Pleasant memories: remembering immune protection while forgetting about graft-versus-host disease.

Graft-versus-host disease (GVHD) represents a major cause of morbidity and mortality following conventional allogeneic hematopoietic stem cell transplantation (HSCT). A study in mice (see related article on pages 101–108) demonstrates that the selective administration of donor memory CD4 T cells results in immune reconstitution without GVHD, a result that, if translatable to humans, has important clinical implications for HSCT.

Perillyl alcohol as a radio-/chemosensitizer in malignant glioma.

The prognosis for patients with malignant glioma has not significantly changed in two decades, despite advances in surgery, radiation, and chemotherapy, emphasizing the growing need for novel approaches to glioma therapy. Perillyl alcohol (POH) is a naturally occurring monoterpene that has been shown to possess chemotherapeutic as well as chemopreventive activity in animal tumor models and is currently in Phase I and Phase II clinical trials. In the present study, we have demonstrated that POH is an effective radiosensitizer at clinically relevant doses of radiation using established glioma cell lines.

Growth inhibition and differentiation in human prostate carcinoma cells induced by the vitamin D analog 1alpha,24-dihydroxyvitamin D2.

Background: Vitamin D has been suggested as a chemopreventive and therapeutic modality for prostate cancer. However, hypercalcemic toxicity has limited the use of 1alpha,25-dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)) in clinical trials, prompting the search for analogs of vitamin D with less toxicity while retaining efficacy as a modality for cancer intervention. In this study, the less hypercalcemic vitamin D analog 1alpha,24-dihydroxyvitamin D(2) (1,24-(OH)(2)D(2)) was examined for its effects on cellular growth inhibition and differentiation induction in the LNCaP human prostate carcinoma cell line.

Pilot study of an HLA-A2 peptide vaccine using flt3 ligand as a systemic vaccine adjuvant.

A pilot vaccine study was conducted to test the safety and immunological efficacy of four monthly immunizations of an MHC class I peptide vaccine, the E75 HLA-A2 epitope from HER-2/neu, using flt3 ligand as a systemic vaccine adjuvant. Twenty HLA-A2-expressing subjects with advanced stage prostate cancer were randomly assigned to one of four immunization or treatment schedules: (a) Flt3 ligand (20 microg/kg per day) administered subcutaneously daily for 14 days on a 28-day cycle, monthly for four months; (b) flt3 ligand course as above with the E75 peptide vaccine administered on day 7 of each flt3 ligand cycle; (c) flt3 ligand course as above with the E75 peptide vaccine administered on day 14 of each flt3 ligand cycle; or (d) E75 peptide admixed with granulocyte-macrophage colony-stimulating factor and administered intradermally once every 28 days, as has previously been reported. The primary endpoints of the study were the determination of safety and immunological efficacy in generating E75-specific T cells as determined by peptide-specific interferon-gamma ELIspot.

Tobacco harm reduction: a call to address the ethical dilemmas.

The 2001 Institute of Medicine report Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction has helped to focus attention on the scientific basis for assessing tobacco harm reduction products. As the tobacco research and policy communities tackle the challenges of evaluating harm reduction, there are ethical issues that must also be addressed. There has, however, been very little writing on the ethics of this field.

Clinical promise tempered by reality in the delivery of combined chemoradiation for common solid tumors.

Until quite recently, there was no firmly established role for cytotoxic chemotherapy in the curative management approach for many of our most common malignancies. Systemic therapy was often reserved for recurrent or metastatic disease after initial surgery and/or radiotherapy. Today, the treatment of many advanced cancer patients involves integration of chemotherapy into the definitive treatment strategy.

Phase I clinical and pharmacokinetic trial of the cyclin-dependent kinase inhibitor flavopiridol.

Purpose: Flavopiridol (NSC 649890) is a synthetic flavone possessing significant antitumor activity in preclinical models. Flavopiridol is capable of inducing cell cycle arrest and apoptosis, presumably through its potent, specific inhibition of cyclin-dependent kinases. We conducted a phase I trial and pharmacokinetic study of flavopiridol given as a 72-h continuous intravenous infusion repeated every 2 weeks.

Phase I study of eniluracil, oral 5-fluororacil and gemcitabine in patients with advanced malignancy.

Purpose: The objectives of this trial were to assess the maximal tolerated dose and toxicity of the combination of oral eniluracil and 5-fluorouracil and intravenous gemcitabine.

Patients And Methods: Patients with histologically confirmed, incurable malignancy (solid tumor or lymphoma) refractory to standard therapy or for which no standard therapy exists were enrolled. The treatment plan consisted of weekly gemcitabine for three weeks with twice daily dosing of 5-FU and eniluracil for 21 days beginning on day one of gemcitabine.

Phase I trial of 1alpha-hydroxyvitamin d(2) in patients with hormone refractory prostate cancer.

This Phase I study of 1alpha-hydroxyvitamin D(2), an p.o. administered vitamin D analogue, in patients with advanced hormone-refractory prostate cancer was designed to assess the toxicity, pharmacokinetic and biological markers of drug activity, and lastly tumor response data to recommend a dose for Phase II studies.

Progress of a Comprehensive Familial Cancer Genetic Counseling Program in the Era of BRCA1 and BRCA2.

BRCA1 and BRCA2 mutation carriers have an increased risk of developing breast and/or ovarian cancer. Technical advances in genetic testing have increased the need for genetic counseling services; therefore, we have developed a counseling program for these individuals. The purpose of this study is to characterize this population, assess level of interest in genetic testing, and evaluate our program over a 5-year period.

The Keap1 BTB/POZ dimerization function is required to sequester Nrf2 in cytoplasm.

Transactivation of phase II detoxification enzymes and antioxidant proteins is mediated by the Cap'N'Collar transcription factor, Nrf2, which is sequestered in the cytoplasm by the actin-binding protein Keap1. Mutation of a conserved serine (S104A) within the Keap1 BTB/POZ domain disrupts Keap1 dimerization and eliminates the ability of Keap1 to sequester Nrf2 in the cytoplasm and repress Nrf2 transactivation. Disruption of endogenous Keap1 dimerization using BTB/POZ dominant negative proteins also inhibits the ability of Keap1 to retain Nrf2 in the cytoplasm.

Endometrial cancer incidence in relation to electric blanket use.

Endometrial cancer is associated with endogenous and exogenous estrogen excess. Some investigators have posited that electromagnetic fields may influence cancer risk through estrogenic hormonal mechanisms; however, there have been no studies reporting on electric blanket exposure in relation to endometrial cancer. The authors examined this possible association between endometrial cancer risk and electric blanket or mattress cover use as part of a population-based, case-control study.

Phase I clinical and pharmacokinetic study of NSC 655649, a rebeccamycin analogue, given in both single-dose and multiple-dose formats.

Purpose: NSC 655649 was given in both single- and multiple-dose formats, to characterize maximum tolerated dose (MTD), toxicity, and pharmacokinetic profile.

Experimental Design: Patients with advanced malignancies were treated with escalating doses of NSC 655649 in either a single-dose format (step 1) or a multiple-dose format (step 2). In step 1, NSC 655649 was given as a 30-60 min infusion.

Postmenopausal estrogen and progestin use in relation to breast cancer risk.

Epidemiological evidence now consistently supports a modest increase in breast cancer risk among women using postmenopausal hormones, usually estrogens. Less is known regarding how the addition of progestin affects breast cancer risk. The objective of this study was to investigate the type and duration of postmenopausal therapy and breast cancer risk.

Oophorectomy and tamoxifen adjuvant therapy in premenopausal Vietnamese and Chinese women with operable breast cancer.

Purpose: In 1992, the Early Breast Cancer Trialists' Collaborative Group reported that a meta-analysis of six randomized trials in European and North American women begun from 1948 to 1972 demonstrated disease-free and overall survival benefit from adjuvant ovarian ablation. Approximately 350,000 new cases of breast cancer are diagnosed annually in premenopausal Asian women who have lower levels of estrogen than western women.

Patients And Methods: From 1993 to 1999, we recruited 709 premenopausal women with operable breast cancer (652 from Vietnam, 47 from China) to a randomized clinical trial of adjuvant oophorectomy and tamoxifen (20 mg orally every day) for 5 years or observation and this combined hormonal treatment on recurrence.

Young age as an adverse prognostic factor in premenopausal women with operable breast cancer.

Data regarding young age as an independent prognostic factor have been conflicting. We investigated this variable in 696 premenopausal Vietnamese and Chinese women with operable breast cancer who participated in a clinical trial of adjuvant surgical oophorectomy and tamoxifen. Tumor size and axillary lymph node status did not vary with age.

Phase I clinical and pharmacokinetic study of oral penclomedine (NSC 338720) in adults with advanced solid malignancy.

Penclomedine is a synthetic alpha-picoline derivative that has shown antitumor activity both in preclinical development and in Phase I work using an i.v. preparation.

Pain management and prescription monitoring.

Preventing diversion and abuse of prescription controlled substances while ensuring their availability for legitimate medical use is an important public health goal in the United States. In one approach to preventing and identifying drug diversion, 17 states have implemented prescription monitoring programs (PMPs) to monitor the prescribing of certain controlled substances. While PMPs are not intended to interfere with legitimate prescribing, some in the pain management community feel that they negatively affect prescribing for pain management.

Phase I and pharmacokinetic study of a micronized formulation of carboxyamidotriazole, a calcium signal transduction inhibitor: toxicity, bioavailability and the effect of food.

Purpose: This Phase I study was conducted to evaluate the toxicity profile and determine the maximum tolerated dose (MTD) of an oral micronized formulation of the signal transduction inhibitor carboxyamidotriazole (CAI). Bioavailability of the micronized formulation relative to a gelatin capsule (gelcap) formulation was assessed. The effects of food intake and timing on CAI steady-state plasma concentrations (C(ss)) were also investigated.

Phase I clinical and pharmacokinetic trial of irofulven.

Purpose: To evaluate the clinical tolerability of a new schedule of 6-hydroxymethylacylfulvene (irofulven, MGI 114, HMAF, NSC 683863), a semisynthetic sesquiterpene derived from the cytotoxic mushroom metabolite illudin S. Irofulven has been shown to induce DNA damage and apoptosis in vitro and has shown activity in a number of human tumor xenograft models. A number of drug-resistant cell lines including those that express the mdr phenotype, retain sensitivity to irofulven.

Role of cyclin-dependent kinase inhibitors in the growth arrest at senescence in human prostate epithelial and uroepithelial cells.

Cellular senescence has been proposed to be an in vitro and in vivo block that cells must overcome in order to immortalize and become tumorigenic. To characterize these pathways, we focused on changes in the cyclin-dependent kinase inhibitors and their binding partners that underlie the cell cycle arrest at senescence. As a model, we utilized normal human prostate epithelial cell (HPEC) and human uroepithelial cell (HUC) cultures.