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Biomedical subjects

S Durrant

Publications and source records attributed to S Durrant.

At least 37 records · Page 2Linked to original sources
PubMed2001

Combination therapy with tacrolimus and anti-thymocyte globulin for the treatment of steroid-resistant acute graft-versus-host disease developing during cyclosporine prophylaxis.

We report our experience with the combination of anti-thymocyte globulin (ATGAM) and tacrolimus in the treatment of 20 patients with steroid refractory and dependent acute graft-versus-host disease (GVHD) transplanted between August 1996 and February 2000. All patients received cyclosporine-based GVHD prophylaxis. Thirteen patients developed a maximum of grade IV, five grade III and two grade II acute GVHD, with 15 patients being refractory to steroids and five dependent on steroids. Patients were treated with ATGAM (15 mg/kg for 5 d) and tacrolimus (0.025--0.1 mg/kg/d) in addition to continuation of their high-dose steroids and cessation of their cyclosporine. Within 28 d of treatment, we observed eight complete responses (CR), six partial responses (PR) and six with no response. Overall response (CR + PR) was predicted by GVHD severity. Infectious complications occurred in 80% of patients. The median survival was 86.5 d (range, 21--1081 d) with 35% of patients remaining alive. Survival following combination therapy was significantly more likely in men (P < 0.001), skin-only GVHD (P = 0.027), less severe GVHD (P = 0.048), and in responders to tacrolimus and ATGAM (P < 0.001). In conclusion, concurrent introduction of ATGAM and tacrolimus is a promising therapeutic combination for GVHD refractory to steroids and cyclosporine.

Acute Disease↗
PubMed2001

Single institution outcomes of treatment of severe aplastic anaemia.

BACKGROUND: In severe aplastic anaemia, the treatment of choice for young patients with a human leucocyte antigen-matched sibling is now established as allogeneic bone marrow transplantation (BMT). In older patients and in those without a matched sibling donor, immunosuppressive therapy is the usual first option. 'Alternative' marrow donors are emerging as an option for those without a matched sibling donor. AIMS: To review 10 years of local experience in treating severe aplastic anaemia with BMT and immunosuppressive therapy with emphasis on long-term outcomes. METHODS: A retrospective analysis was performed of all patients with severe aplastic anaemia presenting to the Royal Brisbane and Royal Children's Hospitals between 1989 and 1999. Data were abstracted regarding patient demographics, pretreatment characteristics and outcome measures, including response rates, overall survival and long-term complications. RESULTS: Twenty-seven consecutive patients were identified, 12 treated with immunosuppression alone and 15 with BMT. In these two groups, transfusion independence was attained in 25% and 100%, respectively, with overall survival being 36% and 100%, respectively. Those treated with immunosuppression were significantly older (median 41.5 versus 22 years, P = 0.008). Long-term survivors of either treatment had extremely low morbidity. Three patients carried pregnancies to term post-transplant. Three patients received alternative donor BMT with correspondingly excellent survival. CONCLUSIONS: Patients treated with allogeneic BMT for severe aplastic anaemia enjoyed extremely good long-term survival and minimal morbidity. Patients treated with immunosuppressive therapy had a poorer outcome reflecting their older age and different usage of therapies over the past decade. Optimal treatment strategies for severe aplastic anaemia remain to be determined.

Adolescent↗
PubMed2000

Dendritic cells are targets for human invariant Valpha24+ natural killer T-cell cytotoxic activity: an important immune regulatory function.

OBJECTIVE: Human invariant Valpha24+ natural killer T (NKT) cells, a subpopulation of NK cell-receptor (NKR-P1A)-expressing T cells with an invariant Valpha24JalphaQ T-cell receptor (TCR), are stimulated by the glycolipid a-galactosylceramide (KRN7000), in a CD1d-dependent, TCR-mediated fashion. Little is known about invariant Valpha24+ NKT cell function or mechanisms of effector activity. Evidence suggests this cell population protects against autoimmunity and has antitumor effects against leukemia and solid tumors. MATERIALS AND METHODS: We compared the phenotype and function of invariant Valpha24+ NKT cells, from patients with chronic myeloid leukemia (CML) and normal donors, generated by stimulation of peripheral blood mononuclear cells with alpha-galactosylceramide pulsed monocyte-derived dendritic cells. The CD4(-)CD8(-) (double negative) population was studied further. RESULTS: Activated human invariant Valpha24+ NKT cells were cytotoxic against autologous and allogeneic peripheral blood dendritic cells and monocyte-derived dendritic cells but not against autologous or allogeneic T-cell PHA blasts, B-cell lymphoblastoid cell lines, monocytes, or leukemic cells from patients with CML. The findings are consistent with previous observations showing the importance of CD1d in target cell recognition. None of the Valpha24+ NKT cell lines expressed the NK markers CD16, CD56, CD94, or killer inhibitory receptors, but all expressed NKR-P1A. There was no difference in phenotype, function, or ease of generation of invariant Valpha24+ NKT cells between normal donors and patients with CML. CONCLUSION: Based on our results and the previous evidence linking reduced Valpha24+ NKT cells to autoimmunity, we propose that double-negative Valpha24+ NKT cells have important immune regulatory functions, including contribution to the prevention of excessive antigen stimulation by virtue of cytotoxic activity against antigen presenting cells, particularly in dendritic cells.

Cytotoxicity, Immunologic↗
PubMed2000

Diagnosis and management of subdural haematoma complicating bone marrow transplantation.

Subdural haematoma (SDH) is a known complication of bone marrow transplantation (BMT). A retrospective review of 657 consecutive patients undergoing allogeneic or autologous bone marrow/stem cell transplantation at the Royal Brisbane Hospital between January 1991 and December 1998 is reported. Seventeen cases of subdural haematoma/hygroma were identified (2.6%). Eleven of these (65%) were bilateral. Four required surgical drainage, with two developing re-accumulation of SDH. All cases presented with a headache and eight of these had associated neurological complications. Diagnosis was made predominately by CT scan: however in 25% of cases definitive diagnosis could only be made in MRI studies. An association with intrathecal methorexate-containing conditioning therapy, post lumbar puncture headache, prolonged thrombocytopenia and coagulopathy was noted. In our experience, conservative management with platelet support and correction of coagulopathy achieved resolution of subdural haematoma in most cases, with surgical intervention being reserved for neurological deterioration. Bone Marrow Transplantation (2000) 25, 549-552.

Adolescent↗
PubMed2000

Sciatic nerve compression following bone marrow harvest.

We describe a donor who suffered pain secondary to sacral plexus and sciatic nerve compression post bone marrow harvest. Haematoma was demonstrated by magnetic resonance image (MRI) scanning. To our knowledge, this is the first reported case of compression neuropathy post bone marrow harvest documented by MRI scanning. Given the increasing number of bone marrow transplants being performed and the paramount importance of donor safety, compressive neuropathies need to be remembered as rare but debilitating complications of bone marrow harvesting. MRI scanning is a useful modality to investigate severe or neuropathic pain post bone marrow harvest.

Adult↗
PubMed2000

Human invariant valpha24+ natural killer T cells activated by alpha-galactosylceramide (KRN7000) have cytotoxic anti-tumour activity through mechanisms distinct from T cells and natural killer cells.

Human Valpha24 + NKT cells, a subpopulation of natural killer cell receptor (NKR-P1A) expressing T cells with an invariant T-cell receptor (TCR; Valpha24JalphaQ) are stimulated by the glycolipid, alpha-galactosylceramide (KRN7000), in a CD1d-dependent, TCR-mediated fashion. Little is known about Valpha24 + NKT-cell function. The murine counterpart, Valpha14 + NKT cells, appear to have an important role in controlling malignancy. There are no human data examining the role of Valpha24 + NKT cells in controlling human malignancy. We report that Valpha24 + NKT cells have perforin-mediated cytotoxicity against haemopoietic malignancies. Valpha24 TCR, CD1d and alpha-galactosylceramide may all play a role in cytotoxicity but are not absolute requirements. The greatest cytotoxicity was observed against the U937 tumour cell line (95 +/- 5% lysis). THP-1, Molt4, C1R cells and allogeneic mismatched dendritic cells were also sensitive to Valpha24 + NKT cytotoxicity but neither the NK target, K562, nor lymphokine-activated killer-sensitive Daudi cells, were sensitive. These results indicate a killing pattern distinct from conventional major histocompatibility complex-restricted T cells, NK cells and other cytotoxic lymphoid cells previously described. We conclude that human Valpha24 + NKT cells have cytotoxic anti-tumour activity against haemopoietic malignancies through effector mechanisms distinct from conventional T cells and NK cells and that their specific stimulator KRN7000 may have therapeutic potential.

Adjuvants, Immunologic↗
PubMed1999

Safe mobilization of normal progenitors in advanced chronic myeloid leukemia with intensive chemotherapy and granulocyte-colony stimulating factor.

Twenty-one patients with advanced chronic myeloid leukemia (late chronic phase (n = 8), accelerated phase (n = 11) and blast crisis (n = 2)) were treated with idarubicin, cytarabine, and etoposide followed by G-CSF and subsequent collection of peripheral blood progenitor cells in the early recovery phase. Treatment was reasonably well tolerated with no deaths or intensive care admissions. Despite the advanced phase of disease and heavy pretreatment with cytotoxics and interferon-alfa, 11 of 21 patients (52%) achieved a cytogenetic response. Of the nine major cytogenetic responses (complete (n = 3) and partial (n = 6)), seven achieved adequate progenitor collections for consideration for autologous transplantation. The only predictor of response was disease duration (P = 0.02). With a median follow-up of 1171 days from treatment it appears unlikely that G-CSF contributed to disease progression. Survival post-IcE was predicted by disease stage (P = 0.0001). Intensive chemotherapy followed by G-CSF allowed adequate yields of predominantly Philadelphia chromosome negative progenitor cells to be obtained from one-third of patients with advanced CML.

Adult↗
PubMed1999

A double-blind comparison of fluconazole and nystatin in the prevention of candidiasis in patients with leukaemia. Antifungal Prophylaxis Study Group.

In this multicentre, randomised, double-blind study, the safety and efficacy of oral fluconazole (200 micrograms/day) and nystatin suspension (6,000,000 IU/day) for the prevention of fungal infections were compared in patients with leukaemia undergoing remission induction chemotherapy. Antifungal prophylaxis was initiated at the time chemotherapy was started and continued throughout the hospital stay or the period of neutropenia to a maximum of 42 days. Prophylaxis was successful (no evidence of fungal infection or fever of unknown origin unresponsive to antibiotics) in 38 of 56 (68%) fluconazole-treated and 25 of 53 (47%) nystatin-treated patients (P = 0.03). 2 patients (4%) in the fluconazole group and 6 (11%) patients in the nystatin group developed systemic fungal infections (P = 0.15). The overall frequency of adverse events was similar among fluconazole-treated (29%) and nystatin-treated (32%); most events in both treatment groups involved the gastrointestinal tract. These results indicated fluconazole was more effective than nystatin in preventing Candida infections in patients with leukaemia; fluconazole was well tolerated.

Acute Disease↗
PubMed1999

Factors affecting the outcome of allogeneic bone marrow transplantation for adult patients with refractory or relapsed acute leukaemia.

We evaluated the outcome of allogeneic bone marrow transplantation (BMT) for advanced acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL) in 383 adult patients in nine Australian adult BMT centres between 1981 and 1997. The median overall survival for the group was 4.8 months, with an estimated 5-year survival of 18%. 28% of patients died of transplant-related toxicities within the first 100 d. Progressive disease was responsible for 48% of deaths. Multi-factor analysis demonstrated that AML (v ALL), disease status (second complete remission [CR2] v others), age (< 40 years) and duration of prior first complete remission (CR1) (> 6 months) were pre-transplant variables significantly associated with improved survival. Acute graft-versus-host disease (GVHD) of any grade reduced the rate of relapse in both AML and ALL, but only grades I-II were associated with improved survival. Both limited and extensive chronic GVHD were associated with increased survival. Only patients with AML in untreated first relapse or CR2, with a duration of CR1 > 6 months, or patients with T ALL, had a 5-year survival > 20%. Transplants for AML in induction failure or pre-B ALL in untreated first relapse or CR2 had an intermediate outcome, with 5-year survival of 10-20%. A 5-year survival of < 10% was observed for patients transplanted for ALL in induction failure or for pre-B ALL or AML in refractory first relapse or beyond CR2. These results suggest that for most adult patients with advanced acute leukaemia an allograft offers only a small chance of cure.

Adolescent↗
PubMed1999

Relationship between Ureaplasma urealyticum vaginal colonization and polymorphism in the interleukin-1 receptor antagonist gene.

The relationship between polymorphisms in the interleukin-1 receptor antagonist (IL-1ra) gene and microbial vaginal colonization was examined in 88 asymptomatic women of reproductive age. Alleles of the intron 2 region of the IL-1ra gene were identified by polymerase chain reaction (PCR). PCR was also used to detect Ureaplasma urealyticum, Mycoplasma hominis, and Candida albicans; bacterial vaginosis (BV) was identified by clinical criteria. Among the 31 women with vaginal U. urealyticum, only 3 (9.7%) were homozygous for allele 2 of the IL-1ra gene; 21 (36.8%) of the 57 women who were negative for this organism were positive for allele 2 (P=.006). Only 7 women were positive for M. hominis; none were allele 2 homozygotes as opposed to 24 (29.6%) of the 81 women negative for M. hominis. There was no relation between C. albicans or BV and any IL-1ra allele. Reduced susceptibility to vaginal colonization with mycoplasmas may be associated with homozygosity of the 2 allele of the IL-1ra gene.

Adult↗
PubMed1999

Multicycle high-dose chemotherapy and filgrastim-mobilized peripheral-blood progenitor cells in women with high-risk stage II or III breast cancer: five-year follow-up.

PURPOSE: To determine the safety and efficacy of multiple cycles of dose-intensive, nonablative chemotherapy in women with poor-prognosis breast cancer. PATIENTS AND METHODS: Women with stage II breast cancer and 10 or more involved nodes or four or more involved nodes and estrogen receptor-negative tumors and women with stage III disease received three cycles of epirubicin 200 mg/m2 and cyclophosphamide 4 g/m2, with progenitor cell and filgrastim support every 28 days (n = 79) or 21 days (n = 20). Patients were reviewed at least twice yearly thereafter. Twenty-six patients had bone marrow and apheresis collections assessed for the presence of micrometastatic tumor cells. RESULTS: Ninety-nine women (median age, 43 years; range, 24 to 60 years) were treated. Ninety-two completed all three cycles of chemotherapy. The major toxicity was severe, reversible myelosuppression that was more prolonged with successive cycles, and this did not differ between patients given treatment every 28 days and those treated every 21 days. Febrile neutropenia occurred in 176 (61%) of 287 cycles. Severe mucositis (grade 3 or 4) occurred in 23% of cycles but tended to be short-lived and was reversible. The cardiac ejection fraction fell by a median of 4% during treatment, and three patients developed evidence of cardiac failure after chemotherapy. Two patients (2%) died of acute toxicity. Three of 26 patients had evidence of circulating micrometastatic tumor cells. The actuarial distant disease-free and overall survival rates at 60-month follow-up were 64% (95% confidence interval [CI], 53% to 75%) and 67% (95% CI, 56% to 78%), respectively. CONCLUSION: Multiple cycles of dose-intensive, nonablative chemotherapy is a feasible and safe approach. Disease control and survival are similar to those in other studies of myeloablative chemotherapy in poor-prognosis breast cancer. The regimen is being evaluated in a randomized trial of the International Breast Cancer Study Group.

Adult↗
PubMed1997

Predictors for optimal mobilization and subsequent engraftment of peripheral blood progenitor cells following intermediate dose cyclophosphamide and G-CSF.

Fifty consecutive patients undergoing cyclophosphamide/G-CSF mobilization were studied for indicators predictive for adequate harvest (CD34+ cells > 2 x 10(6)/kg, CFU-GM > 1 x 10(5)/kg). Target yields following a single leukopheresis were achieved for 66% of patients (89% with no previous alkylation chemotherapy or radiotherapy). Previous alkylation therapy, radiotherapy and low collection day platelet count were predictive of poor collection yields. Following reinfusion, the median time to platelets > 20 x 10(9)/l (PLT > 20) was 10 days and to neutrophils > 500 x 10(6)/l (ANC > 500) was 13 days. Total CD34+ cells infused was predictive of early platelet engraftment. Previous radiotherapy was inversely predictive of neutrophil engraftment. For the majority of patients not exposed to alkylation therapy or radiotherapy, adequate progenitor cells can be collected following a single leukopheresis. In patients suitable for future autologous bone marrow transplantation it would seem appropriate to avoid or minimize radiotherapy and alkylation therapy exposure in the pre-collection period.

Adolescent↗
PubMed1997

Factors influencing the outcome of donor marrow transplantation in adults from less than ideal donors: experience from two Australian centres.

BACKGROUND: This paper reports the results of 78 marrow transplants in two Australian hospitals between 1991 and 1996, using unrelated (n = 54) or mismatched related (n = 24) donors. Twenty-six patients received granulocyte-macrophage colony stimulating factor (GM-CSF) post-transplant as part of a phase II study. Fifty-four patients (74%) had advanced disease. AIMS: To identify factors associated with a superior outcome post-transplant, to evaluate the effect of GM-CSF on engraftment and other transplant parameters, and to compare the overall results with those of published series. METHODS: Review of patient records, a Medline search of the relevant literature and appropriate statistical analysis. RESULTS: The probability of overall survival and event-free survival (EFS) at three years was 35 +/- 6% and 22 +/- 6% respectively. Pre-transplant factors significantly associated with an inferior EFS were advanced disease, poorer performance status and age > 30 years. The EFS in patients with standard risk disease was 51 +/- 13% versus 10 +/- 5% in patients with advanced disease, p < 0.0001. Severe acute graft-versus-host disease was also associated with a poorer outcome. Neutrophil engraftment was faster in patients who received GM-CSF but there was no difference in any other transplant parameters. CONCLUSIONS: These results are consistent with reported series elsewhere and suggest that an extended family or unrelated donor transplant should generally be limited to patients with a good performance status and early phase but otherwise incurable haematological disease.

Acute Disease↗
PubMed1995

Oncocytic metaplasia of bile duct epithelium in hepatic GVHD.

A 15-year-old female underwent matched unrelated BMT for chemotherapy resistant ALL. She died 3 months later from septicaemia complicating grade IV GVHD. Light and electron microscopic examination of the post-mortem liver confirmed GVHD and showed oncocytic metaplasia of interlobular bile duct epithelium. We report that oncocytic metaplasia of bile duct epithelium is part of the pathological spectrum of hepatic GVHD.

Adolescent↗
PubMed1995

Allogeneic BMT from a donor with fragile X syndrome: cytogenetic and molecular evaluation.

We report the first case of engraftment of bone marrow collected from a donor with Fragile X syndrome with subsequent cytogenetic and molecular evaluation. Engraftment was prompt and stable. Whilst the Fragile X abnormality could be detected initially by molecular techniques in the peripheral blood, it could not be detected cytogenetically while the patient was receiving CsA.

Adult↗