Tamoxifen and fenretinide in women with metastatic breast cancer.

BACKGROUND: Tamoxifen and fenretinide combination therapy has been shown to be an active treatment regimen in metastatic breast cancer patients. This pilot study sought to determine whether the addition of fenretinide to tamoxifen would be associated with antitumor activity in metastatic breast cancer patients who had been previously treated with tamoxifen or who had hormone receptor negative disease. The effect of this therapy on circulating plasma transforming growth factor-beta (TGF-beta) levels and serum lipids was also examined. PATIENTS AND METHODS: Thirty-one patients were treated with tamoxifen (20 mg p.o. daily), and fenretinide (400 mg p.o. daily with a 3-day drug holiday each month). Plasma TGF-beta testing was performed using isoform specific sandwich ELISA. RESULTS: Twenty four of the 31 patients were evaluable for an antitumor response including 14 estrogen receptor (ER) positive patients who had failed prior tamoxifen therapy, seven ER-negative patients, and three hormone therapy naive ER-positive patients. There were no objective antitumor responses; three patients had stable disease for 8, 8, and 24 months. Five patients (16%) discontinued therapy for toxicity (one for grade 3 skin rash and four for abnormal dark adaptation). There was a statistically significant decrease in total cholesterol (median change per patient of -13.5 mg/dl; p = 0.049, a 6.5% decrease), and an increase in HDL levels (median change per patient of +18 mg/dl, p = 0.0001, a 35% increase) with tamoxifen and fenretinide therapy. TGF-beta1 plasma levels were normal in 26 of 28 patients, and no changes in these levels post-treatment were demonstrated. CONCLUSIONS: Tamoxifen and fenretinide therapy is not an active combination in ER negative metastatic breast cancer or in patients whose disease has progressed on tamoxifen. This combination had a beneficial effect on total serum cholesterol and HDL levels with no associated rise in serum triglyceride levels. The 400 mg dose of fenretinide was associated with symptomatic nyctalopia in one-third of patients making it an unsuitable dose for use in breast cancer prevention studies.

Markedly elevated serum lactate dehydrogenase levels are a clue to the diagnosis of disseminated histoplasmosis in patients with AIDS.

Disseminated histoplasmosis is a common late manifestation of AIDS, but the diagnosis may be unsuspected in some patients because the clinical presentation of histoplasmosis may mimic other opportunistic infections. High serum lactate dehydrogenase (LDH) levels have been associated with disseminated histoplasmosis. We therefore evaluated whether markedly increased LDH levels were useful for making a diagnosis of disseminated histoplasmosis by comparing admission LDH levels for 15 patients with culture-proven disseminated histoplasmosis with those for 30 patients with advanced AIDS who were admitted to the hospital for evaluation of pulmonary infiltrates and fever. The mean admission LDH level in patients with disseminated histoplasmosis was 1,356 IU/L (range, 145-5,410 IU) whereas it was 332 (range, 77-832 IU) in the patients with other pulmonary processes. Admission LDH levels were >600 IU in 11 (73%) of the 15 patients with disseminated histoplasmosis vs. 3 (10%) of controls (P < .001). We conclude that markedly elevated admission LDH levels may be a clinical clue to the diagnosis of disseminated histoplasmosis in patients with AIDS.

Transforming growth factor-beta: possible roles in carcinogenesis.

TGF-beta is the prototype of a large family of multifunctional regulatory proteins. The principal sources of the peptide, platelets and bone, suggest that it plays a role in healing and remodeling processes. In vitro, TGF-beta is chemotactic for monocytes and fibroblasts and can greatly enhance accumulation of extracellular matrix components by fibroblasts. Its ability to stimulate the formation of granulation tissue locally and the demonstration of specific time- and tissue-dependent expression in embryogenesis suggest that similar mechanisms are operative in vivo. By analogy to its effects in wound healing and embryogenesis, it is proposed that TGF-beta, secreted by tumour cells, can augment tumour growth indirectly by effects on the stromal elements. These effects include suppression of the immune response, and enhancement of both angiogenesis and formation of connective tissue. Many tumour cells have escaped from direct growth inhibitory effects of TGF-beta by a variety of mechanisms including inability to activate the latent form of the peptide, loss of cellular receptors for TGF-beta, and loss of functional intracellular signal transduction pathways.