Nonmyeloablative alternative donor transplants.

The advent of nonmyeloablative preparative regimens and the expected lower regimen-related toxicities associated with them hold significant promise for extension of the use of allogeneic hematopoietic stem cell transplantation. Nonmyeloablative hematopoietic stem cell transplantation using human leukocyte antigen matched sibling donor, which carries a relatively low risk of transplant-related complications and can result in impressive antitumor responses, may benefit older patients and patients with preexisting organ impairment. However, more than 65% of patients in need of this procedure lack a human leukocyte antigen matched sibling donor.

A phase I toxicity and feasibility trial of sequential dose-dense induction chemotherapy with doxorubicin, paclitaxel, and 5-fluorouracil followed by high dose consolidation for high-risk primary breast cancer.

Purpose: We studied sequential dose-dense doxorubicin, paclitaxel, and 5-fluorouracil (A-T-F) before high dose chemotherapy (HDC) with autologous peripheral blood stem cell support (PBSCT). Our aims were to determine the maximum tolerated dose (MTD) of 5-FU in the dose-dense regimen and to determine the impact of dose-dense chemotherapy on HDC/PBSCT.

Methods: Patients with Stage IIIB or Stage II or IIIA breast cancer with > or = 4 involved ipsilateral lymph nodes were treated with nine cycles of chemotherapy at 14-day intervals.

Post-mastectomy radiation in male breast cancer.

Background And Purpose: Previous studies of male breast cancer have suggested that due to the lack of breast tissue, post-mastectomy radiation should be routinely utilized in all stages of this disease. We propose that the pattern of local recurrence in male breast cancer is, stage for stage, similar to female breast cancer and, therefore, the indications for post-mastectomy radiation should be similar.

Materials And Methods: We conducted a retrospective analysis of 44 cases of male breast cancer from 1967 to 1995.

Ongoing US cooperative group trials using taxanes in the adjuvant setting.

The use of systemic adjuvant therapy in women with early-stage breast cancer has been demonstrated to have a profound impact on survival. The role of paclitaxel and docetaxel in the adjuvant setting has attracted a great deal of attention. Both of these agents are highly active in patients with advanced breast cancer.

Chemotherapy and bone marrow reserve: lessons learned from autologous stem cell transplantation.

Cytotoxic chemotherapy is often complicated by hematopoietic toxicity. The degree of aplasia and the rapidity of count recovery following chemotherapy are indicative of bone marrow reserve. Patients who generally have a normal bone marrow function will recover from chemotherapy-induced cytopenia relatively rapidly.

Hypermethylation-associated Inactivation of the Cellular Retinol-Binding-Protein 1 Gene in Human Cancer.

The effects of retinol (vitamin A) depend on its transport and binding to nuclear receptors. The cellular retinol-binding protein 1 (CRBP1) and the retinoic acid receptor beta2 (RARbeta2) are key components of this process. Loss of CRBP1 expression occurs in breast tumors, but the mechanism is not known.

What is the optimal therapy for childhood AML?

The use of intensive therapy overa brief period of time has produced dramatic improvements in outcome for pediatric patients with acute myelogenous leukemia (AML), as has been demonstrated in studies by the major cooperative groups in the United States and Europe. Still, despite high-intensity chemotherapy and bone marrow transplantation, only about half of the children diagnosed with AML are cured. Future improvements are unlikely to come from further increases in chemotherapy intensity.

Growth status significantly affects the response of human lung cancer cells to antitumor polyamine-analogue exposure.

Human solid tumors frequently have a relatively small growth fraction,which interferes with the action of many chemotherapeutic agents that target actively cycling cells. Several polyamine analogues are currently being developed for clinical application against human solid tumors including N1,N11-bis(ethyl)norspermine. Therefore, an effort was made to examine the effects of growth rate on polyamine-analogue efficacy.

Is there a requirement for adjuvant therapy for choroid plexus carcinoma that has been completely resected?

Choroid plexus carcinomas (CPC) are rare central nervous system malignancies. While attempted surgical resection is imperative, the benefit of adjuvant therapy, particularly in the setting of a gross total resection (GTR), is unclear. We reviewed all pediatric cases of CPC reported in the literature between 1985 and 2000.

AML1 stimulates G1 to S progression via its transactivation domain.

Inhibition of AML1-mediated transactivation potently slows G1 to S cell cycle progression. In Ba/F3 cells, activation of exogenous AML1 (RUNX1)-ER with 4-hydroxytamoxifen prevents inhibition of G1 progression mediated by CBFbeta-SMMHC, a CBF oncoprotein. We expressed three AML1-ER variants with CBFbeta-SMMHC in Ba/F3 cells.

Autologous bone marrow transplantation with 4-hydroperoxycyclophosphamide purging for acute myeloid leukaemia beyond first remission: a 10-year experience.

Between January 1987 and January 1997, 69 eligible patients with acute myeloid leukaemia (AML) in either second (CR2) or third (CR3) complete remission (CR2 = 60, CR3 = 9) underwent 4-hydroperoxycyclophosphamide-purged autologous bone marrow transplantation (BMT) at the Johns Hopkins Oncology Center. The patients' median age was 27 years (range 1-62) and all received busulphan and cyclophosphamide as their preparative regimen. The probability of event-free survival (EFS) at 5 years was 30% [95% Confidence Interval (CI): 19-42%] for CR2 patients and 22% (3-51%) for those in CR3, with a median follow up of 8 years in the surviving group.

Early operable breast cancer.

Early operable breast cancer is a potentially curable disease. However, a substantial number of patients are at risk for systemic recurrence and death. Breast conservation therapy (BCT) should be considered the preferred surgical option for most women with early operable breast cancer.

Pediatric glial tumors.

Glial neoplasms in children comprise many heterogeneous tumors that include pilocytic and fibrillary astrocytomas, ependymomas, and the diffuse intrinsic pontine gliomas. In contrast to adults, most of whom present with high-grade fibrillary neoplasms, alternate histologies represent most cases seen in the pediatric setting. In addition, although most adult gliomas are supratentorial in location, in pediatrics infratentorial tumors (posterior fossa and brain stem) predominate.

Polyamine-modulated factor 1 binds to the human homologue of the 7a subunit of the Arabidopsis COP9 signalosome: implications in gene expression.

Polyamines have been identified to play a role in the transcription of various growth-related genes. The recently discovered polyamine responsive element and the associated trans-acting proteins involved in polyamine-regulated transcription have provided a model system for the study of the role of polyamines in transcription. Polyamine-modulated factor 1 (PMF-1) was identified as one of the transacting factors that binds to NF-E2 related factor-2 (Nrf-2) to regulate the transcription of spermidine/spermine N(1)-acetyltransferase (SSAT).

A systematic approach to hepatic complications in hematopoietic stem cell transplantation.

Hepatic injury is a common complication of hematopoietic stem cell transplantation (HSCT) and carries a high risk of early morbidity and mortality. Evaluation of the patient for hepatic complications should begin in the pretransplant period with the identification of pretransplant risk factors, such as hepatitis status, that may predict severe liver complications and continue through the early and late transplant periods. Early hepatic complications include drug toxicity, hepatic veno-occlusive disease (VOD), acute graft-versus-host disease (GVHD), infection, and cholestatic disorders.

A supramicromolar elevation of intracellular free calcium ([Ca(2+)](i)) is consistently required to induce the execution phase of apoptosis.

Many agents, such as the endoplasmic reticulum Ca(2+) ATPase inhibitor, thapsigargin, or the ionophore, ionomycin, induce apoptosis by transiently elevating [Ca(2+)](i). The role of [Ca(2+)](i) in apoptosis induced by agents that do not immediately increase [Ca(2+)](i), such as 5-FdUr, TGF beta-1, doxorubicin, or radiation, is far more controversial. In the present paper, [Ca(2+)](i) was measured continuously for 120 h.

Donor lymphocyte infusions to treat hematologic malignancies in relapse after allogeneic blood or marrow transplantation.

Background: Patients with hematologic malignancies in relapse after allogeneic bone marrow transplantation can be treated by infusing leukocytes from the original stem cell donor.

Methods: The published literature on donor lymphocyte infusion (DLI) was reviewed.

Results: DLI induces complete remissions in the majority of patients with chronic myeloid leukemia (CML) in early-stage relapse and in less than 30% of patients with relapsed acute leukemia, myelodysplasia, and multiple myeloma.

Atrasentan, an endothelin-receptor antagonist for refractory adenocarcinomas: safety and pharmacokinetics.

Purpose: Endothelin receptors, particularly the ET(A) receptor, have been shown to participate in the pathophysiology of prostate and other cancers. Atrasentan, an endothelin antagonist, binds selectively to the ET(A) receptor. This study evaluated the safety, pharmacokinetics, and maximum-tolerated dose of atrasentan in cancer patients.

CD34 selection using three immunoselection devices: comparison of T-cell depleted allografts.

Background: T-cell depletion of allografts markedly reduces the incidence of GvHD following BMT. The approach taken at our Center has utilized the physical separation method of counterflow centrifugal elutriation (CCE), augmented by recovery of stem cells from lymphocyte-rich fractions by immunoaffinity selection of CD34(+) stem cells. We wanted to compare the performance characteristics of three commercially available selection devices, as well as the clinical outcomes of patients who received allografts engineered by the different devices.

Poor outcome in steroid-refractory graft-versus-host disease with antithymocyte globulin treatment.

Treatment of acute graft-versus-host disease (aGVHD) has relied on high-dose steroids, but less than 50% of patients show durable remission. Antithymocyte globulin (ATG) has become a standard salvage therapy. We now report our experience with ATG for the treatment of steroid-refractory GVHD in 69 patients treated from January 1, 1980, to May 1, 1999.