Acute promyelocytic leukemia: recent advances in therapy and molecular basis of response to arsenic therapies

PURPOSE OF REVIEW: While arsenic has long been known as a poison and environmental carcinogen, its dramatic effect in the treatment of acute promyelocytic leukemia (APL) has made its mechanism of action a topic of intense interest. This paper reviews recent findings that reveal why a traditional poison has become a magical potion for a major type of APL, which is characterized by a balanced chromosomal translocation t(15;17). RECENT FINDINGS: Daily IV infusion of arsenic trioxide (As2O3; ATO) for 30 to 40 days can lead to complete remission in about 85% of patients with newly diagnosed or relapsed APL. Oral preparations of ATO and tetra-arsenic tetra-sulfide (As4S4) seem to be as effective as parenteral ATO, with similar toxicity profiles. The combination of all-trans retinoic acid and ATO in patients with newly diagnosed APL has yielded more durable remission than monotherapy. The mechanism of arsenic cytotoxicity is thought to involve posttranslational modification followed by degradation of the PML-retinoic acid receptor-alpha (PML-RARalpha) fusion protein; targeting of PML to nuclear bodies with restoration of its physiologic functions; and production of reactive oxygen species (ROS) by NADPH oxidase in leukemic cells or collapse of the mitochondrial transmembrane potential. The understanding of arsenic cytotoxicity has stimulated modifications that promise to improve efficacy, such as interfering with ROS scavenging or boosting of ROS production to enhance the cytotoxicity, and adding cAMP or interferons to ATO regimens. SUMMARY: Recent advances in the clinical use of arsenic, the mechanism of arsenic-mediated cytotoxicity, and modulations of ATO to increase its efficacy and expand its clinical spectrum are reviewed.     

急性肺损伤抗氧化治疗的研究进展

急性肺损伤／急性呼吸窘迫综合症(ALI／／ARDS)是指由心源性以外的各种肺内、外致病因素导致的急性、进行性呼吸衰竭。ALI和ARDS具有性质相同的病理生理改变，ARDS是严重的ALI。ALI的病因各不相同，发病机制复杂，但被激活的各种细胞经呼吸爆发产生大量活性氧(reactive oxygen species，ROS)引起氧化应激状态，在ALI发病机制中具有重要作用，认为抗氧化剂可以起到保护肺损伤的作用。本文就近年来ALI抗氧化治疗方面的研究进展作一综述。     

Acute myelogenous leukemia in pregnancy

We report on a patient with acute promyelocytic leukemia diagnosed at the 22nd week of pregnancy. She received chemotherapeutic treatment and reached a complete remission. At the 28th week of gestation the patient delivered, by cesarean section, a normal male infant. At present the mother is still disease-free 27 months after diagnosis. The child, too, is in good health. We point out the possibility of producing live babies with current chemotherapy regimens without exposing either the mother or the fetus to excessive risks.     

Acute severe asthma: recent advances

PURPOSE OF REVIEW: Acute severe asthma is challenging to the clinician both in terms of recognition and appropriate treatment. About 30% of these episodes need admission to the medical intensive care unit with a mortality of 8%. Relapse rates vary from 7 to 15% depending on how well the patient is managed. The purpose of this review is to discuss recent advances in identification of risk factors, pathophysiology and management of acute severe asthma. RECENT FINDINGS: Although the exact mechanism for acute severe asthma is unclear, some that are implicated include inflammation, airway remodeling and downregulation of beta-receptors. None of the environmental factors have been clearly related to the development of near fatal attacks. Genetic polymorphisms have been associated with severe asthma. Lack of steroid responsiveness has been linked to severe asthma attacks. Chemokines and basement membrane changes characteristic of severe asthma are reported in a few studies. Lack of symptom perception in a certain group of patients with acute severe asthma leads to delayed interventions. Specific treatment modalities and ventilator management is reviewed. SUMMARY: Severe asthma is a phenotype of asthma with variable pathology and clinical presentation. Early recognition and timely intervention is needed to prevent significant mortality and morbidity.     

Acute myelogenous leukemia following radiation therapy and chemotherapy for osteogenic sarcoma

Patients receiving ionizing radiation therapy or cytotoxic chemotherapy are at increased risk of developing acute myelogenous leukemia. Ten cases of therapy-linked myelogenous leukemia have been reported in patients with sarcoma, and we report here the first case in a patient who received combined-modality therapy for treatment of an osteogenic sarcoma. As treatment for this disease becomes more intensive and survival improves, the incidence of leukemia following therapy for osteogenic sarcoma may increase.     

Acute myelogenous leukemia subsequent to therapy for a different neoplasm: Clinical features and response to therapy

The clinical characteristics of 10 patients with acute myelogenous leukemia (AML) which developed subsequently to treatment for another neoplasm are described. This disease appears to differ from “spontaneous” AML in being associated with lesser degrees of leukemic infiltration of the marrow and more frequent chromosomal aberrations. Only one of the nine patients who received chemotherapy attained remission status, and the mean and median survivals from the initiation of chemotherapy were 2.7 months and one month respectively. Nine of the 10 patients died as a result of infection. The refractoriness of this form of AML to chemotherapy was borne out by a review of the literature, which revealed only two remissions in 32 treated patients. The implications for the management of this disease are discussed.     

Chronic myelogenous leukemia: biology and therapy.

Chronic myelogenous leukemia is a myeloproliferative disorder. It is characterized by a biphasic or triphasic clinical course in which a benign chronic phase is followed by transformation into an accelerated and blastic phase. On a cytogenetic and molecular level, most patients with chronic myelogenous leukemia demonstrate BCR-ABL fusion genes in hematopoietic progenitor cells, which result from a reciprocal translocation between chromosomes 9 and 22; this translocation leads to a shortened chromosome 22, called the Philadelphia chromosome. Translation of the fusion products yields chimeric proteins of variable size that have increased tyrosine kinase activity. Conventional chemotherapy with hydroxyurea or busulfan can achieve hematologic control but cannot modify the natural disease course, which inevitably terminates in a rapidly fatal blastic phase. Since its introduction in the 1980s, allogeneic stem-cell transplantation has provided the groundwork for a cure of chronic myelogenous leukemia. However, few patients are eligible for this treatment because of donor availability and age restrictions. Therapy with interferon-alpha alone or in combination with cytarabine suppresses the leukemic clone, produces cytogenetic remissions, and prolongs survival. It is an effective alternative first-line treatment for patients ineligible for transplantation. New drugs active against chronic myelogenous leukemia may show increased activity in the transformed phases of the disease. Novel therapies and concepts are developing rapidly; targeted molecules are tyrosine kinases, ras, and messenger RNA through antisense oligonucleotides. Alternative transplantation options, such as stem cells from autologous sources and matched unrelated donors, are expanding. Immunomodulation by adoptive immunotherapy and vaccine strategies hold significant promise for the cure of chronic myelogenous leukemia.