Biomedical subjects

N Giri

Publications and source records attributed to N Giri.

At least 19 recordsLinked to original sources

PubMed2001

In vivo persistence of retrovirally transduced murine long-term repopulating cells is not limited by expression of foreign gene products in the fully or minimally myeloablated setting.

Many nonmalignant hematologic disorders could potentially be treated by genetic correction of as few as 5-10% of target lineage cells. However, immune system clearance of cells expressing gene products perceived as foreign could be limiting. There is evidence that tolerance to foreign proteins can result when myeloablative conditioning is used, but this limits the overall applicability of such techniques. Therefore, we sought to evaluate the engraftment of hematopoietic stem cells carrying a foreign transgene after low-dose irradiation by comparing in vivo survival of murine long-term repopulating cells (LTRC) transduced with either a retroviral vector expressing the bacterial neomycin phosphotransferase gene (neo) or a vector containing neo gene sequences but modified to prevent protein expression (nonexpression). First, marrow cells from congenic donors were transduced with either vector and transplanted into recipients treated with standard dose irradiation of 800 rads. High-level engraftment and gene marking resulted, without differences in the marking levels or pattern of persistence of the cells between cells transduced with either vector. Low-dose irradiation at 100 rads was tested using higher cell doses. Marking levels as high as 10% overall were obtained, again with no differences between mice receiving cells transduced with the neo versus the nonexpression vectors. To investigate a potentially more immunogenic protein, marrow cells were transduced with a vector containing the green fluorescent protein (GFP) gene, and their persistence was studied in recipient mice receiving 100 rads. Stable GFP expression in 5-10% of circulating cells was observed long term. We conclude that even with very low dose conditioning, engraftment by genetically modified LTRC cells at clinically significant levels can be achieved without evidence for clearance of cells known to be expressing immunogenic proteins.

Animals↗

PubMed2001

The effects of SCF/G-CSF prestimulation on radiation sensitivity and engraftment in nonmyeloablated murine hosts.

OBJECTIVE: Previous studies have shown improved engraftment in a murine model when granulocyte colony-stimulating factor (G-CSF) and stem cell factor (SCF) were administered for 5 days prior to irradiation, with significant levels of engraftment in the growth factor-preconditioned group even at very low radiation doses. We sought to explore the mechanisms behind this effect. METHODS: The radiation sensitivity of mice with or without 5 days of prestimulation with G-CSF (200 microg/kg/d) and SCF (50 microg/kg/d) was compared. To further evaluate whether growth factor prestimulation enhances engraftment by mobilization of hematopoietic progenitors into peripheral blood, thus creating less endogenous competition within the marrow compartment, female mice were pretreated with 5 days of G-CSF/SCF or control diluent. Engraftment of 40 x 10(6) peripheral blood stem cells (PBSCs) harvested from G-CSF/SCF-mobilized male mice was compared in the two recipient groups. RESULTS: There was no difference in survival between the pretreated and control mice at the radiation doses tested. Additionally, there was no significant difference in the recovery of blood counts, bone marrow cellularity, colony-forming unit (CFU) content, or stem cell numbers assessed 4 months later in a competitive repopulation model. Engraftment levels of male cells did not differ between G-CSF/SCF-pretreated and control recipients, and could be detected in 30% of recipients at 20-24 weeks (4/12 in each group) at overall levels of 0.1-1%. CONCLUSIONS: The enhanced engraftment in cytokine pretreated recipients is unlikely to be due to increased endogenous stem-cell killing or to the creation of endogenous marrow "space" by egress of endogenous stem cells after cytokine prestimulation.

Animals↗

PubMed2000

Comparative efficacy and distribution of lipid formulations of amphotericin B in experimental Candida albicans infection of the central nervous system.

The central nervous system (CNS) distribution and antifungal efficacy of all 4 approved formulations of amphotericin B (AmB) were investigated in a rabbit model of hematogenous Candida albicans meningoencephalitis. Treatment with AmB deoxycholate (1 mg/kg/day) or liposomal AmB (5 mg/kg/day) yielded the highest peak plasma concentration (C(max)), area under concentration versus time curve from zero to 24 h (AUC(0-24)), and time during dosing level tau Ttau>minimum inhibitory complex (MIC) values and led to complete eradication of C. albicans from brain tissue (P<.05 vs. untreated controls). By comparison, AmB colloidal dispersion and AmB lipid complex (5 mg/kg/day each) were only partially effective (not significant vs. untreated controls). There was a strong correlation of C(max), AUC(0-24), C(max)/MIC, AUC(0-24)/MIC, and Ttau>MIC with clearance of C. albicans from brain tissue (P</=.0002). Although pharmacodynamic parameters derived from the MIC of free AmB were highly predictive of antifungal efficacy, parameters derived from MICs of individual formulations were not predictive. AmB deoxycholate and liposomal AmB had the greatest antifungal efficacy. This activity was concentration and time dependent.

Amphotericin B↗

PubMed2000

Introduction of a xenogeneic gene via hematopoietic stem cells leads to specific tolerance in a rhesus monkey model.

Host immune responses against foreign transgenes may be a major obstacle to successful gene therapy. To clarify the impact of an immune response to foreign transgene products on the survival of genetically modified cells, we studied the in vivo persistence of cells transduced with a vector expressing a foreign transgene compared to cells transduced with a nonexpressing vector in the clinically predictive rhesus macaque model. We constructed retroviral vectors containing the neomycin phosphotransferase gene (neo) sequences modified to prevent protein expression (nonexpressing vectors). Rhesus monkey lymphocytes or hematopoietic stem cells (HSCs) were transduced with nonexpressing and neo-expressing vectors followed by reinfusion, and their in vivo persistence was studied. While lymphocytes transduced with a nonexpressing vector could be detected for more than 1 year, lymphocytes transduced with a neo-expressing vector were no longer detectable within several weeks of infusion. However, five of six animals transplanted with HSCs transduced with nonexpression or neo-expression vectors, and progeny lymphocytes marked with either vector persisted for more than 2 years. Furthermore, in recipients of transduced HSCs, infusion of mature lymphocytes transduced with a second neo-expressing vector did not result in elimination of the transduced lymphocytes. Our data show that introduction of a xenogeneic gene via HSCs induces tolerance to the foreign gene products. HSC gene therapy is therefore suitable for clinical applications where long-term expression of a therapeutic or foreign gene is required.

Animals↗

PubMed2000

Clinical and laboratory evidence for a trilineage haematopoietic defect in patients with refractory Diamond-Blackfan anaemia.

Diamond-Blackfan anaemia (DBA) is a constitutional pure red cell aplasia presenting in early childhood. In some patients, neutropenia and/or thrombocytopenia have also been observed during the course of the disease. We have followed 28 patients with steroid-refractory DBA for up to 13 years with serial peripheral blood counts and bone marrow (BM) aspirates and biopsies. In 21/28 (75%) patients, moderate to severe generalized BM hypoplasia developed, with overall cellularities ranging from 0% to 30%. Marrow hypoplasia correlated with the development of neutropenia (9/21; 43%) and/or thrombocytopenia (6/21; 29%) in many patients. No patient had either cytogenetic abnormalities or progressed to acute leukaemia, although one 13-year-old developed marked marrow fibrosis and trilineage dysplasia. We used the in vitro long-term culture-initiating cell (LTC-IC) assay to quantify multilineage, primitive haematopoietic progenitors in a representative subset of these patients. LTC-IC assays showed equivalent frequencies of cobblestone area-forming cells (CAFCs) with a mean of 5.42/10(5) cells +/- 1.9 SD and 6.13/10(5) cells +/- 2.6 SD in nine patients and six normal controls respectively. The average clonogenic cell output per LTC-IC, however, was significantly lower in DBA patients (mean 2.16 +/- 1.2 SD vs. 7. 36 +/- 2.7 SD in normal controls, P = 0.0008). Our results suggest that the underlying defect in patients with severe refractory DBA may not be limited to the erythroid lineage, as was evidenced by the development of pancytopenia, bone marrow hypoplasia and reduced clonogenic cell output in LTC-IC assays.

Adolescent↗

PubMed1999

Liposomal nystatin against experimental pulmonary aspergillosis in persistently neutropenic rabbits: efficacy, safety and non-compartmental pharmacokinetics.

The activity of liposomal nystatin against invasive pulmonary aspergillosis was investigated in persistently neutropenic rabbits. Treatment groups included liposomal nystatin at dosages of 1, 2 and 4 mg/kg/day intravenously, or amphotericin B deoxycholate 1 mg/kg/day administered intravenously after normal saline loading. As compared with untreated controls, liposomal nystatin administered at 2 and 4 mg/kg/day prolonged survival and reduced fungus-mediated tissue injury and excess lung weight at post-mortem in a similar manner to amphotericin B. Although amphotericin B was superior in clearing infected lung tissue, treatment with all regimens of liposomal nystatin led to a significant reduction in pulmonary fungal tissue burden. During treatment, ultrafast CT-scan demonstrated ongoing resolution of pulmonary lesions at 2 and 4 mg/kg/day, but not at 1 mg/kg/day. With the exception of mild increases in blood urea nitrogen (BUN) and serum creatinine values during treatment at 2 and 4 mg/kg/day, which were similar to those found in amphotericin B-treated rabbits, liposomal nystatin was well tolerated. Preliminary pharmacokinetic studies in non-infected animals established linear drug disposition of liposomal nystatin in plasma over the investigated dosage range and peak plasma levels above the MIC for the test strain after multiple daily dosing for 7 days. Liposomal nystatin increased survival and provided reduced tissue injury, effective microbiological clearance and tolerable side effects in experimental pulmonary aspergillosis in persistently neutropenic rabbits, thus providing a rational basis for further investigations in clinical trials.

Amphotericin B↗

PubMed1998

Compartmental pharmacokinetics and tissue drug distribution of the pradimicin derivative BMS 181184 in rabbits.

The pharmacokinetics of the antifungal pradimicin derivative BMS 181184 in plasma of normal, catheterized rabbits were characterized after single and multiple daily intravenous administrations of dosages of 10, 25, 50, or 150 mg/kg of body weight, and drug levels in tissues were assessed after multiple dosing. Concentrations of BMS 181184 were determined by a validated high-performance liquid chromatography method, and plasma data were modeled into a two-compartment open model. Across the investigated dosage range, BMS 181184 demonstrated nonlinear, dose-dependent kinetics with enhanced clearance, reciprocal shortening of elimination half-life, and an apparently expanding volume of distribution with increasing dosage. After single-dose administration, the mean peak plasma BMS 181184 concentration (Cmax) ranged from 120 microg/ml at 10 mg/kg to 648 microg/ml at 150 mg/kg; the area under the concentration-time curve from 0 to 24 h (AUC0-24) ranged from 726 to 2,130 microg . h/ml, the volume of distribution ranged from 0.397 to 0.799 liter/kg, and the terminal half-life ranged from 4.99 to 2.31 h, respectively (P < 0.005 to P < 0.001). No drug accumulation in plasma occurred after multiple daily dosing at 10, 25, or 50 mg/kg over 15 days, although mean elimination half-lives were slightly longer. Multiple daily dosing at 150 mg/kg was associated with enhanced total clearance and a significant decrease in AUC0-24 below the values obtained at 50 mg/kg (P < 0.01) and after single-dose administration of the same dosage (P < 0.05). Assessment of tissue BMS 181184 concentrations after multiple dosing over 16 days revealed substantial uptake in the lungs, liver, and spleen and, most notably, dose-dependent accumulation of the drug within the kidneys. These findings are indicative of dose- and time-dependent elimination of BMS 181184 from plasma and renal accumulation of the compound after multiple dosing.

Animals↗

PubMed1998

Antifungal activity of the pradimicin derivative BMS 181184 in the treatment of experimental pulmonary aspergillosis in persistently neutropenic rabbits.

The activity of the pradimicin derivative BMS 181184 was evaluated in a model of invasive pulmonary aspergillosis in persistently neutropenic rabbits and compared with that of amphotericin B deoxycholate. BMS 181184 at total daily doses of 50 and 150 mg/kg of body weight was at least as effective as amphotericin B at 1 mg/kg once a day in conferring survival and had comparable activity in reducing organism-mediated tissue injury and excess lung weight. Although treatment at all dosing regimens of BMS 181184 resulted in significant reductions in fungal tissue burden compared to untreated controls, equivalence to amphotericin B occurred only at the higher dosage level. Similar observations were made in bronchoalveolar lavage fluid cultures obtained postmortem. Monitoring of the animals through ultrafast computerized tomography scan revealed a marked resolution of pulmonary lesions during treatment with BMS 181184. The compound was well tolerated at all dosing regimens, and no toxicity was noted. Pharmacokinetic studies revealed nonlinear drug disposition with increased clearance at higher dosages and some evidence for extravascular drug accumulation. BMS 181184 had excellent activity in the treatment of experimental invasive pulmonary aspergillosis in persistently neutropenic rabbits, thus underscoring the potential of pradimicin derivatives in therapy of invasive aspergillosis in the neutropenic host.

Animals↗

PubMed1997

Pradimicins: a novel class of broad-spectrum antifungal compounds.

Pradimicins are a new class of antifungal compounds currently undergoing preclinical and early phase I clinical trials. The pradimicin structure is characterized by an aglycone of dihydrobenzo (alpha) naphthacenequinone with substitutions by a D-amino acid and hexose sugar. Pradimicins possess a novel mechanism of action consisting of a specific binding recognition to terminal D-mannosides of the cell wall of Candida albicans, resulting in the formation of a ternary complex consisting of D-mannoside, pradimicin, and calcium that leads to disruption of the integrity of the fungal cell membrane. Pradimicin in the form of BMS-181184 has broad-spectrum in vitro antifungal activity against Candida spp., Cryptococcus neoformans, Aspergillus spp., dematiaceous molds, and the Zygomycetes. Fusarium spp. are comparatively resistant to high concentrations of pradimicin. Initial vivo studies indicate that pradimicins have antifungal activity against experimental murine disseminated candidiasis and disseminated aspergillosis. Early studies indicate an excellent therapeutic index with no major end-organ toxicity. Pradimicins warrant further investigation for treatment of opportunistic mycoses in immuno-compromised hosts.

Antibiotics, Antineoplastic↗

PubMed1997

Invasive aspergillosis in human immunodeficiency virus-infected children.

BACKGROUND: Aspergillosis is an uncommon yet serious opportunistic infection in patients with AIDS. It has been extensively reported in HIV-infected adult patients. To our knowledge there are no studies that describe the epidemiology, clinical manifestations and outcome of aspergillosis in a large HIV-infected pediatric population. METHODS: We reviewed the records of all 473 HIV-infected children followed in the Pediatric Branch of the National Cancer Institute for 9 years from 1987 through 1995 for the presence of Aspergillus infection. RESULTS: Seven (1.5%) patients developed invasive aspergillosis during the study period. All patients had low CD4 counts reflecting severe immunosuppression. Sustained neutropenia (> 7 days) or corticosteroid therapy as a predisposing factor for invasive aspergillosis was encountered in only two patients (28%). Invasive pulmonary aspergillosis developed in five patients and cutaneous aspergillosis in two. The most common presenting features in patients with pulmonary aspergillosis were fever, cough and dyspnea. Patients with cutaneous aspergillosis were diagnosed during life and successfully treated with amphotericin B and surgery, whereas diagnosis of pulmonary aspergillosis was made clinically in only one patient. CONCLUSIONS: Aspergillosis is an uncommon but highly lethal opportunistic infection in HIV-infected children. Invasive pulmonary aspergillosis should be considered in the differential diagnosis in febrile, HIV-infected children with persistent pulmonary infiltrates.

AIDS-Related Opportunistic Infections↗

PubMed1996

Allogeneic bone marrow transplantation for children with acute lymphoblastic leukemia conditioned with busulfan, cyclophosphamide and melphalan.

Children with acute lymphoblastic leukemia (ALL) undergoing allogeneic bone marrow transplantation (BMT) using total body irradiation (TBI)-containing conditioning regimens are at risk of substantial late sequelae affecting growth and endocrine functions. This has lead to the use of non-TBI or chemotherapy conditioning regimens for ALL patients in many centers. However, it is unknown whether chemotherapy conditioning results in improved antileukemic efficacy or reduced transplant-related toxicity. We report our experience using a chemotherapy conditioning regimen (busulfan (Bu), cyclophosphamide (CY) and melphalan (Mel)) in 26 consecutively enrolled children with ALL (group I). At a median follow-up of 58 months, event-free survival (EFS) for Bu/CY/Mel-treated patients was 27% (+/- 8.7), while the leukemic relapse rate was 49% (+/- 13). Regimen-related toxicity was severe in these patients: overall treatment-related mortality was 42%, while 50% of patients had interstitial pneumonitis and 35% of patients had severe hemorrhagic cystitis. A historical control group of 25 consecutively enrolled patients, mostly treated with TBI-containing regimens (group II), had an EFS of 36% (+/- 9.6%) and a leukaemic relapse rate of 45% (+/- 11) at a median follow-up of 117 months. We conclude that the Bu/CY/Mel conditioning regimen leads to severe transplant-related toxicity and did not significantly improve leukemic relapse rates.

Adolescent↗

PubMed1995

Bone marrow transplantation for infantile malignant osteopetrosis.

PURPOSE: Most patients diagnosed with malignant osteopetrosis die during infancy or early childhood from hemorrhage and infection due to bone marrow failure. Allogeneic bone marrow transplantation (BMT) has been reported to provide curative therapy for this disorder. We report our experience with eight patients with malignant osteopetrosis who underwent BMT. PATIENTS AND METHODS: Between May 1987 and August 1992, eight children with malignant osteopetrosis underwent allogeneic BMT. Median age at BMT was 9 months (range, 2-36 months). Six patients received marrow from HLA-identical sibling donors, one from phenotypically matched father, and one from a one antigen mismatched father. BMT conditioning for all patients was busulfan 16 mg/kg and cyclophosphamide 200 mg/kg each administered over 4 days. Graft versus host disease (GVHD) prophylaxis included cyclosporin A in six patients or cyclosporin A and methotrexate in two patients. RESULTS: Six patients, including those who received bone marrow from their father's, engrafted as documented by bone marrow biopsy showing an increase in osteoclasts in all cases and by chromosomal analysis in four patients. Two patients died without engraftment. Three out of six patients engrafted are alive and well at the follow-up of 48, 63, and 81 months. Serum calcium, alkaline, and acid phosphatase levels normalized within 2 months. These patients have full bone marrow reconstitution. Serial radiologic studies revealed bone marrow remodelling and a new nonsclerotic bone formation. Vision improved dramatically in the youngest patient. CONCLUSION: BMT offers cure to patients with malignant osteopetrosis with reconstitution of bone marrow and correction of metabolic disturbances. In our experience, reversibility in neurosensory deficit is possible when BMT is done at an early age.

Bone Marrow Transplantation↗

PubMed1994

HLA non-identical T-cell-depleted bone marrow transplantation for primary immunodeficiency diseases.

BACKGROUND: Bone marrow transplantation (BMT) is usually the only procedure offering cure for children with life-threatening immune deficiency disorders, but compatible sibling donors are frequently unavailable. AIMS AND METHODS: To examine the outcome of HLA non-identical T-cell-depleted BMT carried out between April 1985 and May 1992 in 11 patients with primary immunodeficiency diseases and to seek prognostic factors. RESULTS: Eight patients achieved sustained engraftment, one after a second BMT. One further patient engrafted transiently, but rejected the graft five months later. Acute graft-versus-host disease (GVHD) grade II was seen in one and chronic GVHD was seen in three children. Seven patients survived beyond six months, six with donor T cell and five with donor B cell engraftment. At present, five patients (46%) are alive with immune reconstitution at a median follow-up of 14 months (range 6 to 78 months). The major factor associated with outcome was the presence of any infection within one week of BMT (p = 0.01). The presence of lung infection also tended to be a poor prognostic factor (p = 0.06) but did not reach significance, presumably because of the small sample size. HLA non-identical (parental) T-cell depleted BMT plays an important role in the cure of children with immunodeficiencies who do not have an identical sibling donor. Survival can be further improved if the diagnosis of immunodeficiency disease is made early and BMT undertaken before significant infections occur. CONCLUSIONS: The availability of T-cell depleted haploidentical parental bone marrow transplant can be anticipated to improve outcome significantly for children with severe immunodeficiency, especially when diagnosed early.

Bone Marrow Transplantation↗

PubMed1993

Long-term complications following bone marrow transplantation in children.

Seventeen children who underwent bone marrow transplantation (BMT) between 1975 and 1985 and survived for more than 2 years were evaluated for growth and development. The patients had a follow up of 2.1-13.1 years. Prior to transplant, children with malignancy had received multi-agent chemotherapy and nine had also received central nervous system irradiation. Transplant preparation for malignancy (group 1; n = 13) included high-dose cyclophosphamide (CPA) 120-200 mg/kg and total body irradiation (TBI) 10-13.2 Gy, whereas conditioning for non-malignant disorders (group 2; n = 4) included high-dose CPA 200 mg/kg with or without busulphan. Patients in group 1 showed a steady decline in height velocity following initial chemotherapy and cranial irradiation and the decline was even greater following BMT. Growth hormone (GH) deficiency developed in eight of nine children tested, hypergonadotrophic hypogonadism developed in 11 who reached puberty, thyroid hormone abnormalities were encountered in four out of 10 tested and 11 of 13 developed cataracts. Patients in group 2 did not show decline in linear growth rate, thyroid hormone abnormalities or cataracts after BMT. The only child tested had normal GH levels and the two patients who reached puberty showed delayed but complete gonadal recovery. Our data demonstrate that TBI leads to significant late effects on growth and gonadal function. Contrary to previous reports, a high incidence of cataract formation is observed after fractionated TBI. Conditioning regimens TBI should be considered in children undergoing BMT.

Adolescent↗

PubMed1993

Factors affecting hair regrowth after bone marrow transplantation.

Permanent alopecia after BMT has been reported as a side-effect associated with GVHD or after busulphan conditioning therapy, primarily in adults. We have reviewed children undergoing BMT to document the frequency of incomplete hair regrowth and to evaluate factors associated with this problem. Hair regrowth was studied in 74 children who survived > 6 months following BMT undertaken for malignant and non-malignant diseases. Alopecia was categorised as severe (< 50% of pre-transplant status), moderate (50-75%) or mild (> 75% but less than normal). Overall, 18 (24.3%) of 74 patients had mild (n = 5), moderate (n = 4) or severe (n = 9) alopecia. Risk factors for alopecia were presence of chronic GVHD (67%; p < 0.001), older age (p < 0.001) and prior cranial irradiation (42%; p = 0.03). Alopecia occurred in children receiving either busulphan (31%) or total body irradiation (16%; p = 0.15) as conditioning therapy. The highest frequency was seen in patients conditioned with busulphan with or without melphalan and who received prior cranial irradiation and/or developed chronic GVHD (75%). These data indicate that alopecia after BMT in children is a significant problem and confirm, in children, the previously noted association between alopecia and chronic GVHD and busulphan. Further risk factors of older age and prior cranial irradiation are identified. Consideration needs to be given to the use of an alternative to busulphan in children who are of older age, have received prior cranial irradiation and/or are at increased risk of GVHD.

Adolescent↗

PubMed1992

Failure of allogeneic bone marrow transplantation to benefit HIV infection.

A 16 year old boy underwent allogeneic bone marrow transplantation (BMT) from an human leukocyte antigen (HLA)-identical sibling for severe aplastic anaemia. He was symptomatic for 7 years before transplantation and had received multiple red blood cell and platelet transfusions. Conditioning for BMT consisted of cyclophosphamide, antilymphocyte globulin and total lymphoid irradiation. Engraftment was rapid, there was no evidence of rejection despite the history of multiple blood product transfusions and he did not develop acute or chronic graft versus host disease. He was well for the first 8 months after transplantation but then developed fevers, interstitial pneumonia, herpes simplex infections and cytomegalovirus enteritis. Serological studies revealed antibodies to human immunodeficiency virus (HIV) and he was considered to have acquired immune deficiency syndrome (AIDS). Retrospective analysis of the serum samples showed that he was seronegative for HIV until approximately 10 months before transplantation when his serum became HIV positive. Lymphocyte function studies done after transplantation suggested immunologic recovery at 3 months post-transplant with a brisk though subnormal response to phytohaemagglutinin stimulation. T cell subset analysis performed subsequently showed complete absence of CD4 positive cells indicating immune incompetence which was associated with clinical features of AIDS. Bone marrow transplantation had failed to produce sustained immunologic reconstitution and prevent the progression of HIV to which he ultimately succumbed.

Acquired Immunodeficiency Syndrome↗

PubMed1992

Successful pregnancy after total body irradiation and bone marrow transplantation for acute leukaemia.

We report successful pregnancies in two young women (aged 24 and 20 years) following allogeneic bone marrow transplantation (BMT) for acute non-lymphoblastic leukaemia. Conditioning therapy consisted of cyclophosphamide (120 mg/kg) and total body irradiation (TBI, 12 Gy) in 2 Gy fractions once daily for 6 days or twice daily for 3 days. Graft-versus-host disease prophylaxis was with methotrexate alone. Both women were amenorrhoeic after BMT and gonadal testing indicated hypergonadotrophic hypogonadism. Both women had normal pregnancies (2 years and 5 years after BMT) resulting in normal healthy infants. Previously successful pregnancy has been reported after TBI in three women in whom the TBI dose was less than 8 Gy. Our cases illustrate that normal outcome of pregnancy is possible at even higher doses of TBI.

Adult↗

PubMed1989

Epidemic iatrogenic Acinetobacter spp. meningitis following administration of intrathecal methotrexate.

We report the first outbreak of Acinetobacter species meningitis in a group of children with acute leukaemia following the administration of intrathecal chemotherapy. Eight of twenty patients receiving methotrexate injections on a single day developed signs and symptoms of meningitis within 18 h of treatment, and cases were clustered by time of administration. A cohort study comparing case and non-case patients did not identify any specific host factor associated with meningitis. Acinetobacter calcoaceticus var anitratus was isolated from the cerebrospinal fluid (CSF) of five patients; three patients died. Our investigation determined that the methotrexate was extrinsically contaminated by reused needles, used for reconstitution and administration, which had been inadequately sterilized. Acinetobacter calcoaceticus var anitratus was isolated from an autoclaved needle and a vial of methotrexate used for chemotherapy; these and the clinical isolates had similar antibiograms. After introduction of single-use disposable needles no subsequent cases occurred.

Acinetobacter Infections↗