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BACKGROUND - The incidence of second primary lung cancers (SPLC) after resection of nonsmall cell lung cancer (NSCLC) is estimated to be 1% to 4% per patient year. The overall effect of SPLC on survival after resection of stage I NSCLC is unknown. Here we report the incidence, management, and outcome of SPLC in a large prospective cohort of patients who underwent careful follow-up.
METHODS - National Cancer Institute Intergroup Trial NCI #I91-0001 examined the effectiveness of isotretinoin A for chemoprevention of second primary tumors, the primary endpoint in that trial. Prospective data from patients randomly assigned to the placebo arm were analyzed.
RESULTS - Five hundred sixty-nine patients underwent complete resection of pathologic stage I NSCLC. The median follow-up was 5.9 years. Second primary tumors developed in 88 (15%) patients. Of these, 49 (56%) were SPLC (incidence = 1.99/100 patient-years), with a median interval from initial surgery of 4.2 years. Second primary lung cancer never developed in patients who had never smoked (n = 44, p = 0.046; never versus ever smokers). Current smokers had a higher incidence of SPLC than former smokers (hazard ratio = 1.91, p = 0.03). Age, sex, stage, histology, tumor location and initial surgery had no effect on SPLC development. Despite semiannual follow-up with chest radiographs, 12 (24%) patients had metastatic disease at the time of diagnosis of SPLC. Surgical resection was performed in 31 (63%) SPLC patients. Median survival was 4.1 years in those who underwent surgery and 1.4 years in those who did not (p = 0.003). Overall SPLC-related mortality in the original cohort was 3.7%.
CONCLUSIONS - Patients who undergo surgery for SPLC can achieve prolonged survival. Despite close follow-up however many patients with SPLC present with advanced disease. That indicates a need for continued lifelong postoperative surveillance.
Retinoids are a plausible family of therapeutic agents for fibrodysplasia ossificans progressiva due to their ability to inhibit differentiation of mesenchymal tissue into cartilage and bone. A prospective study was conducted to assess the efficacy of isotretinoin (13-cis-retinoic acid) in the prevention of heterotopic ossification in patients who had fibrodysplasia ossificans progressiva. Eleven anatomic regions were assessed in each of 21 patients by clinical examination, radiographs, and bone scans. An anatomic region was considered to be involved if there was clinical, radiographic, or radionuclide evidence of orthotopic or heterotopic ossification anywhere in the region. There were 143 involved anatomic regions and 88 uninvolved anatomic regions at the beginning of the study. Only one of the 88 anatomic regions that was completely uninvolved at the beginning of the study became involved during isotretinoin therapy. However, 16 of the 21 patients (76%) had major flare ups develop in 38 of 143 (27%) previously involved anatomic regions while administered isotretinoin therapy. Isotretinoin at steady state doses of 1 to 2 mg/kg per day decreased the incidence of heterotopic ossification at uninvolved anatomic regions compared with an external control group, as long as the medication was started before the appearance of any orthotopic or heterotopic ossification in that anatomic region. The data did not allow the determination of whether isotretinoin was effective or detrimental in preventing disease flareups in regions that had even minimal orthotopic or heterotopic ossification at the time the therapy began. Extreme caution should be exercised when using this medication in patients who have fibrodysplasia ossificans progressiva.
The present study was designed to investigate the effects of 13-cis-retinoic acid (13-cis-RA) (100 micrograms/mouse/day) and androgen ablation (castration) alone and in combination on growth of a human prostatic carcinoma line (LNCaP) transplanted to athymic nude mice as an experimental model. The results of these studies suggest that; (1) androgen ablation (castration) significantly decreased the size of LNCaP xenograft as compared to untreated animals; (2) when 13-cis-RA was administered to nude mice carrying established tumors (0.51 +/- 0.04 cm3), the tumor size was significantly reduced as compared to untreated controls (0.65 +/- 0.06 cm3 versus 1.63 +/- 0.12 cm3). About 50% of the animals in this group showed xenografts necrosis followed by complete regression of tumors by five months; (3) the combination of androgen ablation and 13-cis-RA treatment to nude mice carrying tumors showed synergistic effect in decreasing the tumor size. These results indicate that combination therapies based on androgen ablation and retinoid administration may be a useful approach for the treatment of prostate cancer.
Two patients with fibrodysplasia ossificans progressiva who presented with jaw immobilization due to formation of bone between the maxilla and mandible were treated with surgical resection of their ectopic bone in conjunction with experimental, adjunctive medical therapy using isotretinoin. Both patients had recurrence of their ectopic ossification within 2 months of surgery. Surgery to remove joint-bridging ossifications in FOP is not recommended.
Isotretinoin is a potent retinoic acid used in the treatment of skin disorders. Though very effective, it is teratogenic if administered during pregnancy, and its teratogenic effect may be related to the normal activity of retinoids as signalling molecules in the embryo. Although its exact mechanism of action is unknown, it has been suggested that it causes its characteristic pattern of defects that includes heart defects, by inhibiting the migration of neural crest cells. However, other effects on cells are known. We studied early cardiac cell proliferation using incorporation of bromodeoxyuridine (BrdU) and detection with a monoclonal anti-BrdU. Proliferation in heart tissue of whole embryo cultures was inhibited in medium with 10(-6) M isotretinoin to 62% of the control level in myocardium. We studied its effects in culture on precardiac explant development in the absence of the neural crests. Culture of precardiac mesodermal-endodermal explants revealed that development of heart vesicles from the mesoderm was little affected, but the development of heartbeat was inhibited depending on dose in the 10(-5) to 10(-7) M range. The effect on development of contractions was augmented in the presence of serum; it could be duplicated by all-trans-retinoic acid, and it was reversible. Synthesis of the alpha-actin isotype, analyzed by isoelectric focusing, was found to be inhibited or delayed. The results suggest multiple effects of retinoids on growth, morphogenesis, and differentiation of early cardiac tissue, and are discussed in relation to the potential role of retinoids in early embryogenesis.