bluuebunny/crossref_metadata_2025 huggingface dataset:
Early B-cell Factor gene association with multiple sclerosis in the Spanish population
Authors: Martínez Alfonso , Mas Ana , de las Heras Virginia , Arroyo Rafael , Fernández-Arquero Miguel , de la Concha Emilio G , Urcelay Elena
Published: October 2005

Background

The etiology of multiple sclerosis (MS) is at present not fully elucidated, although it is considered to result from the interaction of environmental and genetic susceptibility factors. In this work we aimed at testing the Early B-cell Factor (EBF1) gene as a functional and positional candidate risk factor for this neurological disease. Axonal damage is a hallmark for multiple sclerosis clinical disability and EBF plays an evolutionarily conserved role in the expression of proteins essential for axonal pathfinding. Failure of B-cell differentiation was found in EBF-deficient mice and involvement of B-lymphocytes in MS has been suggested from their presence in cerebrospinal fluid and lesions of patients.

Methods

The role of the EBF1 gene in multiple sclerosis susceptibility was analyzed by performing a case-control study with 356 multiple sclerosis patients and 540 ethnically matched controls comparing the EBF1 polymorphism rs1368297 and the microsatellite D5S2038.

Results

Significant association of an EBF1-intronic polymorphism (rs1368297, A vs. T: p = 0.02; OR = 1.26 and AA vs. [TA+TT]: p = 0.02; OR = 1.39) was discovered. This association was even stronger after stratification for the well-established risk factor of multiple sclerosis in the Major Histocompatibility Complex, DRB1*1501 (AA vs. [TA+TT]: p = 0.005; OR = 1.78). A trend for association in the case-control study of another EBF1 marker, the allele 5 of the very informative microsatellite D5S2038, was corroborated by Transmission Disequilibrium Test of 53 trios (p = 0.03).

Conclusion

Our data support EBF1 gene association with MS pathogenesis in the Spanish white population. Two genetic markers within the EBF1 gene have been found associated with this neurological disease, indicative either of their causative role or that of some other polymorphism in linkage disequilibrium with them.
Antimetastatic gene expression profiles mediated by retinoic acid receptor beta 2 in MDA-MB-435 breast cancer cells
Authors: Wallden Brett , Emond Mary , Swift Mari E , Disis Mary L , Swisshelm Karen
Published: October 2005

Background

The retinoic acid receptor beta 2 (RARβ2) gene modulates proliferation and survival of cultured human breast cancer cells. Previously we showed that ectopic expression of RARβ2 in a mouse xenograft model prevented metastasis, even in the absence of the ligand, all-trans retinoic acid. We investigated both cultured cells and xenograft tumors in order to delineate the gene expression profiles responsible for an antimetastatic phenotype.

Methods

RNA from MDA-MB-435 human breast cancer cells transduced with RARβ2 or empty retroviral vector (LXSN) was analyzed using Agilent Human 1A Oligo microarrays. The one hundred probes with the greatest differential intensity (p < 0.004, jointly) were determined by selecting the top median log ratios from eight-paired microarrays. Validation of differences in expression was done using Northern blot analysis and quantitative RT-PCR (qRT-PCR). We determined expression of selected genes in xenograft tumors.

Results

RARβ2 cells exhibit gene profiles with overrepresentation of genes from Xq28 (p = 2 × 10-8), a cytogenetic region that contains a large portion of the cancer/testis antigen gene family. Other functions or factors impacted by the presence of exogenous RARβ2 include mediators of the immune response and transcriptional regulatory mechanisms. Thirteen of fifteen (87%) of the genes evaluated in xenograft tumors were consistent with differences we found in the cell cultures (p = 0.007).

Conclusion

Antimetastatic RARβ2 signalling, direct or indirect, results in an elevation of expression for genes such as tumor-cell antigens (CTAG1 and CTAG2), those involved in innate immune response (e.g., RIG-I/DDX58), and tumor suppressor functions (e.g., TYRP1). Genes whose expression is diminished by RARβ2 signalling include cell adhesion functions (e.g, CD164) nutritional or metabolic processes (e.g., FABP6), and the transcription factor, JUN.
Treatment of dyslipidemia with lovastatin and ezetimibe in an adolescent with cholesterol ester storage disease
Authors: Tadiboyina Venu T , Liu Dora M , Miskie Brooke A , Wang Jian , Hegele Robert A
Published: October 2005

Background

Cholesterol ester storage disease (CESD) is an autosomal recessive illness that results from mutations in the LIPA gene encoding lysosomal acid lipase. CESD patients present in childhood with hepatomegaly and dyslipidemia characterized by elevated total and low-density lipoprotein cholesterol (LDL-C), with elevated triglycerides and depressed high-density lipoprotein cholesterol (HDL-C). Usual treatment includes a low fat diet and a statin drug.

Results

In an 18-year old with CESD, we documented compound heterozygosity for two LIPA mutations: a novel frameshift nonsense mutation and a deletion of exon 8. The patient had been treated with escalating doses of lovastatin for ~80 months, with ~15% decline in mean LDL-C. The addition of ezetimibe 10 mg to lovastatin 40 mg resulted in an additional ~16% decline in mean LDL-C.

Conclusion

These preliminary anecdotal findings in a CESD patient with novel LIPA mutations support the longer term safety of statins in an adolescent patient and provide new data about the potential efficacy and tolerability of ezetimibe in this patient group.
Changes in infant segment inertias during the first three months of independent walking
Authors: Chester Victoria L , Jensen Robert K
Published: October 2005

Background

During infancy, rapid changes in physical growth affect the size and shape of the body segments. To understand the effects of growth on movement, it is first necessary to quantify rates of development during the acquisition of important motor milestones. The goal of this longitudinal study was to quantify the physical growth of infant body segments during the initial stages of independent walking.

Methods

Ten infants (N = 10) aged between 28 and 55 weeks at the beginning of the study were tested biweekly (every two weeks) for three months. A 13-segment mathematical model of the human body was used to estimate the inertial parameters of the infant body segments at each session. An analysis of variance was used to test for significant differences in segment masses between biweekly measures. Polynomial contrasts were used to test for linear trends in the growth data.

Results

Significant differences between biweekly measures of segment mass were found only for the head/neck (F(5,45) = 3.42, p < 0.05), upper trunk (F(5,45) = 4.04, p < 0.01), and lower trunk (F(5,45) = 3.49, p < 0.01). The lower trunk demonstrated a linear increase in mass (F(1,9) = 4.56, p < 0.05). However, the upper trunk demonstrated a quadratic trend in growth (F(1,9) = 9.13, p < 0.01), while the head/neck segment showed a cubic trend in growth (F(1,9) = 3.80, p < 0.05). Significant differences in axial segment masses were also found between subjects (F(9,45) = 5.92, p < 0.001).

Conclusion

Given that postural control proceeds in a cephalocaudal manner, the lower trunk segment would be brought under control last, in terms of the axial segments. Increases in the mass of this segment could constrain the system, thereby acting as a control parameter for the onset and development of motor patterns.
Cultural Approach to HIV/AIDS Harm Reduction in Muslim Countries
Authors: Hasnain Memoona
Published: October 2005

Muslim countries, previously considered protected from HIV/AIDS due to religious and cultural norms, are facing a rapidly rising threat. Despite the evidence of an advancing epidemic, the usual response from the policy makers in Muslim countries, for protection against HIV infection, is a major focus on propagating abstention from illicit drug and sexual practices. Sexuality, considered a private matter, is a taboo topic for discussion. Harm reduction, a pragmatic approach for HIV prevention, is underutilized. The social stigma attached to HIV/AIDS, that exists in all societies is much more pronounced in Muslim cultures. This stigma prevents those at risk from coming forward for appropriate counseling, testing, and treatment, as it involves disclosure of risky practices. The purpose of this paper is to define the extent of the HIV/AIDS problem in Muslim countries, outline the major challenges to HIV/AIDS prevention and treatment, and discuss the concept of harm reduction, with a cultural approach, as a strategy to prevent further spread of the disease. Recommendations include integrating HIV prevention and treatment strategies within existing social, cultural and religious frameworks, working with religious leaders as key collaborators, and provision of appropriate healthcare resources and infrastructure for successful HIV prevention and treatment programs in Muslim countries.
Synergistic inhibition of human melanoma proliferation by combination treatment with B-Raf inhibitor BAY43-9006 and mTOR inhibitor Rapamycin
Authors: Molhoek Kerrington R , Brautigan David L , Slingluff Craig L
Published: October 2005

Background

Targeted inhibition of protein kinases is now acknowledged as an effective approach for cancer therapy. However, targeted therapies probably have limited success because cancer cells have alternate pathways for survival and proliferation thereby avoiding inhibition. We tested the hypothesis that combination of targeted agents would be more effective than single agents in arresting melanoma cell proliferation.

Methods

We evaluated whether BAY43-9006, an inhibitor of the B-Raf kinase, and rapamycin, an inhibitor of the mTOR kinase, would inhibit serum-stimulated proliferation of human melanoma cell lines, either alone or in combination. Proliferation was measured by quantitating melanoma cell numbers with a luciferase for ATP. Phosphorylation of proteins downstream of targeted kinase(s) was assayed by immunoblots. Statistical significance was determined with the Student-T test. Isobologram analysis was performed to distinguish additive versus synergistic effects of combinations of drugs.

Results

Serum-stimulated proliferation of multiple human melanoma cell lines was inhibited by BAY43-9006 and by rapamycin. Melanoma cells containing the B-Raf mutation V599E were more sensitive than cells with wild-type B-raf to 10 nM doses of both BAY43-9006 and rapamycin. Regardless of B-Raf mutational status, the combination of low dose rapamycin and BAY43-9006 synergistically inhibited melanoma cell proliferation. As expected, rapamycin inhibited the phosphorylation of mTOR substrates, p70S6K and 4EBP1, and BAY43-9006 inhibited phosphorylation of ERK, which is dependent on B-Raf activity. We also observed unexpected rapamycin inhibition of the phosphorylation of ERK, as well as BAY43-9006 inhibition of the phosphorylation of mTOR substrates, p70S6K and 4EBP1.

Conclusion

There was synergistic inhibition of melanoma cell proliferation by the combination of rapamycin and BAY 43-9006, and unexpected inhibition of two signaling pathways by agents thought to target only one of those pathways. These results indicate that combinations of inhibitors of mTOR and of the B-raf signaling pathways may be more effective as a treatment for melanoma than use of either agent alone.
Barriers to the implementation of programs for the prevention of mother-to-child transmission of HIV: A cross-sectional survey in rural and urban Uganda
Authors: Bajunirwe Francis , Muzoora Michael
Published: October 2005

Background

Implementation of programs for the prevention of mother-to-child transmission (PMTCT) of HIV faces a variety of barriers and challenges. The assessment of these challenges has generally been conducted in large urban health facilities. As programs expand into rural areas, the potential barriers that may be encountered there also need to be assessed. This study examines potential barriers that might affect the acceptability of interventions for PMTCT in rural and urban settings.

Results

Four hundred and four women at a large urban hospital and three rural clinics that had recently started implementing PMTCT were interviewed. Level of knowledge of MTCT and preference for rapid HIV testing were equally high in both areas, but rural women had a higher tendency to think that they should consult their husbands before testing, with borderline statistical significance (72% vs. 64% p = 0.09). Health facility-based deliveries were significantly lower among mothers in rural areas compared to those in the urban setting. Overall, significant predictors of willingness to test for HIV were post-primary education (OR = 3.1 95% CI 1.2, 7.7) and knowledge about rapid HIV tests (OR = 1.8, 95% CI 1.01, 3.4). The strongest predictor of willingness to accept an HIV test was the woman's perception that her husband would approve of her testing for HIV. Women who thought their husbands would approve were almost six times more likely to report a willingness to be tested compared to those who thought their husbands would not approve (OR = 5.6, 95% CI 2.8, 11.2).

Conclusion

Lessons learned in large urban hospitals can be generalized to rural facilities, but the lower proportion of facility-based deliveries in rural areas needs to be addressed. Same-day results are likely to ensure high uptake of HIV testing services but male spousal involvement should be considered, particularly for rural areas. Universal Primary Education will support the success of PMTCT programs.
Opportunities for Targeted Therapies in Hepatocellular Carcinoma
Authors: Thomas Melanie B. , Abbruzzese James L.
Published: October 2005

Hepatocellular cancer (HCC) is the fifth most common solid tumor worldwide, accounting for 500,000 new cases annually. Although less common in the United States, HCC is expected to increase in incidence over the next two decades largely because of the prevalence of hepatitis C virus infection. A majority of patients present with advanced disease and are not candidates for liver transplantation, surgical resection, or regional therapy. In 60% to 80% of patients with HCC, treatment is complicated by underlying liver cirrhosis and hepatic dysfunction. Systemic treatments are minimally effective, can have significant toxicity, and have not been shown to improve patient survival. New approaches targeting molecular abnormalities specific to HCC are needed to improve patient outcome. This review summarizes the state of knowledge of those key aspects of the molecular pathogenesis of HCC that may represent rational therapeutic targets in this disease. Relevant preclinical and clinical information on novel compounds directed toward abnormalities in HCC is reviewed.
Phase I and Pharmacokinetics Trial of ABI-007, a Novel Nanoparticle Formulation of Paclitaxel in Patients With Advanced Nonhematologic Malignancies
Authors: Nyman David W. , Campbell Kimberley J. , Hersh Evan , Long Kristen , Richardson Kelly , Trieu Vuong , Desai Neil , Hawkins Michael J. , Von Hoff Daniel D.
Published: October 2005

Purpose

ABI-007 is a novel solvent-free, albumin-bound, 130-nm particle formulation of paclitaxel designed to avoid solvent-related toxicities and to deliver paclitaxel to tumors via molecular pathways involving an endothelial cell-surface albumin receptor (gp60) and an albumin-binding protein expressed by tumor cells and secreted into the tumor interstitium (secreted protein acid rich in cysteine). This study determined the maximum-tolerated dose (MTD) of ABI-007 monotherapy administered weekly (three weekly doses, repeated every 4 weeks) and assessed the pharmacokinetics of paclitaxel administered as ABI-007.

Patients and Methods

Patients with advanced nonhematologic malignancies received ABI-007 without premedication at dose levels from 80 to 200 mg/m2 as a 30-minute intravenous infusion once a week for 3 weeks, followed by 1 week of rest (one cycle).

Results

Thirty-nine patients were treated with an average of five cycles of ABI-007; 33% of patients received ≥ six cycles of treatment. MTDs for heavily and lightly pretreated patients were 100 and 150 mg/m2, respectively; and the dose-limiting toxicities were grade 4 neutropenia and grade 3 peripheral neuropathy, respectively. Maximum paclitaxel concentration and area under the curve increased linearly with dose. Dose-dependent changes in plasma clearance did not occur. Partial responses were observed in five patients with breast, lung, and ovarian cancers, all of whom had previously been treated with paclitaxel containing polyoxyethylated castor oil in the formulation.

Conclusion

This study demonstrated that weekly ABI-007 can be administered at doses exceeding those typically used for paclitaxel containing polyoxyethylated castor oil. Pharmacokinetics were linear over the dose range studied. Antitumor responses occurred in patients previously treated with paclitaxel containing polyoxyethylated castor oil.
Gonadotropin-Releasing Hormone Agonists and Fracture Risk: A Claims-Based Cohort Study of Men With Nonmetastatic Prostate Cancer
Authors: Smith Matthew R. , Lee Won Chan , Brandman Jane , Wang Qin , Botteman Marc , Pashos Chris L.
Published: October 2005

Purpose

Gonadotropin-releasing hormone (GnRH) agonists decrease bone mineral density, a surrogate for fracture risk, in men with prostate cancer. We conducted a claims-based cohort study to characterize the relationship between GnRH agonists and risk for clinical fractures in men with nonmetastatic prostate cancer.

Patients and Methods

Using medical claims data from a 5% national random sample of Medicare beneficiaries, we identified a study group of men with nonmetastatic prostate cancer who initiated GnRH agonist treatment from 1992 to 1994 (n = 3,887). A comparison group of men with nonmetastatic prostate cancer who did not receive GnRH agonist treatment during the study period (n = 7,774) was matched for age, race, geographic location, and comorbidity. Clinical fractures were identified using inpatient, outpatient, and physician claims during 7 years of follow-up.

Results

In men with nonmetastatic prostate cancer, GnRH agonists significantly increased fracture risk. The rate of any clinical fracture was 7.88 per 100 person-years at risk in men receiving a GnRH agonist compared with 6.51 per 100 person-years in matched controls (relative risk, 1.21; 95% CI, 1.14 to 1.29; P < .001). Rates of vertebral fractures (relative risk, 1.45; 95% CI, 1.19 to 1.75; P < .001) and hip/femur fractures (relative risk, 1.30; 95% CI, 1.10 to 1.53; P = .002) were also significantly higher in men who received a GnRH agonist. GnRH agonist treatment independently predicted fracture risk in multivariate analyses. Longer duration of treatment conferred greater fracture risk.

Conclusion

GnRH agonists significantly increase risk for any clinical fracture, hip fractures, and vertebral fractures in men with prostate cancer.
Prevention of Chemotherapy-Induced Febrile Neutropenia by Prophylactic Antibiotics Plus or Minus Granulocyte Colony-Stimulating Factor in Small-Cell Lung Cancer: A Dutch Randomized Phase III Study
Authors: Timmer-Bonte Johanna N. , de Boo Theo M. , Smit Hans J. , Biesma Bonne , Wilschut Frank A. , Cheragwandi Samia A. , Termeer Arien , Hensing Cornelis A. , Akkermans Janine , Adang Eddy M. , Bootsma Geeben P. , Tjan-Heijnen Vivianne C.
Published: October 2005

Purpose

Febrile neutropenia (FN) is a major complication of chemotherapy. Antibiotics as well as granulocyte colony-stimulating factor (G-CSF) are effective in preventing FN. This multicenter randomized phase III trial determines whether the addition of G-CSF to antibiotic prophylaxis can further reduce the incidence of FN in patients with small-cell lung cancer (SCLC) at the risk of FN.

Patients and Methods

Patients (N = 175) were stratified for stage of disease, performance status, age, and prior chemotherapy treatment, and were randomly assigned for treatment with cyclophosphamide, doxorubicin, and etoposide (CDE), followed by prophylactic antibiotics alone (ciprofloxacin and roxithromycin) or by antibiotics in combination with G-CSF on days 4 to 13.

Results

In cycle 1, 20 patients (24%) in the antibiotics group developed FN compared with nine patients (10%) in the antibiotics plus G-CSF group (P = .01). In cycles 2 to 5, the incidences of FN were practically the same in both groups (17% v 11%). Only the treatment parameters (odds ratio, 0.33; 95% CI, 0.14 to 0.78) and age (1.067 per year; 95% CI, 1.013 to 1.0124) were related to the probability of FN in cycle 1.

Conclusion

Primary G-CSF prophylaxis added to primary antibiotic prophylaxis is effective in reducing FN and infections in SCLC patients at the risk of FN with the first cycle of CDE chemotherapy. For patients with similar risk of FN, the combined use of prophylactic antibiotics plus G-CSF can be considered, specifically in the first cycle of chemotherapy.
Squamous Cell Carcinoma of the Breast
Authors: Hennessy Bryan T. , Krishnamurthy Savitri , Giordano Sharon , Buchholz Thomas A. , Kau Shu W. , Duan Zhigang , Valero Vicente , Hortobagyi Gabriel N.
Published: October 2005

Purpose

Squamous cell carcinoma (SCC) of the breast is rare and generally aggressive. In this study, we analyzed 33 patients treated at The University of Texas M.D. Anderson Cancer Center (Houston, TX) and a series of 137 patients identified through the Surveillance, Epidemiology, and End Results (SEER) database to make therapy recommendations.

Methods

Records of The University of Texas M.D. Anderson Cancer Center were searched for patients diagnosed with breast SCC from 1985 to 2001. All biopsy material was reviewed by a dedicated breast pathologist who performed immunohistochemistry for hormone receptors and the epidermal growth factor receptor (EGFR). We searched the SEER database for patients with breast SCC diagnosed between 1988 and 2001.

Results

We identified 33 patients with breast SCC, of whom two patients had metastatic disease at diagnosis. The median relapse-free survival (RFS) of 31 patients with localized disease was 20 months (range, 1 to 108 months), with a 26% RFS rate at 5 years. The median overall survival in these patients was 37 months (range, 12 to 108 months), with 40% surviving at 5 years. Median survival from the time recurrent disease was recognized was 14 months (range, 2 to 86 months). Tumors were usually hormone receptor–and HER2/neu-negative, though EGFR was frequently overexpressed. Information from the SEER database was consistent with most of our findings.

Conclusion

SCC of the breast is aggressive and often treatment-refractory. The role of platinum salts, EGFR inhibitors, and other novel agents needs to be explored.
Randomized Trial of Prevention of Catheter-Related Bloodstream Infection by Continuous Infusion of Low-Dose Unfractionated Heparin in Patients With Hematologic and Oncologic Disease
Authors: Abdelkefi Abderrahman , Torjman Lamia , Ladeb Saloua , Ben Othman Tarek , Achour Wafa , Lakhal Amel , Hsairi Mohamed , Kammoun Leila , Ben Hassen Assia , Abdeladhim Abdeladhim Ben
Published: October 2005

Purpose

Infection is a serious complication of central venous catheters in immunocompromised patients. Catheter-related infection may be caused by fibrin deposition associated with catheters. Interventions designed to decrease fibrin deposition have the potential to reduce catheter-related infections. The purpose of this study was to evaluate the role of low-dose unfractionated heparin in preventing catheter-related bloodstream infection in patients with hemato-oncological disease.

Patients and Methods

This study was a randomized, controlled trial in which patients with nontunneled catheters were randomly assigned to receive either intravenous unfractionated heparin (continuous infusion of 100 U/kg per day) or 50 mL/day of normal saline solution as a continuous infusion (control group). Heparin was continued until the day of discharge. Catheter-related bloodstream infection was defined according to Infectious Disease Society of America guidelines.

Results

Two hundred and eight patients were randomly assigned. Four patients were excluded after assignment. Ultimately, 204 patients were analyzed. Catheter-related bloodstream infection occurred in 6.8% (7 of 102 catheters) of those in the heparin group (2.5 events per 1,000 days) and in 16.6% (17 of 102 catheters) of those in the control group (6.4 events per 1,000 days) (P = .03). No other risk factors were found for the development of catheter-related bloodstream infection. Four and five patients experienced severe bleeding in the heparin and control groups, respectively (P = .2). We did not observe heparin-induced thrombocytopenia.

Conclusion

The use of continuous infusion of low-dose unfractionated heparin (100 U/kg per day) can be a practical and economical approach to the prevention of catheter-related bloodstream infection in patients with hemato-oncological disease.
Risk of Adverse Events After Completion of Therapy for Childhood Acute Lymphoblastic Leukemia
Authors: Pui Ching-Hon , Pei Deqing , Sandlund John T. , Campana Dario , Ribeiro Raul C. , Razzouk Bassem I. , Rubnitz Jeffrey E. , Howard Scott C. , Hijiya Nobuko , Jeha Sima , Cheng Cheng , Downing James R. , Evans William E. , Relling Mary V. , Hudson Melissa
Published: October 2005

Purpose

We studied the frequency, causes, and predictors of adverse events in children with acute lymphoblastic leukemia (ALL) who had completed treatment on contemporary clinical protocols between 1984 and 1999. Our goal was to use the information to further refine therapy and advance cure rates.

Methods

Cumulative incidence functions of any post-treatment failure or any post-treatment relapse were estimated by the method of Kalbfleisch and Prentice and compared with Gray's test. The Cox proportional hazards model was used to identify independent prognostic factors.

Results

Of the 827 patients who completed all treatment while in initial complete remission, 134 patients subsequently had major adverse events, including 90 leukemic relapses, 40 second malignancies, and four deaths in remission. The cumulative incidence of any adverse event was 14.0% ± 1.2% (SE) at 5 years and 16.9% ± 1.4% at 10 years. The risk of any leukemic relapse was 10.0% ± 1.1% at 5 years and 11.4% ± 1.2% at 10 years. Male sex was the only independent predictor of relapse (hazard ratio, 1.74; 95% CI, 1.11 to 2.74; P = .02).

Conclusion

Further treatment refinements for children with ALL should aim not only to decrease the leukemic relapse rate, but also to reduce the risk of development of second malignancies.
Long-Term Outcome in Children With Relapsed ALL by Risk-Stratified Salvage Therapy: Results of Trial Acute Lymphoblastic Leukemia-Relapse Study of the Berlin-Frankfurt-Münster Group 87
Authors: Einsiedel Hagen Graf , von Stackelberg Arend , Hartmann Reinhard , Fengler Rüdiger , Schrappe Martin , Janka-Schaub Gritta , Mann Georg , Hählen Karel , Göbel Ulrich , Klingebiel Thomas , Ludwig Wolf-Dieter , Henze Günter
Published: October 2005

Purpose

Approximately 20% of children with acute lymphoblastic leukemia (ALL) suffer a relapse, and their prognosis is unfavorable. Between 1987 and 1990, the multicenter trial Acute Lymphoblastic Leukemia-Relapse Study of the Berlin-Frankfurt-Münster Group (ALL-REZ BFM) 87 was conducted to establish a uniform treatment for these children in Germany and Austria.

Patients and Methods

Of 207 registered patients, 183 patients were stratified into three groups according to the protocol: A, early bone marrow (BM) relapse (n = 56); B, late BM relapse (n = 101); C, isolated extramedullary relapse (n = 26). Treatment consisted of risk-adapted alternating short-course multiagent systemic and intrathecal chemotherapy, cranial irradiation, if indicated, and conventional maintenance therapy. Additionally, 24 patients with an exceptionally poor prognosis (early BM or any relapse of T-cell ALL) were treated with individual regimens. In 35 patients, stem-cell transplantation was performed.

Results

The probability of event-free survival (EFS) and overall survival of all registered patients at 15 years was 0.30 ± 0.03 and 0.37 ± 0.03, respectively, with significant differences between the strategic groups (A, 0.18 ± 0.05 and 0.20 ± 0.05; B, 0.44 ± 0.05 and 0.52 ± 0.05; C, 0.35 ± 0.09 and 0.42 ± 0.10). Despite risk-adapted treatment, an early time point of relapse and T-lineage immunophenotype were significant predictors of inferior EFS in uni- and multivariate analyses.

Conclusion

With the ALL-REZ BFM 87 protocol, more than one-third of patients may be regarded as cured from recurrent ALL with second complete remissions lasting more than 10 years. Immunophenotype and time point of relapse are important prognostic factors that allow us to adapt more precisely treatment intensity to individual prognosis in future trials.
Therapy Tolerance in Selected Patients With Androgen-Independent Prostate Cancer Following Strontium-89 Combined With Chemotherapy
Authors: Tu Shi-Ming , Kim Jeri , Pagliaro Lance C. , Vakar-Lopez Funda , Wong Frankin C. , Wen Sijin , General Rosales , Podoloff Donald A. , Lin Sue-Hwa , Logothetis Christopher J.
Published: October 2005

Purpose

Clinicians may have reservations about using strontium-89 for the treatment of bone metastases because of concerns that it may limit future use of chemotherapy. We assessed the rate of bone marrow failure in patients with prostate cancer who had received a dose of strontium-89.

Patients and Methods

This subgroup analysis involved 34 patients with androgen-independent prostate cancer who had been given a dose of strontium-89 and six weekly doses of doxorubicin after response to induction chemotherapy. We assessed subsequent hematotoxicity in terms of bone marrow failure and the ability to tolerate additional treatments during a median of 25 months (range, 7 to 76 months) after the strontium-89 was administered.

Results

No patients developed bone marrow failure within 6 months of receiving strontium-89. Five (15%) of 34 patients developed bone marrow failure at a median 23 months (range, 6 to 53 months) after the strontium-89 treatment. Bone marrow biopsy performed in two of these five patients showed complete replacement of the marrow by tumor. Thirty-one patients (91%) received subsequent cytotoxic treatments at a median 11 months (range, 1 to 33 months) after the strontium-89 treatment.

Conclusion

This analysis demonstrated that a single dose of strontium-89 combined with chemotherapy did not affect the delivery of subsequent courses of chemotherapy in a select group of patients. However, a majority of these therapies were given off protocol and were administered at a dose schedule that might be considered inappropriate or inadequate. The clinical role and safety profile of radiopharmaceuticals combined with chemotherapy in prostate cancer therapy deserve further exploration.
β-Catenin Status Predicts a Favorable Outcome in Childhood Medulloblastoma: The United Kingdom Children's Cancer Study Group Brain Tumour Committee
Authors: Ellison David W. , Onilude Olabisi E. , Lindsey Janet C. , Lusher Meryl E. , Weston Claire L. , Taylor Roger E. , Pearson Andrew D. , Clifford Steven C.
Published: October 2005

Purpose

Identifying pathobiological correlates of clinical behavior or therapeutic response currently represents a key challenge for medulloblastoma research. Nuclear accumulation of the β-catenin protein is associated with activation of the Wnt/Wg signaling pathway, and mutations affecting components of this pathway have been reported in approximately 15% of sporadic medulloblastomas. We tested the hypothesis that nuclear immunoreactivity for β-catenin is a prognostic marker in medulloblastoma, and assessed the relationship between nuclear β-catenin immunoreactivity and mutations of CTNNB1 and APC.

Patients and Methods

Medulloblastomas from children entered onto the International Society for Pediatric Oncology (SIOP)/United Kingdom Children's Cancer Study Group (UKCCSG) PNET3 trial (n = 109) were examined for β-catenin immunoreactivity, and where tissue was available, evidence of CTNNB1 and APC mutations. The results were correlated with clinicopathologic variables, principally outcome.

Results

Children with medulloblastomas that showed a nucleopositive β-catenin immunophenotype (27 of 109; 25%) had significantly better overall (OS) and event-free (EFS) survivals than children with tumors that showed either membranous/cytoplasmic β-catenin immunoreactivity or no immunoreactivity (P = .0015 and P = .0026, respectively). For β-catenin nucleopositive and nucleonegative medulloblastomas, 5-year OS was 92.3% (95% CI, 82% to 100%) versus 65.3% (95% CI, 54.8 to 75.7%), and 5-year EFS was 88.9% (95% CI, 77% to 100%) versus 59.5% (95% CI, 48.8 to 70.2%), respectively. Mutations in CTNNB1 were found exclusively among medulloblastomas that demonstrated nuclear β-catenin immunoreactivity, but no evidence of APC mutation was found in these cases. All children with β-catenin nucleopositive large cell/anaplastic medulloblastomas and β-catenin nucleopositive medulloblastomas presenting with metastatic disease are alive at least 5 years postdiagnosis.

Conclusion

Nuclear accumulation of β-catenin appears to be a marker of favorable outcome in medulloblastoma, and should be investigated further in large group-wide trials.
Fatigue, Menopausal Symptoms, and Cognitive Function in Women After Adjuvant Chemotherapy for Breast Cancer: 1- and 2-Year Follow-Up of a Prospective Controlled Study
Authors: Fan Helen G. Mar , Houédé-Tchen Nadine , Yi Qi-Long , Chemerynsky Irene , Downie Fiona P. , Sabate Kathryn , Tannock Ian F.
Published: October 2005

Purpose

We previously evaluated fatigue, menopausal symptoms, and cognitive dysfunction in patients receiving adjuvant therapy for breast cancer and matched healthy women. Here we report assessment of these women 1 and 2 years later.

Patients and Methods

Patients without relapse and controls were evaluated by the Functional Assessment of Cancer Treatment-General Quality of Life questionnaire, with subscales for fatigue and endocrine symptoms, and by the High Sensitivity Cognitive Screen.

Results

There were 104, 91, and 83 patients and 102, 81, and 81 controls assessed at baseline and at 1 and 2 years, respectively. Median Functional Assessment of Cancer Treatment-Fatigue scores (range, 0 to 52) for patients improved from 31 (on chemotherapy) to 43 and 45 at 1 and 2 years, respectively, but were stable in controls (46 to 48). Median Functional Assessment of Cancer Treatment-Endocrine Symptoms scores (range, 0 to 72) for patients improved from 57 (on chemotherapy) to 59 and 61 at 1 and 2 years, respectively, and were stable in controls (64 to 65). Differences between patients and controls remained significant for these scales. The incidence of moderate-severe cognitive dysfunction by the High Sensitivity Cognitive Screen decreased in patients from 16% (on chemotherapy) to 4.4% and 3.8% and in controls from 5% to 3.6% and 0% at 1 and 2 years, respectively. There were minimal differences between estrogen receptor–positive patients who started hormonal therapy (mainly tamoxifen) after chemotherapy and estrogen receptor–negative patients who did not. Differences in quality of life between patients and controls were significant only at baseline.

Conclusion

Fatigue, menopausal symptoms, and cognitive dysfunction are important adverse effects of chemotherapy that improve in most patients. Hormonal treatment has minimal impact on them.
Prospective Study Using the Risk of Ovarian Cancer Algorithm to Screen for Ovarian Cancer
Authors: Menon Usha , Skates Steven J. , Lewis Sara , Rosenthal Adam N. , Rufford Barnaby , Sibley Karen , MacDonald Nicola , Dawnay Anne , Jeyarajah Arjun , Bast Robert C. , Oram David , Jacobs Ian J.
Published: October 2005

Purpose

To evaluate prevalence screening in the first prospective trial of a new ovarian cancer screening (OCS) strategy (risk of ovarian cancer or ROC algorithm) on the basis of age and CA125 profile.

Patients and Methods

Postmenopausal women, ≥ 50 years were randomly assigned to a control group or screen group. Screening involved serum CA125, interpreted using the ROC algorithm. Participants with normal results returned to annual screening; those with intermediate results had repeat CA125 testing; and those with elevated values underwent transvaginal ultrasound (TVS). Women with abnormal or persistently equivocal TVS were referred for a gynecologic opinion.

Results

Thirteen thousand five hundred eighty-two women were recruited. Of 6,682 women randomly assigned to screening, 6,532 women underwent the first screen. After the initial CA125, 5,213 women were classified as normal risk, 91 women elevated, and 1,228 women intermediate. On repeat CA125 testing of the latter, a further 53 women were classified as elevated risk. All 144 women with elevated risk had TVS. Sixteen women underwent surgery. Eleven women had benign pathology; one woman had ovarian recurrence of breast cancer; one woman had borderline; and three women had primary invasive epithelial ovarian cancer (EOC). The specificity and positive predictive value (PPV) for primary invasive EOC were 99.8% (95% CI, 99.7 to 99.9) and 19% (95% CI, 4.1 to 45.6), respectively.

Conclusion

An OCS strategy using the ROC algorithm is feasible and can achieve high specificity and PPV in postmenopausal women. It is being used in the United Kingdom Collaborative Trial of Ovarian Cancer Screening and in the United States in both the Cancer Genetics Network and the Gynecology Oncology Group trials of high-risk women.
Phase II Trial of Bevacizumab Plus Gemcitabine in Patients With Advanced Pancreatic Cancer
Authors: Kindler Hedy L. , Friberg Gregory , Singh Deepti A. , Locker Gershon , Nattam Sreenivasa , Kozloff Mark , Taber David A. , Karrison Theodore , Dachman Abraham , Stadler Walter M. , Vokes Everett E.
Published: October 2005

Purpose

Vascular endothelial growth factor (VEGF) plays a key role in the biology and prognosis of pancreatic cancer. Inhibitors of VEGF suppress the growth of pancreatic cancer in preclinical models. The objectives of this phase II study were to assess the response rate and overall survival of pancreatic cancer patients who received gemcitabine with the recombinant humanized anti-VEGF monoclonal antibody bevacizumab.

Patients and Methods

Patients with previously untreated advanced pancreatic cancer received gemcitabine 1,000 mg/m2 intravenously over 30 minutes on days 1, 8, and 15 every 28 days. Bevacizumab, 10 mg/kg, was administered after gemcitabine on days 1 and 15. Tumor measurements were assessed every two cycles. Plasma VEGF levels were obtained pretreatment.

Results

Fifty-two patients were enrolled at seven centers between November 2001 and March 2004. All patients had metastatic disease, and 83% had liver metastases. Eleven patients (21%) had confirmed partial responses, and 24 (46%) had stable disease. The 6-month survival rate was 77%. Median survival was 8.8 months; median progression-free survival was 5.4 months. Pretreatment plasma VEGF levels did not correlate with outcome. Grade 3 and 4 toxicities included hypertension in 19% of the patients, thrombosis in 13%, visceral perforation in 8%, and bleeding in 2%.

Conclusion

The combination of bevacizumab plus gemcitabine is active in advanced pancreatic cancer patients. Additional study is warranted. A randomized phase III trial of gemcitabine plus bevacizumab versus gemcitabine plus placebo is ongoing in the Cancer and Leukemia Group B.
Biologic and Prognostic Significance of Dermal Ki67 Expression, Mitoses, and Tumorigenicity in Thin Invasive Cutaneous Melanoma
Authors: Gimotty Phyllis A. , Van Belle Patricia , Elder David E. , Murry Todd , Montone Kathleen T. , Xu Xiaowei , Hotz Susan , Raines Shane , Ming Michael E. , Wahl Peter , Guerry DuPont
Published: October 2005

Purpose

Tumor cell proliferation is a central feature of melanoma progression. In this study, we characterized three biomarkers of proliferation (Ki67 expression, dermal mitotic rate [MR], and tumorigenicity) in thin (≤ 1.00 mm) primary cutaneous melanomas and examined their association with prognosis.

Patients and Methods

We used immunohistochemistry to determine Ki67 expression using the monoclonal antibody MIB-1 in lesions from a prospective cohort that included 396 patients with thin invasive primary melanomas seen between 1972 and 1991. A multivariate Cox proportional hazards model was used to define independent prognostic factors, and recursive partitioning was used to develop a prognostic tree identifying risk groups.

Results

Dermal Ki67 expression was lower than epidermal Ki67 expression in radial growth phase (RGP) melanomas (n = 171), and dermal Ki67 expression and MR were higher in tumorigenic vertical growth phase (VGP) melanomas (n = 193) compared with RGP and nontumorigenic VGP melanomas (n = 42). Dermal Ki67 expression, MR greater than 0, growth phase, thickness, ulceration, tumor-infiltrating lymphocytes, and sex were associated with metastasis at 10 years, however, only dermal Ki67 expression, MR greater than 0, and sex were independent prognostic factors. Two high-risk groups were identified: men and women with dermal MR greater than 0 and dermal Ki67 expression ≥ 20% in tumor cells and men with MR greater than 0 and Ki67 expression less than 20%, with 10-year metastasis rates of 39% and 20%, respectively.

Conclusion

Proliferation slows as melanoma cells enter the dermis and then increases with the onset of tumorigenic VGP. Ki67 expression and dermal MR provide independent prognostic information that can potentially be used in risk-based management of patients.
Serial Monitoring of Circulating Melanoma Cells During Neoadjuvant Biochemotherapy for Stage III Melanoma: Outcome Prediction in a Multicenter Trial
Authors: Koyanagi Kazuo , O'Day Steven J. , Gonzalez Rene , Lewis Karl , Robinson William A. , Amatruda Thomas T. , Wang He-Jing , Elashoff Robert M. , Takeuchi Hiroya , Umetani Naoyuki , Hoon Dave S.B.
Published: October 2005

Purpose

Circulating tumor cells (CTCs) in blood may be important in assessing tumor progression and treatment response. We hypothesized that quantitative real-time reverse transcriptase polymerase chain reaction using multimarker mRNA assays could detect CTCs and be used as a surrogate predictor of outcome in patients receiving neoadjuvant biochemotherapy (BC) for melanoma.

Patients and Methods

Blood specimens were collected at four sampling points from 63 patients enrolled on a prospective multicenter phase II trial of BC before and after surgical treatment of American Joint Committee on Cancer stage III melanoma. Each specimen was assessed by quantitative real-time reverse transcriptase polymerase chain reaction for expression of four melanoma-associated markers: melanoma antigen recognized by T cells 1; β1 → 4-N-acetylgalactosaminyltransferase; paired box homeotic gene transcription factor 3; and melanoma antigen gene-A3 family, and the changes of CTCs during treatment and prognostic effect of CTCs after overall treatment on recurrence and survival were investigated.

Results

At a median postoperative follow-up time of 30.4 months, 44 (70%) patients were clinically disease free. In relapse-free patients, the number of detected markers significantly decreased during preoperative BC (P = .036), during postoperative BC (P = .002), and during overall treatment (P < .0001). Marker detection after overall treatment was associated with significant decreases in relapse-free and overall survival (P < .0001). By multivariate analysis using a Cox proportional-hazards model, the number of markers detected after overall treatment was a significant independent prognostic factor for overall survival (risk ratio, 12.6; 95% CI, 3.16 to 50.5; P = .0003).

Conclusion

Serial monitoring of CTCs in blood may be useful for indicating systemic subclinical disease and predicting outcome of patients receiving neoadjuvant BC for metastatic melanoma.
Prognostic Significance of BACH2 Expression in Diffuse Large B-Cell Lymphoma: A Study of the Osaka Lymphoma Study Group
Authors: Sakane-Ishikawa Emiko , Nakatsuka Shin-ichi , Tomita Yasuhiko , Fujita Shigeki , Nakamichi Itsuko , Takakuwa Tetsuya , Sugiyama Haruo , Fukuhara Shirou , Hino Masayuki , Kanamaru Akihisa , Soma Toshihiro , Tsukaguchi Machiko , Igarashi Kazuhiko , Kanakura Yuzuru , Aozasa Katsuyuki
Published: October 2005

Purpose

BACH2, a B-cell–specific transcription repressor, is abundantly expressed in lymphocytes of B-cell lineage as well as B-cell lymphoma cell lines. BACH2 possesses an inhibitory effect on proliferation of Raji cell lines derived from Burkitt's lymphoma. In this study, the prognostic significance of BACH2 expression was examined in diffuse large B-cell lymphoma (DLBCL).

Patients and Methods

BACH2 expression was immunohistochemically examined on the paraffin-embedded sections obtained by biopsy from 108 patients (62 males and 46 females; age range, 23 to 85 years) with DLBCL. Staining intensity in the cytoplasm of the tumor cells was categorized as equal to or stronger (level 1) or weaker (level 2) than that in the endothelial cells in the same specimens.

Results

Level 1 and 2 expression of BACH2 was found in 32.4% and 67.6% of patients, respectively. Patients with level 1 expression showed significantly better disease-free and overall survival rate than those with level 2 expression (both P < .05). Multivariate analysis revealed BACH2 expression level together with performance status, elevated serum level of lactate dehydrogenase, and treatment response to be independent factors for prognosis of the patients.

Conclusion

BACH2 expression level is a useful marker to predict disease-free and overall survival of patients with DLBCL.
Assessment of Cardiac Dysfunction in a Randomized Trial Comparing Doxorubicin and Cyclophosphamide Followed by Paclitaxel, With or Without Trastuzumab As Adjuvant Therapy in Node-Positive, Human Epidermal Growth Factor Receptor 2–Overexpressing Breast Cancer: NSABP B-31
Authors: Tan-Chiu Elizabeth , Yothers Greg , Romond Edward , Geyer Charles E. , Ewer Michael , Keefe Deborah , Shannon Richard P. , Swain Sandra M. , Brown Ann , Fehrenbacher Louis , Vogel Victor G. , Seay Thomas E. , Rastogi Priya , Mamounas Eleftherios P. , Wolmark Norman , Bryant John
Published: October 2005

Purpose

Trastuzumab is effective in treating human epidermal growth factor receptor 2 (HER2) –positive breast cancer, but it increases frequency of cardiac dysfunction (CD) when used with or after anthracyclines.

Patients and Methods

National Surgical Adjuvant Breast and Bowel Project trial B-31 compared doxorubicin and cyclophosphamide (AC) followed by paclitaxel with AC followed by paclitaxel plus 52 weeks of trastuzumab beginning concurrently with paclitaxel in patients with node-positive, HER2-positive breast cancer. Initiation of trastuzumab required normal post-AC left ventricular ejection fraction (LVEF) on multiple-gated acquisition scan. If symptoms suggestive of congestive heart failure (CHF) developed, source documents were blindly reviewed by an independent panel of cardiologists to determine whether criteria were met for a cardiac event (CE), which was defined as New York Heart Association class III or IV CHF or possible/probable cardiac death. Frequencies of CEs were compared between arms.

Results

Among patients with normal post-AC LVEF who began post-AC treatment, five of 814 control patients subsequently had confirmed CEs (four CHFs and one cardiac death) compared with 31 of 850 trastuzumab-treated patients (31 CHFs and no cardiac deaths). The difference in cumulative incidence at 3 years was 3.3% (4.1% for trastuzumab-treated patients minus 0.8% for control patients; 95% CI, 1.7% to 4.9%). Twenty-seven of the 31 patients in the trastuzumab arm have been followed for ≥ 6 months after diagnosis of a CE; 26 were asymptomatic at last assessment, and 18 remained on cardiac medication. CHFs were more frequent in older patients and patients with marginal post-AC LVEF. Fourteen percent of patients discontinued trastuzumab because of asymptomatic decreases in LVEF; 4% discontinued trastuzumab because of symptomatic cardiotoxicity.

Conclusion

Administering trastuzumab with paclitaxel after AC increases incidence of CHF and lesser CD. Potential cardiotoxicity should be carefully considered when discussing benefits and risks of this therapy.