Citations

Purpose: A phase III, randomized, double-blind study was conducted by the North Central Cancer Treatment Group to determine the efficacy and toxicity of oral glutamine for the prevention of acute diarrhea in patients receiving pelvic radiation therapy (RT). Patients and Methods: All 129 patients enrolled from 14 institutions between February 1998 and October 1999 were eligible. Patients received 4 g of glutamine or placebo orally, twice a day, beginning with the first or second day of RT and continuing for 2 weeks after RT. During treatment, patients were assessed weekly for toxicity, and a bowel function questionnaire was administered. The primary measures of treatment efficacy were diarrhea levels measured by maximum grade of diarrhea, incidence of diarrhea, and average diarrhea score. After completion of RT, the bowel function questionnaire was administered weekly for 4 weeks and at 12 and 24 months. Toxicity was measured by National Cancer Institute common toxicity criteria. Results: The median age of patients was 69 years (range, 34 to 86 years). The two treatment arms were balanced with respect to all baseline factors. There were no significant differences in toxicity by treatment. Quality-of-life scores and the mean number of problems reported on the bowel function questionnaire were virtually identical for both treatment groups. The incidence of grade 3 or higher diarrhea was 20% for the glutamine arm and 19% for the placebo arm (P = .99). The maximum number of stools per day was 5.1 for the glutamine arm and 5.2 for the placebo arm (P = .99). Conclusion: There is no evidence of a beneficial effect of glutamine during pelvic RT.

Purpose: This phase II study was undertaken to define the efficacy and pharmacodynamics of R115777, a farnesyl transferase inhibitor, in the first-line treatment of patients with advanced non–small-cell lung cancer. Patients and Methods: Forty-four patients with measurable stage IIIB (pleural effusion) or stage IV disease received 193 courses of treatment (median, 2.0; range, 1 to 22) with R115777 300 mg administered orally twice daily for 21 of every 28 days. Buccal mucosa samples and peripheral blood mononuclear cells (PBMCs) were collected before and after 8 days of treatment to evaluate inhibition of farnesyl transferase in vivo. Results: No objective complete or partial responses were documented. Seven patients (16%; 95% confidence interval [CI], 8% to 31%) had disease stabilization for greater than 6 months. Median survival was 7.7 months (95% CI, 6.5 to 10.5) and time to progression was 2.7 months (95% CI, 1.9 to 3.1). The most severe toxicity was neutropenia (9% grade 3, 7% grade 4) and the most common toxicities were anemia (50% grade 1 or 2, 5% grade 3) and anorexia (50% grade 1 or 2, 2% grade 3). Mild peripheral neuropathy occurred in 25% of patients. Evidence of farnesyl transferase inhibition was documented in 83% of patients. Conclusion: Single-agent R115777 was well tolerated in patients with advanced NSCLC, but demonstrated minimal clinical activity. Inhibition of farnesylation in vivo was consistently documented. On the basis of promising results of farnesyl transferase inhibitor combinations with standard chemotherapy agents, future studies of this agent in NSCLC should be in combination with systemic chemotherapy.

AbstractWe reported recently the induction of androgen-dependent iodide uptake activity in the human prostatic adenocarcinoma cell line LNCaP using a prostate-specific antigen (PSA) promoter-directed expression of the sodium iodide symporter (NIS) gene. This offers the potential to treat prostate cancer with radioiodine. In the current study, we examined the regulation of PSA promoter-directed NIS expression and therapeutic effectiveness of 131I in LNCaP cells by all-trans-retinoic acid (atRA). For this purpose, NIS mRNA and protein expression levels in the NIS-transfected LNCaP cell line NP-1 were examined by Northern and Western blot analysis following incubation with atRA (10 −9 to 10−6m) in the presence of 10−9m mibolerone (mib). In addition, NIS functional activity was measured by iodide uptake assay, and in vitro cytotoxicity of 131I was examined by in vitro clonogenic assay. Following incubation with atRA, NIS mRNA levels in NP-1 cells were stimulated 3-fold in a concentration-dependent manner, whereas NIS protein levels increased 2.3-fold and iodide accumulation was stimulated 1.45-fold. This stimulatory effect of atRA, which has been shown to be retinoic acid receptor mediated, was completely blocked by the pure androgen receptor antagonist casodex (10−6m), indicating that it is androgen receptor dependent. The selective killing effect of 131I in NP-1 cells was 50% in NP-1 cells incubated with 10−9m mib. This was increased to 90% in NP-1 cells treated with atRA (10−7m) plus 10−9m mib. In conclusion, treatment with atRA increases NIS expression levels and selective killing effect of 131I in prostate cancer cells stably expressing NIS under the control of the PSA promoter. Therefore atRA may be used to enhance the therapeutic response to radioiodine in prostate cancer cells following PSA promoter-directed NIS gene delivery.

Abstract Multiple myeloma (MM) and primary systemic amyloidosis (AL) remain incurable disorders, and new treatments targeted to the malignant plasma cells are needed. Alemtuzumab is a humanized monoclonal antibody to CD52 and has activity in chronic lymphocytic leukemia. We examined the CD52 expression on CD45+ and CD45- plasma cell populations to evaluate the potential for using alemtuzumab for these disorders. Bone marrows from 61 patients (29 AL, 23 MM, and 9 MGUS [monoclonal gammopathies of undetermined significance]) were studied using 3-color (CD38/45/52) flow cytometry. Among those with MGUS, MM, and AL, 67%, 52%, and 35%, respectively, were positive for CD52 expression. The CD52 expression was predominantly confined to the clonal CD38+/CD45+ plasma cell fraction with median expression of 68%, 88%, and 82% in MGUS, MM, and AL, respectively, compared with 18%, 6%, and 9% among the CD45- plasma cell population. Clinical trials are warranted in these diseases to learn the therapeutic benefit of anti-CD52 immunotherapy.

AbstractT cells are produced through 2 mechanisms, thymopoiesis and proliferative expansion of postthymic T cells. Thymic output generates diversity of the pool, and proliferation achieves optimal clonal size of each individual T cell. To determine the contribution of these 2 mechanisms to the formation of the initial T-cell repertoire, we examined neonates of 30 to 40 weeks' gestation. Peripheral T cells were in a state of high proliferative turnover. In premature infants, 10% of T cells were dividing; the proliferation rates then declined but were still elevated in mature newborns. Throughout the third trimester, concentrations of T-cell–receptor excision circles (TRECs) were 10 per 100 T cells. Stability of TREC frequencies throughout the period of repertoire generation suggested strict regulation of clonal size to approximately 10 to 20 cells. Neonatal naive CD4+ and CD8+ T cells were explicitly responsive to IL-7; growth-promoting properties of IL-15 were selective for newborn CD8+ T cells. Neonatal T cells expressed telomerase and, in spite of the high turnover, built up a telomeric reserve. Thus, proliferative expansion, facilitated by increased cytokine responsiveness, and thymopoiesis complement each other as mechanisms of T-cell production in neonates. Maintaining optimal clonal size instead of filling the space in a lymphopenic host appears to regulate homeostatic T-cell proliferation during fetal development.

Exposure and ritual prevention (EX/RP) is an effective treatment for obsessive compulsive disorder (OCD), although it is neither universally nor completely helpful. Compliance with EX/RP treatment procedures has been linked theoretically to posttreatment outcome, yet empirical exploration of this relationship has been insufficient. In this study, therapists were asked to rate the treatment compliance of 28 consecutive patients who received EX/RP on a fee-for-service basis. Results indicated that understanding the treatment rationale and compliance with insession and homework exposure instructions, but not with ritual prevention and self-monitoring of rituals, was significantly related to posttreatment OCD symptom severity. Clinical implications of these findings and future directions in treatment compliance research with OCD patients are discussed.

This study identified the salient issues of caregiving for family members of persons with dementia using computer-assisted content analysis followed by factor analysis. Differences in responses between caregivers in two treatment groups were also noted. Caregivers (N = 226) were interviewed on three occasions over 12 months. They consistently identified the following themes of caregiving in order of significance: (a) making meaning of the experience; (b) defining the caregiver role; (c) identifying specific caregiving strategies; (d) dealing with change, unpredictability, and vulnerability; (e) evaluating past and future decisions and quality of care; and (f) finding help and support. This representation of the caregiving experience is useful to home care nurses by providing a framework to address issues most important to caregivers and upon which therapeutic interventions can be developed.

Abstract Glucocorticoids (GCs) are commonly used to treat inflammatory disease; unfortunately, the long-term use of these steroids leads to a large number of debilitating side effects. The antiinflammatory effects of GCs are a result of GC receptor (GR)-mediated inhibition of expression of proinflammatory genes as well as GR-mediated activation of antiinflammatory genes. Similarly, side effects are most likely due to both activated and repressed GR target genes in affected tissues. An as yet unachieved pharmaceutical goal is the development of a compound capable of separating detrimental side effects from antiinflammatory activity. We describe the discovery and characterization of AL-438, a GR ligand that exhibits an altered gene regulation profile, able to repress and activate only a subset of the genes normally regulated by GCs. When tested in vivo, AL-438 retains full antiinflammatory efficacy and potency comparable to steroids but its negative effects on bone metabolism and glucose control are reduced at equivalently antiinflammatory doses. The mechanism underlying this selective in vitro and in vivo activity may be the result of differential cofactor recruitment in response to ligand. AL-438 reduces the interaction between GR and peroxisomal proliferator-activated receptor γ coactivator-1, a cofactor critical for steroid-mediated glucose up-regulation, while maintaining normal interactions with GR-interacting protein 1. This compound serves as a prototype for a unique, nonsteroidal alternative to conventional GCs in treating inflammatory disease.