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Biomedical subjects

D Joshua

Publications and source records attributed to D Joshua.

At least 37 records · Page 2Linked to original sources
PubMed1995

Idiotypic oligonucleotide probes to detect myeloma cells by mRNA in situ hybridization.

An mRNA in situ hybridization (ISH) method which used non-radioactive idiotypic oligonucleotide probes has been used to detect malignant cells in the bone marrow and peripheral blood of patients with multiple myeloma. For each of two patients with multiple myeloma a pair of biotinylated antisense oligonucleotide probes (18-22mer) was prepared from non-germline sequences of the rear-ranged immunoglobulin heavy chain (IgH) gene. These oligonucleotide sequences were not homologous with any previously published sequence. The probes from each patient were specific as shown by a failure to hybridize to any cells from six other myeloma patients and four normal individuals. Specific staining of IgH gene mRNA occurred only when the myeloma cells and the sequence of the probe used were from the same patient. Using simultaneous fluorescent immunocytochemistry it was shown that more than 95% of the ISH-positive cells expressed the malignant light chain in their cytoplasm. ISH positive cells were found in 1-4% of the peripheral blood mononuclear fraction of these two patients. These studies show that idiotypic oligonucleotide IgH gene probes can be used to identify individual cells belonging to the malignant clone and offer the possibility of developing innovative tumour-specific therapeutic procedures using antisense technology for patients with myeloma.

Base Sequence↗
PubMed1995

Prophylactic ganciclovir is more effective in HLA-identical family member marrow transplant recipients than in more heavily immune-suppressed HLA-identical unrelated donor marrow transplant recipients. Australasian Bone Marrow Transplant Study Group.

A multi-centre Australasian study of the efficacy of prophylactic ganciclovir in 88 recipients of marrow allografts at high risk for post-transplant cytomegalovirus (CMV) disease was conducted. The actuarial incidence of CMV disease was 10% in 74 recipients of HLA-identical family member transplants given ganciclovir but was 33% in 14 recipients of HLA-identical unrelated donor transplants given more immune-suppression pre- and post-transplant (P = 0.006). CMV disease developed in 4 of the 14 recipients of HLA-identical unrelated donor transplants at a median of 59 days post-transplant and was associated with concurrent graft-versus-host disease (GVHD) in 2 of the 4. CMV disease occurred in 5 of 74 recipients of an HLA-identical family member transplant at a median of 137 days post-transplant and was associated with concurrent moderate to severe GVHD in 4 of the 5. Thus the risk of CMV disease was higher in recipients who were not genotypically identical for HLA with their donors and who (in consequence) were given more immune-suppression than HLA-identical family member transplant recipients. Additionally, CMV disease can occur beyond the period of prophylactic ganciclovir administration (first 3 months post-transplant) in patients developing significant chronic GVHD and prophylaxis should be reintroduced at that time in such patients.

Adolescent↗
PubMed1994

Trends in bacterial infections in febrile neutropenic patients: 1986-1992.

BACKGROUND: Bacterial infection is a major cause of morbidity and mortality in neutropenic patients. AIMS: (1) To review patterns and trends in bacterial infections in three cohorts of febrile neutropenic patients managed by a single unit over a seven year period. (2) To relate any changes to the use of central venous (Hickman's) catheters and high-dose cytosine arabinoside chemotherapy. METHODS: Retrospective review of the results of initial bacteriological work-up performed on 344 episodes of febrile neutropenia. The three cohorts were 1986-87 (n = 102), 1989-90 (n = 92) and 1991-92 (n = 150). RESULTS: (1) The ratio of gram-negative to gram-positive bacteraemias fell from 1.36 in the first cohort to 1.05 in the second and 0.40 in the third (p = 0.03). There was a fall in both percentage and number of gram-negative isolates coupled with a rise in the frequency of gram-positive isolates. (2) Coincidentally there was a rise in the frequency of positive cultures from Hickman catheter entry wounds and an increasing frequency of simultaneous isolation of the same organism from the catheter entry site and the blood. The types of organisms isolated from catheter entry wounds showed a trend towards fewer gram-negative and more gram-positive. (3) A relationship was observed between the use of high-dose cytosine arabinoside chemotherapy and the incidence of bacteraemia (p = 0.025) but not with the change in types of organisms. CONCLUSIONS: Over seven years we have documented a major change in the types of infections, particularly bacteraemias, seen in febrile neutropenic patients. In our institution the more widespread use of intravenous catheters and high-dose cytosine arabinoside chemotherapy have been identified as two possible contributing factors.

Bacteremia↗
PubMed1994

Peripheral blood lymphocyte surface antigen expression and prognosis in myeloma: Australian Leukaemia Study Group Study.

The Australian Leukaemia Study Group myeloma study (MM1) aimed to determine the prognostic significance of clinical and immunophenotypic markers in patients with multiple myeloma. All patients were treated with standard dose melphalan and prednisone. Seventy-four patients were entered and the median survival was 27 months. Serum beta 2-microglobulin (beta 2M) and albumin levels were the only significant clinical factors influencing survival (p = 0.007 and p = 0.008, respectively). Patients with raised levels of CD38+ lymphocytes at presentation had a significantly shorter survival than patients with normal levels (p = 0.01, logrank test, median 19 months vs 33 months). CD38 antigen expression was independent of beta 2M but patients with raised levels of CD38 had significantly lower levels of albumin than patients with normal levels (p = 0.001) which may explain their poorer survival. Salmon and Durie stage was not associated with antigen expression. No other B-cell antigens (CD10, CD19, CD20, CD21, CD22, CD23, FMC1 or FMC7) or plasma cell antigens tested (PCA-1) were found to be associated with prognosis. Patients who achieved plateau phase had a better prognosis than those who did not (p = 0.04 in a landmark analysis). Patients who achieved plateau phase following an objective response appeared to have a better prognosis than those who were in plateau phase at presentation (p = 0.09 in a landmark analysis). Light chain isotype suppression (LCIS) was not associated with a significant survival advantage and did not correlate with any known prognostic indicator.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1994

The oncoprotein phenotype of plasma cells from patients with multiple myeloma.

The expression of 6 different oncoproteins and 2 tumour suppressor gene products in the plasma cells of 63 bone marrow samples was used to determine a profile of the oncogenic phenotype of patients with multiple myeloma. Dual label flow cytometry after periodatelysine paraformaldehyde fixation was used to detect cell surface phenotype and intracellular protein expression simultaneously. The normal range for both the incidence and intensity of expression was determined for each protein by analysing plasma cells (high CD38 intensity) in 22 normal bone marrow samples. The percentage of myeloma patients with a greater than normal incidence of plasma cells expressing these proteins was 53% for c-myc, 28% for Rb, 28% for bcl-2, 27% for c-fos, 24% for p53 wild, 22% for p53 mutant, 13% for c-neu and 13% for pan-ras. When a panel of 8 antibodies was used, 82% of the samples (n = 28) had an increased incidence of expression by at least one oncoprotein or tumour suppressor gene product. The 5 patients with a normal incidence of expression of all 8 proteins were in plateau stage and 4 had not received chemotherapy for more than 12 months. The number of patients with an increased incidence of expression by 2 or more oncoproteins was significantly greater (X2 = 9.0; p < 0.005) in progressive disease (55%) than in stable disease (14%) but there was no specific phenotype pattern associated with progressive disease. All 6 oncoproteins and both tumour suppressor gene products had a greater incidence and intensity of expression in progressive than in stable disease. The expression of c-myc oncoprotein correlated with c-myc mRNA expression in the same samples (n = 10) but c-myc did not correlate with either the plasma cell labelling index (r = -0.15) nor serum thymidine kinase (r = 0.10). Our results suggest that there is a heterogeneous, non-systematic but almost universal presence of activated oncogenes and tumour suppressor genes in the plasma cells of patients with multiple myeloma and that disease progression is associated with the accumulation of a variety of secondary genetic changes which confer increased malignant behaviour.

Biomarkers, Tumor↗
PubMed1994

A randomised dosage study of ceftazidime with single daily tobramycin for the empirical management of febrile neutropenia in patients with hematological diseases.

A single-institution, randomised trial was conducted to compare the clinical and microbiological efficacy of two different doses of ceftazidime in combination with a single daily dose of tobramycin for the empirical management of febrile neutropenic patients with hematologic disorders (absolute neutrophil count < 1 x 10(9)/l). Upon the development of fever or signs of sepsis, patients received either 2 g ceftazidime every 8 h plus a single daily dose tobramycin (5 mg/kg/day) (C2T, n = 73) or 1 g ceftazidime every 8 h plus a single daily dose of tobramycin (C1T, n = 77). In addition, flucloxacillin (1-2 g every 4 h) could be added if there was clinical suspicion of staphylococcal infection. Analysis was performed for the whole group and for the subset which did not receive flucloxacillin. When evaluated at 96 h, 70% (95% CI, +/- 11%) of patients randomised to C2T and 60% (95% CI, +/- 11%) randomised to C1T had responded (chi 2 = 1.27, P = 0.26). The response rates at 96 h for those who did not receive flucloxacillin were 77% (+/- 12%) and 74% (+/- 13%), respectively (chi 2 = 0.01, P = 0.92). Overall, 68 (93% +/- 6%) and 72 (94% +/- 6%) patients, respectively, eventually became afebrile (chi 2 = 0.06, P = 0.81). Renal function, as judged by serum creatinine, was unaffected by either antibiotic schedule. Within 10 days of antibiotic commencement there was one death in each arm and overall there were five deaths in each arm.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

C-reactive protein (CRP) levels do not reflect disease status in patients with multiple myeloma.

It has recently been suggested that a combination of C-Reactive Protein (CRP) and beta-2-microglobulin (beta 2M) can be used to devise a simple prognostic model for patients with multiple myeloma. In this study we have measured serum beta 2M, CRP and thymidine kinase (STK) in a series of 215 samples to determine their value as a monitor of disease status. A longitudinal study was also performed with 6 individual patients. CRP levels did not correlate with disease status. The mean of the stable (23.62 mg/L) and the progressive disease 23.64 mg/L) groups were almost identical (t = 0.003; p = NS) with ranges of < 5-150 mg/L and < 5-100 mg/L respectively. There was no correlation between CRP and STK (r = 0.11) or CRP and beta 2M (r = 0.05). In longitudinal studies, CRP did not necessarily reflect changes in disease activity. We conclude that CRP measurements are not valuable as a monitor of disease activity in patients with myeloma.

C-Reactive Protein↗
PubMed1993

Single daily ceftriaxone and tobramycin in the empirical management of febrile neutropenic patients: a randomised trial.

A single-institution, randomised pilot trial was conducted to compare the clinical efficacy, microbiological efficacy and possible toxicity of empirical single daily antibiotic administration in febrile neutropenic patients with haematologic disorders (absolute neutrophil count < 1 x 10(9)/l). Upon the development of signs of sepsis, patients received either single daily dose tobramycin (5 mg/kg per day) plus ceftriaxone (2 g/day) (C + T, n = 47) or tobramycin (1.5 mg/kg, every 8 h) plus azlocillin (4 g, every 6 h) (A + T, n = 45). In addition, flucloxacillin (1-2 g, every 4 h) could be added if there was clinical suspicion of staphylococcal infection (17 in each arm). Analysis was performed for the whole group and for the subset which did not receive flucloxacillin. When evaluated at 96 h, 62% of patients randomised to C + T and 67% randomised to A + T had responded (95% confidence interval (CI) for the difference in rates, -25% to +15%). Ninety-six hour response rates for those who did not receive flucloxacillin were 73% and 78%, respectively (95% CI, -17% to +27%). Overall, 42 (89%) and 41 (91%) patients, respectively, eventually became afebrile (95% CI, -14 to 10%) and there was no evidence of altered renal function or electrolyte imbalance in patients randomised to single daily antibiotic therapy compared with the conventional (multi-daily dose) arm. Within 10 days of antibiotic commencement there was 1 death in the C + T arm and 4 deaths in the A + T arm, although overall there were 4 deaths in each arm. Our results suggest that single daily empirical antibiotic therapy with tobramycin and ceftriaxone is efficacious and is not associated with an increased incidence of renal dysfunction or electrolyte imbalance compared with conventional administration schedules of azlocillin plus tobramycin. Single daily therapy has the potential to lead to savings in nursing-staff time and materials and may well contribute to an improved quality of life for febrile neutropenic patients.

Adolescent↗
PubMed1993

Interleukin-6 receptor expression and saturation on the bone marrow cells of patients with multiple myeloma.

Expression of the interleukin-6 (IL-6) receptor on B cells and plasma cells in the bone marrow (n = 18) and peripheral blood (n = 32) of patients with multiple myeloma and the relative saturation of these receptors with endogenous IL-6 has been determined by dual-labelled flow cytometric analyses. B cells were identified using an anti-CD19 monoclonal antibody and plasma cells were identified by gating on cells with high fluorescent staining with anti-CD38. With the exception of one patient, very few bone marrow plasma cells expressed the IL-6 receptor (IL-6R) (mean = 2%). This was in contrast to cells from the U-266 plasma cell line, 90% of which had IL-6R. IL-6R expression was lower on bone marrow B cells (mean = 11%) than on peripheral blood B cells (mean = 69%). Studies using either monoclonal or polyclonal anti-human IL-6 to detect endogenous receptor-bound IL-6 found that the IL-6R on bone marrow B cells and plasma cells from patients with multiple myeloma were not saturated with endogenous IL-6 and the presence of receptor-bound IL-6 tended to be associated with stable disease. Thus dysregulated IL-6R expression was not evident on the B cells and plasma cells of patients with multiple myeloma and the increased IL-6R expression on the U-266 plasma cell line was not found on patients' cells.

B-Lymphocytes↗
PubMed1991

Etoposide in leukemia.

Etoposide (VP16-213, NSC 141540) induces a complete response (CR) in 15% to 25% of previously treated patients with acute nonlymphocytic leukemia (ANLL) when used as a single agent. Etoposide has been used successfully in combination with cytarabine, daunorubicin, and amsacrine for salvage and consolidation therapies. Previously untreated ANLL patients 15 to 70 years of age were randomly assigned to cytarabine (100 mg/m2) on days 1 to 7 plus daunorubicin (50 mg/m2) on days 1 to 3 (7-3) or to the same drugs plus etoposide (75 mg/m2) on days 1 to 7 (7-3-7). Patients achieving a CR received two consolidation courses (5-2, attenuated 7-3 or 5-2-5). Among 264 eligible patients, there was a 56% CR rate with 7-3 therapy and a 59% CR rate with 7-3-7 therapy. Remission duration was significantly improved with 7-3-7 (median, 12 months with 7-3 and 18 months with 7-3-7; P = 0.01), but survival was not. Subset analysis in patients younger than 55 years of age revealed prolonged remission (median, 12 months with 7-3 and 27 months with 7-3-7; P = 0.01) and survival (median, 9 months with 7-3 and 17 months with 7-3-7; P = 0.04) with the 7-3-7 regimen. Hematologic toxicity was similar for both regimens during induction, but significantly more severe for 7-3-7 during consolidation therapy. Etoposide is active in ANLL and prolongs remission when used in induction therapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

Etoposide in acute nonlymphocytic leukemia. Australian Leukemia Study Group.

Previously untreated patients with acute nonlymphocytic leukemia (ANLL) aged 15 to 70 years were randomized to either cytosine arabinoside 100 mg/m2/d continuous intravenous (IV) infusion days 1 through 7, daunorubicin 50 mg/m2/d IV days 1 through 3 (7-3), or the same drugs intensified with etoposide 75 mg/m2/d IV days 1 through 7 (7-3-7) as induction therapy. Patients achieving complete remission (CR) received two courses of consolidation therapy (5-2 or 5-2-5) followed by maintenance therapy. Of 264 eligible patients, CR occurred in 56% of 7-3 and 59% of 7-3-7 patients; 7-3-7 significantly improved remission duration (P = .01). The median remission duration was 12 months for 7-3 and 18 months for 7-3-7. Survival was similar when the two arms were compared overall. Subset analysis performed to identify patients with the most benefit showed that etoposide significantly prolonged remission duration in younger patients (less than 55 years) with a median of 12 months for 7-3 and 27 months for 7-3-7 (P = .01). Survival appeared to be prolonged with 7-3-7 in patients aged less than 55 years, with a median of 9 months for 7-3 as compared with 17 months for 7-3-7 (P = .03). In older patients (aged greater than or equal to 55 years), 7-3-7 was more toxic, with significantly more severe [World Health Organization (WHO) grade 3 or 4] stomatitis (P = .02) and no additional clinical benefit. Hematologic toxicity for induction courses was similar, with granulocytopenia less than 0.5 x 10(9)/L for a median of 16 days per course for 7-3 and 15 days for 7-3-7. Hematologic toxicity was more severe for 5-2-5 consolidation courses (P = .003). Induction and consolidation therapy intensified with etoposide resulted in significantly improved remission duration but not survival.

Adolescent↗
PubMed1988

Clinical response of hairy-cell leukaemia to interferon-alpha: results of an Australian study.

Twelve patients with documented, progressive hairy-cell leukaemia were treated with human lymphoblastoid interferon-alpha. All patients initially received a three-month course of interferon-alpha (3 x 10(6) U each day) which resulted in two complete remissions and 10 partial remissions. All eight patients who were dependent upon packed red-cell transfusions became independent of them and the three patients with the most severe, pretreatment pancytopenia also became independent of platelet transfusions. The histological appearance of the bone marrow improved in all patients; in three patients, a complete resolution of the leukaemic infiltrate was recorded. Adverse reactions occurred in 10 patients, but these were mild and did not interrupt treatment in seven patients. Moderate reactions that required a temporary reduction in the dose of interferon-alpha were seen in three patients. Ten patients subsequently received maintenance therapy with interferon-alpha (3 x 10(6) U, three times a week). A haematological improvement continued to be seen in all patients, and the results, with a minimum of one year of follow-up, are presented.

Adult↗