bluuebunny/crossref_metadata_2025 huggingface dataset:
Macrophage Hemoglobin Scavenger Receptor and Ferritin Accumulation in Human Atherosclerotic Lesions
Authors: LI WEI , XU LI‐HUA , YUAN XI‐MING
Published: January 2005

Abstract: We previously proposed that erythrophagocytosis and iron metabolism by macrophages may contribute to iron‐driven oxidative stress in atherogenesis. Recent studies have indicated that the macrophage hemoglobin scavenger receptor (HbSR/CD163) is a key molecule in the process of removing hemoglobin released from senescent erythrocytes. In this study we investigated erythrophagocytosis and its relation to ferritin accumulation and the involvement of CD163 in ferritin induction in human atheroma lesions. Normal and atherosclerotic human arterial segments obtained at autopsy and surgery were collected for iron histochemistry, hemoglobin and ferritin immunohistochemistry, and computerized image analysis. The lesion‐dependent accumulation of ferritin and hemoglobin was seen in atherosclerotic carotid and coronary arteries. The immunoreactivity of hemoglobin was significantly correlated to the same regions of ferritin immunoreactivity on serial sections. The staining intensity of hemoglobin and ferritin was also significantly correlated. Hemoglobin deposition is often associated with microvessels adjacent to the lipid core areas in advanced lesions, where most CD68‐positive macrophages were. CD163 expression appeared in both early and advanced lesions. The accumulation of tissue iron and ferritin also frequently occurs in CD163‐positive and vessel‐rich regions in the advanced atheroma. Although they were not always correspondingly positive on the serial sections, tissue iron and ferritin were significantly correlated. We conclude that erythrophagocytosis and hemoglobin catabolism by macrophages contribute to iron deposition and ferritin induction in human atheroma. The involvement of CD163 during ferritin induction may play an important role in modulating inflammatory processes in atherogenesis.
Regulation of Tumor Cell Motility by ERK Mitogen‐Activated Protein Kinases
Authors: VIAL EMMANUEL , POUYSSÉGUR JACQUES
Published: January 2005

Abstract: Metastasis is the main cause of human cancer deaths, and cell motility is one key component of the process of metastasis. The ERK mitogen‐activated protein kinase (MAPK) signaling pathway is probably one of the most commonly activated in malignant human cancers. We describe the molecular mechanisms by which ERK MAPK signaling regulates cell motility and its importance for cancer cell dissemination.
The Phosphotyrosine Phosphatase η Mediates Somatostatin Inhibition of Glioma Proliferation via the Dephosphorylation of ERK1/2
Authors: MASSA ALESSANDRO , BARBIERI FEDERICA , AIELLO CINZIA , IULIANO RODOLFO , ARENA SARA , PATTAROZZI ALESSANDRA , CORSARO ALESSANDRO , VILLA VALENTINA , FUSCO ALFREDO , ZONA GIANLUIGI , SPAZIANTE RENATO , SCHETTINI GENNARO , FLORIO TULLIO
Published: January 2005

Abstract: Somatostatin (SST) controls the proliferation of a variety of cell types. Its effects are mediated by five G protein‐coupled receptors (SSTR1‐SSTR5), variably expressed in normal and cancer tissues. SST inhibition of cell proliferation can be exploited by both direct and indirect mechanisms: the main direct pathway involves the modulation of phosphotyrosine phosphatase (PTP) activity. Here we show that SST cytostatic activity is mediated by the activation of a receptor‐like PTP, named PTPη. The role of this PTP in the antiproliferative activity of SST in five glioma cell lines (C6, U87MG, U373MG, DBTRG05MG, and CAS1) and in four postsurgical human glioblastoma specimens, has been studied. SST inhibited growth only in C6 and U87MG that express PTPη. In C6 cells, SST antiproliferative effects were reverted by pretreatment with pertussis toxin and vanadate, indicating the involvement of G proteins and PTPs. The role of PTPη in the SST inhibitory effects was demonstrated by testing the PTPη activity: it was increased by SST treatment and paralleled by inhibition of ERK1/2 activation. Since basic fibroblast growth factor‐dependent MEK phosphorylation was not affected by SST, we propose a direct effect of SST‐activated PTPη on ERK1/2 phosphorylation. Finally, the SSTR mRNAs were identified in all of the 36 gliomas analyzed, whereas PTPη expression was found in 33% of cases. Culturing four gliomas, a precise correlation between the expression of PTPη and the SST antiproliferative effects was identified. In conclusion, in glioma cells, SST antiproliferative activity requires the expression and activation of PTPη, which directly dephosphorylates ERK1/2.
Lack of N1L Gene Expression Results in a Significant Decrease of Vaccinia Virus Replication in Mouse Brain
Authors: BILLINGS B , SMITH S A. , ZHANG Z , LAHIRI D K. , KOTWAL G J.
Published: January 2005

Abstract: Vaccinia virus encodes secretory proteins termed virokines. One of the major virokines encoded by the N1L open reading frame is the 13.8 kDa protein. A recombinant virus, termed vGK5, lacking this protein when injected intracranially into mice, has one of the highest levels of in vivo attenuation achieved by deletion of any single open reading frame of vaccinia virus. Here we show that the 13.8 kDa protein significantly enhances viral replication within brain tissue; however, analysis of histology, neutrophil infiltrate, and nitric oxide synthase activity of brain tissue shows no significant differences between wild‐type vaccinia virus and vGK5. Since there is poor growth of vGK5 virus in the brain, the possibility of postvaccinial encephalitis is significantly diminished. Mice injected with vGK5 became resistant to the lethal effects of vaccinia virus, indicating that vGK5 is immunogenic in the brain without being virulent and therefore is a vaccine candidate. This suggests that should vGK5 reach the brain it will not replicate efficiently but still serve as a live vaccine.
Effect of Metal Complexes on Thioredoxin Reductase and the Regulation of Mitochondrial Permeability Conditions
Authors: BRAGADIN M , SCUTARI G , FOLDA A , BINDOLI A , RIGOBELLO M P
Published: January 2005

Abstract: Gold(I) compounds such as auranofin, chloro(triethylphosphine) gold(I), and aurothiomalate act on mitochondrial functional parameters by determining an extensive permeability transition and a decrease of membrane potential. On the contrary, pyridine nucleotides and glutathione are not modified, whereas a slight but significant decrease of total thiols is apparent. The effect of gold(I) compounds is essentially referable to the inhibition, in the nanomolar range, of thioredoxin reductase activity and to an increase of hydrogen peroxide production. Metal ions and metal complexes (zinc and cadmium acetate, cisplatin, tributyltin) are also good inhibitors of thioredoxin reductase, although in the micromolar range, and in addition, they act as inducers of permeability transition and of membrane potential decrease. At variance with gold(I) compounds, which appear to work almost exclusively on thioredoxin reductase, metal ions and complexes are less specific, since they are active on different mitochondrial targets, including the respiratory chain.
The Antiapoptotic Protein ICBP90 Is a Target for Protein Kinase 2
Authors: BRONNER CHRISTIAN , TROTZIER MARIE‐ALINE , FILHOL ODILE , COCHET CLAUDE , ROCHETTE‐EGLY CÉCILE , SCHÖLLER‐GUINARD MARIE , KLEIN JEAN‐PAUL , MOUSLI MARC
Published: January 2005

Abstract: Protein kinase 2 (casein kinase 2 [CK2]) is a protein serine/threonine kinase involved in cell proliferation with an expression that is dysregulated in tumors. ICBP90, a transcription factor exhibiting antiapoptotic properties, has several putative CK2 phosphorylation sites. The aim of the present study was to investigate whether ICBP90 could behave as a CK2 substrate. We observed that ICBP90 was more efficiently phosphorylated by the free CK2a subunit than by the heterotetrameric CK2 (α2, β2). Our results suggest that CK2 is an important regulator of the transcriptional activity of ICBP90 and therefore of the antiapoptotic properties of ICBP90. We propose that the “ICBP90 family” members may be substrates for CK2.
Docosahexaenoic Acid from a Cultured Microalga Inhibits Cell Growth and Induces Apoptosis by Upregulating Bax/Bcl‐2 Ratio in Human Breast Carcinoma MCF‐7 Cells
Authors: CHIU LAWRENCE C.‐M. , WONG ELAINE Y.‐L. , OOI VINCENT E.C.
Published: January 2005

Abstract: Docosahexaenoic acid (DHA) is an ω‐3 fatty acid that comprises 22 carbons and 6 alternative double bonds in its hydrocarbon chain (22:6ω3). Previous studies have shown that DHA from fish oil controls the growth and development of different cancers; however, safety issues have been raised repeatedly about contamination of toxins in fish oil that makes it no longer a clean and safe source of the fatty acid. We investigated the cell growth inhibition of DHA from the cultured microalga Crypthecodinium cohnii (algal DHA [aDHA]) in human breast carcinoma MCF‐7 cells. aDHA exhibited growth inhibition on breast cancer cells dose‐dependently by 16.0% to 59.0% of the control level after 72‐h incubations with 40 to 160 μM of the fatty acid. DNA flow cytometry shows that aDHA induced sub‐G1 cells, or apoptotic cells, by 64.4% to 171.3% of the control levels after incubations with 80 mM of the fatty acid for 24, 48, and 72 h. Western blot studies further show that aDHA did not modulate the expression of proapoptotic Bax protein but induced the downregulation of anti‐apoptotic Bcl‐2 expression time‐dependently, causing increases of Bax/Bcl‐2 ratio by 303.4% and 386.5% after 48‐ and 72‐h incubations respectively with the fatty acid. Results from this study suggest that DHA from the cultured microalga is also effective in controlling cancer cell growth and that downregulation of antiapoptotic Bcl‐2 is an important step in the induced apoptosis.
Expression of the Insulin‐Like Growth Factor‐I Receptor and Proapoptotic Bax and Bak Proteins in Human Colorectal Cancer
Authors: KODA MARIUSZ , RESZEC JOANNA , SULKOWSKA MARIOLA , KANCZUGA‐KODA LUIZA , SULKOWSKI STANISLAW
Published: January 2005

Abstract: Insulin‐like growth factor‐I (IGF‐I) and IGF‐I receptor (IGF‐IR), despite their well‐known roles in cell survival and proliferation, can also weakly enhance apoptosis. To study the relationships between the IGF‐IR and Bax as well as Bak, 144 cases of colorectal cancer were examined by immunohistochemistry, using the avidin‐biotin‐peroxidase method. The results were correlated with selected clinicopathological features of colorectal cancer and with the expression of IGF‐IR, Bax, and Bak in normal colon mucosa. In Bax‐, Bak‐, or IGF‐IR‐positive cancers, the adjacent colorectal mucosa revealed positive immunostaining for these proteins. In the majority of Bax‐, Bak‐, or IGF‐IR‐negative tumors, we observed no staining for these proteins in adjacent mucosa. The strong immunostaining for IGF‐IR, Bax, and Bak was noted in 50.8, 55.5, and 49.3% of tumors, respectively. We observed positive correlations between IGF‐IR and Bax (P < 0.002, r= 0.302), between IGF‐IR and Bak (P < 0.0001, r= 0.407), and between Bax and Bak (P < 0.0001, r= 0.474). No relationship was noted between IGF‐IR expression and tumor grade, stage, or lymph node status. We found negative associations between Bax, Bak, and tumor grade (P < 0.01 and P < 0.003, respectively), but no relationships between Bax and Bak and tumor stage or between Bax and Bak and lymph node status. Our results demonstrate that, in addition to overexpressed IGF‐IR, there are relationships between IGF‐IR and proapoptotic proteins in colorectal carcinomas that could contribute to increased cell turnover and the progression of colorectal cancer.
Mitochondria of Human Spermatozoa Are Preferentially Susceptible to Apoptosis
Authors: PAASCH UWE , GRUNEWALD SONJA , DATHE SYLVIA , GLANDER HANS‐JUERGEN
Published: January 2005

Abstract: Although elements of type I and II apoptosis have been demonstrated in human spermatozoa, their functionality has not been evaluated. The first dynamic studies revealed no type I apoptosis signal transduction via CD95. The aim of our study was to clarify whether type II apoptosis can be induced in human spermatozoa. Betulinic acid, a cytotoxic agent and highly specific inductor of type II apoptosis, acts by a direct effect on mitochondria. Motility, mitochondrial transmembrane potential, and active caspase‐9 and ‐3 were examined in human ejaculated spermatozoa of 33 semen samples from healthy volunteers after incubation with 60 μg/mL betulinic acid for 10 and 60 min, respectively. Untreated aliquots of each sample served as negative controls. Treatment with betulinic acid resulted in the induction of type II apoptosis measured by disruption of mitochondrial transmembrane potential and activation of caspase‐9 and ‐3. The loss of mitochondrial energy supply resulted in a significant decrease of spermatozoal motility and velocity. In spermatozoa, mitochondria are tightly packed and located exclusively in the midpiece region. This might contribute to their susceptibility against the induction of type II apoptosis and should be considered for therapeutic interventions and might have a future in the development of advanced birth control methods.
Alternatively Spliced Protein Variants as Potential Therapeutic Targets for Male Infertility and Contraception
Authors: FARDILHA MARGARIDA , WU WENJUAN , SÁ ROSÁLIA , FIDALGO SARA , SOUSA CRISTINA , MOTA CATARINA , DA CRUZ E SILVA ODETE A.B. , DA CRUZ E SILVA EDGAR F.
Published: January 2005

Abstract: Mammalian sperm were previously shown to express the PP1γ2 isoform of protein phosphatase 1 (PP1) as well as its regulatory proteins inhibitor 2 and glycogen synthase kinase 3. Furthermore, the development of sperm motility during transit through the epididymis correlates with changes in PP1 activity. Thus, since PP1 cellular activity is determined by the partners it binds, we embarked on a study aimed at defining the specific interactomes of PP1γ1 and PP1γ2 (the two known alternatively spliced variants of PP1γ). To this end, exhaustive screens were performed on a human testis cDNA library using the yeast two‐hybrid method. Among the various proteins detected, the most abundant interactors with PP1γ2 were Nek2A and R15B. Closer sequence analysis revealed novel alternatively spliced variants of Nek2A and NIPP1, which we designated Nek2A‐T and NIPP1‐T, respectively. They were shown to be highly expressed in rat and human testis by Northern analysis and to result from alternative splicing events by RT‐PCR. Thus, both the previously known Nek2A isoform and the novel Nek2A‐T and NIPP1‐T variants appear to bind PP1γ2 in vitro (blot overlays) and in vivo by coexpression in yeast. The usefulness of testis‐specific alternatively spliced proteins as targets for the development of novel therapeutic strategies for male infertility and contraception is discussed. PP1γ2, Nek2A‐T, and NIPP1‐T are currently being investigated as alternatively spliced targets for signal transduction therapeutics.
GATA‐1: Friends, Brothers, and Coworkers
Authors: MORCEAU FRANCK , SCHNEKENBURGER MICHAEL , DICATO MARIO , DIEDERICH MARC
Published: January 2005

Abstract: GATA‐1 is the founding member of the GATA family of transcription factors. GATA‐1 and GATA family member GATA‐2 are expressed in erythroid and megakaryocytic lineages, in which they play a crucial role in cell maturation and differentiation. GATA‐1 regulates the transcription of many specific and nonspecific erythroid genes by binding to DNA at the consensus sequence WGATAR, which is recognized by all of the GATA family of transcription factors. However, it was identified in eosinophilic cells and also in Sertoli cells in testis. Its activity depends on close cooperation with a functional network of cofactors, among them Friend of GATA, PU.1, and CBP/p300. The GATA‐1 protein structure has been well described and includes two zinc fingers that are directly involved in the interaction with DNA and other proteins in vivo. GATA‐1 mutations in the zinc fingers can cause deregulation of required interactions and lead to severe dysfunction in the hematopoietic system.
Tetramethoxy Hydroxyflavone p7F Downregulates Inflammatory Mediators via the Inhibition of Nuclear Factor κB
Authors: LEE HEE‐GU , KIM HYOSON , OH WON‐KEUN , YU KYUNG‐AE , CHOE YONG‐KYUNG , AHN JONG‐SEOG , KIM DONG‐SOO , KIM SOO‐HYUN , DINARELLO CHARLES A. , KIM KILHYOUN , YOON DO‐YOUNG
Published: January 2005

Abstract: Artemisia has been traditionally used in Korean herbal medicine to clear damp heat and to treat uteritis and jaundice. Flavonoids isolated from Artemisia are also known to possess anti‐inflammatory activities. In this study, 5,6,3′,5′‐tetramethoxy 7,4′‐hydroxyflavone (p7F) was isolated from Artemisia absinthium. We examined in vitro and in vivo regulatory functions of p7F on the production of nitric oxide (NO), prostaglandin E2 (PGE2), and tumor necrosis factor‐α (TNF‐α) as well as the expression of inducible NO synthase (iNOS), cyclooxygenase‐2 (COX‐2), and collagen‐induced arthritis. p7F inhibited the expression or production of proinflammatory mediators such as COX‐2/PGE2 and iNOS/NO in lipopolysaccharide (LPS)‐stimulated RAW 264.7 cells. p7F also suppressed the serum level of TNF‐α in mice treated with collagen and inhibited nuclear factor‐κB (NF‐κB) activation as well as NF‐κB promoter activity in RAW 264.7 cells stimulated with LPS. This compound directly inhibited the intracellular accumulation of reactive oxygen species in hydrogen peroxide‐stimulated RAW 264.7 cells. p7F has antioxidant activity and inhibits NF‐κB activation. Taken together, these results suggest that p7F can be clinically applied to the treatment of inflammatory diseases.
Effects of Curcumin (Diferuloylmethane) on Nuclear Factor κB Signaling in Interleukin‐1β‐Stimulated Chondrocytes
Authors: SCHULZE‐TANZIL GUNDULA , MOBASHERI ALI , SENDZIK JUDITH , JOHN THILO , SHAKIBAEI MEHDI
Published: January 2005

Abstract: Curcumin (diferuloylmethane) is a nontoxic dietary pigment in tumeric and curry and a potent inhibitor of the common transcription factor Nuclear Factor κB (NF‐κB) in several cell types. It is well established that some of the catabolic effects of the proinflammatory cytokines interleukin‐1β (IL‐1β) and tumor necrosis factor‐α in osteoarthritis are regulated by the activation of NF‐κB. Therefore, the aim of this study was to determine whether curcumin modifies the catabolic response of chondrocytes to IL‐1β. Human articular chondrocytes were prestimulated with 10 ng/mL IL‐1β for 0, 4, 8, 12, or 24 h and then cotreated with 50 μM curcumin for 0, 12, 24, 36, or 48 h. Synthesis of the cartilage‐specific collagen type II and matrix‐degrading enzyme matrix metalloproteinase‐3 (MMP‐3) was investigated in chondrocytes by Western blot analysis. Activation and nuclear translocation of NF‐κB were observed by immunofluorescence microscopy. IL‐1β induced a decrease in collagen type II and upregulation of MMP‐3 in a time‐dependent manner. Upregulation of MMP‐3 was inhibited by curcumin in a time‐dependent manner. In addition, IL‐1β‐induced a decrease in type II collagen, which was relieved by curcumin treatment. In response to IL‐1β, NF‐κB translocated to the nucleus, but translocation was inhibited by curcumin, as revealed by immunofluorescence microscopy. Taken together, these results confirmed an IL‐1β‐mediated upregulation of proinflammatory MMP‐3 in chondrocytes via an NF‐κB activation mechanism. Curcumin protected chondrocytes from the catabolic effects of IL‐1β, such as MMP‐3 upregulation, and interestingly also relieved cytokine‐induced suppression of matrix protein synthesis. Therefore, curcumin antagonizes crucial catabolic effects of IL‐1β signaling that are known to contribute to the pathogenesis of osteoarthritis.
Role of Acetylases and Deacetylase Inhibitors in IRF‐1‐Mediated HIV‐1 Long Terminal Repeat Transcription
Authors: MARSILI GIULIA , REMOLI ANNA LISA , SGARBANTI MARCO , BATTISTINI ANGELA
Published: January 2005

Abstract: There is strong evidence that both transcriptional activation and silencing are mediated through the recruitment of enzymes that control reversible protein acetylation: histone acetylase (HAT) and histone deacetylase proteins. Acetylation is also a critical post‐translational modification of general and tissue‐specific transcription factors. In HIV‐1‐infected cells, the long terminal repeat (LTR) promoter, once organized into chromatin, is transcriptionally inactive in the absence of stimulation. LTR transcription is regulated by protein acetylation, since treatment with deacetylase inhibitors markedly induces transcriptional activity of the LTR. Besides cellular transcription factors involved in LTR activation, early in infection, and during reactivation from latency, we have previously shown that proteins of the IRF family play an important role. In particular, IRF‐1 is able per se to stimulate HIV‐1 LTR transcription even in the absence of Tat. IRF‐1 is also acetylated and associates with HATs such as p300/CBP and PCAF to form a multiprotein complex that assembles on the promoter of target genes. Here we show that CBP can be recruited by IRF‐1 to the HIV‐1 LTR promoter even in the absence of Tat and that treatment with deacetylase inhibitors, such as trichostatin A (TSA), increases LTR transactivation in response to both IRF‐1 and Tat. These results help to define the architecture of interactions between transcription factors binding HIV‐1 LTR and confirm the possibility that deacetylase inhibitors, such as TSA, combined with antiviral therapy may represent a valuable approach to control HIV‐1 infection.
Prognostic Implications of Multiple Lymphatic Basin Drainage in Patients With Truncal Melanoma
Authors: Jimenez Ramon E. , Panageas Katherine , Busam Klaus J. , Brady Mary S.
Published: January 2005

Purpose

Lymphatic drainage to multiple basins (MLBD) is frequently observed in patients with truncal melanoma undergoing sentinel lymph node (SLN) mapping. Recently published data suggest that patients with MLBD are at increased risk of nodal metastases compared with those with single lymphatic basin drainage (SLBD). We studied the impact of MLBD on SLN positivity and survival.

Patients and Methods

We identified 266 patients with truncal melanoma undergoing SLN mapping and biopsy from 1995 to 2001. MLBD was defined as lymphoscintigraphic and intraoperative identification of an SLN in more than one nodal basin. Clinical and pathologic variables were recorded and analyzed for their impact on survival.

Results

MLBD occurred in 76 patients (29%), and SLBD occurred in 190 patients (71%). Clinical and pathologic variables were similar between the two groups, although there were more males in the MLBD group (78% v 64%; P = .034). Patients with MLBD did not have higher risk for positive SLNs compared with those with SLBD (22% v 21%, respectively). Five-year survival for patients with MLBD was less favorable than that of patients with SLBD (68% v 78%, respectively; log-rank P = .04). Multivariate analysis revealed that increasing Breslow thickness (P < .001), SLN metastasis (P < .001), and MLBD (P = .04) were independent predictors of poor overall and relapse-free survival. The negative prognostic implication of MLBD remained significant when only patients with negative SLNs were analyzed (relative risk, 2.7; P = .03).

Conclusion

MLBD in patients with truncal melanoma undergoing SLN mapping is associated with a less favorable survival compared with patients with SLBD, independent of SLN status.
Ewing Sarcomas With p53 Mutation or p16/p14ARF Homozygous Deletion: A Highly Lethal Subset Associated With Poor Chemoresponse
Authors: Huang Hsuan-Ying , Illei Peter B. , Zhao Zhiquan , Mazumdar Madhu , Huvos Andrew G. , Healey John H. , Wexler Leonard H. , Gorlick Richard , Meyers Paul , Ladanyi Marc
Published: January 2005

Purpose

EWS-FLI1 fusion type, p53 mutation, and homozygous deletion of p16/p14ARF have each been shown to be prognostically significant in Ewing sarcoma (ES). We provide the first combined prognostic analysis of these three molecular parameters in ES.

Patients and Methods

We studied 60 patients with ES (stage: localized in 54, metastatic in six). All cases were confirmed to contain the EWS-FLI1 (29 type 1, 12 type 2, 14 other types) or EWS-ERG fusions (five cases). Homozygous deletion of p16/p14ARF, and p53 mutations were determined by fluorescent in situ hybridization and Affymetrix (Santa Clara, CA) p53 GeneChip microarray hybridization, respectively.

Results

Eight cases (13.3%) contained point mutations of p53, and eight cases (13.3%) showed p16/p14ARF deletion, including one case with both alterations. Among 32 cases with data on histologic chemoresponse, all 10 with alterations in p53 or p16/p14ARF showed a poor chemoresponse (P = .03). Variables predicting poorer overall survival included p53 mutation alone (P < .001), either p53 or p16/p14ARF alteration (P < .001), and stage (P < .01). In multivariate analysis, alterations of p53 and/or p16/p14ARF as a single variable, was the most adverse prognostic factor (P < .001), followed by stage (P = .04). In a multivariate analysis with alterations of p53 and p16/p14ARF as separate variables, both were significant (P < .001 and P = .03, respectively). Six cases with p16/p14ARF deletion were also studied for co-deletion of the contiguous methylthioadenosine phosphorylase gene, and this was detected in four cases.

Conclusion

Alterations in p53 or p16/p14ARF are found in a fourth of ES cases and define a subset with highly aggressive behavior and poor chemoresponse.
Docetaxel and Continuous-Infusion Fluorouracil Versus Epirubicin, Cisplatin, and Fluorouracil for Advanced Gastric Adenocarcinoma: A Randomized Phase II Study
Authors: Thuss-Patience Peter C. , Kretzschmar Albrecht , Repp Michael , Kingreen Dorothea , Hennesser Dirk , Micheel Simone , Pink Daniel , Scholz Christian , Dörken Bernd , Reichardt Peter
Published: January 2005

Purpose

A combination of docetaxel and fluorouracil (DF) was evaluated in an outpatient setting and compared with epirubicin, cisplatin, and fluorouracil (ECF), which served as an internal control arm to avoid selection bias.

Patients and Methods

Patients with metastatic or locally advanced gastric adenocarcinoma without prior chemotherapy were randomly assigned to receive either ECF (epirubicin 50 mg/m2 day 1, cisplatin 60 mg/m2 day 1, and fluorouracil 200 mg/m2 days 1 through 21, every 3 weeks) or DF (docetaxel 75 mg/m2 day 1, and fluorouracil 200 mg/m2 days 1 through 21, every 3 weeks).

Results

Ninety patients were randomly assigned. Toxicity was rarely severe. Major toxic effects included diarrhea, stomatitis, and leukopenia in the DF arm and nausea, vomiting, and leukopenia in the ECF arm. Forty-three of 45 patients in each arm were assessable. In the DF arm, two patients (4.4%, intent to treat) experienced a confirmed complete tumor remission as best response, and 15 patients (33.3%) experienced a confirmed partial remission (overall response rate [ORR], 37.8%; 95% CI, 25.9% to 51.9%). Two patients (4.4%) in the ECF arm showed confirmed complete remission, and 14 (31.1%) showed confirmed partial remission (ORR, 35.6%; 95% CI, 24.8% to 48.7%). For the DF and ECF arms, the median survival was 9.5 and 9.7 months, and the median time to tumor progression 5.5 and 5.3 months, respectively.

Conclusion

DF can be safely given in an ambulant setting. Compared with ECF, the dual combination of DF shows promising efficacy and may be an alternative treatment option that avoids cisplatin.
Long-Term Health-Related Quality of Life, Growth, and Spiritual Well-Being After Hematopoietic Stem-Cell Transplantation
Authors: Andrykowski Michael A. , Bishop Michelle M. , Hahn Elizabeth A. , Cella David F. , Beaumont Jennifer L. , Brady Marianne J. , Horowitz Mary M. , Sobocinski Kathleen A. , Rizzo J. Douglas , Wingard John R.
Published: January 2005

Purpose

To examine health-related quality of life (HRQOL) and growth, and spiritual well-being in adult survivors of hematopoietic stem-cell transplantation (HSCT) for a malignant disease.

Methods

HSCT survivors (n = 662) were recruited through the International Bone Marrow Transplant Registry/Autologous Blood and Marrow Transplant Registry and were drawn from 40 transplantation centers. HSCT survivors completed a telephone interview and a set of questionnaires a mean of 7.0 years post-HSCT (range, 1.8 to 22.6 years). Study measures included a variety of standardized measures of HRQOL and growth and spiritual well-being. An age- and sex-matched healthy comparison (HC) group (n = 158) was recruited using a peer nomination method. The HC group completed a parallel telephone interview and set of questionnaires.

Results

Multivariate analysis of variance analyses found the HSCT survivor group reported poorer status relative to the HC group for all HRQOL outcome clusters including physical health, physical functioning, social functioning, psychological adjustment, and dyadic adjustment. In contrast, the HSCT survivor group reported more psychological and interpersonal growth. Mean effect size for the 24 outcome indices examined was 0.36 standard deviations, an effect size often considered clinically meaningful or important. The largest group differences were found for measures of general health, physical function and well-being, depression, cognitive function, and fatigue.

Conclusion

The experience of HSCT for a malignant disease has a wide-ranging, longstanding, and profound impact on adult recipients. Relative to healthy controls, HSCT survivors reported poorer physical, psychological, and social functioning but, conversely, more psychological and interpersonal growth, differences that appeared to persist many years after HSCT.
Osteosarcoma Relapse After Combined Modality Therapy: An Analysis of Unselected Patients in the Cooperative Osteosarcoma Study Group (COSS)
Authors: Kempf-Bielack Beate , Bielack Stefan S. , Jürgens Heribert , Branscheid Detlev , Berdel Wolfgang E. , Exner G. Ulrich , Göbel Ulrich , Helmke Knut , Jundt Gernot , Kabisch Hartmut , Kevric Mathias , Klingebiel Thomas , Kotz Rainer , Maas Rainer , Schwarz Rudolf , Semik Michael , Treuner Jörn , Zoubek Andreas , Winkler Kurt
Published: January 2005

Purpose

To evaluate the impact of patient, tumor, and treatment-related factors on outcome in unselected patients with recurrent osteosarcoma.

Patients and Methods

Five hundred seventy-six consecutive patients who had achieved a first complete surgical remission (CR) during combined-modality therapy on neoadjuvant Cooperative Osteosarcoma Study Group (COSS) protocols and then developed recurrent osteosarcoma were analyzed (median time from biopsy to relapse, 1.6 years; range, 0.1 to 14.3 years). There were 501 patients with metastases, 44 with local recurrences, and 31 with both. Metastases involved lungs (469 patients), bones (90 patients), and/or other sites (54 patients).

Results

After a median follow-up of 1.2 years for all patients and 4.2 years for survivors, actuarial overall survival (OS) rates at 2, 5, and 10 years were 0.38, 0.23, and 0.18, respectively. Five-year OS was 0.39 for 339 patients with and 0.00 for 229 patients without a second surgical CR (P < .0001). A long time to relapse, a solitary lesion, and, in the case of pulmonary metastases, unilateral disease and the absence of pleural disruption, were of positive prognostic value in uni- and multivariate analyses, as were a second surgical CR and the use of second-line chemotherapy. Radiotherapy was associated with moderately prolonged survival in patients without a second CR. The very limited prognostic differences associated with the use of second-line chemotherapy appeared to be more pronounced with polychemotherapy.

Conclusion

Time to relapse and tumor burden correlate with postrelapse outcome in osteosarcoma. Complete surgery is an essential component of curative second-line therapy. Chemotherapy, particularly chemotherapy with more than one agent, may contribute to limited improvements in outcome.
Intensive Systemic Chemotherapy Combined With Surgery for Metastatic Colorectal Cancer: Results of a Phase II Study
Authors: Taïeb Julien , Artru Pascal , Paye François , Louvet Christophe , Perez Nathalie , André Thierry , Gayet Brice , Hebbar Mohamed , Goebel Frédérique Maindrault , Tournigand Christophe , Parc Rolland , de Gramont Aimery
Published: January 2005

Purpose

To evaluate the efficacy and tolerability of the metastatic irinotecan plus oxaliplatin (MIROX) strategy (adjuvant FOLFOX-7 followed by FOLFIRI), in patients with resectable metastatic colorectal cancer.

Patients and Methods

Forty-seven patients with resectable metastases of colorectal cancer were prospectively enrolled onto this study. Treatment consisted of six cycles of leucovorin 400 mg/m2, oxaliplatin 130 mg/m2 in a 120-minute infusion, and fluorouracil (FU) 2,400 mg/m2 in a 46-hour infusion, every 2 weeks (FOLFOX-7), followed by six cycles of leucovorin 400 mg/m2, irinotecan 180 mg/m2 in a 90-minute infusion, bolus FU 400 mg/m2, and FU 2,400 mg/m2 as a 46-hour infusion, every 2 weeks (FOLFIRI). Surgery was performed before chemotherapy in 25 patients and after six cycles of FOLFOX-7 in 22 patients (six cycles of FOLFIRI were administered after surgery).

Results

All but one of the patients underwent curative surgery. Two patients refused postoperative chemotherapy. Tolerability was generally good. The main toxicities were grade 3 to 4 neutropenia (13%) and thrombocytopenia (11%); no febrile neutropenia or bleeding occurred, and there were no deaths caused by toxicity. Two pathologically confirmed complete responses and 15 partial responses were obtained with FOLFOX-7 in the 22 patients who received this regimen before surgery (overall response rate, 77%; 95% CI, 68 to 86). The median disease-free survival time was 21 months; the median overall survival has not yet been reached. The 2-year overall and disease-free survival rates were 89% and 47%, respectively.

Conclusion

The MIROX strategy is feasible and well tolerated by patients with resectable metastatic colorectal cancer. Progression-free and overall survival rates are promising, with a median of 38 months of follow-up. This strategy currently is being compared with the leucovorin and FU regimen in a phase III trial.
Racial Differences in Surgical Evaluation, Treatment, and Outcome of Locoregional Esophageal Cancer: A Population-Based Analysis of Elderly Patients
Authors: Steyerberg Ewout W. , Earle Craig C. , Neville Bridget A. , Weeks Jane C.
Published: January 2005

Purpose

We investigated racial disparities in access to surgical evaluation, receipt of surgery, and survival among elderly patients with locoregional esophageal cancer.

Methods

We selected 2,946 white patients and 367 black patients who were older than 65 years and had clinically locoregional esophageal cancer in the Surveillance, Epidemiology, and End Results (SEER) registry (1991 to 1999). Treatment and outcome data were obtained from the linked SEER-Medicare databases. We used logistic regression analysis to estimate odds ratios (ORs) for being seen by a surgeon and for undergoing surgery. Cox proportional hazards analyses were performed to estimate hazard ratios (HRs) for survival adjusted for medical, nonmedical, and treatment characteristics.

Results

The rate of surgery for black patients was half that of white patients (25% v 46%; OR, 0.38; P < .001), which was caused by both a lower rate of seeing a surgeon (70% v 78%; OR, 0.66; P < .001) and a lower rate of surgery once seen (35% v 59%; OR, 0.38; P < .001). These racial disparities were only partly explained by differences in patient and cancer characteristics, and not by nonmedical factors, such as socioeconomic status. The 2-year survival rate was lower for black patients (18% v 25%; HR, 1.18; P = .004), but this racial difference disappeared when corrected for treatment received (adjusted HR, 1.02; P = .80).

Conclusion

Underuse of potentially curative surgery is an important potential explanation for the poorer survival of black patients with locoregional esophageal cancer. Barriers to surgical evaluation and treatment need to be reduced, whether related to patient or healthcare system factors.
Polymorphisms in FcγRIIIA (CD16) Receptor Expression Are Associated With Clinical Response to Rituximab in Waldenström’s Macroglobulinemia
Authors: Treon Steven P. , Hansen Mark , Branagan Andrew R. , Verselis Sigitas , Emmanouilides Christos , Kimby Eva , Frankel Stanley R. , Touroutoglou Nikolaos , Turnbull Barry , Anderson Kenneth C. , Maloney David G. , Fox Edward A.
Published: January 2005

Purpose

Rituximab is an important therapeutic for Waldenström’s macroglobulinemia (WM). Polymorphisms in FcγRIIIA (CD16) receptor expression modulate human immunoglobulin G1 binding and antibody-dependent cell-mediated cytotoxicity, and may therefore influence responses to rituximab.

Patients and Methods

Sequence analysis of the entire coding region of FcγRIIIA was undertaken in 58 patients with WM whose outcomes after rituximab were known.

Results

Variations in five codons of FcγRIIIA were identified. Two were commonly observed (FcγRIIIA-48 and FcγRIIIA-158) and predicted for amino acid polymorphisms at FcγRIIIA-48: leucine/leucine (L/L), leucine/arginine (L/R), and leucine/histidine (L/H). Polymorphisms at FcγRIIIA-158 were phenylalanine/phenylalanine (F/F), phenylalanine/valine (F/V), and valine/valine (V/V). A clear linkage between these polymorphisms was detected and all patients with FcγRIIIA-158F/F were always FcγRIIIA-48L/L, and patients with either FcγRIIIA-L/R or -L/H always expressed at least one valine at FcγRIIIA-158 (P ≤ .001). The response trend was higher for patients with FcγRIIIA-48L/H (38.5%) versus -48L/R (25.0%) and LL (22.0%), and was significantly higher for patients with FcγRIIIA-158V/V (40.0%) and -V/F (35%) versus -158F/F (9.0%; P = .030). Responses for patients with FcγRIIIA-48L/L were higher when at least one valine was present at FcγRIIIA-158 (P = .057), thereby supporting a primary role for FcγRIIIA-158 polymorphisms in predicting rituximab responses. With a median follow-up of 13 months, no significant differences in the median time to progression and progression-free survival were observed when patients were grouped according to their FcγRIIIA-48 and -158 polymorphisms.

Conclusion

The results of these studies therefore support a predictive role for FcγRIIIA-158 polymorphisms and responses to rituximab in WM.
Up-Front Tandem High-Dose Chemotherapy Compared With Standard Chemotherapy With Doxorubicin and Paclitaxel in Metastatic Breast Cancer: Results of a Randomized Trial
Authors: Schmid Peter , Schippinger Walter , Nitsch Thorsten , Huebner Gerdt , Heilmann Volker , Schultze Wolfgang , Hausmaninger Hubert , Wischnewsky Manfred , Possinger Kurt
Published: January 2005

Purpose

The role of high-dose chemotherapy (HDCT) in metastatic breast cancer remains controversial. Trials with late intensification HDCT have failed to show an advantage in overall survival. This study was initiated to compare up-front tandem HDCT and standard combination therapy in patients with metastatic breast cancer.

Patients and Methods

Patients without prior chemotherapy for metastatic disease were randomly assigned to standard combination therapy with doxorubicin and paclitaxel (AT) or double HDCT with cyclophosphamide, mitoxantrone, and etoposide followed by peripheral-blood stem-cell transplantation. HDCT was repeated after 6 weeks. Patients were stratified by menopausal and hormone-receptor status. The primary objective was to compare complete response (CR) rates.

Results

A total of 93 patients were enrolled onto the trial. Intent-to-treat CR rates for patients randomized to HDCT and AT were 12.5% and 11.1%, respectively (P = .84). Objective response rates were 66.7% for patients in the high-dose group and 64.4% for patients in the AT arm (P = .82). In an intent-to-treat analysis, there were no significant differences between the two treatments in median time to progression (HDCT, 11.1 months; AT, 10.6 months; P = .67), duration of response (HDCT, 13.9 months; AT, 14.3 months; P = .98), and overall survival (HDCT, 26.9 months; AT, 23.4 months; P = .60). HDCT was associated with significantly more myelosuppression, infection, diarrhea, stomatitis, and nausea and vomiting, whereas patients treated with AT developed more neurotoxicity.

Conclusion

This trial failed to show a benefit for up-front tandem HDCT compared with standard combination therapy. HDCT was associated with more acute adverse effects.
Imatinib Mesylate in Patients With Adenoid Cystic Cancers of the Salivary Glands Expressing c-kit: A Princess Margaret Hospital Phase II Consortium Study
Authors: Hotte Sébastien J. , Winquist Eric W. , Lamont Elizabeth , MacKenzie Mary , Vokes Everett , Chen Eric X. , Brown Shirley , Pond Gregory R. , Murgo Anthony , Siu Lillian L.
Published: January 2005

Purpose

This study aimed to assess the antitumor activity of imatinib in adenoid cystic carcinoma (ACC) of the salivary gland expressing c-kit. A high level of c-kit expression has been identified in more than 90% of ACCs. Imatinib specifically inhibits autophosphorylation of the bcr-abl, platelet-derived growth factor receptor beta, and c-kit tyrosine kinases.

Patients and Methods

In a single-arm, two-stage, phase II clinical trial, adult patients with unresectable or metastatic ACC measurable by Response Evaluation Criteria in Solid Tumors Group criteria and expressing c-kit by immunohistochemistry were treated with imatinib 400 mg orally bid. Response was assessed every 8 weeks.

Results

Sixteen patients have been enrolled onto the study; 10 were female. Median age was 47 years (range, 31 to 69 years). Median Eastern Cooperative Oncology Group performance status was 1 (range, 0 to 2). Fourteen patients had lung metastases, 14 had prior radiotherapy, and six had prior chemotherapy. Toxicities occurring in at least 50% of patients included fatigue, nausea, vomiting, diarrhea, anorexia, edema, dyspnea, and/or headache, usually of mild to moderate severity. In 15 patients assessable for response, no objective responses have been observed. Nine patients had stable disease as best response. Six patients had progressive disease after two cycles.

Conclusion

Because of the lack of activity, the study has been stopped after the first stage and additional evaluation of imatinib in this population is not warranted. Overexpression of wild-type c-kit was not sufficient for clinical benefit from imatinib in ACC. Accrual to this study was rapid for a relatively rare cancer, encouraging additional efforts to identify more effective systemic therapy for these patients.
Prediction of Docetaxel Response in Human Breast Cancer by Gene Expression Profiling
Authors: Iwao-Koizumi Kyoko , Matoba Ryo , Ueno Noriko , Kim Seung Jin , Ando Akiko , Miyoshi Yasuo , Maeda Eisaku , Noguchi Shinzaburo , Kato Kikuya
Published: January 2005

Purpose

Docetaxel is one of the most effective anticancer drugs available in the treatment of breast cancer. Nearly half of the treated patients, however, do not respond to chemotherapy and suffer from side effects. The ability to reliably predict a patient's response based on tumor gene expression will improve therapeutic decision making and save patients from unnecessary side effects.

Patients and Methods

A total of 44 breast tumor tissues were sampled by biopsy before treatment with docetaxel, and the response to therapy was clinically evaluated by the degree of reduction in tumor size. Gene expression profiling of the biopsy samples was performed with 2,453 genes using a high-throughput reverse transcriptase polymerase chain reaction technique. Using genes differentially expressed between responders and nonresponders, a diagnostic system based on the weighted-voting algorithm was constructed.

Results

This system predicted the clinical response of 26 previously unanalyzed samples with over 80% accuracy, a level promising for clinical applications. Diagnostic profiles in nonresponders were characterized by elevated expression of genes controlling the cellular redox environment (ie, redox genes, such as thioredoxin, glutathione-S-transferase, and peroxiredoxin). Overexpression of these genes protected cultured mammary tumor cells from docetaxel-induced cell death, suggesting that enhancement of the redox system plays a major role in docetaxel resistance.

Conclusion

These results suggest that the clinical response to docetaxel can be predicted by gene expression patterns in biopsy samples. The results also suggest that one of the molecular mechanisms of the resistance is activation of a group of redox genes.
Proteasome Inhibition As a Novel Therapeutic Target in Human Cancer
Authors: Rajkumar S. Vincent , Richardson Paul G. , Hideshima Teru , Anderson Kenneth C.
Published: January 2005

The 26S proteasome is a large intracellular adenosine 5′-triphosphate–dependent protease that identifies and degrades proteins tagged for destruction by the ubiquitin system. The orderly degradation of cellular proteins is critical for normal cell cycling and function, and inhibition of the proteasome pathway results in cell-cycle arrest and apoptosis. Dysregulation of this enzymatic system may also play a role in tumor progression, drug resistance, and altered immune surveillance, making the proteasome an appropriate and novel therapeutic target in cancer. Bortezomib (formerly known as PS-341) is the first proteasome inhibitor to enter clinical practice. It is a boronic aid dipeptide that binds directly with and inhibits the enzymatic complex. Bortezomib has recently shown significant preclinical and clinical activity in several cancers, confirming the therapeutic value of proteasome inhibition in human malignancy. It was approved in 2003 for the treatment of advanced multiple myeloma (MM), with approximately one third of patients with relapsed and refractory MM showing significant clinical benefit in a large clinical trial. Its mechanism of action is partly mediated through nuclear factor-kappa B inhibition, resulting in apoptosis, decreased angiogenic cytokine expression, and inhibition of tumor cell adhesion to stroma. Additional mechanisms include c-Jun N-terminal kinase activation and effects on growth factor expression. Several clinical trials are currently ongoing in MM as well as several other malignancies. This article discusses proteasome inhibition as a novel therapeutic target in cancer and focuses on the development, mechanism of action, and current clinical experience with bortezomib.