Methemoglobinemia secondary to clofazimine treatment for chronic graft-versus-host disease.
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Child↗
Biomedical subjects
R Pasquini
Publications and source records attributed to R Pasquini.
In vitro genotoxic effects of the insecticide deltamethrin in human peripheral blood leukocytes: DNA damage ('comet' assay) in relation to the induction of sister-chromatid exchanges and micronuclei.
Deltamethrin, a synthetic dibromo-pyrethroid insecticide, is extensively used in agriculture, forestry and in household products because of its high activity against a broad spectrum of insect pests (both adults and larvae), its low animal toxicity and its lack of persistence in the environment. Data on the genotoxicity and carcinogenicity of deltamethrin are rather controversial, depending on the genetic system or the assay used. The aim of this study was to further evaluate the potential genotoxic activity of deltamethrin. The in vitro genotoxicity of deltamethrin has been evaluated by assessing the ability of the insecticide to damage DNA (as evaluated using the single-cell microgel-electrophoresis or 'comet' assay) or induce sister-chromatid exchanges (SCE) and micronuclei (MN) in human peripheral blood leukocytes. All treatments were conducted with and without the presence of an external bioactivation source (+/- S9mix). The results indicate that deltamethrin, in the presence of metabolic activation (+ S9mix), is able to induce DNA damage (double- and single-strand breaks, alkali-labile sites and open excision repair sites) as revealed by the increasing tail moment values observed with increasing doses. The frequency of SCE and MN were not statistically increased in deltamethrin-treated cells as compared to controls, both with and without S9mix. However, lower deltamethrin doses were tested, as compared to 'comet' assay, because of cytotoxicity.
Adult↗
[Peripheral neuropathy investigation in the early stage of bone marrow transplantation].
Forty-three patients with several hematological diseases in the early stage of bone marrow transplantation were prospectively studied. All patients underwent a complete neurological examination, vibratory sense perception test and nerve conduction study both before and after the bone marrow transplantation. The following nerves were studied: median, peroneal, posterior tibial (motor), median and sural (sensitive). Most patients were in busulphan, cyclophosphamide, cyclosporine A, methotrexate and corticosteroids. Although the results showed statistical differences in the nerve conduction study, all of these differences were not sufficient to induce or diagnose peripheral nerve injury. Therefore, it was concluded that drugs used in the bone marrow transplantation do not induce peripheral neuropathy.
Adolescent↗
Effect of all-trans retinoic acid on newly diagnosed acute promyelocytic leukemia patients: results of a Brazilian center.
Thirty-seven patients with acute promyelocytic leukemia (APL) were treated with all-trans retinoic acid (ATRA). Patients received 45 mg m-2 day-1 po of ATRA until complete remission (CR) was achieved, defined as: a) presence of less than 5% blasts in the bone marrow, with b) white blood cells > 10(3)/mm3, c) platelets > 10(5)/mm3 and d) hemoglobin concentration > 8 g/dl, with no blood or platelet transfusions. Thirty-one (83.7%) patients achieved CR by day 50, and 75% of these before day 30. Correction of the coagulopathy, achieved between days 2 and 10 (mean, 3 days), was the first evidence of response to treatment. Only one patient had been previously treated with chemotherapy and three had the microgranular variant M3 form. Dryness of skin and mucosae was the most common side effect observed in 82% of the patients. Thrombosis, hepatotoxicity and retinoid acid syndrome (RAS) were observed in 7 (19%), 6 (16%) and 4 (11%) patients, respectively. Thirteen (35%) patients had to be submitted to chemotherapy due to hyperleukocytosis (above 40 x 10(3)/mm3) and six of these presented with new signs of coagulopathy after chemotherapy. Four (11%) patients died secondarily to intracerebral hemorrhage (IH) and two (5.4%) dropped out of the protocol due to severe ATRA side effects (one RAS and one hepatotoxicity). RAS and IH were related strictly to hyperleukocytosis. The reduced use of platelets and fresh frozen plasma probably lowered the total cost of treatment. We conclude that ATRA is an effective agent for inducing complete remission in APL patients.
Adolescent↗
Allogeneic stem cell transplantation for Fanconi Anaemia. Severe Aplastic Anaemia Working Party of the EBMT and EUFAR. European Group for Blood and Marrow Transplantation.
Fanconi anaemia is a hereditary disorder characterised by chromosomal breaks increased by cross-linking agents. Bone marrow transplantation is the treatment of choice when a HLA identical sibling donor has been identified. The use of low-dose cyclophosphamide with thoraco-abdominal irradiation for the conditioning regimen of FA patients has lead to a dramatic improvement of survival, with a long-term survival of 75% at our institution. However, if most patients are completely cured of their haematological disease, there is concern about an increased frequency of secondary tumours, mostly head and neck squamous cell carcinomas of poor prognosis. Results of BMT using alternative donors (HLA mismatched related and unrelated donors) have also improved during the last decade. A better selection of the donor via high-resolution techniques for class-II HLA matching, and more recently the use of T cell depleted grafts are probably the main explanations. Despite a short follow-up and the small number of patients analysed, transplants using HLA matched family cord blood give some promising results. On the other hand, first results with unrelated cord blood remind that this approach is clearly an experimental one that has to be evaluated through international registries and prospective studies. New approaches including autologous stem cell transplantations and gene therapy are currently explored.
Fanconi Anemia↗
Related cord blood transplants: the Eurocord experience from 78 transplants. Eurocord Transplant group.
Eurocord Transplant has established a registry for studying results of cord blood transplant. We have analyzed 78 patients who have received a related CBT between October 1988 and December 1996. The median follow-up time was 29 months (1-99). The median age was 5 years (0.2-20), median weight 19 kg (5-50). Forty-six patients had a malignant disease: 32 acute leukemia (AL), six chronic myeloid leukemia (CML), four myelodysplastic syndrome, two neuroblastoma and two non-Hodgkin lymphoma. Thirty-two patients were transplanted for non-malignant diseases including 17 bone marrow failure syndromes (BMFS), three sickle cell anemia, five thalassemia and seven inborn errors. The donor was an HLA-identical sibling in 60 cases and an HLA-mismatched donor in 18 cases. As conditioning, 36 patients received irradiation and 40 patients received associated busulfan-containing regimens. GVHD prophylaxis consisted of CsA alone in 36 cases, CsA associated with prednisone in eight cases, CsA, methotrexate (Mtx) with or without prednisone in 28 cases and CsA with monoclonal antibody or ATG in four cases. The median number of nucleated cells (NC) infused/kg was 3.9 x 10(7) (0.7-15). One-year survival was 63 +/- 6%. Age, weight, HLA identity and negative cytomegalovirus (CMV) serology in the recipient were significant favorable prognostic factors. Among these 78 patients, the incidence of grade > or = II GVHD was 9% in HLA-matched CBT and 50% in mismatched CBT (P < 0.001). Neutrophil engraftment was associated with age <6 years (P = 0.02) and weight <20 kg (P = 0.02). It was 73% in patients receiving <3.7 x 10(7) nucleated cells (NC) infused/kg and 85% in patients receiving more (P = 0.06). Favorable factors for platelets engraftment were age <6 years (P = 0.03), weight <20 kg (P = 0.002) and HLA identity (P < 0.0001). Related cord blood transplantation offers a good alternative to BMT. Theses results are in favor of freezing cord blood in families in whom a transplant might be indicated.
Adolescent↗
Cord blood transplantation for children with acute leukemia. Eurocord Transplant Group.
Over the past decade, allogeneic cord blood transplantation (CBT) has been widely used for treating patients with malignant disorders. However, the reported low incidence of GVHD observed after allogeneic CBT might be a major drawback in leukemic recipients and at present it is not clear whether CBT really predisposes patients to an increased risk of leukemia relapse. In order to further elucidate the role of CBT in children with hematological malignancies, 54 patients with ALL or AML given either a related (31 cases) or an unrelated (23 cases) CBT in 25 centers participating in the Eurocord Registry were analyzed. Overall survival of related and unrelated CBT recipients was substantially similar, the most important factor influencing patients' outcome being disease state at time of transplantation. In fact, due to a markedly increased relapse rate, poor-risk children (ie patients transplanted in more advanced disease) experienced a significantly worse EFS than those given CBT in a more favorable disease phase (ie CR1 or CR2). These data confirm that allogeneic CBT from either a related or an unrelated donor is a feasible procedure able to cure a significant proportion of children with acute leukemia, especially if transplanted in a favorable phase of disease.
Acute Disease↗
Outcome of cord-blood transplantation from related and unrelated donors. Eurocord Transplant Group and the European Blood and Marrow Transplantation Group.
BACKGROUND: Cord-blood banks have increased the use of cord-blood transplantation in patients with hematologic disorders. We have established a registry containing information on the outcome of cord-blood transplantation. METHODS: We sent questionnaires to 45 transplantation centers for information on patients receiving cord-blood transplants from 1988 to 1996. Reports on 143 transplantations, performed at 45 centers, were studied, and the responses were analyzed separately according to whether the donor was related or unrelated to the recipient. RESULTS: Among 78 recipients of cord blood from related donors, the Kaplan-Meier estimate of survival at one year was 63 percent. Younger age, lower weight, transplants from HLA-identical donors, and cytomegalovirus-negative serologic results in the recipient were favorable prognostic factors. Graft-versus-host-disease of at least grade II occurred at estimated rates of 9 percent in 60 recipients of HLA-matched cord blood and 50 percent in 18 recipients of HLA-mismatched cord blood. Neutrophil engraftment was associated with an age of less than six years (P = 0.02) and a weight of less than 20 kg (P = 0.02), and it occurred in 85 percent of patients receiving 37 million or more nucleated cells per kilogram of body weight. Among 65 patients who received cord blood from unrelated donors, the Kaplan-Meier estimate of survival at one year was 29 percent. Cytomegalovirus-negative serologic status in these recipients was associated with improved survival (P = 0.03) and was the most important predictor of graft-versus-host disease (P = 0.04). Neutrophil recovery occurred in 94 percent of the patients who received 37 million or more nucleated cells per kilogram from unrelated donors. CONCLUSIONS: Cord blood is a feasible alternative source of hematopoietic stem cells for pediatric and some adult patients with major hematologic disorders, particularly if the donor and the recipient are related.
Acute Disease↗
Bone marrow transplantation for severe aplastic anemia: has outcome improved?
Bone marrow transplants for severe aplastic anemia were first performed in the 1970s. Transplant regimens, supportive care, and patient selection have changed substantially since then. Our objective was to determine the impact of these changes on transplant outcome. We studied 1,305 recipients of HLA-identical sibling transplants for aplastic anemia between 1976 and 1992, reported to the IBMTR by 179 centers. We compared survival of transplants performed in three intervals (1976 through 1980 [n = 186], 1981 through 1987 [n = 648], and 1988 through 1992 [n = 471]) using Cox proportional hazards regression. Five-year survival (+/-95% confidence interval) increased from 48% +/- 7% in the 1976-1980 cohort to 66% +/- 6% in the 1988-1992 cohort (P < .0001). Risks of graft-versus-host disease (GVHD) and interstitial pneumonia decreased over time, but the risk of graft failure did not. Higher long-term survival resulted primarily from decreased mortality in the first 3 months posttransplantation. Late mortality risks were low and changed little over the intervals studied. In multivariate analysis, changes in transplantation strategies accounted for most but not all of the improved outcome. Use of cyclosporine to prevent GVHD was the most important factor. Changes in patient selection did not seem to explain improved survival. Survival after HLA-identical sibling bone marrow transplantations for aplastic anemia has improved since 1976. Changes in GVHD prophylaxis account for much of this improvement. Other changes may also operate.
Age Factors↗
In vivo studies on genotoxicity of pure and commercial linuron.
The ureic herbicide linuron [3-(3, 4-dichlorophenyl)-1-methoxy-1-methylurea] (CAS 330-55-2) was investigated for genotoxicity in a series of in vivo experiments. Since human exposure to herbicides is not only to the active principles, but also to all the chemicals present in the commercial formulation, we tested both pure and commercial linuron. Groups of rats were treated with gavage containing different doses of the herbicide (pure compound or commercial formulation) for 14 days. The doses were 150, 300 and 450 mg/kg b.wt. for the pure compound and 315.8, 631.6 and 947.4 mg/kg b.wt. for the commercial formulation (47.5% of linuron). Faeces and urine were collected at regular intervals. Urine specimens were analysed for their mutagenic metabolites, thioethers and D-glucaric acid content. Faeces extracts were tested for mutagenicity. Linuron's ability to cause DNA damage and cytogenetic effects was also investigated after treating groups of rats once with different doses of pure or commercial linuron. DNA single-strand breaks were assessed in rat liver using the alkaline elution technique and the single-cell microgel electrophoresis assay (SCGE: 'comet' assay), and in rat testes cells with the SCGE assay. Micronuclei induction was analysed in rat bone marrow erythrocytes. Results obtained were mainly negative when the excretion of mutagenic metabolites in urine and faeces of animals treated with the pure compound or with the linuron-based commercial formulation were monitored, whereas an increase in the urinary excretion of thioethers and D-glucaric acid was observed in rats treated with the commercial formulation. No increase in the frequency of micronucleated polychromatic erythrocytes was observed in the treated animals. However, linuron affected the viability of hepatocytes isolated from animals treated with higher doses. This cytotoxicity was accompanied by the induction of DNA single-strand breaks in the liver, as seen by the alkaline elution assay. The potential of pure linuron to induce in vivo DNA damage was confirmed with the microgel-electrophoresis technique ('comet' assay). Cytotoxicity was also seen in rat testes cells. However, no indication of DNA damage was visible.
Administration, Oral↗
Applicability of aspecific noninvasive methods for biomonitoring of occupational exposure to deltamethrin: preliminary study using an animal model.
Deltamethrin (CAS registry No. 52918-63-5), a synthetic dibromo-pyrethroid insecticide is highly effective against a broad spectrum of insects, and is widely used on crops and in public health programs. Data on the genotoxicity and carcinogenicity of deltamethrin are rather controversial, depending on the genetic system or the assay used. The aim of the present study was to analyze previously demonstrated metabolic changes using aspecific noninvasive methods in rats which are potentially applicable for monitoring occupational exposure. Since human exposure to pesticides occurs not only to active principles but to all chemicals present in a commercial formulation, we tested both the pure compound and a deltamethrin-based commercial formulation. Groups of rats were treated, i.p., consecutively for 7 days. The daily doses tested were 5 and 10 mg/kg body weight for pure deltamethrin, corresponding to volumes of 178.57 and 377.14 microliter/kg body weight for the commercial formulation (containing 2.8% deltamethrin). Urine was analyzed for mutagenic metabolites, thioethers, and D-glucaric acid content. Faeces extracts were tested for mutagenicity. Results show that DGA urinary excretion values did not mirror the phase I enzyme induction capability of the insecticide. Results obtained for urinary thioethers do not agree completely with those obtained on the influence of deltamethrin on glutathione S-transferase activity in rat liver. In fact, after administration of the deltamethrin commercial formulation, highest thioether excretion values were obtained during the treatment time for treated animals, as compared to controls. The mean values (+/-SEM) of thioether excretion were 0. 033 +/- 0.002 micromole -SH/24 h for control animals, 0.122 +/- 0. 004 and 0.185 +/- 0.025 for the two treatment groups. Thence, thioether determination in urine samples seems to be a suitable aspecific noninvasive method for assessing exposure to deltamethrin-based formulations, particularly those containing xylene and mesitylene as solvents, as in the tested formulation. Negative or toxic results obtained in the urinary and faecal mutagenicity test seem to exclude the formation and excretion of mutagenic metabolites following treatment with deltamethrin.
Animals↗
Iatrogenic Wernicke's encephalopathy in allogeneic bone marrow transplantation: a study of eight cases.
Wernicke's encephalopathy (WE) is a neuropsychiatric condition generally caused by acute thiamine deficiency and classically involves the triad of altered mentation, ataxia and ophthalmoplegia. It is most common among alcoholics, but several other causes have been identified, including total parenteral nutrition (TPN) use. We present eight cases of WE in patients undergoing allogeneic BMT, where thiamine deficiency was caused by a lack of vitamin supplementation during TPN administration. Clinically, WE presented as a severe refractory metabolic acidosis, preceded by 'raspberry tongue', and ophthalmologic and neurologic dysfunction. The sites most affected were the periventricular structures and the thalamus, and no mammilary bodies lesions were found.
Acidosis↗
[Intrathecal immunoglobulin synthesis evaluation in bone marrow transplantation].
The central nervous system involvement in chronic graft versus host disease (GVHD) has been suggested. Chronic GVHD resembles auto immune connective tissue disorders. In order to investigate the immunoglobulin intra blood brain barrier (BBB) synthesis during chronic GVHD, and contribute to understanding the pathophysiology of the disease, we studied 33 patients who underwent allogeneic bone marrow transplants (BMT) from HLA identical related donors. Immunoglobulin intra BBB synthesis was investigated quantitative and qualitatively. The samples were collected pre BMT, pos BMT and during chronic GVHD. There were no evidence of immunoglobulin intra BBB synthesis, and no oligoclonal bands were found. Only isolated cases suggested IgO and IgA intra BBB synthesis, and in one case IgM during GVHD.
Adult↗
Age-related increase of baseline frequencies of sister chromatid exchanges, chromosome aberrations, and micronuclei in human lymphocytes.
Intra- and interindividual variations of baseline frequencies of cytogenetic end points in lymphocytes of human populations have been reported by various authors. Personal characteristics seem to account for a significant proportion of this variability. Several studies investigating the role of age as a confounding factor in cytogenetic biomonitoring found an age-related increase of micronucleus (MN) frequency, whereas contradictory results were reported for chromosomal aberrations (CAs) and sister chromatid exchanges (SCEs). We have quantitatively evaluated the effect of age on SCE, CA, and MN through the analysis of a population sample that included data from several biomonitoring studies performed over the last few decades in 12 Italian laboratories. The large size of the data set, i.e., more than 2000 tests for each end point, allowed us to estimate the independent effect of age, taking into account other covariates, such as sex, smoking habits, occupational exposure, and inter- and intralaboratory variability. A greater frequency of the mean standardized values by increasing of age was observed for all of the end points. A leveling off was evident in the last age classes in the trend of MN frequencies. Frequency ratios (FRs), which express the increase of the cytogenetic damage with respect to the first age classes, i.e., 1-19 years, were estimated using Poisson regression analysis after adjustment for the potential confounding factors and confirmed the increasing trend by age class for all three end points. The most dramatic increase was observed for MN, with a FR that approaches the value of 2 at the age class 50-59 (FR, 1.97; 95% confidence interval, 1.43-2.71) and remains substantially unchanged thereafter. The trend of FRs for CA is more homogeneous, with a constant rise even in the older classes, whereas the frequency of SCE increases with age to a lesser extent, reaching a plateau in the age class 40-49 and the maximum value of FR in the age class over 70 (FR, 1.14; 95% confidence interval, 1.07-1.23). In conclusion, our results point to an age-related increase of the chromosome damage in lymphocytes and emphasize the need to take into account the potential confounding effect of this variable in the design of biomonitoring studies based on chromosome damage.
Adolescent↗
Cytogenetic analysis in human bone marrow transplantation.
Bone marrow transplantation (BMT) is a therapeutic process used to treat a variety of hematologic diseases. After BMT, the documentation of engrafting with the use of genetic markers is obligatory. C-band polymorphism is an excellent genetic marker because it occurs with high frequency in all populations studied and shows a high stability in vitro and in vivo. We studied a total of 36 patients: 15 with myeloid leukemia and 21 with severe aplastic anemia (SAA), submitted to BMT. The majority of the patients with chronic granulocyte leukemia (CGL; 10/15, 67%) and with SAA (17/21, 81%) showed a frequency of host cells around 15% (CGL) and 8% (SAA) in the first period analyzed (day +30 post-BMT); with a decrease in the others (+90, +180 to CGL and SAA and +365 only to CGL). In our study, the persistence of host cells in these proportions did not imply an unfavorable prognosis. On the contrary, some patients with myeloid leukemia (5/15 33%) and SAA (4/21, 19%) showed high proportions of host cells in one or more periods analyzed. If compared to the first group, these patients had, in general, a poor clinical evolution, with rejections, relapses, and deaths in greater numbers. These results show the important contribution of cytogenetic analysis in the follow-up of patients submitted to BMT.
Adolescent↗
Urine mutagenicity and biochemical effects of the drinking water mutagen, 3-chloro-4-(dichloromethyl)-5-hydroxy-2[5H]-furanone (MX), following repeated oral administration to mice and rats.
Mutagenicity analysis of urine from rats treated by oral gavage with MX at a dose of 64 mg/kg for 14 days revealed that only 0.3% of the administered compound was excreted in a genotoxically active form. At lower doses, mutagenicity was not detectable. No evidence of micronucleus induction in peripheral blood erythrocytes was observed in mice treated similarly. These findings indicate that MX is extensively detoxified in vivo and is unlikely to cause genetic damage in systemic tissues except at relatively high doses where detoxification pathways become saturated. In a separate experiment, significant depressions were observed in D-glucaric acid and thioether excretion and in levels of several liver enzymes involved in xenobiotic metabolism. The mechanism for these metabolic alterations and their relevance to the in vivo metabolism of the compound require further investigation.
Administration, Oral↗
Marrow transplantation for Fanconi anaemia: conditioning with reduced doses of cyclophosphamide without radiation.
Nine patients with Fanconi anaemia (FA) were conditioned for HLA-identical sibling bone marrow transplant (BMT) with reduced dose of cyclophosphamide (Cy) without radiation or antithymocyte globulin (ATG). The total dose of Cy was 140 mg/kg (n = 2) or 120 mg/kg (n = 7). The median patient age was 8 years (range 4-19). Graft-versus-host disease (GVHD) prophylaxis was with methotrexate and cyclosporine (n = 8) or cyclosporine alone (n = 1). All patients had sustained engraftment and two developed grade>/= II acute GVHD. Cy toxicity included grade >/= 2 mucositis seen in all evaluable patients and haemorrhagic cystitis in two patients. The Kaplan-Meler survival estimate is 89% with a median follow-up of 285 d (range 56-528). For the purpose of comparison, this report also reviews and updates long-term follow-up data on 32 previously reported FA patients conditioned with 140-200 mg Cy/kg without radiation. The lowest dose of Cy (without radiation or ATG) after which HLA-identical sibling marrow transplant can be successfully performed in FA patients has yet to be determined, but it appears that uniform and sustained engraftment can be achieved with a Cy dose of as low as 120 mg/kg.
Adolescent↗
Biological monitoring of workers exposed to N-nitrosodiethanolamine in the metal industry.
Biological monitoring of occupational hazards was performed in workers using cutting fluids containing N-nitrosodiethanolamine (NDELA). The study involved a group of 25 male subjects from some metal factories in central Italy who used cutting fluids with an NDELA content of > or = 5 mg/l (high-exposure group) and a group of 37 males exposed to cutting fluids with an NDELA content < 5 mg/l (low-exposure group). For comparison, we recruited a control group consisting of 37 subjects living in the same area. For all subjects, internal dose (urinary excretion of NDELA, mutagens, and thioethers), early biological effects (sister chromatid exchanges in blood peripheral lymphocytes), and urinary excretion of D-glucaric acid (DGA) as an endpoint product in the glucuronidation pathway were assessed. The results showed that only the workers using cutting fluids with NDELA concentrations of > or = 5 mg/l excreted trace amounts of NDELA in their urine. Urine excretion of mutagens was similar in the two exposure groups and in the controls. High-exposure subjects had a higher mean value of urinary thioethers than low-exposure and control subjects, but no differences were found in urinary DGA or lymphocyte sister chromatid exchange among the three groups. Smoking status increased the mean values of all the biomarkers, and coffee drinking was associated with urinary DGA excretion.
Adult↗