Does occupational exposure to formaldehyde cause hematotoxicity and leukemia-specific chromosome changes in cultured myeloid progenitor cells?

Several cross-sectional studies of a single population of workers exposed to formaldehyde at one of two factories using or producing formaldehyde-melamine resins in China have concluded that formaldehyde exposure induces damage to hematopoietic cells that originate in the bone marrow. Moreover, the investigators interpret observed differences between groups as evidence that formaldehyde induces myeloid leukemias, although the mechanisms for inducing these diseases are not obvious and recently published scientific findings do not support causation. Our objective was to evaluate hematological parameters and aneuploidy in relation to quantitative exposure measures of formaldehyde.

Successful long-term treatment of Philadelphia chromosome-negative myeloproliferative neoplasms with combination of hydroxyurea and anagrelide.

Background: Resistance or intolerance to either of the 2 favored therapeutic choices for MPN is a common clinical challenge. To overcome this, we report our successful long-term experience with the combination of low-dose HU and AG.

Patients And Methods: Retrospective review identified 12 patients with essential thrombocythemia or polycythemia vera using combination therapy.

Acquired myelodysplasia or myelodysplastic syndrome: clearing the fog.

Myelodysplastic syndromes (MDS) are clonal myeloid disorders characterized by progressive peripheral blood cytopenias associated with ineffective myelopoiesis. They are typically considered neoplasms because of frequent genetic aberrations and patient-limited survival with progression to acute myeloid leukemia (AML) or death related to the consequences of bone marrow failure including infection, hemorrhage, and iron overload. A progression to AML has always been recognized among the myeloproliferative disorders (MPD) but occurs only rarely among those with essential thrombocythemia (ET).

Extreme thrombocytosis and cardiovascular surgery: risks and management.

Extreme thrombocytosis is a major risk factor for excessive bleeding and for thrombosis, either of which can complicate cardiovascular surgical and interventional procedures. Extreme thrombocytosis can also cause an unusual syndrome, erythromelalgia, that results in a type of chronic microvascular occlusive arterial disease. We present the differential diagnosis of conditions that may lead to extreme thrombocytosis, 3 cases (each of which illustrates a different potential complication), and a review of the pertinent medical literature.

Temozolomide-induced myelodysplasia.

A patient who had received temozolomide (TMZ) as a single agent in treatment of malignant glioma developed therapy-induced myelodysplasia (T-MDS). TMZ is an orally active imidazotetrazine which methylates guanine residues in DNA, ultimately causing single and double-strand DNA breaks leading to apoptotic cell death. TMZ does not chemically cross-link DNA and is considered a nonclassical alkylating agent, similar in structure and activity to dacarbazine.

Is inhalation exposure to formaldehyde a biologically plausible cause of lymphohematopoietic malignancies?

The United States Environmental Protection Agency (EPA) recently proposed a hypothetical mode of action (MOA) to explain how inhaled formaldehyde (FA) might induce leukemia, lymphoma and a variety of other lymphohematopoietic (LHP) malignancies in occupationally exposed workers. The central hypothesis requires that B lymphocytes or hematopoietic progenitor cells (HPC) present at the "portal of entry (POE)" undergo sustained mutagenic change as a result of direct FA exposure. These modified cells would then migrate back to the bone marrow or primary lymphatic tissue and subsequently develop into specific LHP disease states.

Benzene exposure and refractory sideroblastic erythropoiesis: is there an association?

The myelodysplastic syndromes (MDS) consist of a group of diverse hematological disorders that carry an increased risk of transforming into acute myeloid leukemia. They may appear de novo and without obvious cause (primary or de novo MDS) or be induced by certain mutagenic environmental or therapeutic toxins (secondary MDS). Excessive exposures to benzene are generally considered to be a potential environmental risk factor for both MDS and acute myeloid leukemia.

Benzene-induced acute myeloid leukemia: a clinician's perspective.

Benzene-induced acute myeloid leukemia (AML) is considered a secondary form of AML, based both in theory and on limited cohort observations. Its latency, cytogenetic aberrations, and clinical features are thought similar to, or identical with, AML resulting from the use of modern day cytotoxic agents for chemotherapy and immunotherapy. Although distinction between secondary AML and the far more common de novo AML is difficult to establish with certainty in any given case, latency from toxic therapeutic and environmental exposure and certain clinical and pathological features generally separate these two entities.

Pregnancy-induced pancytopenia with cellular bone marrow: distinctive hematologic features.

Three patients with pregnancy-induced pancytopenia also exhibited variable features of sideroblastic anemia and amegakaryocytic thrombocytopenia. Treatment with anti-thymocyte globulin proved highly effective in two cases and a spontaneous remission occurred in the third. This illness is distinct from the more commonly reported incidental association of pregnancy with classic aplastic anemia.

Myelodysplasia with isolated trisomy 15: a 15-year follow-up without specific therapy.

A 41-year-old patient manifested pancytopenia with macrocytosis following pesticide exposure. She was later found to have myelodysplasia with trisomy 15. Over a 15-year period of observation, and with no specific therapy, her hematological disorder remains stable, despite persistence of the chromosomal aberration.

Atypical mycobacterial infection in a patient with hairy cell leukemia.

A case of a cutaneous tumor caused by atypical mycobacterial infection (Mycobacterium kansasii) in a patient with hairy cell leukemia is reported. Surgical removal of the lesion and subsequent combination antituberculotic treatment led to a cure of this infection. Remission of the leukemia was achieved with interferon alfa.

A study of 9-nitrocamptothecin (RFS-2000) in patients with advanced pancreatic cancer.

This ongoing study evaluates the efficacy of oral 9-nitrocamptothecin (9NC), or RFS-2000, in the treatment of advanced pancreatic cancer. Patients received 9NC orally for 5 days/week; 8 weeks of therapy is required to achieve minimum effective dose. Starting dose was 1.

A phase I clinical and pharmacological study of oral 9-nitrocamptothecin, a novel water-insoluble topoisomerase I inhibitor.

9-Nitrocamptothecin (9NC) is a water-insoluble topoisomerase I inhibitor with a broad antitumor activity in animal models. To determine the maximum tolerated oral dose (MTD), a phase I study was performed in patients with advanced cancer refractory to conventional chemotherapy. 9NC was administered orally with escalating doses to cohorts of five patients beginning at 1 mg/m2/day for five consecutive days every week for 4 weeks.

Phase I clinical and pharmacological studies of 20-(S)-camptothecin and 20-(S)-9-nitrocamptothecin as anticancer agents.

Groups of 52 and 29 patients with refractory cancers received either native camptothecin (CPT) or 9-nitrocamptothecin (9NC), respectively, in Phase I clinical trials designed to determine the maximum tolerated dose, toxicity and potential efficacy of orally administered camptothecins. Favorable responses occurred with both compounds (11% after CPT, 24% after 9NC). Although both agents could be taken safely for extended periods, dose limiting toxicities were substantial.

Protocols for the treatment of human tumor xenografts with camptothecins.

Thirty-five human tumors of various histological types xenografted at various sites into nude mice and rats have been used to assess the anticancer activity of camptothecin and derivatives administered by different routes (subcutaneous, intramuscular, intravenous, intrastomach, and transdermal). Camptothecins are active against human tumors at every site including the brain. So far, the best anticancer/toxicity ratio has been found with 9-nitrocamptothecin (9NC) and 9-aminocamptothecin (9AC) to which 9NC converts in the body of mammals.

L-homoserine hydroxamic acid as an antitumor agent.

This report confirms the potent mutagenic and antitumor activity of L-homoserine hydroxamic acid in both in vitro and in vivo test systems. Its mutagenic potential is evident in the developing tadpoles of Xenopus laevis eggs exposed to the compound. Cytotoxic effects are demonstrated against human leukemia and melanoma cell lines proliferating in tissue culture and against xenografts of human breast cancer and sarcoma growing in nude mice.

Pharmacokinetics of the in vivo and in vitro conversion of 9-nitro-20(S)-camptothecin to 9-amino-20(S)-camptothecin in humans, dogs, and mice.

We have determined that 9-nitro-20(S)-camptothecin (9NC) converts to 9-amino-20(S)-camptothecin (9AC) in humans, dogs, and mice. Following a single oral dose of 0.1 mg/kg of 9NC, the human plasma concentration reached a maximum concentration of 483 ng/ml at 3.

9-Nitro-camptothecin delays growth of U-937 leukemia tumors in nude mice and is cytotoxic or cytostatic for human myelomonocytic leukemia lines in vitro.

The camptothecin derivatives 9-nitro-camptothecin (9NC) and 9-amino-camptothecin (9AC) inhibit similarly growth of HL-60, KG-1, and U-937 cells in vitro, whereas growth of THP-1 cells is inhibited by 9AC, but not by 9NC. Growth inhibition is accompanied by enlargement of cells which contain one (HL-60, THP-1) or more (KG-1, U-937) nuclei. Flow cytometry studies showed that 9NC-treated HL-60 and U-937 cells accumulate in the S and G2 phases of the cell cycle; then they die by apoptosis, with the HL-60 cells being more sensitive than U-937 cells to 9NC.