Oral 13-cis Retinoic Acid Research Articles

Defibrotide for Prophylaxis of Hepatic Veno-Occlusive Disease in Autologous, Non-Purged Peripheral Stem Cell Transplantation for High Risk Neuroblastoma Patients

High-dose chemotherapy (HDC) represents the standard of treatment for high-risk neuroblastoma(NBL), hepatic veno-occlusive disease (VOD) is a common, 10-50% and serious complication of haematological stem cell transplantation (HSCT), with up to 90% mortality rates. We planned study to assess whether the use of prophylactic defibrotide in paediatric patients who were heavily treated with chemo-radiotherapy before transplant, and then underwent autologous HSCT.Seventeen patients who underwent autologous, unpurged peripheral stem cell transplantation PBSC with a high risk of developing VOD, between January 2003-July 2014, were given Defibrotide prophylaxis 25mg/kg/day for 30 days, commencing on -1 of conditioning regimen. All patients were stratified by INSS stage, age, N-MYC status. All were treated with six cycles of induction chemotherapy, myeloablative intensification, surgery for primary site, radiation therapy to the primary tumour site plus metastatic sites i.e bone metastases including skull. Meta-iodobenzylguanidin treatment as targeted radiotherapy was given on -21 prior to myeloablative chemotherapy. Oral 13-cis retinoic acid was employed on day +90 post-transplant. CD34+ cell mobilization and PBSC collection was carreid out after two-four cycles of induction cycles. Conditioning regimen and stem cell infusion was done following four-six weeks of last chemotherapy cycle, in order to reduce the toxicitiy. Conditioning regimen CEM consisted Carboplatin, Etoposide, Melfalan. There were no toxic deaths. All of the patients receieved antimicrobial prophylaxis and total parenteral nutrition support when was needed. Myeloid engraftment on day+13, erythroid engraftment on day+18 and thrombocyte engraftment was achieved on day +23.Defibrotide prophylaxis seems to reduce incidence of VOD and is well tolerated. VOD incidence and severity was reduced in the defibrotide group which suggests that defibrotide might be effective in preventing and treating VOD. Sufficiently powered randomised trials are now required to definitively test the role of defibrotide in this setting. DisclosuresNo relevant conflicts of interest to declare.

NCI 6896: A phase I trial of suberoylanilide hydroxamic acid (SAHA) and 13-cis retinoic acid in the treatment of patients with advanced renal cell carcinoma (RCC).

349 Background: Retinoid resistance in RCC inversely correlates with levels of intracellular retinol and retinyl esters suggesting that increasing intracellular levels of all-trans retinoic acid (RA) or enabling RA to become a more potent initiator of transcription will improve RA mediated anti-tumor effects. The combination of all-trans RA and a histone deacetylase (HDAC) inhibitor inhibited renal cancer cell proliferation and tumor growth in a xenograft model more than either drug alone. We performed a phase I clinical trial to evaluate the safety and preliminary efficacy of combining the oral HDAC inhibitor SAHA (vorinostat) plus oral 13-cis RA (isotretinoin) in patients with advanced RCC. Secondary endpoints include analysis of peripheral blood samples to study the effects on retinoid metabolites and retinoid related genes. Methods: Patients (pts) with metastatic RCC (any histology) who have failed at least two lines of prior therapy were eligible. Vorinostat (300 mg bid x 3 consecutive days per week + isotretinoin co-administered at 0.25 mg/kg, 0.375 mg/kg, or 0.5 mg/kg PO bid x 3 days per week in cohorts using standard 3+3 dose escalation. Dose limiting toxicity (DLT) was defined as any grade > 3 toxicity during the first cycle. Results: 14 pts have enrolled on the trial of which 12 are evaluable for toxicity (6 cohort 1; 3 cohort 2; 3 cohort 3) and 11 for tumor response. Common grade 1-2 toxicities included fatigue and GI effects (nausea, diarrhea, anorexia). One pt on dose-level 1 experienced a DLT (grade 3 depression). One patient experienced a partial response and 10 patients had stable disease lasting a median of 4 months (range 2–10 mos). Three patients progressed with brain metastases in the setting of stable systemic disease for at least 6 months. Pharmacokinetic and correlative studies examining expression of retinoid related genes are ongoing. Conclusions: The recommended phase II dose is vorinostat (300 mg bid) + isoretinoin (0.5 mg/kg PO bid) 3 days per week. The combination of vorinostat and isotretinoin was well tolerated, and there was evidence of antitumor activity in this heavily pretreated population of patients with refractory metastatic RCC. [Table: see text]

ONE-YEAR RESULTS OF A PILOT STUDY USING ORAL 13-CIS RETINOIC ACID AS A TREATMENT FOR SUBFOVEAL PREDOMINANTLY OCCULT CHOROIDAL NEOVASCULARIZATION IN PATIENTS WITH AGE-RELATED MACULAR DEGENERATION

To evaluate the safety and evidence of efficacy for oral 13-cis retinoic acid as a treatment for patients with subfoveal occult choroidal neovascularization (CNV) due to age-related macular degeneration (ARMD). Patients with active, subfoveal occult CNV with no prior treatment of the subfoveal component were eligible for inclusion. Patients received 40 mg of 13-cis retinoic acid twice daily for 5 months, stopped treatment for 2 months, and then resumed treatment for 5 months. Patients were observed monthly with Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA), clinical examination, fluorescein angiography, and laboratory testing. Eleven patients, aged 64 to 88 years, were enrolled and followed for 1 year. Initial VA ranged from 55 (20/40) to 5 (20/400) ETDRS letters (median 48 letters). Mild drug-related side effects (dry skin, chapped lips) occurred in all 11 patients. Three patients experienced more severe side effects (muscle aches, mood swings) and did not resume treatment after the drug holiday. Moderate VA loss occurred in 36% at both 6 and 12 months. Oral 13-cis retinoic acid is too toxic to be useful in patients with ARMD. Oral 13-cis retinoic acid did not improve vision although it may have slowed visual acuity loss in patients with ARMD with occult subfoveal CNV.

CO2, Argon, and Pulsed Dye Laser Treatment of Angiofibromas

Tuberous sclerosis is a complex disorder of hamartoma formation in many organs, particularly the skin, brain, eye, kidney, and heart. The characteristic skin lesions are angiofibromas (AF), the shagreen patch, periungual fibromas, and "ash-leaf" white macules. Treatment for AF has previously included electrocoagulation, electrodesiccation and curettage, dermabrasion, excision, cryosurgery, and oral 13-cis retinoic acid. Both argon and CO2 lasers have been used in isolated cases to treat AF. The purpose of this work is the study of the application of three different lasers in the treatment of facial AF. Ten patients with facial AF were treated with CO2, argon, and pulsed dye lasers. Patients' AF were graded with regard to the size and color of the lesions. A 2-3-cm2 test was assayed on the face of all patients with each laser before performing a complete treatment and in order to choose the best laser. Results were considered excellent in seven patients and good in three patients, with decrease of erythema and flattening of the AF. Minimal scarring was noted in two patients. Transient erythema was observed in patients treated with the CO2 laser. All patients or their parents considered the treatment cosmetically satisfactory. We found the CO2 laser to be a better therapeutic tool than the argon laser to treat AF, especially in those patients with multiple and protuberant AF. The argon laser would be more useful in those patients with very red AF and light complexion, and the pulsed dye laser in those with very red and flat AF.

Historical aspects of the oral use of retinoids in acne.

A number of investigations of the effects of vitamin A deficiency in animals and man and its treatment with natural products containing vitamin A were carried out in the twenties and thirties. In 1942, a clinical study in patients with acne treated with vitamin A yielded encouraging results. Further trials in the forties and fifties, trying to confirm the beneficial effect of oral vitamin A in acne, met with equivocal success. In the sixties, all-trans retinoic acid (tretinoin) became clinically available, and its topical efficacy in acne could be demonstrated. In 1971, oral tretinoin also was shown to be active in patients with acne. Coincidentally, the efficacy of oral 13-cis retinoic acid (isotretinoin) became evident in a series of unpublished studies in Europe. Then, in 1978, a trial carried out at the NIH, Bethesda, Maryland, yielded convincing evidence that isotretinoin is a potent new drug for the treatment of severe cystic acne. In 1982, isotretinoin was registered in the United States and one year later in Europe for the treatment of severe, recalcitrant, cystic acne. Since then, many thousands of patients suffering psychologically and physically from the severity of their disease have been treated successfully with this drug. However, the main concern of physicians prescribing isotretinoin has to focus on its potentially severe side effects, particularly its teratogenicity.