Posttransplantation cyclophosphamide facilitates engraftment of major histocompatibility complex-identical allogeneic marrow in mice conditioned with low-dose total body irradiation.

Cyclophosphamide (Cy) has been studied extensively for its immunosuppressive properties and is frequently combined with total body irradiation (TBI) as conditioning prior to HLA-identical allogeneic blood or marrow transplantation (alloBMT) in humans. Because Cy is most effective at suppressing host-versus-graft reactions when the drug is given after the transplantation (Mayumi H et al. Transplant Proc.

Von Willebrand factor-cleaving protease activity and proteolysis of von Willebrand factor in bone marrow transplant-associated thrombotic microangiopathy.

Introduction: Thrombotic microangiopathy (TM) of the fulminant type occurring in patients following bone marrow transplant (BMT) has clinical manifestations that are similar to thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome, but the outcome is generally fatal despite conventional therapy. Idiopathic acquired TTP has been associated with IgG inhibitors to the cleaving protease of von Willebrand factor (vWF) in plasma. In this study, we investigated the role of the vWF protease and vWF proteolysis in the pathogenesis of BMT-associated TM of the fulminant type.

Long-term follow-up of intensive ara-C-based chemotherapy followed by bone marrow transplantation for adult acute lymphoblastic leukemia: impact of induction Ara-C dose and post-remission therapy.

We report single institution outcome of brief, intensive ara-C-based chemotherapy using bone marrow transplantation as primary intensification for untreated adult patients with acute lymphoblastic leukemia (ALL). Overall disease-free and overall survival were inferior to those reported with prolonged chemotherapy modeled on pediatric protocols. Survival and disease-free survival were superior for patients receiving allogeneic BMT compared with chemopurged autologous transplant or maintenance chemotherapy (patients ineligible for or declining BMT).

Multiple sebaceous adenomas and extraocular sebaceous carcinoma in a patient with multiple sclerosis: case report and review of literature.

Background: Sebaceous carcinomas are relatively rare cutaneous tumors; there are fewer than 600 cases reported. They most commonly arise within the meibomian gland of the eyelid; fewer than 150 of the reported cases were extraocular. These tumors have a high incidence of local recurrence and regional metastasis.

Chromosome segregation and cancer: cutting through the mystery.

Mitosis is the most dramatic--and potentially dangerous--event in the cell cycle, as sister chromatids are irreversibly segregated to daughter cells. Defects in the checkpoints that normally maintain the fidelity of this process can lead to chromosomal instability (CIN) and cancer. However, CIN--a driving force of tumorigenesis--could be the cancer cell's ultimate vulnerability.

Nonsteroidal anti-inflammatory drugs, apoptosis, and colon-cancer chemoprevention.

Nonsteroidal anti-inflammatory drugs (NSAIDs) can inhibit colorectal tumorigenesis and are among the few agents known to be chemopreventive. Epidemiological studies and experiments with animals have shown that NSAIDs have powerful anticolorectal cancer properties, but the mechanism of these effects remains unclear. NSAIDs can inhibit neoplastic growth by inducing apoptosis in cancer cells; the way they do this is currently an area of intense investigation.

GM-CSF-based cellular vaccines: a review of the clinical experience.

Immunotherapy is playing an increasing role in the treatment of many cancers. The recent advances in antibody therapy gives much optimism that both passive (antibody therapy) as well as active (vaccine therapy) immunotherapeutic interventions will acquire an increasing presence in oncology. Granulocyte macrophage-colony stimulation factor (GM-CSF)-based vaccines have now been tested in several diseases in a variety of formulations.

Phase I study of N(1),N(11)-diethylnorspermine in patients with non-small cell lung cancer.

Purpose: Polyamines are essential for tumor growth; consequently, agents that interfere with their metabolisms have been developed as antineoplastic agents. Diethylnorspermine (DENSPM) is one such agent. A focused Phase I clinical trial in patients with advanced non-small cell lung cancer was undertaken.

High-dose cyclophosphamide for aplastic anemia and autoimmunity.

High-dose cyclophosphamide was developed as a conditioning regimen for allogeneic bone marrow transplantation. Later, it was discovered that high-dose cyclophosphamide spares early hematopoietic stem cells because of their relatively high levels of the enzyme aldehyde dehydrogenase; thus, high-dose cyclophosphamide is a potent immunosuppressive agent, but nonmyeloablative. Recent reports demonstrate that high-dose cyclophosphamide without bone marrow transplantation induces durable treatment-free remissions in severe aplastic anemia and a variety of other autoimmune disorders; however, there is lingering concern about the safety of this approach.

Trk receptor inhibition induces apoptosis of proliferating but not quiescent human osteoblasts.

Prostate cancer frequently metastasizes to the skeleton, producing painful osteoblastic lesions, which are associated with significant morbidity and mortality. This bone tropism involves the bidirectional paracrine interactions between prostate cancer cells and osteoblasts. These interactions enhance prostate cancer cell survival and proliferation of osteoblasts.

Opportunistic fungal infections in the critically ill.

Opportunistic fungal infections are increasingly common in acute care and now represent 10% to 15% of all nosocomial infections. Few references and clinical resources are readily available for nurses in planning care for these patients (as opposed to bacterial diseases, which are better known). Nurses must recognize patients at high risk for fungal infections and develop more detailed assessment plans that include orifice and breath sound assessments.

Yttrium 90 ibritumomab tiuxetan radioimmunotherapy for relapsed or refractory low-grade non-Hodgkin's lymphoma.

The treatment of malignant lymphoma has improved over the past 20 years, but the majority of patients are not cured. New modalities using targeted therapy based on new information in molecular biology and immunology hold promise for better outcomes with less toxicity. We review data on the use of radiolabeled monoclonal antibodies directed against the CD20 antigen on malignant B cells.

Uracil-DNA glycosylase-deficient yeast exhibit a mitochondrial mutator phenotype.

Mutations in mitochondrial DNA (mtDNA) have been reported in cancer and are involved in the pathogenesis of many mitochondrial diseases. Uracil-DNA glycosylase, encoded by the UNG1 gene in Saccharomyces cerevisiae, repairs uracil in DNA formed due to deamination of cytosine. Our study demonstrates that inactivation of the UNG1 gene leads to at least a 3-fold increased frequency of mutations in mtDNA compared with the wild-type.

Use of SERMs for the adjuvant therapy of early-stage breast cancer.

Tamoxifen was the first in a class of drugs now commonly referred to as selective estrogen receptor modulators or SERMs. SERMs exhibit tissue-specific estrogenic agonist/antagonist activity through their ability to bind to the estrogen receptor alpha (ER) protein and interact with coregulatory proteins, thereby modulating transcription of estrogen target genes. Since its first approval by the United States Food and Drug Administration (FDA) in 1977, tamoxifen has been found to (a) lower the risk of recurrence and death for women with early-stage hormone receptor-positive breast cancer, irrespective of menopausal and node status or use of adjuvant chemotherapy; (b) reduce the risk of invasive breast cancer following breast conservation in women with ductal carcinoma in situ (DCIS); and (c) reduce the risk of breast cancer in high-risk women.

Human cell knockouts.

One of the most productive areas of biologic research has been the utilization of model organisms for the systematic study of gene function. Although the experimental manipulation of these model genetic systems has provided important insights into the function of homologous genes in humans, such studies are necessarily limited by the need to extrapolate among divergent species and cell types. Researchers have now begun to apply the technology of gene targeting to human cell lines.

Targeting transgene expression to antigen-presenting cells derived from lentivirus-transduced engrafting human hematopoietic stem/progenitor cells.

Hematopoietic stem cells (HSCs) represent an important target for the treatment of various blood disorders. As the source of critical cells within the immune system, genetic modification of HSCs can also be used to modulate immune responses. The effectiveness of HSC-mediated gene therapy largely depends on efficient gene delivery into long-term repopulating progenitors and targeted transgene expression in an appropriate progeny of the transduced pluripotent HSCs.

Hypermethylation of the DNA repair gene O(6)-methylguanine DNA methyltransferase and survival of patients with diffuse large B-cell lymphoma.

Background: The gene encoding the DNA repair enzyme O(6)-methylguanine DNA methyltransferase (MGMT) is transcriptionally silenced by promoter hypermethylation in several human cancers, including diffuse large B-cell lymphoma (B-DLCL). MGMT promoter hypermethylation is a favorable prognostic marker in patients with brain tumors treated with alkylating agents.

Methods: In a retrospective cohort study, we used methylation-specific polymerase chain reaction to analyze the MGMT promoter methylation status in tumor DNA of B-DLCL patients receiving cyclophosphamide as part of multidrug regimens.

A cyclooxygenase-2 (COX-2) inhibitor compared with dexamethasone in a survival study of rats with intracerebral 9L gliosarcomas.

Although dexamethasone is very effective for controlling peritumoral cerebral edema, it is associated with distressing side effects that decrease the quality of life for many patients. One potential mechanism to explain the ability of dexamethasone to repair blood-brain barrier dysfunction is through the inhibition of cyclooxygenase-2 (COX-2). The purpose of this study was to determine in a rat brain tumor model whether SC-236, a selective COX-2 inhibitor, is as effective as dexamethasone.

DNA methylation patterns in hereditary human cancers mimic sporadic tumorigenesis.

Cancer cells have aberrant patterns of DNA methylation including hypermethylation of gene promoter CpG islands and global demethylation of the genome. Genes that cause familial cancer, as well as other genes, can be silenced by promoter hypermethylation in sporadic tumors, but the methylation of these genes in tumors from kindreds with inherited cancer syndromes has not been well characterized. Here, we examine CpG island methylation of 10 genes (hMLH1, BRCA1, APC, LKB1, CDH1, p16(INK4a), p14(ARF), MGMT, GSTP1 and RARbeta2) and 5-methylcytosine DNA content, in inherited (n = 342) and non-inherited (n = 215) breast and colorectal cancers.

Cancer as an epigenetic disease: DNA methylation and chromatin alterations in human tumours.

Cancer is an epigenetic disease at the same level that it can be considered a genetic disease. In fact, epigenetic changes, particularly DNA methylation, are susceptible to change and are excellent candidates to explain how certain environmental factors may increase the risk of cancer. The delicate organization of methylation and chromatin states that regulates the normal cellular homeostasis of gene expression patterns becomes unrecognizable in the cancer cell.

Evolving therapies: farnesyltransferase inhibitors.

Farnesyltransferase inhibitors (FTIs) are compounds designed to interfere with the signal transduction of cancer cells containing ras gene mutations. Specifically, FTIs were designed to prevent the farnesylation of Ras and other intracellular proteins, and they have been shown to have an effect on malignant cell proliferation and survival. However, the actual intracellular target of FTIs and the cellular determinants of drug action that correlate with antitumor effects currently are unknown.

Long-term results of blood and marrow transplantation for Hodgkin's lymphoma.

Purpose: To evaluate the long-term outcome after allogeneic (allo) and autologous (auto) blood or marrow transplantation (BMT) in patients with relapsed or refractory Hodgkin's lymphoma (HL).

Patients And Methods: We analyzed the outcome of 157 consecutive patients with relapsed or refractory HL, who underwent BMT between March 1985 and April 1998. Patients View Article and Find Full Text PDF

Combination bacteriolytic therapy for the treatment of experimental tumors.

Current chemotherapeutic approaches for cancer are in part limited by the inability of drugs to destroy neoplastic cells within poorly vascularized compartments of tumors. We have here systematically assessed anaerobic bacteria for their capacity to grow expansively within avascular compartments of transplanted tumors. Among 26 different strains tested, one (Clostridium novyi) appeared particularly promising.

Durable engraftment of major histocompatibility complex-incompatible cells after nonmyeloablative conditioning with fludarabine, low-dose total body irradiation, and posttransplantation cyclophosphamide.

Treatment of leukemia by myeloablative conditioning and transplantation of major histocompatibility complex (MHC)-mismatched stem cells is generally avoided because of the high risk of graft rejection or lethal graft-versus-host disease (GVHD). This study shows that MHC-incompatible cells can engraft stably after nonmyeloablative conditioning with immunosuppressive chemotherapy and low-dose total body irradiation (TBI). Long-term mixed hematopoietic chimerism, clonal deletion of donor-reactive T cells, and bidirectional cytotoxic T-cell tolerance were achieved by transplanting MHC-mismatched marrow cells into recipients conditioned with pretransplantation fludarabine or cyclophosphamide (Cy), 50 to 200 cGy TBI on day -1, and Cy 200 mg/kg intraperitoneally on day 3.