Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We describe 4 cases of non-Hodkin's lymphomas that were interesting because of their curiosal clinical courses and spontaneous complete remissions during the course of high malignancy lymphoma. We present three of them for the first time in Poland. Case 1: a 61-year old woman was admitted to the hospital because of the headache, lasting for 4 months before hospitalization and right hemiparesis. CT scans revealed the presence of tumor in the temporo-occipital region. The diagnosis of B-cell lymphoma was established at histopathological examination of the postoperative material. Co60--therapy of these region was applied after the operation with good response. Case 2: a 38-year woman was admitted to the hospital because of L5-S1 spondylolisthesis to operate it. During the hospitalization haemolytic anaemia of unknown origin, thrombocytopoenia, splenomegaly, fever and rising acute insufficiency of kidneys, heart, liver and CNS were occurred. The patient died, despite applying corticosteroidotherapy. The diagnosis of intravascular lymphoma was established at postmortem examination. Case 3: a 51-year old woman was admitted to the hospital with diagnosis: anaplastic non-Hodgkin lymphoma B-cell type high malignancy established after the double histopathological examination of lymph nodes and biopsy of the lung. At the admission to the Department of Haematology we stated absolute regression of these changes. The patient had been only observed in the Outpatient Department over 1 year. She died after 6 months since the beginning of the relapse despite intensive chemotherapy. Case 4: a 43-year old man was admitted to the hospital because of great hyperleukocytosis, hepatosplenomegaly and neurological symptoms. The diagnosis: chronic prolymphocytic leukaemia was established. The cerebrospinal fluid examination showed presence of mononuclears which infiltrated CNS. CT scans of the brain revealed leucaemic infiltrations of the hemispheres and cerebellum. The patient died despite intensive therapy due to rising progressive multiorgan failure.
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PMID:[Unusual cases of non-Hodgkin's lymphomas--case reports]. 1123 49

Chronic lymphocytic leukaemia (CLL) is a disease of late middle age and older. The majority of patients are diagnosed because of a lymphocytosis of at least 5 x 10(9)/L on an incidental blood count. It needs to be distinguished from mantle cell lymphoma and splenic marginal zone lymphoma by lymphocyte markers. The immunophenotype of CLL is sparse surface immunoglobulin, CD5+, CD19+, CD23+, CD79b-, and FMC7-. The disease is staged according to the presence of lymphadenopathy and/or splenomegaly and the features of bone marrow suppression. Most patients have an early stage of disease when diagnosed and perhaps 50% will never progress. This group of patients have a normal life expectancy and do not require treatment beyond reassurance. Progression involves an increasing white cell count, enlarging lymph nodes and spleen, anaemia and thrombocytopenia. Complications of progression include autoimmune haemolytic anaemia and thrombocytopenia, immunodeficiency, and the development of a more aggressive lymphoma. A range of prognostic factors is available to predict progression, but most haematologists rely on close observation of the patient. Intermittent chlorambucil remains the first choice treatment for the majority of patients. Combination chemotherapy offers no advantage. Intravenous fludarabine is probably more effective than chlorambucil, but no trial has yet shown a survival advantage for using it first rather than as a salvage treatment in patients not responding to chlorambucil. It is at least 40 times as expensive as chlorambucil. Cladribine may be as effective as fludarabine, although it has been used less and is even more expensive. Patients who relapse after chlorambucil should be offered retreatment with the same agent and if refractory should be switched to fludarabine, which may also be offered for retreatment on relapse. For patients refractory to both drugs, a variety of options are available. High dose corticosteroids, high dose chlorambucil, CHOP (cyclophosphamide, prednisolone, vincristine and doxorubicin), anti-CD52, anti-CD20 and a range of experimental drugs which are being evaluated in clinical trials. Younger patients should be offered the chance of treatment with curative intent, preferably in the context of a clinical trial. Autologous stem cell transplantation after achieving a remission with fludarabine has relative safety and may produce molecular complete remissions. Only time will tell whether some of these patients are cured but it seems unlikely. Standard allogeneic bone marrow transplant is probably too hazardous for most patients, but non-myeloablative regimens hold out the hope of invoking a graft-versus-leukaemia effect without a high tumour-related mortality. Trials of immunotherapy are exciting options for a few patients in specialised centres.
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PMID:Achieving optimal outcomes in chronic lymphocytic leukaemia. 1136 85

This review addresses three related bone marrow failure diseases, the study of which has generated important insights in hematopoiesis, red cell biology, and immune-mediated blood cell injury. In Section I, Dr. Young summarizes the current knowledge of acquired aplastic anemia. In most patients, an autoimmune mechanism has been inferred from positive responses to nontransplant therapies and laboratory data. Cytotoxic T cell attack, with production of type I cytokines, leads to hematopoietic stem cell destruction and ultimately pancytopenia; this underlying mechanism is similar to other human disorders of lymphocyte-mediated, tissue-specific organ destruction (diabetes, multiple sclerosis, uveitis, colitis, etc.). The antigen that incites disease is unknown in aplastic anemia as in other autoimmune diseases; post-hepatitis aplasia is an obvious target for virus discovery. Aplastic anemia can be effectively treated by either stem cell transplantation or immunosuppression. Results of recent trials with antilymphocyte globulins and high dose cyclophosphamide are reviewed. Dr. Abkowitz discusses the diagnosis and clinical approach to patients with acquired pure red cell aplasia, both secondary and idiopathic, in Section II. The pathophysiology of various PRCA syndromes including immunologic inhibition of red cell differentiation, viral infection (especially human parvovirus B19), and myelodysplasia are discussed. An animal model of PRCA (secondary to infection with feline leukemia virus [FeLV], subgroup C) is presented. Understanding the mechanisms by which erythropoiesis is impaired provides for insights into the process of normal red cell differentiation, as well as a rational strategy for patient management. Among the acquired cytopenias paroxysmal nocturnal hemoglobinuria (PNH) is relatively rare; however, it can pose formidable management problems. Since its first recognition as a disease, PNH has been correctly classified as a hemolytic anemia; however, the frequent co-existence of other cytopenias has hinted strongly at a more complex pathogenesis. In Section III, Dr. Luzzatto examines recent progress in this area, with special emphasis on the somatic mutations in the PIG-A gene and resulting phenotypes. Animal models of PNH and the association of PNH with bone marrow failure are also reviewed. Expansion of PNH clones must reflect somatic cell selection, probably as part of an autoimmune process. Outstanding issues in treatment are illustrated through clinical cases of PNH. Biologic inferences from PNH may be relevant to our understanding of more common marrow failure syndromes like myelodysplasia.
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PMID:New Insights into the Pathophysiology of Acquired Cytopenias. 1170 33

We report a case of a female patient with portal hypertension due to liver cirrhosis. In this case, MR imaging revealed small siderotic nodules of the spleen, called Gamna-Gandy bodies. These lesions are found in patients with portal vein or splenic vein thrombosis, hemolytic anemia, leukemia, or lymphoma, patients receiving blood transfusions, acquired hemochromatosis, or paroxysmal nocturnal hemoglobinuria. There are only few reports in the literature about these siderotic nodules which are not very familiar. MR imaging seems to be the superior imaging method for detection of these lesions. It is important to consider Gamna-Gandy bodies in the differential diagnosis of portal hypertension and the other diseases mentioned above.
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PMID:Gamna-Gandy bodies of the spleen detected with MR imaging: a case report. 1175 37

The case study reported is of a patient initially misdiagnosed as chronic lymphocytic leukemia. Immunophenotyping studies ultimately identified the nature of the disease as B-cell prolymphocytic leukemia with concomitant warm autoimmune hemolytic anemia. The leukemia and hemolytic anemia were refractory to all conventional treatments administered. The patient survived a significantly shorter period of time than the median time of three years reported in the literature. The patient expired from complications resulting from B-cell PLL, warm autoimmune hemolytic anemia, and combination chemotherapy.
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PMID:B-Prolymphocytic leukemia: a case study. 1176 Aug 20

In order to investigate the significance of apoptosis and proliferation rates in differential diagnosis, evaluating curative effect and leukemia transformation in myelodysplastic syndromes, apoptosis index (AI) and proliferating index (PI) were assayed in marrow smears from 60 cases of MDS, 30 AML, 21 chronic aplastic anemia (CAA), 16 hemolytic anemia, 15 megaloblastic anemia and 30 normal controls. The apoptotic cells were assayed with TUNEL technique and proliferating cell nuclear antigen (PCNA) by immunohistochemical method in situ. The results showed that average AI in marrow smears from 39 cases with MDS prior therapy was (11.2 +/- 8.8)% and PI was (17.3 +/- 8.7)%, significant differences were observed in MDS group and normal control group, as well as in AML, CAA, megaloblastic anemia and hemolytic anemia groups. Hypoplastic MDS can be distinguished from CAA by AI and PI. Clinical therapy induced significant alteration of AI and PI in MDS, AML and CAA. After therapy of MDS, the AI dropped from (11.2 +/- 8.8)% to (6.6 +/- 0.7)%. It was concluded that examination of AI and PI of marrow cells in situ may provide valuable prognostic information, also can contribute to evaluate therapeutic effectiveness.
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PMID:[Significance of in situ identification of apoptosis and proliferation rates in diagnosis of myelodysplastic syndromes]. 1251 42

p-Nitrobenzoic acid is produced in large volumes for organic synthesis and as an intermediate in the manufacture of pesticides, dyes, and industrial solvents. Groups of male and female F344/N rats and B6C3F1 mice were exposed to p-nitrobenzoic acid (>99% pure) in feed for 14 days, 13 weeks, or 2 years for toxicity and carcinogenicity studies. Genetic toxicology studies were conducted in in vitro assays with Salmonella typhimurium and cultured Chinese hamster ovary cells, and in studies of erythrocyte micronucleus formation in mice in the 13-week study. 14-DAY STUDY IN RATS: Groups of five male and five female rats were given 0, 2,500, 5,000, 10,000, 20,000, or 40,000 ppm p-nitrobenzoic acid in feed for 14 days. All rats survived until the end of the study. Male and female rats given 20,000 and 40,000 ppm lost weight. The final mean body weights of 10,000, 20,000, and 40,000 ppm males were 82%, 60%, or 52% that of the controls, and the final mean body weights of 10,000, 20,000, and 40,000 ppm females were 87%, 68%, and 65% that of the controls. There were no clinical findings that were characteristic of organ-specific toxicity. Absolute and relative spleen weights were significantly increased in rats exposed to 10,000, 20,000, and 40,000 ppm. There were decreases in erythrocyte count and hemoglobin and hematocrit values and increases in reticulocyte count, nucleated erythrocytes, and methemoglobin concentration that were most pronounced in the 20,000 and 40,000 ppm groups. Congestion of the spleen occurred in 10,000 ppm males and in 20,000 and 40,000 ppm females. Hypertrophy of the follicular epithelium of the thyroid gland was present in male and female rats exposed to 10,000, 20,000, or 40,000 ppm p-nitrobenzoic acid, while follicular hyperplasia was observed in the 40,000 ppm males and females. Atrophy of the testis was observed in 20,000 and 40,000 ppm males. Other lesions observed in 20,000 and 40,000 ppm rats included atrophy of the thymus in males and atrophy of the ovary, bone marrow, and thymus in females. 14-DAY STUDY IN MICE: Groups of five male and five female mice were given 0, 2,500, 5,000, 10,000, 20,000, or 40,000 ppm p-nitrobenzoic acid in feed for 14 days. Three males and two females given 40,000 ppm died during the study. All other animals survived until the end of the study. Male mice given 20,000 and 40,000 ppm and females given 20,000 ppm lost weight. Mean body weight gains of 20,000 and 40,000 ppm males and 10,000, 20,000, and 40,000 ppm females were significantly lower than those of the controls. There were no clinical findings related to organ-specific toxicity although lethargy and ataxia were observed in 40,000 ppm mice. Relative liver weights were significantly increased in 20,000 and 40,000 ppm males and females and in 10,000 ppm females. Absolute and relative thymus weights of 20,000 and 40,000 ppm males and of 10,000, 20,000, and 40,000 ppm females were reduced. No significant differences in hematology parameters occurred in exposed mice. Testicular degeneration was observed in three 20,000 ppm and two 40,000 ppm males. Bone marrow hemorrhage and atrophy occurred in 40,000 ppm females. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were given 0, 630, 1,250, 2,500, 5,000, or 10,000 ppm pnitrobenzoic acid in feed for 13 weeks resulting in approximate daily doses of 40, 70, 160, 310, or 660 mg/kg to males and 40, 80, 170, 340, or 680 mg/kg to females. All rats survived until the end of the study. Mean body weight gains and final mean body weights were significantly less than those of the controls in 2,500, 5,000, and 10,000 ppm males and in 5,000 and 10,000 ppm females. There were no clinical findings related to organ-specific toxicity. Differences in spleen weights and hematology parameters characteristic of regenerative anemia were observed in males and females, primarily in groups given 10,000 ppm. The absolute and relative spleen weights were significantly increased in 10,000 ppm males and females and the relative spleen weights were significantly increased in 5,000 ppm males hts were significantly increased in 5,000 ppm males and females. Methemoglobin, Heinz bodies, and reticulocyte counts were increased and erythrocyte counts, hemoglobin, and hematocrit values were decreased in 10,000 ppm males and females. Congestion, pigmentation, and accumulation of macrophages in the spleen and pigmentation in the kidney occurred in 2,500, 5,000, and 10,000 ppm males. Congestion and pigmentation of the spleen occurred in 10,000 ppm females. A yellowish brown pigment (hemosiderin) in the spleen and kidney was associated with hemolytic anemia. Mild cytoplasmic hyaline droplet accumulation was present in renal tubule epithelial cells in 10,000 ppm males while karyomegaly was present in male and female rats exposed to 2,500, 5,000, and 10,000 ppm p-nitrobenzoic acid. A chemical-related testicular lesion, consisting of atrophy of the seminiferous tubules, occurred in 10,000 ppm males. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were given 0, 1,250, 5,000, 10,000, or 20,000 ppm pnitrobenzoic acid in feed for 13 weeks resulting in approximate daily doses of 170, 330, 670, 1,900, or 4,000 mg/kg body weight to males and 240, 460, 970, 2,500, or 4,900 mg/kg to females. All mice survived until the end of the study, except one 1,250 ppm female that was killed accidentally. Final mean body weights and mean body weight gains of all exposed males and of 5,000, 10,000, and 20,000 ppm females were significantly lower than those of the controls. No clinical findings or differences in organ weights or histopathology related to organ-specific toxicity were observed in exposed mice. 2-YEAR STUDY IN RATS: Groups of 60 male and 60 female rats were given 0, 1,250, 2,500, or 5,000 ppm p-nitrobenzoic acid in feed for 2 years. Ten males and 10 females from each exposure group were evaluated at 15 months. Survival, Body Weights, Feed Consumption, and Clinical Findings: Two-year survival rates of 1,250 and 2,500 ppm males were similar to that of the controls. Two-year survival of 5,000 ppm males was marginally greater than that of the controls and was attributed in part to a decrease in the severity of nephropathy and a decrease in the incidence of mononuclear cell leukemia. Survival of exposed females was similar to that of the controls. Mean body weights of 5,000 ppm males were 2% to 8% lower than those of the controls through week 80. Final mean body weights of exposed males were similar to that of the controls. Mean body weights of 5,000 ppm females were 2% to 9% lower than those of the controls during the first year of the study and were 10% to 16% lower during the second year of the study. Final mean body weights of exposed females were 97% (1,250 ppm), 92% (2;500 ppm), and 84% (5,000 ppm) that of the controls. Feed consumption by exposed males and females was similar to that by the controls. Dietary levels of 1,250, 2,500, or 5,000 ppm p-nitrobenzoic acid delivered approximately 50, 100, or 210 mg/kg body weight per day to males and 60, 125, or 250 mg/kg per day to females. There were no clinical findings attributable to organ-specific toxicity. Pathology Findings: There were increases in the incidences of clitoral gland adenoma and of clitoral gland adenoma or carcinoma (combined) (4/50, 14/49, 15/49, 15/50) in exposed females. The incidences of clitoral gland adenoma or carcinoma (combined) in the exposed groups (29% to 31%) exceeded the historical control mean incidence (11%) and range (2% to 21%) in female F344/N rats in recent 2-year NTP feed studies. The increased incidences of clitoral gland neoplasms were considered to be some evidence of carcinogenic activity in female rats exposed to p-nitrobenzoic acid. The incidences of hyperplasia of the clitoral gland in exposed females were marginally lower than that of the controls (10/50, 6/49, 6/ 49, 7/50). There was a chemical-related decrease in the severity of nephropathy in male rats. Male rat kidneys were examined using both single and step-section analyses, and the incidences of renal tubule neoplasms were not statistically greater than those of the controls. Mild hyaline droplet accumulation was observed in renal tubule epithelial cells in 10,000 ppm males in the 13-week study, but this effect was not severe enough to lead to a chemical-related neoplastic response in the 2-year study as has been observed with other chemicals. At the 15-month interim evaluation, hematologic parameters characteristic of a mild regenerative anemia and significant differences in spleen weights were noted in 5,000 ppm females. These differences included decreases in erythrocyte count, hemoglobin, and hematocrit, increases in spleen weights, and hemosiderin accumulation in splenic macrophages. At 2 years, significant decreases in the incidences of mononuclear cell leukemia were observed in 5,000 ppm males and 2,500 and 5,000 ppm females (males: 29/50, 35/50, 26/50, 2/50; females: 17/50, 11/50, 3/50, 0/50). While the mechanism for this decrease is unknown, decreases in the incidence of mononuclear cell leukemia have also been observed in 2year studies with other amine/nitro compounds. 2-YEAR STUDY IN MICE: Groups of 60 male and 60 female mice were given 0, 1,250, 2,500, or 5,000 ppm p-nitrobenzoic acid in feed for 2 years. Ten males and 10 females from each exposure group were evaluated at 15 months. Survival, Body Weights, Feed Consumption, and Clinical Findings: Two-year survival rates of exposed mice were similar to those of the controls. Mean body weights of 5,000 ppm males were 6% to 12% lower than those of the controls after week 17, and mean body weights of 5,000 ppm females were 12% to 24% lower than those of the controls after week 16. The final mean body weight of 5,000 ppm females was 19% less than that of the controls; final mean body weights of males were similar to that of the controls. Feed consumption by exposed mice was similar to that by the controls. Dietary levels of 1,250, 2,500, or 5,000 ppm p-nitrobenzoic acid delivered approximately 150, 300, or 675 mg/kg per day to males and 170, 365, or 905 mg/kg per day to females. There were no clinical findings of organ-specific toxicity. No chemical-related effects on hematology parameters were noted at the 15-month interim evaluation. Pathology Findings: There were no increases or decreases in neoplasms in male or female mice that were considered to be related to chemical administration. GENETIC TOXICOLOGY: p-Nitrobenzoic acid was mutagenic in Salmonella typhimurium strain TA100 with and without S9. No mutagenic activity was noted in strains TA98, TA1535, or TA1537, with or without S9. p-Nitrobenzoic acid induced sister chromatid exchanges and chromosomal aberrations in cultured Chinese hamster ovary cells in the absence of S9; with S9, results of both tests were negative. In vivo, no increase in micronuclei was observed in peripheral blood erythrocytes of male or female mice administered p-nitrobenzoic acid in dosed feed for 13 weeks. CONCLUSIONS: Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of p-nitrobenzoic acid in male F344/N rats exposed to 1,250, 2,500, or 5,000 ppm. There was some evidence of carcinogenic activity of p-nitrobenzoic acid in female F344/N rats based on increases in the incidences of clitoral gland adenoma and of clitoral gland adenoma or carcinoma (combined). There was no evidence of carcinogenic activity of p-nitrobenzoic acid in male or female B6C3F1 mice exposed to 1,250, 2,500, or 5,000 ppm. There were chemical-related decreases in the incidences of mononuclear cell leukemia in exposed male and female rats. p-Nitrobenzoic acid caused mild hematologic toxicity in female rats. Synonyms: 4-Nitrobenzoic acid; nitrodracylic acid; p-nitrobenzenecarboxylic acid; p-carboxynitrobenzene
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PMID:NTP Toxicology and Carcinogenesis Studies of p-Nitrobenzoic Acid (CAS No. 62-23-7) in F344/N Rats and B6C3F1 Mice (Feed Studies). 1259 21

The clinical pathology of paroxysmal nocturnal hemoglobinuria (PNH) involves 3 complications: hemolytic anemia, thrombosis, and hematopoietic deficiency. The first 2 are clearly the result of the cellular defect in PNH, the lack of proteins anchored to the membrane by the glycosylphosphatidylinositol anchor. The hemolytic anemia results in syndromes primarily related to the fact that the hemolysis is extracellular. Thrombosis is most significant in veins within the abdomen, although a number of other thrombotic syndromes have been described. The hematopoietic deficiency may be the same as that in aplastic anemia, a closely related disorder, and may not be due to the primary biochemical defect. The relationship to aplastic anemia suggests a nomenclature that emphasizes the predominant clinical manifestations in a patient. This relationship does not explain cases that appear to be related to myelodysplastic syndromes or the transition of some cases of PNH to leukemia. Treatment, except for bone marrow transplantation, remains noncurative and in need of improvement.
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PMID:Clinical manifestations of paroxysmal nocturnal hemoglobinuria: present state and future problems. 1262 45

p-Chloroaniline has a large production volume and is used as a dye intermediate. Toxicology and carcinogenesis studies of p-chloroaniline (greater than 99% pure) were conducted by administering p-chloroaniline hydrochloride in water by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 16 days, 13 weeks, or 2 years. Vehicle controls were given deionized water by gavage. All doses were calculated as p-chloroaniline; the chemical was administered as the hydrochloride after dissolution in water containing molar equivalents of hydrochloric acid. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse L5178Y lymphoma cells, and Chinese hamster ovary (CHO) cells. Hematologic parameters were measured at the end of the 13-week studies and at 6, 12, 18, and 24 months in the 2-year studies. Supplemental studies of the distribution and disposition of p-chloroaniline were conducted in male F344 rats. Sixteen-Day and Thirteen-Week Studies: In the 16-day studies, male and female rats and mice received 25, 50, 100, or 400 mg/kg of body weight. The vehicle controls received deionized water. All rats and mice that received 200 or 400 mg/kg died during the first 6 days of the studies. Some deaths occurred in each of the lower dose groups of mice. Splenic enlargement was observed at necropsy in rats administered 25, 50, or 100 mg/kg. Congestion of the spleen and hemosiderin deposition in the renal cortical tubular epithelial cells were observed at 100 mg/kg in male and female rats. Compound-related lesions in mice included hemosiderosis of the liver Kupffer cells and congestion of the spleen. In the 13-week studies, 10 rats of each sex were administered doses of 0, 5, 10, 20, 40, or 80 mg/kg. All male rats lived to the end of the 13-week studies. One of 10 female rats that received 80 mg/kg died from unknown causes. The final mean body weights of rats that received 80 mg/kg were 16% lower than that of vehicle controls for males and 4% lower for females. In the 13-week studies in mice, 10 animals of each sex were administered doses of 0, 7.5, 15, 30, 60, or 120 mg/kg. Deaths in mice were not related to p-chloroaniline hydrochloride administration. The final mean body weights of dosed and vehicle control mice were similar. In both rats and mice, no chemically related effects on organ weights were observed at necropsy, except for the spleen, which was enlarged as a function of increasing dose. Methemoglobin was increased in dosed groups and resulted in a secondary anemia, the severity of which was dose related. Compound-related lesions observed histologically, including pigmentation (hemosiderin) in the kidney, spleen, and liver and hematopoiesis in the liver and spleen, reflected the response to the hemolytic anemia and methemoglobinemia induced by p-chloroaniline hydrochloride. Based on these results, groups of 50 rats of each sex were administered 2, 6, or 18 mg/kg p-chloroaniline hydrochloride in water by gavage, 5 days per week for 103 weeks. Groups of 50 mice of each sex were administered 3, 10, or 30 mg/kg on the same schedule. Metabolism and Disposition Studies in Rats: The metabolism and disposition studies in F344/N rats showed that metabolic and excretory pathways were not saturated by p-chloroaniline administered orally at doses ranging from 0.3 to 30 mg/kg. p-Chloroaniline was rapidly metabolized and excreted primarily in urine with a half-life of approximately 2 hours. Body Weight and Survival in the Two-Year Studies: Mean body weights of dosed rats were generally within 5% of those of vehicle controls throughout the studies. The survival of the low and mid dose groups of male rats and of the low and high dose groups of female rats was significantly greater than that of the vehicle controls (male: vehicle control, 18/49; low dose, 32/50; mid dose, 32/50; high dose, 21/50; female: 27/50; 39/50; 36/50; 37/50). The increased survival was attributed to the decreased incidences of mononuclear cell leukemia. Mean body weights of high dose male and female mice were generally within 5% of those of vehiclwithin 5% of those of vehicle controls throughout the studies. The survival of the mid dose group of male mice was lower than that of the vehicle controls after week 99 (male: 43/50; 36/50; 29/50; 35/50; female: 39/50; 42/50; 44/50; 41/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Fibrosis of the spleen was increased in dosed male and high dose female rats (male: vehicle control, 3/49; low dose, 11/50; mid dose, 12/50; high dose, 41/50; female: 1/50; 2/50; 3/50; 42/50). Cellular infiltration of lipocytes (fatty metaplasia) was observed in the spleen at increased incidences in high dose rats (male: 0/49; 0/50; 0/50; 24/50; female: 0/50; 0/50; 0/50; 11/50). The incidence of uncommon sarcomas of the spleen in high dose male rats was significantly greater than that in the vehicle controls (fibrosarcomas, osteosarcomas, or hemangiosarcomas, combined: 0/49; 1/50; 3/50; 38/50). Many of these tumors metastasized to one or more sites. In female rats, one fibrosarcoma of the spleen was found in a mid dose animal, and one osteosarcoma of the spleen was found in a high dose animal. The historical incidence of splenic connective tissue sarcomas (all types) in water gavage vehicle controls is 1/298 (0.3%) for male rats and 0/297 for female rats. The historical incidence of hemangiosarcomas in water gavage controls is 0/300 for male rats and 1/297 (0.3%) for female rats. Adrenal medullary hyperplasia was observed at an increased incidence in high dose female rats (4/50; 4/50; 7/50; 24/50). Marginally increased incidences of pheochromocytomas were seen in high dose male (13/49; 14/48; 15/48; 26/49) and female (2/50; 3/50; 1/50; 6/50) rats. The historical incidence of pheochromocytomas in water gavage vehicle control male F344/N rats is 121/299 (40% ± 16%); the historical incidence in water gavage vehicle control female F344/N rats is 20/295 (7% ± 2%). The incidences of mononuclear cell leukemia in dosed male and female rats were lower than those in vehicle controls (male: 21/49; 3/50; 2/50; 3/50; female: 10/50; 2/50; 1/50; 1/50). The incidences of malignant lymphomas in dosed male and female mice were lower than those in vehicle controls (male: 10/50; 3/49; 9/50; 3/50; female: 19/50; 12/50; 5/50; 10/50). Hematologic and methemoglobin measurements were made on blood samples collected from 15 randomly selected male and female rats per dose group at 6, 12, 18, and 24 months. In general, the high dose group at various intervals showed mild hemolytic anemia and dose-related increases in methemoglobin. In rats, compound-related nonneoplastic lesions were seen histopathologically in the bone marrow, spleen, and liver. These lesions included bone marrow hyperplasia, hepatic hemosiderosis, and splenic fibrosis and suggest compound-related effects on the hematopoietic system in general, the erythropoietic system specifically, and mesenchymal cells in the spleen. In male mice, the incidence of hemangiosarcomas of the liver or spleen in high dose male mice was greater than that in the vehicle controls (4/50; 4/49; 1/50; 10/50). The historical incidence of hemangiomas or hemangiosarcomas at all sites (combined) in water gavage vehicle control male B6C3F1 mice is 11/350 (3% ± 3%). The incidences of hepatocellular adenomas or carcinomas (combined) were increased in dosed male mice (11/50; 21/49; 20/50; 21/50), primarily due to increased incidences of hepatocellular carcinomas (3/50; 7/49; 11/50; 17/50). Hepatocellular carcinomas metastasized to the lung in 1/50 vehicle control, 1/49 low dose, 2/50 mid dose, and 9/50 high dose male mice. The historical incidence ofhepatocellular neoplasms in water gavage vehicle controls is 106/347 (31 ± 6%). Genetic Toxicology: p-Chloroaniline was mutagenic in S. typhimurium strains TA98 and TA100 in the presence of exogenous metabolic activation; no increase in revertant colonies was observed in strains TA97, TA1535, or TA1537. p-Chloroaniline induced trifluorothymidine (Tft) resistance in mouse L5178Y lymphoma cells with and without metabolic activation. In cultured CHO cells, treatment with p-chloroaniline produced significant increases in sister chromatid exchanges (SCEs) both with and without metabolic activation (S9); chromosomal aberrations were significantly increased only in the presence of S9. Audit: The data, documents, and pathology materials from the 2-year studies of p-chloroaniline have been audited. The audit findings show that the conduct of the studies is documented adequately and support the data and results given in this Technical Report. Conclusions: Under the conditions of these 2-year water gavage studies, there was clear evidence of carcinogenic activity of p-chloroaniline hydrochloride for male F344/N rats, as indicated by increased incidences of uncommon sarcomas of the spleen. Pheochromocytomas of the adrenal gland may also have been associated with chemical administration. There was equivocal evidence of carcinogenic activity of p-chloroaniline hydrochloride for female F344/N rats, as indicated by the presence of uncommon sarcomas of the spleen in one mid and one high dose animal and the increased incidence of pheochromocytomas of the adrenal gland. There was some evidence of carcinogenic activity of p-chloroaniline hydrochloride for male B6C3F1 mice, as indicated by increased incidences of hepatocellular neoplasms and of hemangiosarcomas of the liver or spleen. There was no evidence of carcinogenic activity of p-chloroaniline hydrochloride for female B6C3F1 mice administered 3, 10, or 30 mg/kg by gavage for 2 years. The incidences of mononuclear cell leukemia in male and female rats and of malignant lymphomas in male and female mice were decreased by administration of p-chloroaniline hydrochloride. Compound-related splenic fibrosis was present in male and female rats. Synonyms: 1-amino-4-chlorobenzene hydrochloride; 4-chlorophenylamine hydrochloride; 4-chlorobenzeneamine hydrochloride
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PMID:NTP Toxicology and Carcinogenesis Studies of para-Chloroaniline Hydrochloride (CAS No. 20265-96-7) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1270 33

Nijmegen breakage syndrome (NBS) is characterized by growth retardation, microcephaly, mental retardation, immunodeficiency, and predisposition to malignancies, especially B-cell lymphomas. In contrast, leukemia is rare. A 23-year-old NBS patient presented with anemia, thrombocytopenia, and hyperlymphocytosis. The diagnosis of T-cell prolymphocytic leukemia (T-PLL) was confirmed by cytological and immunological assays (TdT(-), CD2(+), CD5(+), CD3m, and CD7(+)). Biological assays also showed a hemolytic anemia and a clotting factor V decrease. The patient was first treated by methylprednisone for 3 weeks. During this period the lymphocyte count decreased. The simultaneous normalization of the hemolysis and of factor V suggested that both could be related to T-PLL. Since T-PLL is refractory to conventional therapies with a poor prognosis, an intensive chemotherapy such as 2'-deoxycoformycin with anti-CDw52 monoclonal antibodies is usually favored. In the present case, however, because of the specific context (i.e., NBS-induced immunodepression, severe hemolytic anemia, and acquired factor V deficiency), he received pentostatin weekly during 1 month and in maintenance during 6 months. At last follow-up (7 months) he showed a persistent control of the lymphocytosis with no side effect.
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PMID:T-cell prolymphocytic leukemia with autoimmune manifestations in Nijmegen breakage syndrome. 1284 81


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