of results between studies could be influenced by different case-mix, measurement instruments and country of origin.

Conclusion: A number of factors predict cardiac rehabilitation attendance and some of these are potentially modifiable.
Derivatives of dehydrocrotonin, a diterpene lactone isolated fromCroton cajucara: cytotoxicity in rat cultured hepatocytes and in V79 cells
Authors: Melo P S , Durán N , Haun M
Published: October 2002

Derivatives of dehydrocrotonin (DHC; Compound I) with different anti-ulcerogenic properties but less toxicity were produced by reducing the cyclohexenone moiety of DHC with NaBH4 (Compound II), reducing the cyclohexenone and lactone moieties with LiAlH4 (Compound III) and transforming the lactone moiety into an amide (Compound IV) using dimethylamine. Derivatives of DHC were assayed in cultured hepatocytes and V79 fibroblasts. Three independent endpoints assays for cytotoxicity were used, namely, the DNA content, tetrazolium reduction (MTT) and neutral red uptake (NRU). Compound III was less toxic than the other DHC derivatives in both cell cultures. IC50values ranging from 250 to 600 m M were obtained for Compounds II and IV in the NRU and DNA content tests evaluated in 4-hour hepatocyte cultures. Although Compound II showed relatively low cytotoxicity in rat hepatocytes based on the NRU and DNA content assays, a very high toxicity (IC50=10 m M) was observed in the MTT test. Metabolites of Compound II in conditioned medium from 4-hour old hepatocyte cultures enhanced the MTT-reducing ability of V79 fibroblasts. The cytotoxicity of the derivatives was greater in recently isolated hepatocytes (only a 4-hour incubation for cell attachment prior to treating with the derivatives) than in hepatocytes previously cultured (24-hour incubation) before the treatment. Thus, aging reduced the cytotoxic effects of DHC derivatives in isolated hepatocytes, suggesting that P450-mediated biotransformation of such derivatives may lead to the formation of more toxic metabolites.
A toxicologist's guide to biomarkers of hepatic response
Authors: Amacher D E
Published: October 2002

Biological markers (biomarkers) are used to recognize, characterize and monitor treatment-related responses following exposure to xenobiotics. Biomarkers serve three primary applications in toxicology: 1) to confirm exposure to a deleterious agent, 2) to provide a system for monitoring individual susceptibility to a toxicant, and 3) to quantitatively assess deleterious effects of a toxicant to an organism or individual. Because the liver is a general target for adverse effects of drugs and other chemicals, biomarkers of untoward hepatic response to xenobiotics are of particular interest to the pharmaceutical toxicologist. General requirements for the latter category of biomarkers are sample availability, target organ specificity, sensitivity for the toxicity of interest, accessibility, a relatively short half-life, and available detection systems. Biomarkers that can be assayed in biological fluids from both human and animal subjects are particularly desirable. Histologically, acute and subacute hepatic toxicity commonly involves necrosis, steatosis, cholestasis, vascular disorders, or multiple lesions. The purpose of this review is to summarize reported applications using clinical analytes and biochemical indicators of hepatic dysfunction with emphasis on those that show promise of supplementing or improving upon standard laboratory procedures. Liver function markers refer to peripheral indicators of hepatic synthetic and secretory activities, enterohepatic function, or perturbations of the hepatic uptake and clearance of circulating biomolecules. Liver injury biomarkers include various peripheral proteins released in response to a cellular damage or locally, proteins that are significantly altered within the liver. These include both circulating cytosolic, mitochondrial, or canalicular membrane markers, and the up-regulation or depletion of radical scavengers, modulators, and stabilizers of intracellular damage. Subsequent recovery from a toxic insult involves repair, regenerative, and proliferative responses that constitute the third class of biomarkers. Of these, protein markers found either in sera, plasma, or urine either during or just prior to the early manifestation of histological hepatic lesions are of greatest interest. Examples of a number of these markers, their documented applications in humans or animals, and potential advantages as well as limitations are presented.
The pharmacologic stability of 35-year old theophylline
Authors: Regenthal R , Stefanovic D , Albert T , Trauer H , Wolf T
Published: October 2002

The propensity to preserve and to hoard drugs over the years at home is a well-known phenomenon and offers the possibility for intentional and accidental drug poisoning in man. We report a case of acute theophylline poisoning in an 80-year old women after ingestion of ‘Asthmo-Kranit1 ’, a 35-year old combined preparation containing theophylline and aminopyrine as the main ingredients. The patient developed the typical clinical picture of a symptomatic theophylline poisoning with flush, tremor, tachycardia, hyperventilation, hypotonia, and hyperglycaemia. The clinical course after treatment with beta-blockers was without complications. The determination of theophylline in tablets showed stability of 90% of the labelled amount of the drug 30 years beyond the expiration date. The case illustrates the prolonged shelf stability and pharmacological potency of some pharmaceuticals and points to the risk of longoutdated prescriptions. Physicians should primarily not underestimate drug toxicity in consequence of old-age pharmaceuticals.
Capecitabine: a novel, orally administered, tumour-activated treatment for breast cancer
Authors: Summerhayes Maxwell
Published: October 2002

Objective. To provide a comprehensive review of the preclinical and clinical pharmacology and toxicology of the fluoropyrimidine, capecitabine, with particular reference to its use in metastatic breast cancer.

Data Sources. A MEDLINE search was conducted using the term ‘capecitabine’ for the period 1995 -2001. The reference lists from retrieved articles were reviewed and other relevant papers identified. The abstract books from the annual meetings of the American Society of Clinical and Oncology and the European Society of Medical Oncology were also reviewed.

Data Extraction. The aim of the review was to be comprehensive and descriptive. All studies containing information deemed to be of interest were reviewed by the author; none was excluded on grounds of quality.

Data Summary. Capecitabine is a prodrug of the widely used cytotoxic agent 5-fluorouracil (5-FU). Unlike 5-FU, it is extensively and reliably absorbed after oral administration and does not require folinate (FA) potentiation. The activation of capecitabine is a three-step enzymatic process. The final activating enzyme - thymidine phosphorylase - is found in unusually high concentrations in many solid tumours including breast cancers, resulting in preferential delivery of 5-FU to tumour tissues, and suggesting a greater potential for selective cytotoxicity than is seen with 5-FU.

Capecitabine has been examined both alone and in combination with a variety of cytotoxic drugs in the treatment of metastatic breast cancer. To date, clinical evidence supports the use of capecitabine monotherapy in patients relapsing after prior treatment with anthracyclines and taxanes and in combination with docetaxel in patients failing anthracycline treatment.

Data from phase II studies indicate that in the first of these situations, capecitabine elicits a response in about one-fifth of patients and that responses are associated with symptomatic relief and extended survival. In the latter situation, a phase III study has shown that the combination of docetaxel and capecitabine elicits superior response rates, remission durations, and overall survival compared with the taxane alone and with no clinically important increase in toxicity.

Used alone or in combination, the most notable adverse effect associated with capecitabine is palmar-plantar erythrodysasthesia (hand -foot syndrome), a characteristic complex of reddening, dryness, and soreness of the palms of the hands and soles of the feet, which is rarely disabling and readily managed by treatment interruption and dose reduction.
Clinical effectiveness of trastuzumab: early experience
Authors: Chambers Carole , Dimaculangan Dawn Michelle , Grindrod KA , Hanson John , Pataky Fruzsina , Vu Thanh Thi
Published: October 2002

Objective. To assess the clinical effectiveness of trastuzumab among metastatic breast cancer (MBC) patients and compare the results to those reported in the two pivotal clinical trials and product monograph.

Design. Retrospective chart review of all patients who had initiated trastuzumab monotherapy or combination therapy for MBC within the Alberta Cancer Board (ACB) from August 1998 to May 2001.

Setting. Two public tertiary cancer centres in the Canadian province of Alberta.

Patients. Of 90 patients reviewed within the ACB, 72 women were eligible for the study.

Main outcome measures. The primary endpoints measured were time to treatment failure (TTF) and survival. Secondary end-points measured included adverse events and compliance with ACB guidelines for trastuzumab administration.

Results. Among all 72 patients, median TTF was 7.6 months and median survival was 14.4 months. Trastuzumab combination therapy was associated with a significantly longer median TTF compared to trastuzumab monotherapy (P= 0.011). With respect to survival, no significant advantage was seen with combination therapy over monotherapy (P= 0.438). Infusion-related reactions were reported in 11.1% of our patients, while cardiotoxicity was reported in12.5%.

Conclusions. Overall, we found that trastuzumab performs better in the clinical setting than it did in the pivotal trials with respect to TTF (2.5 vs. 2.4 months and 8.2 vs. 6.9 months), but not as well with respect to survival (10.0 vs. 13.0 months and 21.0 vs. 25.1 months). In comparison to the product monograph, we report a significantly lower incidence of infusion-related reactions and a slightly higher incidence of cardiotoxicity.