bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Age on Clinical and Morphological Characteristics in Patients With Brain Arteriovenous Malformation
Authors: Stapf C. , Khaw A.V. , Sciacca R.R. , Hofmeister C. , Schumacher H.C. , Pile-Spellman J. , Mast H. , Mohr J.P. , Hartmann A.
Published: October 2003

Background and Purpose—

The goal of this work was to determine the effect of age at initial presentation on clinical and morphological characteristics in patients with brain arteriovenous malformation (AVM).

Methods—

The 542 consecutive patients from the prospective Columbia AVM database (mean±SD age, 34±15 years) were analyzed. Univariate statistical models were used to test the effect of age at initial presentation on clinical (AVM hemorrhage, seizures, headaches, neurological deficit, other/asymptomatic) and morphological (AVM size, venous drainage pattern, AVM brain location, concurrent arterial aneurysms) characteristics.

Results—

Hemorrhage was the presenting symptom in 46% (n=247); 29% (n=155) presented with seizures, 13% (n=71) with headaches, 7% (n=36) with a neurological deficit, and 6% (n=33) without AVM-related symptoms. Increasing age correlated positively with intracranial hemorrhage (
P
=0.001), focal neurological deficits (
P
=0.007), infratentorial AVMs (
P
<0.001), and concurrent arterial aneurysms (
P
<0.001); an inverse correlation was found with seizures (
P
<0.001), AVM size (
P
=0.001), and lobar (
P
<0.001), deep (
P
=0.008), and borderzone (
P
=0.014) location. No age differences were found for sex, headache, asymptomatic presentation, and venous drainage pattern.

Conclusions—

Our data suggest a significant interaction of patient age and clinical and morphological AVM features and argue against uniform AVM characteristics across different age classes at initial presentation. In particular, AVM patients diagnosed at a higher age show a higher fraction of AVM hemorrhage and are more likely to harbor additional risk factors such as concurrent arterial aneurysms and small AVM diameter. Longitudinal population-based AVM data are necessary to confirm these findings.
Stroke Unit Care Combined With Early Supported Discharge
Authors: Fjærtoft Hild , Indredavik Bent , Lydersen Stian
Published: October 2003

Background and Purpose—

Early supported discharge from a stroke unit reduces the length of hospital stay. Evidence of a benefit for the patients is still unknown. The aim of this trial was to evaluate the long-term effects of an extended stroke unit service (ESUS), characterized by early supported discharge. The short-term effects were published previously.

Methods—

We performed a randomized controlled trial in which 320 acute stroke patients were allocated to either ordinary stroke unit service (OSUS) (160 patients) or stroke unit care with early supported discharge (160 patients). The ESUS consists of a mobile team that coordinates early supported discharge and further rehabilitation. Primary outcome was the proportion of patients who were independent as assessed by modified Rankin Scale (RS) (RS ≤2=global independence). Secondary outcomes measured at 52 weeks were performance on the Barthel Index (BI) (BI ≥95=independent in activities of daily living), differences in final residence, and analyses to identify patients who benefited most from an early supported discharge service. All assessments were blinded.

Results—

We found that 56.3% of the patients in the ESUS versus 45.0% in the OSUS were independent (RS ≤2) (
P
=0.045). The number needed to treat to achieve 1 independent patient in ESUS versus OSUS was 9. The odds ratio for independence was 1.56 (95% CI, 1.01 to 2.44). There were no significant differences in BI score and final residence. Patients with moderate to severe stroke benefited most from the ESUS.

Conclusions—

Stroke service based on treatment in a stroke unit combined with early supported discharge appears to improve the long-term clinical outcome compared with ordinary stroke unit care. Patients with moderate to severe stroke benefit most.
Endothelial Nitric Oxide Synthase T-786C Single Nucleotide Polymorphism
Authors: Khurana Vini G. , Sohni Youvraj R. , Mangrum Wells I. , McClelland Robyn L. , O’Kane Dennis J. , Meyer Fredric B. , Meissner Irene
Published: October 2003

Background and Purpose—

Anecdotal evidence exists for at least 2 subpopulations of intracranial saccular aneurysms, namely, those that may form rapidly and rupture when small versus those that enlarge slowly and may rupture particularly when ≥10 mm in diameter. We sought to determine whether the endothelial nitric oxide synthase (eNOS) T-786C single nucleotide polymorphism (SNP), implicated in cardiovascular disease susceptibility, could facilitate differentiation between small (≤5 mm) versus large (≥10 mm) ruptured aneurysms.

Methods—

In accordance with institutional guidelines, clinical data were recorded prospectively and genomic DNA was isolated from blood samples obtained from 52 aneurysmal subarachnoid hemorrhage (SAH) patients (cases) and 90 randomly selected controls. Samples were assayed for eNOS gene promoter T-786C SNP with the use of gene microarray technology. Statistical analyses included multiple logistic regression.

Results—

Although there was no difference in genotype distributions between cases and controls, all 13 patients with large aneurysms were (
T
/
C
) heterozygous for the polymorphism, while 9 of 22 patients (41%) with small aneurysms were (
T
/
T
or
C
/
C
) homozygous (
P
=0.01). The mean (±SD) ruptured aneurysm diameter among all heterozygotes (8.5±5.2 mm) was significantly greater than that for
C
/
C
(6.0±2.3 mm) or
T
/
T
(4.7±1.8 mm) homozygotes (
P
=0.04). With the use of multivariate analysis, heterozygosity remained significantly associated with aneurysm size ≥10 mm (
P
=0.03).

Conclusions—

The eNOS T-786C SNP distinguishes genetically between small and large ruptured aneurysms. Although not predictive of SAH in the population at large, our data suggest that among persons with known intracranial aneurysms, eNOS T-786C genotype may be a factor influencing the size at which an aneurysm ruptures, a finding that should be taken into consideration along with other anatomic features of the aneurysm.
Cyclooxygenase-2 Inhibitors
Authors: Hankey Graeme J. , Eikelboom John W.
Published: October 2003

Background and Summary—

Selective cyclooxygenase (COX)-2 inhibitors are increasingly being used in place of “conventional” nonsteroidal anti-inflammatory drugs (NSAIDs). This is because they are just as effective as NSAIDs in relieving arthritic pain and yet less gastrotoxic. However, the cardiovascular safety of selective COX-2 inhibitors has been questioned because they selectively reduce prostacyclin production, thus disrupting the normal homeostatic balance and promoting a prothrombotic state. These theoretical concerns appear to be supported by the results of clinical trials demonstrating an increased risk of myocardial infarction with COX-2 inhibitors compared with a conventional NSAID, and indirect comparisons of the rates of myocardial infarction among patients treated with a selective COX-2 inhibitor compared with aspirin in different trials. However, emerging data from animal, experimental and clinical studies suggest that COX-2 is atherogenic and thrombogenic, and that selective COX-2 inhibitors may be cardioprotective. Meta-analyses of randomized trials of selective COX-2 inhibitors compared with placebo have demonstrated no excess of cardiovascular events among patients allocated COX-2 inhibitors, and preliminary data from a randomized controlled trial of the selective COX-2 inhibitor meloxicam, in patients with acute coronary syndrome who were treated with aspirin, demonstrated a reduction in cardiovascular events among patients allocated the COX-2 inhibitor.

Conclusions—

Continuing uncertainty regarding the direction and magnitude of any cardiovascular effects of selective COX-2 inhibitors, coupled with their widespread and increasing use, mandates prospective randomized evaluation of their efficacy and safety in patients at increased risk of future cardiovascular events.
CXCR4 engagement is required for HIV-1–induced L-selectin shedding
Authors: Wang JiangFang , Marschner Susanne , Finkel Terri H.
Published: October 2003

The chemokine receptor, CXCR4, serves as the primary coreceptor for entry of T-cell tropic human immunodeficiency virus (HIV). Binding of either the CXC-chemokine, stromal-derived factor 1α (SDF-1α), or a CXCR4 antagonist, AMD3100, to CXCR4 inhibits infection of CD4+ T cells by T-tropic HIV-1, although only SDF-1α triggers T-cell signaling cascades. We have previously demonstrated that ligation of CD4 by T-cell tropic HIV-1 NL4-3 induces metalloproteinase-dependent L-selectin (CD62L) shedding on resting CD4+ T cells. However, the role of CXCR4 in HIV-induced L-selectin shedding is unclear. Here, we show that L-selectin shedding induced by HIV-1 NL4-3 is completely reversed by AMD3100, but not SDF-1α, although SDF-1α alone does not induce L-selectin shedding. These results indicate that engagement of both CD4 and CXCR4 is required for HIV-induced shedding of L-selectin on primary resting CD4+ T cells.
Dual roles of the C-terminal Src kinase (Csk) during developmental vascularization
Authors: Duan Li-Juan , Imamoto Akira , Fong Guo-Hua
Published: October 2003

Here we report that C-terminal Src kinase (Csk), a tyrosine kinase that negatively regulates the activity of Src and related kinases, is important for vascular development. In Csk–/– embryos, although vascular tubules were formed and organized into capillary-like networks during the initial genesis of blood vessels, the vessels failed to engage in normal sprout formation. In chimeric embryos containing both wild-type and Csk–/– cells, the presence of wild-type cells enabled Csk–/– endothelial cells to participate in branching morphogenesis. We suggest that wild-type cells may have supplied an angiogenic factor absent in Csk–/– cells. Despite the partial rescue of vascular development in chimeric embryos, the embryos failed to form vitelline vessels and died at E9.5. These results indicate that Csk is required both for angiogenic sprouting and vascular remodeling.
Signaling by ephrinB1 and Eph kinases in platelets promotes Rap1 activation, platelet adhesion, and aggregation via effector pathways that do not require phosphorylation of ephrinB1
Authors: Prévost Nicolas , Woulfe Donna S. , Tognolini Massimiliano , Tanaka Takako , Jian Wenying , Fortna Ryan R. , Jiang Hong , Brass Lawrence F.
Published: October 2003

We have previously shown that platelets express 2 receptor tyrosine kinases, EphA4 and EphB1, and the Eph kinase ligand, ephrinB1, and proposed that transcellular Eph/ephrin interactions made possible by the onset of platelet aggregation promote the further growth and stability of the hemostatic plug. The present study examines how this might occur. The results show that clustering of either ephrinB1 or EphA4 causes platelets to adhere to immobilized fibrinogen via αIIbβ3. Adhesion occurs more slowly than with adenosine diphosphate (ADP) and requires phosphatidylinositol 3 (PI3)–kinase and protein kinase C activity but not ephrinB1 phosphorylation. By itself, Eph and ephrin signaling is insufficient to cause aggregation or the binding of soluble fibrinogen, but it can potentiate aggregation initiated by a Ca++ ionophore or by agonists for thrombin and thromboxane receptors. It also enhances Rap1 activation without requiring ADP secretion, ephrinB1 phosphorylation, or the activation of PI3-kinase and Src. From this we conclude that (1) Eph/ephrin signaling enhances the ability of platelet agonists to cause aggregation provided that those agonists can increase cytosolic Ca++; (2) this is accomplished in part by activating Rap1; and (3) these effects require oligomerization of ephrinB1 but not phosphotyrosine-based interactions with the ephrinB1 cytoplasmic domain.
Raf-1 is not required for megakaryocytopoiesis or TPO-induced ERK phosphorylation
Authors: Kamata Tamihiro , Pritchard Catrin A. , Leavitt Andrew D.
Published: October 2003

Thrombopoietin stimulates extracellular signal-related kinase 1/2 (ERK1/2) phosphorylation in megakaryocytes, and the classic mitogen-activated protein (MAP) kinase (Raf/mitogen-induced extracellular kinase [MEK]/ERK) pathway has been implicated directly and indirectly to play a critical role in megakaryocytopoiesis. However, the involvement of specific Raf family members in megakaryocytopoiesis is unknown. raf-1-/- mice were therefore used to directly determine the role of Raf-1 in megakaryocytopoiesis. Surprisingly, raf-1-/- mice have a modestly higher platelet count than their raf-1+/+ littermates. Nonetheless, the absence of Raf-1 does not alter thrombopoietin-induced expansion of primary megakaryocyte-lineage cells, the development of apoptotic megakaryocytes in the presence or absence of thrombopoietin, or the development of megakaryocyte DNA ploidy distribution. Moreover, raf-1-/- megakaryocytes do not have a compensatory increase in A-Raf or B-Raf expression, and thrombopoietin-induced ERK1/2 phosphorylation is similar in raf-1-/- and raf-1+/+ megakaryocytes. These unexpected findings demonstrate that Raf-1 is dispensable for megakaryocytopoiesis, and for thrombopoietin-induced ERK1/2 activation in primary megakaryocyte-lineage cells.
Relative increase in leukemia-specific DNA in peripheral blood plasma from patients with acute myeloid leukemia and myelodysplasia
Authors: Rogers Anna , Joe Youngson , Manshouri Taghi , Dey Amanda , Jilani Iman , Giles Francis , Estey Elihu , Freireich Emil , Keating Michael , Kantarjian Hagop , Albitar Maher
Published: October 2003

Using loss of heterozygosity (LOH) and X-chromosome inactivation, we compared peripheral blood (PB) plasma with bone marrow (BM) cells in detecting genomic abnormalities in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). We detected LOH in the PB plasma of all 45 patients who had cytogenetically documented chromosomal abnormalities (5q-, 7-, +8, 17-, or 20-). BM cells from the same patients showed LOH in 89% of patients with MDS and 70% of patients with AML. Posttherapy samples from 16 of these patients demonstrated complete concordance between LOH and cytogenetics in detecting residual disease in 15 samples. Of the 16 samples, 4 showed LOH in plasma with normal BM morphology. Using X-chromosome inactivation, clonality was detectable in 19 (73%) of 26 BM samples, whereas all PB plasma samples showed clonality. These data support the conclusion that PB plasma is enriched by tumor-specific DNA and can replace BM cells for studying genomic abnormalities. (Blood. 2004;103:2799-2801)
Antibody-induced intracellular signaling works in combination with radiation to eradicate lymphoma in radioimmunotherapy
Authors: Du Yong , Honeychurch Jamie , Cragg Mark S. , Bayne Mike , Glennie Martin J. , Johnson Peter W. M. , Illidge Tim M.
Published: October 2003

Radioimmunotherapy (RIT) has emerged as an effective treatment for lymphoma, however the underlying mechanisms are poorly understood. We therefore investigated the relative contributions of antibody and targeted radiation to the clearance of tumor in vivo, using 2 different syngeneic murine B-cell lymphoma models. Although RIT with 131I–anti–major histocompatibility complex class II (MHCII) was effective in targeting radiation to tumor, no improvement in survival was seen by escalating the radiation dose alone and there were no long-term survivors. In contrast, using the combination of 131I anti-MHCII in the presence of unlabeled anti-idiotype (anti-Id), 100% prolonged disease-free survival was seen in both B-cell lymphoma models at the higher radiation dose. Using in vivo tracking we show that treatment with radiation plus anti-Id monoclonal antibody (mAb) results in a substantially greater reduction of splenic tumor cells than with either treatment alone. Prolonged survival could also be achieved using 131I anti-MHCII plus the signaling anti-CD19 mAb. Furthermore, the ability of these anti–B-cell mAbs to improve survival with targeted radiotherapy appeared to correlate with their ability to initiate intracellular signal transduction. Together these data illustrate that using 1 mAb to target radiation to tumor and a second to induce cell signaling is an effective new strategy in RIT.
Long-term outcome of hepatitis C infection after bone marrow transplantation
Authors: Peffault de Latour Régis , Lévy Vincent , Asselah Tarik , Marcellin Patrick , Scieux Catherine , Adès Lionel , Traineau Richard , Devergie Agnès , Ribaud Patricia , Espérou Hélène , Gluckman Eliane , Valla Dominique , Socié Gérard
Published: October 2003

Chronic hepatitis C is often asymptomatic, at least during the first decade following hematopoietic stem cell transplantation. Progression to advanced liver disease or cirrhosis in patients surviving more than 10 years is currently thought to be rare. Among 1078 patients who underwent an allogeneic transplantation between January 1973 and January 1995, 96 patients infected by hepatitis C virus (HCV) during the transplantation period were studied. Cumulative incidence and analysis of risk factors for cirrhosis were analyzed, and the rate and risk of cirrhosis in transplant recipients were compared with those of 158 HCV-infected controls who did not receive transplants. At a median follow-up of 15.7 years, 15 patients developed biopsy-proven cirrhosis, leading to a cumulative incidence of cirrhosis of 11% and 24% at 15 and 20 years, respectively. By multivariate analysis, extrahepatic HCV manifestations and HCV genotype 3 were associated with risk of cirrhosis. The median time to cirrhosis in transplant recipients was 18 years as compared with 40 years in the control population. The risk of cirrhosis in transplant recipients relative to controls was significantly higher by multivariate analysis (P = .0008). Roughly a quarter of long-term HCV-infected survivors with transplants progressed to cirrhosis that is much more rapid than in patients without transplants. Systematic detection of HCV infection, liver biopsy, and therapeutic intervention are therefore warranted in long-term marrow transplant recipients.
Prognosis at diagnosis: integrating molecular biologic insights into clinical practice for patients with CLL
Authors: Shanafelt Tait D. , Geyer Susan M. , Kay Neil E.
Published: October 2003

Heterogeneity in the clinical behavior of patients with chronic lymphocytic leukemia (CLL) makes it difficult for physicians to accurately identify which patients may benefit from an early or more aggressive treatment strategy and to provide patients with relevant prognostic information. Given the potential efficacy of newer therapies and the desire to treat patients at “optimum” times, it is more important than ever to develop sensitive stratification parameters to identify patients with poor prognosis. The evolution of risk stratification models has advanced from clinical staging and use of basic laboratory parameters to include relevant biologic and genetic features. This article will review the dramatic progress in prognostication for CLL and will propose statistical modeling techniques to evaluate the utility of these new measures in predictive models to help determine the optimal combination of markers to improve prognostication for individual patients. This discussion will also elaborate which markers and tools should be used in current clinical practice and evaluated in ongoing clinical trials.
Novel concatameric heparin-binding peptides reverse heparin and low-molecular-weight heparin anticoagulant activities in patient plasma in vitro and in rats in vivo
Authors: Schick Barbara P. , Maslow David , Moshinski Adrianna , Antonio James D. San
Published: October 2003

Patients given unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) for prophylaxis or treatment of thrombosis sometimes suffer serious bleeding. We showed previously that peptides containing 3 or more tandem repeats of heparin-binding consensus sequences have high affinity for LMWH and neutralize LMWH (enoxaparin) in vivo in rats and in vitro in citrate. We have now modified the (ARKKAAKA)n tandem repeat peptides by cyclization or by inclusion of hydrophobic tails or cysteines to promote multimerization. These peptides exhibit high-affinity binding to LMWH (dissociation constant [Kd], ≈ 50 nM), similar potencies in neutralizing anti–Factor Xa activity of UFH and enoxaparin added to normal plasma in vitro, and efficacy equivalent to or greater than protamine. Peptide (ARKKAAKA)3VLVLVLVL was most effective in all plasmas from enoxaparin-treated patients, and was 4- to 20-fold more effective than protamine. Several other peptide structures were effective in some patients' plasmas. All high-affinity peptides reversed inhibition of thrombin-induced clot formation by UFH. These peptides (1 mg/300 g rat) neutralized 1 U/mL anti–Factor Xa activity of enoxaparin in rats within 1 to 2 minutes. Direct blood pressure and heart rate measurements showed little or no hemodynamic effect. These heparin-binding peptides, singly or in combination, are potential candidates for clinical reversal of UFH and LMWH in humans.
Ineffective hematopoiesis linked with a mitochondrial tRNA mutation (G3242A) in a patient with myelodysplastic syndrome
Authors: Gattermann Norbert , Wulfert Michael , Junge Bärbel , Germing Ulrich , Haas Rainer , Hofhaus Götz
Published: October 2003

In a patient with refractory anemia with excess blasts (RAEB), a somatic mutation of mitochondrial transfer RNALeu(UUR) was detected in bone marrow cells. Heteroduplex analysis indicated that 40% to 50% of mitochondrial DNA (mtDNA) molecules in the bone marrow (BM) carried the novel G3242A mutation. The proportion of mutant mtDNA was higher in CD34+ cells than in the unfractionated sample. Surprisingly, the mutation was not detectable by heteroduplex analysis in the peripheral blood (PB). However, PB CD34+ cells selected by immunomagnetic beads harbored the mutation with a proportion of approximately 50%. In hematopoietic colony assays, CD34+ cells from BM and PB yielded only colonies with wild-type mtDNA. These results indicate that the mtDNA mutation in CD34+ cells was associated with a maturation defect. Mitochondrial tRNA mutations impair mitochondrial protein synthesis, thereby causing dysfunction of the mitochondrial respiratory chain. We propose that this effect contributed to ineffective hematopoiesis in our patient.
DC-SIGN promotes exogenous MHC-I–restricted HIV-1 antigen presentation
Authors: Moris Arnaud , Nobile Cinzia , Buseyne Florence , Porrot Françoise , Abastado Jean-Pierre , Schwartz Olivier
Published: October 2003

Dendritic cells (DCs) facilitate HIV-1 spread in the host by capturing virions and transferring them to permissive lymphocytes in lymphoid organs. Lectins such as DC-specific ICAM-grabbing non-integrin (DC-SIGN) are involved in HIV-1 uptake by DCs, through high-affinity binding to viral envelope glycoproteins. We examined the role of DC-SIGN on the fate of incoming virions and on major histocompatibility complex class I (MHC-I)–restricted HIV-1 antigen presentation. We show that DC-SIGN expression in B-cell lines dramatically enhances viral internalization. In these cells, and also in primary DCs, most of the captured virions are rapidly degraded, likely in a lysosomal compartment. In addition, a fraction of incoming viral material is processed by the proteasome, leading to activation of anti–HIV-specific cytotoxic T lymphocytes (CTLs) by DC-SIGN–expressing cells. In DCs, DC-SIGN is not the only receptor involved, and redundant pathways of virus capture leading to antigen presentation likely coexist. Altogether, our results highlight new aspects of DC-SIGN interactions with HIV-1. The lectin does not significantly protect captured virions against degradation and promotes MHC-I exogenous presentation of HIV-1 antigens.
Specific inhibition of HIV-1 coreceptor activity by synthetic peptides corresponding to the predicted extracellular loops of CCR5
Authors: Agrawal Lokesh , VanHorn-Ali Zainab , Berger Edward A. , Alkhatib Ghalib
Published: October 2003

We used synthetic peptides to the extracellular loops (ECLs) of CCR5 to examine inhibitory effects on HIV infection/fusion with primary leukocytes and cells expressing recombinant CCR5. We show for the first time that peptides derived from the first, second, or third ECL caused dose-dependent inhibition of fusion and infection, although with varying potencies and specificities for envelope glycoproteins (Envs) from different strains. The first and third ECL peptides inhibited Envs from the R5 Ba-L strain and the R5X4 89.6 strain, whereas the second ECL peptide inhibited Ba-L but not 89.6 Env. None of the peptides affected fusion mediated by Env from the X4 LAV strain. Fusion mediated by Envs from several primary HIV-1 isolates was also inhibited by the peptides. These findings suggest that various HIV-1 strains use CCR5 domains in different ways. Experiments involving peptide pretreatment and washing, modulation of the expression levels of Env and CCR5, analysis of CCR5 peptide effects against different coreceptors, and inhibition of radiolabeled glycoprotein (gp) 120 binding to CCR5 suggested that the peptide-blocking activities reflect their interactions with gp120. The CCR5-derived ECL peptides thus provide a useful approach to analyze structure–function relationships involved in HIV-1 Env-coreceptor interactions and may have implications for the design of drugs that inhibit HIV infection.
Role of tissue factor and protease-activated receptors in a mouse model of endotoxemia
Authors: Pawlinski Rafal , Pedersen Brian , Schabbauer Gernot , Tencati Michael , Holscher Todd , Boisvert William , Andrade-Gordon Patricia , Frank Rolf Dario , Mackman Nigel
Published: October 2003

Sepsis is associated with a systemic activation of coagulation and an excessive inflammatory response. Anticoagulants have been shown to inhibit both coagulation and inflammation in sepsis. In this study, we used both genetic and pharmacologic approaches to analyze the role of tissue factor and protease-activated receptors in coagulation and inflammation in a mouse endotoxemia model. We used mice expressing low levels of the procoagulant molecule, tissue factor (TF), to analyze the effects of TF deficiency either in all tissues or selectively in hematopoietic cells. Low TF mice had reduced coagulation, inflammation, and mortality compared with control mice. Similarly, a deficiency of TF expression by hematopoietic cells reduced lipopolysaccharide (LPS)–induced coagulation, inflammation, and mortality. Inhibition of the down-stream coagulation protease, thrombin, reduced fibrin deposition and prolonged survival without affecting inflammation. Deficiency of either protease activated receptor-1 (PAR-1) or protease activated receptor-2 (PAR-2) alone did not affect inflammation or survival. However, a combination of thrombin inhibition and PAR-2 deficiency reduced inflammation and mortality. These data demonstrate that hematopoietic cells are the major pathologic site of TF expression during endotoxemia and suggest that multiple protease-activated receptors mediate crosstalk between coagulation and inflammation.
Deletion of the α-globin gene cluster as a cause of acquired α-thalassemia in myelodysplastic syndrome
Authors: Steensma David P. , Viprakasit Vip , Hendrick Alex , Goff David K. , Leach Joanne , Gibbons Richard J. , Higgs Douglas R.
Published: October 2003

Rarely, myelodysplastic syndrome (MDS) is complicated by an acquired form of α-thalassemia (α-thalassemia in myelodysplastic syndrome [ATMDS]) characterized by hypochromic, microcytic, anisopoikilocytic red blood cells with hemoglobin H (HbH) inclusions. Acquired mutations in ATRX, a chromatin remodeling gene, have recently been found in 12 patients with typical features of ATMDS, though they have not been detected in MDS patients with similar red blood cell findings but little HbH. The α-globin genes themselves have appeared normal in all ATMDS patients studied to date. Here we characterize the molecular defect in a unique MDS patient with rare HbH inclusions in which an abnormal clone lost a greater than 1.9-Mb segment of the telomeric region of the short arm of one allele of chromosome 16, including both α-globin genes. Red blood cell changes associated with this acquired somatic genotype (––/αα) are surprisingly severe, demonstrating that a minor globin chain imbalance may be unexpectedly deleterious during the abnormal erythropoiesis that occurs in the context of MDS.
Phenotypic and functional alterations of peripheral blood monocytes in neutrophil-specific granule deficiency
Authors: Shiohara Masaaki , Gombart Adrian F , Sekiguchi Yukio , Hidaka Eiko , Ito Susumu , Yamazaki Takashi , Koeffler H Phillip , Komiyama Atsushi
Published: October 2003

Neutrophil-specific granule deficiency (SGD) is a rare, congenital disease characterized by atypical neutrophil structure and function, resulting in recurrent bacterial infections from early infancy. Homozygous recessive mutations in the CCAAT/enhancer-binding protein ɛ (C/EBPɛ) gene were described in two of five SGD patients, indicating loss of C/EBPɛ function as the primary genetic defect in this disease. C/EBPɛ is expressed in murine and human macrophages. Macrophages from the C/EBPɛ-deficient mice show impaired differentiation, phagocytic activity, and transcription of macrophage-specific genes. To determine if monocyte/macrophage cells are impacted in SGD, we analyzed phenotypic features of peripheral blood (PB) monocytes in a SGD individual lacking functional C/EBPɛ. Flow cytometric analysis of PB leukocytes revealed aberrant expression of CD45, CD11b, CD14, CD15, and CD16 on cells from the SGD individual. Also, the PB CD14+ cells from this individual, weakly stained for the monocyte-specific enzyme, nonspecific esterase, and electron microscopic examination, indicated morphologic differences between the SGD cells and those from normal controls. Serum interleukin (IL)-6 levels in the SGD individual during a severe bacterial infection were lower compared with levels in other non-SGD individuals with sepsis. In contrast, serum IL-8 levels were markedly elevated in the SGD individual compared with those of non-SGD individuals in sepsis. PB CD14+ cells from the SGD individual expressed higher IL-8 mRNA levels compared with normal controls in response to lipopolysaccharide and interferon-γ. These phenotypic and functional alterations of PB monocytes in the SGD individual suggest that C/EBPɛ plays a critical role in monocyte/macrophage development of humans and is consistent with observations in the murine system. This study implicates abnormalities in monocytes/macrophages and neutrophils in the onset and development of SGD.
Autocrine inhibitory influences of α-melanocyte-stimulating hormone in malignant pleural mesothelioma
Authors: Catania Anna , Colombo Gualtiero , Carlin Andrea , Garofalo Letizia , Gatti Stefano , Buffa Roberto , Carboni Nadia , Rosso Lorenzo , Santambrogio Luigi , Cantalamessa Luigi , Lipton James M
Published: October 2003

Malignant pleural mesothelioma is a highly aggressive tumor arising from the mesothelial cells that line the pleural cavities. This tumor is resistant to most conventional anticancer treatments and appears to be very sensitive to growth-promoting influences of cytokines and growth factors. Identification of natural inhibitory pathways that control growth should aid discovery of novel therapeutic approaches. We hypothesized that α-melanocyte-stimulating hormone (α-MSH), which is produced by many cell types and antagonizes cytokines and growth factors, could be an endogenous inhibitory molecule in mesothelioma. Twelve mesothelioma cell lines were established from pleural effusions of patients with malignant mesothelioma. Mesothelioma cells were found to express mRNA for proopiomelanocortin and its processing enzymes; release α-MSH peptide into supernatants; and express melanocortin 1 receptor (MC1R), the high-affinity receptor for α-MSH. Immunoneutralization of MC1R in the cell lines enhanced expression of interleukin-8 (IL-8), IL-6, and transforming growth factor-β. These molecules promote mesothelioma proliferation and are considered therapeutic targets in this tumor. Coincubation of mesothelioma cells with synthetic α-MSH significantly reduced cell proliferation. The present research shows an autocrine-inhibitory circuit based on α-MSH and its receptor MC1R. Activation of MC1R by selective peptides or peptidomimetics might provide a novel strategy to reduce mesothelioma cell proliferation by taking advantage of this endogenous inhibitory circuit.
Autologous stem-cell transplantation restores the functional properties of CD14+CD16+ monocytes in patients with myeloma and lymphoma
Authors: Dayyani Farshid , Joeinig Anke , Ziegler-Heitbrock Löms , Schmidmaier Ralf , Straka Christian , Emmerich Bertold , Meinhardt Gerold
Published: October 2003

The CD14+CD16+ monocytes appear to be important to immune defense against infection, as these cells are very potent with respect to tumor necrosis factor (TNF) production, phagocytosis, and antigen presentation. Myeloablative high-dose chemotherapy (HDT) and subsequent autologous stem-cell transplantation (ASCT) are being used increasingly for therapy of hematological malignancies, but the pronounced immunosuppression renders the patients prone to infection. To determine the functional properties of CD14+CD16+ monocytes under these conditions, 15 patients with lymphoma or myeloma were examined. Before HDT, the ratio of CD14+CD16+ cells to the population of the classical CD14++ monocytes was 0.28 ± 0.12; this ratio changed during the course of HDT and ASCT in favor of the CD14+CD16+ monocytes to a maximum of 12.4 ± 7.8 (P<0.001) on day 3.5 ± 1.6 after transplanation (Tx) and returned to 0.11 ± 0.07 (P<0.001) after engraftment on day 11.3 ± 2.2. Although the absolute number of classical CD14++ monocytes declined to less than 1/μl at the nadir, the number of CD14+CD16+monocytes fell from 29.7 ± 9.8/μl to 4.5 ± 3.0/μl at the nadir and increased to 13.8 ± 9.8/μl at the day of discharge from the hospital. Flow cytometric analysis of phagocytosis of fluorescein isothiocyanate (FITC)-labeled Escherichia coli showed that 30 ± 10% CD14+CD16+ monocytes of patients were FITC-positive before Tx, and at engrafment, the percentage of FITC-positive cells had doubled to 60 ± 6% (healthy controls, 41±7%). When determining generation of reactive oxygen species after E. coli ingestion, the CD14+CD16+ monocytes showed a decreased response before Tx (32±12% positve cells), which increased to 53 ± 24% after ASCT. The median fluorescence intensity of human leukocyte antigen (HLA)-DR expression on the CD14+CD16+ monocytes increased from 11 ± 6 before Tx to 17 ± 11 after Tx, and the production of TNF after lipopolysaccharide showed no remarkable difference (46±13 vs. 49±14 channels). At the same time, expression of TNF and of HLA-DR showed a dramatic decrease in the CD14++ monocytes. Taken together after stem-cell Tx, the function of the CD14++ monocytes is impaired, and the functional properties of CD14+CD16+ monocytes recover, indicating that these cells may be important for defense against infections post-ASCT.
Multicentric Study Comparing Intravesical Chemotherapy Alone and With Local Microwave Hyperthermia for Prophylaxis of Recurrence of Superficial Transitional Cell Carcinoma
Authors: Colombo Renzo , Da Pozzo Luigi Filippo , Salonia Andrea , Rigatti Patrizio , Leib Zvi , Baniel Jack , Caldarera Emanuele , Pavone-Macaluso Michele
Published: October 2003

Purpose: To compare the efficacy and local toxicity of the intravesical instillation of a cytostatic drug versus the same cytostatic agent in combination with local hyperthermia as an adjuvant treatment, after complete transurethral resection (TURB) of superficial transitional cell carcinoma (TCC) of the bladder.

Patients and Methods: The study was designed as a prospective, multicentric, randomized trial. Eighty-three patients suffering from primary or recurrent superficial (Ta-T1) TCC of the bladder, after a complete TURB, were randomly assigned to receive intravesical instillations of mitomycin C (MMC) alone, for 41 patients, and MMC in combination with local microwave-induced hyperthermia, for 42 patients. For the combined approach, a new system, Synergo101–1 (Medical Enterprises, Amsterdam, the Netherlands) was used. The effectiveness evaluation end points of the study were evaluation of recurrence-free survival and the estimated probability of recurrence. The safety evaluation end points included subjective and objective side effects and clinical complications. For the efficacy end point, Kaplan-Meier analysis was employed, with the log-rank test for significance. Minimum follow-up time was 24 months.

Results: Of the 83 randomly assigned patients, 75 completed the study according to the protocol and had valid cystoscopy results. Survival analysis of the 75 assessable patients demonstrated a highly significant difference in the survival curves in favor of thermochemotherapy. Subjective intolerance and clinical complications were significantly higher but transient and moderate in the combined treatment group.

Conclusion: In our series, endovesical thermochemotherapy appears to be more effective than standard endovesical chemotherapy as an adjuvant treatment for superficial bladder tumors at 24-month follow-up, despite an increased but acceptable local toxicity.
Time Course and Predictors of Symptoms After Primary Prostate Cancer Therapy
Authors: Talcott James A. , Manola Judith , Clark Jack A. , Kaplan Irving , Beard Clair J. , Mitchell Sonya P. , Chen Ronald C. , O’Leary Michael P. , Kantoff Philip W. , D’Amico Anthony V.
Published: October 2003

Purpose: Understanding the distinctive patterns of treatment-related dysfunction after alternative initial treatments for early prostate cancer (PC) may improve patients’ choice of treatment and later help them adjust to its consequences. We characterized the time course of treatment complications while adjusting for potentially confounding pretreatment factors hindering other observational studies.

Patients and Methods: In a prospective cohort study of 417 men we assessed urinary, bowel, and sexual function from before primary treatment to 24 months after. To control for potential confounding, we measured sociodemographic and PC prognostic factors, medical comorbidity, and pretreatment function commonly affected by PC and its treatment.

Results: Patients who underwent external beam radiotherapy (EBRT), radical prostatectomy (RP), and brachytherapy (BT) differed significantly in sociodemographic factors, cancer prognostic factors, and pretreatment symptom status, especially sexual function. Urinary incontinence increased sharply after RP, while bowel problems and urinary irritation/obstruction rose after EBRT and BT. Sexual dysfunction increased in all patients, particularly after radical prostatectomy, and nerve-sparing surgical technique had little apparent benefit. There was no change in urinary function and little change in overall bowel function after 12 months, but the time course of sexual dysfunction varied by treatment and, for bowel function, by symptom. Multiple regression modeling confirmed that treatment influences all 24-month outcomes, but residual confounding persisted.

Conclusion: Pretreatment function and the primary treatment modality for early stage PC strongly predict the affected organ systems and time course of dysfunction. With this information, patients and their physicians may refine their choice of treatment and better anticipate its consequences.
Preoperative Mitomycin, Ifosfamide, and Cisplatin Followed by Esophagectomy in Squamous Cell Carcinoma of the Esophagus: Pathologic Complete Response Induced by Chemotherapy Leads to Long-Term Survival
Authors: Darnton S.J. , Archer V.R. , Stocken D.D. , Mulholland P.J. , Casson A.G. , Ferry D.R.
Published: October 2003

Purpose: Squamous cell carcinoma of the esophagus remains an aggressive disease with a poor prognosis, even after curative-intent surgery. This article analyzes the impact of preoperative chemotherapy with mitomycin, ifosfamide, and cisplatin (MIC) on a cohort of 68 patients.

Patients and Methods: From 1988 to 1994, 68 patients with potentially operable squamous cell carcinoma of the esophagus were entered onto two phase II trials of neoadjuvant chemotherapy with mitomycin 6 mg/m2, ifosfamide 3 g/m2, and cisplatin 50 mg/m2 and received between two and four cycles of treatment at 3-weekly intervals. Two patients were removed from the analysis when they were found to have malignancy other than squamous cell carcinoma of the esophagus.

Results: Forty (61%) of 66 patients had a radiologic response to chemotherapy (18 complete responses and 22 partial responses), and 52 (79%) of 66 patients went on to have the primary tumor resected. There were nine pathologic complete responders, seven of whom remain fit and well after at least 60 months of follow-up. The overall median survival was 12.4 months (95% confidence interval, 9.6 to 18.8 months). The complete response and node-negative patients survived significantly longer than those in other categories (log-rank χ2 = 18.8; P < .001): on average 13 months longer than the node-positive or nonresected category (22.0 v 9.4 months). The toxicity of the regimen was low.

Conclusion: MIC is an easily administered, well-tolerated, and efficacious regimen as neoadjuvant therapy for patients with squamous cell carcinoma of the esophagus. These results warrant further investigation.
Subcutaneous Interleukin-2 and Interferon Alfa Administration in Patients With Metastatic Renal Cell Carcinoma: Final Results of SCAPP III, a Large, Multicenter, Phase II, Nonrandomized Study With Sequential Analysis Design—The Subcutaneous Administration Propeukin Program Cooperative Group
Authors: Tourani Jean-Marc , Pfister Christian , Tubiana Nicole , Ouldkaci Mahmoud , Prevot Gilles , Lucas Virginie , Oudard Stéphane , Malet Maxime , Cottu Paul , Ferrero Jean-Marc , Mayeur Didier , Rixe Olivier , Sun Xu-Shan , Bernard Olivier , Andre Thierry , Tournigand Christophe , Muracciole Xavier , Guilhot Joelle
Published: October 2003

Purpose: This outpatient multicenter trial tested the hypothesis that subcutaneous administration of an interleukin-2 (IL-2)/interferon alfa (IFNα) combination produces a response rate greater than 20% in patients with renal cell carcinoma (RCC).

Patients and Methods: Patients with metastatic RCC received a 12-week induction treatment with subcutaneous IL-2 (5 days/wk, 9 and 18 million U/d)/IFNα (3 days/wk, 6 million U/d). After evaluation, patients with objective response or stable disease were randomly assigned to maintenance treatment or short consolidation treatment.

Results: Lack of benefit was shown at the 12th sequential analysis, and the trial was closed. At the end of the induction period, 26 (21%) of 122 patients had objective responses (including six complete responses). Thirty-three patients (27%) developed severe toxicity requiring dose reductions, delayed treatment, or treatment termination. Survival rates at one, two, and four years were 63%, 38%, and 17%, respectively. Three-year survival was 20% in patients with two poor prognosis factors and 37% in patients with one or no poor prognosis factors (P = .016). Three-year survival was significantly better (P < 10−3) in patients with erythrocyte sedimentation rate less than 35 mm (43%) compared with those with 1-hour sedimentation rate greater than 35 mm (19%).

Conclusion: This study confirms the importance of prognostic factors when initiating cytokine immunotherapy in patients with metastatic RCC and underlines the prognostic value of erythrocyte sedimentation rate before treatment initiation. Nonetheless, this subcutaneous IL-2/IFNα combination does not improve response rate or survival compared with subcutaneous IL-2 alone, although a definitive conclusion cannot be drawn in the absence of a randomized study comparing the two treatments.
Binet’s Staging System and VH Genes Are Independent but Complementary Prognostic Indicators in Chronic Lymphocytic Leukemia
Authors: Vasconcelos Yuri , Davi Frédéric , Levy Vincent , Oppezzo Pablo , Magnac Christian , Michel Ariane , Yamamoto Mihoko , Pritsch Otto , Merle-Béral Hélène , Maloum Karim , Ajchenbaum-Cymbalista Florence , Dighiero Guillaume
Published: October 2003

Purpose: Rai’s and Binet’s staging systems have contributed significantly to the identification of major prognostic groups in chronic lymphocytic leukemia (CLL), though they fail to accurately predict disease progression at the individual level. Biologic factors, such as the mutational status of the immunoglobulin heavy-chain variable genes (VH, cytogenetics, CD38 expression, and some serum markers, have recently improved prognostic assessment in CLL. In this study, we analyzed the prognostic value of VH mutational status within the different stages of Binet’s classification in 145 patients.

Patients and Methods: Our series consisted of 83 VH mutated (MT) and 62 VH unmutated (UM) patients. MT cases predominated within Binet’s stage A (70%), whereas UM cases predominated among stages B and C (62%).

Results: Median overall survival (OS) was 84 months for UM patients and was not achieved for the MT group (70% 12-year survival, P < .0001). Concerning Binet’s stage A, both median OS and progression-free survival were significantly shorter for UM patients when compared with those of MT patients (97 months v not achieved, P = .0017; and 42 v 156 months, P < .0001), which compared favorably with the classical A′ and A″ substaging. The VH mutational profile could also segregate stage B and C patients into two groups with different survival patterns (median OS, 78 v 120 months for UM and MT patients, respectively; P = .002).

Conclusion: The significant survival differences observed between the VH mutational groups, among stage A and stage B and C patients, indicate that Binet’s classification and VH genes are independent prognostic variables and are most likely complementary.
Assessment of Differences in Patient Populations Selected for or Excluded From Participation in Clinical Phase III Acute Myelogenous Leukemia Trials
Authors: Mengis Catherine , Aebi Stefan , Tobler Andreas , Dähler Werner , Fey Martin F.
Published: October 2003

Purpose: To compare patients treated in or outside clinical protocols, using de novo acute myeloid leukemia (AML) as a model disorder.

Patients and Methods: We retrospectively compared the characteristics of all patients with de novo AML diagnosed in the referral area of our university hospital between 1985 and 1994.

Results: Of a total of 170 AML patients, 45% were included in a phase III trial for the treatment of AML and 55% were treated outside a protocol. Another 45 patients were registered only at diagnosis but were treated elsewhere. Nonstudy patients differed significantly from patients included in clinical trials with respect to age and performance status at clinical presentation, comorbidity, and type of AML. The great majority of patients excluded from trial participation showed distinct exclusion criteria, such as advanced age and severe comorbidity. Study patients were treated significantly more often with curative intent and achieved better response and survival. Patients treated in an equivalent manner but outside a protocol showed no significant difference in survival compared with patients enrolled onto a trial.

Conclusion: Study patients were not representative for the entire population of patients with AML; many patients were excluded from phase III trial participation for failure to meet stringent entry criteria. Therefore, results of phase III studies may not be extrapolated to all AML patients but should only be applied to patients who do not differ in substantial characteristics from the study population.