Differentiation induction therapy with all-trans retinoic acid (ATRA) in a patient with secondary 11q23 leukemia

This study was performed in an urban neighborhood of the capital city of the province of San Juan, Argentina. Erected as a housing complex, the place consists of 768 flats distributed in buildings of three and seven floors each. A survey was carried out in 33% of the dwellings, enquiring about the number of Triatoma infestans found indoors, stage of the bug development-nymph or adult- and how these insects had entered their homes. Adult T.infestans were found on all floors; 163 people (64%) had found them at least once, and 130 (51%) several times. Dispersal flight seems to have been the main mechanism of infestation by adult bugs in this area, and a total of 51% of the surveyed inhabitants reported that the insects had flown into their flats.     

Terson''s syndrome in a patient with acute promyelocytic leukemia on all-trans retinoic acid treatment

Hypothermia induced by surface cooling has shown to protect vulnerable regions of the brain during an ischemic insult. This study evaluated the neuroprotective efficacy of neurotensin, a potent hypothermic agent, using a 5-min carotid occlusion procedure in the gerbil. In Experiment 1, the dose-response and time course of neurotensin-induced hypothermia were evaluated (n = 5/dose). Central infusion of 10, 20, and 30 micrograms neurotensin were found to significantly decrease core body temperature of conscious gerbils within 30 min of administration. In Experiment 2, gerbils pretreated with 30 micrograms neurotensin were permitted to become hypothermic or were maintained at 37 degrees-38 degrees C (rectal) during ischemic insult. Other gerbils were pretreated with peptide vehicle prior to ischemic insult (at 37 degrees -38 degrees C) or underwent a sham procedure (n = 6/condition). At 24 h after surgery, gerbils were tested for increased locomotor activity in an open-field apparatus. Gerbils pretreated with peptide vehicle or neurotensin and maintained at 37 degrees-38 degrees C during ischemia had significantly higher activity levels compared to the other treated groups. In contrast, gerbils made hypothermic with neurotensin exhibited activity levels similar to sham gerbils. Histological assessment revealed that neurotensin-induced hypothermia protected the CA1 region from ischemic damage.     

Scrotal ulcer occurring in patients with acute promyelocytic leukemia during treatment with all-trans retinoic acid

STUDY OBJECTIVE: To evaluate the efficacy of conservative laparoscopic surgery in a series of patients with stage III-IV endometriosis. DESIGN: Prospective study (Canadian Task Force classification II-1). SETTING: University-affiliated hospital. PATIENTS: All 141 women who underwent conservative operative laparoscopy for stage III-IV endometriosis between January 1993 and December 1996 and were followed for a minimum of 6 months. INTERVENTIONS: Laparoscopic procedures performed with scissors, bipolar coagulation, and hydrodissection. MEASUREMENTS AND MAIN RESULTS: Clinical examination, transvaginal ultrasonography, and pain questionnaire were scheduled every 6 months postoperatively. The cumulative proportion of pregnant patients and cumulative recurrence rate were calculated by Kaplan-Meier method. Twenty-five women (44%) with infertility became pregnant. Twenty-three (51%) had stage III and two (16.7%, p <0.05) had stage IV endometriosis. The 24-month cumulative pregnancy rate was 57.5%. Thirty-one women (22%) reported pain recurrence during follow-up. Five (3.5%) recurrences were confirmed by histologic examination and eight (5.7%) were documented only by clinical and ultrasonographic findings. No recurrence occurred in the first 6 months of follow-up. CONCLUSION: Operative laparoscopy seems to be effective treatment for stage III endometriosis. A larger series with longer follow-up is necessary to clarify its role in the management of stage IV disease. (J Am Assoc Gynecol Laparosc 6(1):55-58, 1999)     

Sweet's syndrome during treatment with all-trans retinoic acid in a patient with acute promyelocytic leukemia

A 46 year old male with acute promyelocytic leukemia treated with all-trans retinoic acid (ATRA), developed fever, bilateral erythematous nodules in his axillary area, lower abdomen and inguinal region. Histopathologic examination of the skin biopsy revealed dense neutrophil infiltration in the dermis without vasculitis. The diagnosis of Sweet's syndrome was made. High dose methylprednisolone was administered and the lesions started to improve within 24 hours.     

Scrotum exfoliative dermatitis with ulcers associated with treatment of acute promyelocytic leukemia with all-trans retinoic acid]

We present a case of leukemia cutis associated with a prominent giant cell component. This lesion was initially diagnosed as chronic granulomatous inflammation 1 year before the definitive diagnosis of leukemia cutis was made. Skin biopsy specimens showed numerous Langhans-type giant cells occurring singly and as poorly formed granulomas. However, the majority of the infiltrate consisted of immature myeloid cells, positive for chloroacetate esterase, lysozyme, and CD 68. Subsequent peripheral blood and bone marrow examinations confirmed the progression of the disease to acute myeloid leukemia.     

Molecular follow-up of patients with promyelocytic leukaemia treated with all-trans retinoic acid

Historically, University teaching hospitals have been the primary providers of health care to the indigent population. With the advent of managed health-care plans, the university hospitals have seen a rapid decline in their obstetrical patient populations. This decrease is reflected in the numbers of deliveries and gynecological surgeries. From 1990 to 1995, these changes resulted in a significant decline in deliveries at our hospital, the Lyndon B. Johnson General Hospital. To reverse this ominous trend, we instituted a variety of changes resulting in a more patient-centered system and found an improvement in the numbers of obstetrical patients. In the following report, we describe these changes and the subsequent outcome.     

Relapsed acute promyelocytic leukemia previously treated with all-trans retinoic acid: clinical experience with a new synthetic retinoid, Am-80

All-trans retinoic acid (ATRA), a potent differentiating drug for acute promyelocytic leukemia (APL), induces a high incidence of complete remission (CR) in patients with APL and is now established as a first-line therapy. However, ATRA resistance has become a clinical problem. Patients who relapsed after ATRA-induced CR have had difficulty in obtaining a second CR with ATRA therapy. Although several mechanisms have been postulated, treatment strategies to overcome resistance have not been established. We used a new synthetic retinoid, Am-80, as reinduction therapy for APL relapse after from ATRA-induced CR. Am-80 was several times more potent than ATRA in inducing differentiation in vitro. At a 6 mg/m2 dose, there were 24 evaluable patients; 14 (58%) achieved CR between days 20 and 58 (median, 37 days). Clinical response correlated with the in vitro response to Am-80. Adverse effects included retinoic acid syndrome (n = 1), hyperleukocytosis (n = 1), xerosis (n = 9), cheilitis (n = 8), hypertriglyceridemia (n = 16), and hypercholesterolemia (n = 15). Am-80 is active in APL after relapse from ATRA-induced CR. Further clinical trials are needed to establish strategies to overcome ATRA resistance.     

Treatment of newly diagnosed acute promyelocytic leukemia (APL) by all transretinoic acid (ATRA) combined with chemotherapy: The European experience. European APL Group

All transretinoic acid (ATRA) gives complete remission (CR) rates of 80 to 90% in newly diagnosed acute promyelocytic leukemia (APL). However, it has two major drawbacks (1) a rapid rise in WBC in some patients, with potentially fatal ATRA syndrome (2) rapid relapse with maintenance therapy using ATRA alone or low dose chemotherapy. The French APL group therefore designed a treatment approach with ATRA followed by intensive chemotherapy. The latter was administered after CR achievement with ATRA, or was rapidly added to ATRA in case of rapid rise in leukocyte counts. This combined approach, in a pilot study and in a randomized trial, proved superior to intensive chemotherapy alone, by slightly increasing the CR rate but more importantly by reducing the relapse rate. These results were confirmed by the Chinese, Japanese and New York groups. Our group (and other European groups) are now testing in a new randomized trial the better timing of ATRA and chemotherapy administration (ATRA followed by chemotherapy or ATRA plus chemotherapy) and the role (after an intensive consolidation) of maintenance treatment with intermittent ATRA, continuous low dose chemotherapy or both.     

Differentiation of t(5;17) variant acute promyelocytic leukemic blasts by all-trans retinoic acid

All-trans retinoic acid (ATRA) induces differentiation of acute promyelocytic leukemic (APL) blasts from patients with t(15;17) APL. However, blasts from patients with the t(11;17) variant do not differentiate in response to ATRA. Our group has identified a variant of APL characterized by t(5;17) and expression of the NPM-RAR fusion gene product. From case reports it has been difficult to establish whether ATRA induces clinical responses in patients with this variant. In order to determine whether t(5;17) blasts differentiate with ATRA, we harvested mononuclear bone marrow cells from a patient with t(5;17) APL at time of relapse and cultured them in medium containing ATRA. Morphologic analysis of cytospins after 7 days of culture revealed that 60% of cells in the ATRA-treated culture had differentiated into mature neutrophilic forms, as opposed to less than 1% in the control culture. Seventy-three percent of cells acquired NBT positivity after exposure to ATRA, compared with 1% in the control culture. These results indicate that t(5;17) blasts retain the ability to terminally differentiate in response to retinoic acid.     

Effects of prostaglandin E2 and all-trans retinoic acid combination on induced differentiation of human acute promyelocytic leukemia NB4 cells

OBJECTIVE: A human promyelocytic leukemia (APL) cell line NB4 was used to demonstrate the synergistic effects between all-trans retinoic acid (ATRA) and prostaglandin E2 (PGE2) on growth inhibition and cytodifferentiation induction. METHODS: NB4 cells were cultured in the presence of either ATRA or PGE2 as a single agent or in combinations at various ratio. Cell growth was measured and myeloid differentiation was tested on consecutive days over the whole course of culture. RESULTS: PGE2 and ATRA synergistically induced the myeloid differentiation of NB4 cells. In comparison with ATRA alone, the combination of PGE2 with ATRA caused an almost 20-fold decrease of effective concentration of ATRA. CONCLUSION: The combination of ATRA and PGE2 at an appropriate ratio may provide a convenient oral regimen of combined differentiation therapy for a better clinical outcome in APL patients.     

Prediction of growth sensitivity of acute promyelocytic leukemia cells to granulocyte colony-stimulating factor using 7AAD/PY during administration of all-trans retinoic acid

OBJECTIVE: The traditional goal of obesity therapy has been the reduction of body weight to an ideal standard. Patient difficulties, however, in reaching this goal have led to a reassessment of weight loss criteria. The Institute of Medicine of the National Academy of Sciences recently proposed that successful long-term weight loss be defined as the reduction of initial weight by 5% or more and the maintenance of this loss for at least 1 year. The present study used these criteria to evaluate the long-term efficacy of a proprietary weight loss program. METHODS: Patients were 621 persons who had completed a 26-week weight loss program that included 12 weeks of treatment by a very-low-calorie diet. They were recruited from a total of 1,283 eligible persons who had been treated at 36 clinics nationwide. Clinics were randomly selected to participate. Patients' weights were determined in telephone interviews initially conducted 2 years after treatment and then at yearly intervals through 5 years of follow-up. RESULTS: At the end of treatment, men achieved a mean reduction in initial weight of 25.5 +/- 1% and women 22.6 +/- 1%. Subjects regained substantial amounts of weight by the 2-year follow-up but 77.5% of men and 59.9% of women still maintained losses of 5% or more of body weight. At the 3-year follow-up, 53% of the original sample (of 621 persons) maintained losses of 5% or more and 35% losses of 10% or more. These trends were apparent 4 and 5 years after treatment but the dwindling sample sizes prevented definitive assessments. DISCUSSION: The findings showed that a program of lifestyle modification combined with the brief use of a very-low-calorie diet was associated with successful weight control in a substantial portion of patients several years after treatment. Long-term weight losses of 5% or more of initial weight are likely to be associated with improvements in health complications.     

Neplanocin A, a potent inhibitor of S-adenosylhomocysteine hydrolase, potentiates granulocytic differentiation of acute promyelocytic leukemia cells induced by all-trans retinoic acid

Several neplanocin A analogs were synthesized and their growth-inhibiting and differentiation-inducing activities on myelogenous leukemia cells were examined. An adenosine kinase-ineffective analog of neplanocin A was effective in inducing differentiation, suggesting that phosphorylation of the nucleoside is not essential for inducing the differentiation of leukemia cells. Neplanocin A induced functional and morphological differentiation of HL-60 cells, but did not effectively induce differentiation of NB4, a cell line derived from a leukemia patient with t(15;17). However, these cells have been known to undergo granulocytic differentiation upon treatment with all-trans retinoic acid (ATRA), and are used as a model for differentiation therapy in acute promyelocytic leukemia. Preexposure of NB4 cells to low concentrations of neplanocin A greatly enhanced the ATRA-induced differentiation of the cells, whereas representative antileukemic drugs such as cytosine arabinoside and daunomycin did not enhance this differentiation. A clinical strategy that combines intermittent treatment with neplanocin A analogs and a low dose of ATRA may increase the clinical response and decrease the adverse effects of ATRA.     

Mutations in the E-domain of RAR portion of the PML/RAR chimeric gene may confer clinical resistance to all-trans retinoic acid in acute promyelocytic leukemia

In the normal heart, cardiomyocytes are surrounded by extracellular matrix (ECM) and latent matrix metalloproteinases (MMPs), which are produced primarily by cardiac fibroblasts. An activator of latent MMPs might be induced by ischemic conditions or pressure-induced stretching. To test the hypothesis that an activator of latent MMP is induced in the ischemic heart during transformation of a compensatory hypertrophic response to a decompensatory failing response in cardiac fibroblast cells, we stretched the human cardiac fibroblasts at 25 cycles/min in serum-free or 5% serum culture condition. The membrane type (MT)-MMP activity in stretched cells was measured by zymography and immuno-blot analyses using MT-MMP-2 antibody. The MT-MMP activity was further characterized by transverse-urea gradient (TUG)-zymography. The results suggested that stretch induced a membrane MMP in the fibroblasts that was similar to the MT-MMP induced in ischemic heart. Furthermore, we observed that membrane MMP has distinct mobility in TUG-zymography. To localize the MT-MMP and tissue plasminogen activator (tPA) of latent MMPs, the membrane and cytosol were separated by a method employing a detergent and sedimentation. The MT-MMP and tPA activities of cytosol and membrane fractions were measured by gelatin- and plasminogen-zymography, respectively. Differential-display mRNA analysis was performed on control and stretched cells. In situ immuno-labelling was performed to localize the MT-MMP. The results indicate that induction of MT-MMP occurred in the membrane fractions. The secretion of tPA was elevated in the stretched cells. The MT-MMP activity was inhibited by prior incubation with an antibody generated to membrane MMP. The tPA activity was inhibited by using tPA antibody. These results suggest that, under stretched conditions, neutral transmembrane matrix proteinases are induced in the cardiac fibroblasts. This may lead to activation of adverse ECM remodeling, cardiac dilatation, and failure.     

三氧化二砷联合全反式维甲酸治疗初发急性早幼粒细胞白血病50例疗效观察

目的 观察三氧化二砷(ATO)联合全反式维甲酸(ATRA)治疗初发急性早幼粒细胞白血病(APL)的疗效.方法 98例初发APL患者分为对照组和治疗组,对照组48例,治疗组50例.对照组采用常规ATRA+DA双诱导方案治疗;治疗组采用ATRA每天25 mg/m2,ATO每天0.15 mg/kg(ATRA后第10天开始)联合治疗,直至完全缓解(CR),CR后接受ATO和ATRA联合巩固治疗.比较两组CR率、PML-RAR α融合基因转阴时间及5年无病生存率.结果 对照组和治疗组CR率分别为89.5%(43/48)和90.0%(45/50),获得CR时间分别为(30.0±5.1)d和(28.1±4.4)d,两组CR率(x2=-0.068,P=0.946)及获得CR时间(t=1.757,P=0.083)相比差异均无统计学意义.在所有获得CR的患者中,3例分别在CR后第276、385和394天复发.所有患者发病时PML-RAR α融合基因均阳性,对照组和治疗组CR时分别有25.0%(5/20)和29.4%(5/17)转阴,巩固后分别有92.5%(37/40)和97.6%(41/42)转阴.对照组和治疗组5年无病生存率分别为(85.3±5.9)%和(87.6±5.6)%,差异无统计学意义(x2=0.232,P=0.630).结论 ATO联合ATRA能有效治疗初发APL患者,可以作为常规化疗方案外的另一选择.     

Molecular motion in solid all-trans retinoic acid (vitamin A acid) by proton NMR

Case report on a rape-homicide by manual strangulation involving a 59 year old female. The autopsy disclosed a peculiar cross-shaped superficial incised wound of the abdomen, encircled by 12 stab-wounds, furthermore multiple superficial and deep incised wounds of the genitalia. The injury pattern was in good agreement with the psychiatric interpretation of the sexual behaviour as outlet of severe aggressive impulses originating from non-sexual motives.     

Potentiated maturation with a high proliferating activity of acute promyelocytic leukemia induced in vitro by granulocyte or granulocyte/macrophage colony-stimulating factors in combination with all-trans retinoic acid

All-trans retinoic acid (ATRA) induces differentiation of acute promyelocytic leukemia (APL), but the effect of cytokines regulating myeloid differentiation on ATRA-induced APL cells is poorly understood. In this study, maturation and proliferation of fresh APL cells were examined when induced in vitro by granulocyte or granulocyte/macrophage colony-stimulating factors (G-CSF or GM-CSF) in combination with ATRA. APL cells showed a low proliferating activity when induced by ATRA alone. In contrast, cells induced by G-CSF or GM-CSF alone showed increased DNA syntheses, the levels of which were not significantly affected by the combination of ATRA with CSFs. Interestingly, G-CSF or GM-CSF potentiated the capability of ATRA-induced cells to reduce nitroblue tetrazolium (NBT), while G-CSF or GM-CSF alone induced no NBT reduction. Furthermore, in several patients examined, APL cells induced by ATRA with G-CSF showed an increased activity of chemotaxis and CD11a expression. These findings suggest that G-CSF or GM-CSF can potentiate differentiation of ATRA-induced APL cells while stimulating their proliferating activity as well, and that G-CSF, rather than GM-CSF, may be a useful adjunct to promote ATRA-induced differentiation of APL.     

Cross-talk between retinoic acid and interferons: molecular mechanisms of interaction in acute promyelocytic leukemia cells

All-trans retinoic acid (ATRA) and interferons (IFNs) are active anticancer agents. ATRA is capable of inducing complete remission in acute promyelocytic leukemia (APL) patients, whereas IFNalpha is successfully used in the treatment of the stable phase of chronic myeloid leukemia. ATRA and IFNs have shown synergistic interactions in various experimental conditions and represent a potentially useful therapeutic combination in the treatment of various types of leukemias and solid tumors. The molecular basis of these interactions are poorly understood and need to be elucidated. In this review, we summarize a series of recent observations concerning the molecular mechanisms underlying the cross-talk between the intracellular pathways activated by ATRA and IFNs in APL cells. In APL blasts, IFNs regulate the expression of retinoic acid receptors, and ATRA, in turn, modulates the levels and the state of activation of members of the Jak-STAT second messenger pathway. This demonstrates a two-way interaction between ATRA and IFNs, which leads to cross-modulation of genes normally under the control of the retinoid and the cytokine. These data may be relevant in the context of a rational use of the combination between ATRA and IFNs in the clinical management of myeloid leukemias.     

The PML/RAR alpha oncoprotein is a direct molecular target of retinoic acid in acute promyelocytic leukemia cells

Acute promyelocytic leukemia (APL) is characterized by the translocation, t(15;17) and the expression of a PML/RAR alpha fusion protein that is diagnostic of the disease. There is evidence that PML/RAR alpha protein acts as a dominant negative inhibitor of normal retinoid receptor function and myeloid differentiation. We now show that the PML/RAR alpha fusion product is directly downregulated in response to retinoic acid (tRA) treatment in the human APL cell line, NB4. tRA treatment induces loss of PML/RAR alpha at the protein level but not at the level of mRNA, as determined by Northern blots, by Western blots, and by ligand binding assays and in binding to RA-responsive DNA elements. We present evidence that this regulation is posttranslational. This evidence suggests that tRA induces synthesis of a protein that selectively degrades PML/RAR alpha. We further show that this loss of PML/ RAR-alpha is not limited to the unique APL cell line. NB4, because PML/RAR alpha protein is selectively downregulated by tRA when expressed in the transfected myeloid cell line U937. The loss of PML/RAR alpha may be directly linked to tRA-induced differentiation, because in a retinoid-resistant subclone of NB4, tRA does not decrease PML/RAR alpha protein expression. In NB4 cells, the specific downregulation of the fusion protein decreases the ratio of PML/RAR alpha to wild-type RAR alpha. Because the ratio of expression of PML/RAR alpha to wild-type RAR alpha and PML may be important in maintaining the dominant negative block of myelocytic differentiation, these data suggest a molecular mechanism for restoration by tRA normal myeloid differentiation in APL cells.