The use of granulocyte colony-stimulating factor in volunteer blood and marrow registry donors.
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Adolescent↗
Biomedical subjects
N Russell
Publications and source records attributed to N Russell.
A study to determine the safety profile and maximum tolerated dose of micafungin (FK463) in patients undergoing haematopoietic stem cell transplantation.
This open-label, dose-escalation study assessed the maximum tolerated dose (MTD) of the new antifungal micafungin in patients undergoing haematopoietic stem cell transplantation (HSCT). Participants received 3, 4, 6 or 8 mg/kg/day micafungin intravenously from 7 days to a maximum of 28 days or until neutropaenia resolved. The MTD was defined as the highest dose not causing the same Grade 3 or 4 adverse event in three or more patients. All 36 participants received >/=8 days treatment for a median of 18 days (range: 8-28); 1 patient withdrew consent and a further 11 discontinued to receive another systemic antifungal agent for a suspected infection. No case of confirmed invasive fungal infection occurred. Adverse events were those expected for patients undergoing HSCT and showed no evidence of dose-related toxicity. Criteria for MTD were not met; no patient had a Grade 3 or 4 adverse event considered causally related to micafungin. Thus, the MTD of micafungin can be inferred to be 8 mg/kg/day or higher.
Adult↗
Ancestim associated with Filgrastim and/or chemotherapy can improve blood progenitor yields in patients who previously failed mobilisation.
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Filgrastim↗
Reduced-intensity conditioning lowers treatment-related mortality of allogeneic stem cell transplantation for chronic lymphocytic leukemia: a population-matched analysis.
To elucidate whether reduced-intensity conditioning (RIC) decreases treatment-related mortality (TRM) after allogeneic stem cell transplantation (allo-SCT) for chronic lymphocytic leukemia (CLL), we retrospectively compared 73 RIC cases from a recent EBMT survey with 82 patients from the EBMT database who had undergone standard myeloablative conditioning (MC) for CLL during the same time period. The two populations were matched by adjusting the primary risk factor, the conditioning regimen, in a series of Cox models for age, sex, donor type, remission status at transplant and analyzed for its effect on TRM, relapse incidence, event-free (EFS) and overall survival (OS). After adjustment, a significant reduction of TRM became evident for the RIC population (hazard ratio (HR) 0.4 (95% confidence interval 0.18-0.9); P=0.03). On the other hand, RIC was associated with an increased relapse incidence (HR 2.65 (0.98-7.12); P=0.054). There was no significant difference between RIC and MC in terms of EFS (HR 0.69 (0.38-1.25); P=0.22) and OS (HR 0.65 (0.33-1.28); P=0.21). We conclude that RIC appears to favorably influence TRM after allo-SCT for CLL. This observation, as well as possible detrimental effects of RIC on relapse risk, should be confirmed by prospective studies.
Adult↗
Strategies for overcoming p-glycoprotein-mediated drug resistance in acute myeloblastic leukaemia.
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ATP Binding Cassette Transporter, Subfamily B↗
What drives quality of life in multiple sclerosis?
BACKGROUND: Extensive use of the EDSS measure of disease severity by clinicians, and the EQ-5D measure of quality of life by healthcare decision-makers, may not adequately reflect patient perceptions of the range and impact of their symptoms. AIM: To investigate the perceptions of MS patients in relation to specific symptoms and their general health-related quality of life. DESIGN: Questionnaire-based surveys. METHODS: Two consecutive postal surveys were sent to people whose contact details were on the database of the MS Trust. The first was sent to all 8,614. Of 3,403 respondents, 1992 agreed to participate in a second survey. RESULTS: In the first survey (response rate 40%), 1993 respondents (88%) reported moderate or severe fatigue; of 266 receiving disease-modifying therapy, 109 (41%) felt it improved their fatigue. In the second (response rate 78%), mean EQ-5D Index and z scores on the related quality of life deficit were significantly lower for respondents with relapsing or progressive disease than for those with benign disease. In the former groups (total n=1178), over 90% reported problems with mobility and usual activities, and over 80% reported problems with pain. The lowest mean SF-36 scores were for role-physical, physical functioning and vitality, vitality being higher in respondents receiving beta interferon vs. those who were not (p <0.0001). Vitality was highly correlated with social functioning (0.58), general health (0.51) and mental health (0.50). DISCUSSION: Fatigue can profoundly disrupt the occupational and social functioning of MS patients, but is not directly captured in either the EDSS or the EQ-5D. Further investigation of the patient-perceived benefits of disease-modifying therapy, particularly in relation to symptoms of fatigue, may be valuable.
Activities of Daily Living↗
Augmentation mammoplasty and "silicone-osis".
BACKGROUND: Claims have been made that breast augmentation induces a previously unrecognized disease ("silicone-osis"). AIMS: To confirm the existence of "silicone-osis", qualify and quantify its characteristics. METHODS: In this population-based retrospective cohort study, the health status of 458 female Sydney residents who had augmentation mammoplasty for cosmetic reasons ("augmentation mammoplasty-exposed" or "exposed" cohort) between 1979 and 1983 was compared with the health status of 687 female Sydney residents who had non-silicone-associated plastic surgery ("augmentation mammoplasty-nonexposed" or "non-exposed" cohort). Both groups were matched for age (+/- 5 years), year of plastic surgery (+/- 2 years), plastic surgeon, anaesthetist and mode of anaesthesia. Outcome measures comprised dummy symptoms to assess reporting bias, as well as symptoms and symptom clusters from a comprehensive 78-symptom list. RESULTS: Dummy variables were not over-reported by the exposed cohort. The following individual symptoms developed more commonly in the exposed cohort after index plastic surgery: "memory loss/confusion", "altered bowel habit", "chest pain made worse by deep breathing", "shortness of breath after walking up 10 steps", "breast pain", "sweating mainly at night" and "tunnel vision". Of eight identified symptom clusters, three were rejected as biologically unimportant: "joint swelling of the bunion joint", "haemorrhoids" and "breast lumps" (the latter two occurring more commonly in the non-exposed cohort). In contrast, five symptom clusters were thought to have potential biological importance and occurred more commonly in the exposed cohort. The symptom "night sweats" was common to all five clusters, and comprised the sole symptom in one instance. The other four multisymptom clusters were also characterized by "low energy" (lethargy) and "pins and needles", whereas "breast pain", "impaired memory", "muscle pain" and "reflux", occurred in three of the four clusters. CONCLUSION: Cluster analysis suggested the existence of a multisystem disorder occurring more commonly in the exposed cohort and characterized by night sweats, lethargy, breast pain, impaired mentation, reflux, paraesthesiae, hand muscle weakness and myalgia. The argument against this being a new disease entity --"silicone-osis"-- however, was its presence, albeit at lower frequency, in the silicone-unexposed cohort. Thus this study did not confirm the existence of a new disease entity "silicone-osis" uniquely and causally associated with silicone exposure. The possible interpretations of these findings are discussed.
Autoimmune Diseases↗
Differences between graft product and donor side effects following bone marrow or stem cell donation.
We report graft product stem cell yields and donor safety results of a randomized multicenter study comparing allogeneic peripheral blood stem cell (PBSC) PBSC transplantation with BM transplantation. Matched HLA-identical sibling donors (n=329) were randomized to filgrastim-mobilized PBSC or bone marrow (BM) donation groups. Median yields per kg recipient weight of CD34(+) cells, T cells, and natural killer (NK) cells, respectively, were approximately two-fold, eight-fold, and greater than eight-fold in the PBSC group than in the BM group (CD34(+) cells, 5.8 x 10(6)/kg vs 2.7 x 10(6)/kg; T cells, 300.1 x 10(6)/kg vs 35.7 x 10(6)/kg; NK cells, 28.2 x 10(6)/kg vs 3.6 x 10(6)/kg; P<0.001 for each). In connection with the cell collection procedures, PBSC donors spent a shorter median time in hospital than BM donors (0 vs 2 days; median difference -2 days, 95% CI -2 to 2) and had fewer median days of restricted activity (2 vs 6 days; median difference -3 days, 95% CI -4 to 2). Overall, 65% of PBSC donors and 57% of BM donors reported at least one adverse event (AE), most of which were transient, mild-moderate in severity, and without clinical sequelae. PBSC donors experienced predominantly filgrastim-related AEs, while BM donors experienced predominantly harvest-related AEs.
Adolescent↗
Treatment-related mortality and graft-versus-leukemia activity after allogeneic stem cell transplantation for chronic lymphocytic leukemia using intensity-reduced conditioning.
Allogeneic stem cell transplantation (SCT) using reduced-intensity conditioning (RIC) has potential to be a promising treatment of aggressive chronic lymphocytic leukemia (CLL). Since available clinical data obtained with this novel approach are very limited, we have performed a survey on this issue. Data of 77 patients were collected from 29 European Group for Blood and Marrow Transplantation centers. Median age was 54 (30-66) years, and the median number of previous chemotherapy regimens was 3 (0-8). HLA-identical sibling donors were used in 81% of the cases. Moderate conditioning regimens (mainly low-dose total body irradiation (TBI) or fludarabine-cyclophosphamide combinations) were administered to 56% of the patients, whereas the remainder received more intense conditioning consisting of fludarabine-busulfan or high-dose melphalan combinations. In 40% of the patients, in vivo T-cell depletion (TCD) with anti-thymocyte globulin or CAMPATH-1H was part of the conditioning regimen. Cumulative treatment-related mortality (TRM) was 18% (95% CI 9; 27) after 12 months. Complete chimerism as well as best response was not achieved immediately post-transplant but took a median of 3 months to develop. The 2-year probability of relapse was 31% (95% CI 18; 44), with no event occurring later than 12 months post transplant in the absence of TCD. With one exception, relapses were not observed after onset of chronic graft-versus-host disease. Event-free and overall survival at 24 months were 56% (95% CI 43; 69) and 72% (95% CI 61; 83), respectively. The median follow-up was 18 (1-44) months. Donor lymphocyte infusions or secondary transplants were performed in 19 patients with insufficient disease control and/or incomplete donor chimerism post-transplant, leading to a response in seven patients (37%). Preliminary multivariate analysis identified less than PR at transplant (hazard ratio (HR) 3.5; P&<0.01) and alternative donor (HR 3.1; P=0.02) as significant risk factors for relapse, whereas number of previous regimens >2 (HR 5.4; P=0.03), TBI (HR 2.5; P=0.05), and alternative donor (HR 2.3; P=0.08) were risk factors for survival. We conclude that RIC might favorably influence the outcome after allogeneic SCT for CLL by reducing TRM while preserving graft-versus leukemia activity.
Adult↗
The role of prisons in the HIV epidemic among female injecting drug users.
The objective of this study was to describe factors associated with imprisonment of female injecting drug users (IDUs) and to assess if female IDUs who have been in prison have different HIV risk behaviours when compared to females IDUs who have never been incarcerated. A seroepidemiological survey was conducted of 304 female IDUs recruited in outreach and treatment programmes in Madrid, Spain. Data on sociodemographic characteristics and recent and lifetime risk factors, sexual and reproductive history and history of imprisonment were collected. Bivariate analysis and a logistic regression model were used to identify factors associated with imprisonment. Risk factors for imprisonment were having illegal sources of income, not having a fixed address, leaving education before finishing primary school and starting injection of drugs early in adolescence. HIV risk behaviours were highly prevalent among this population of female IDUs and drug injection in prison was reported by more than one-third of those who had ever been imprisoned. In addition, recent HIV risk behaviour indicators were not associated with imprisonment, suggesting that incarceration did not lead to risk reduction after release from prison. Female IDUs who have been in prison have substantial reproductive health problems that require gynaecological care. These results point to the urgent need for prevention programmes which address HIV and other blood-borne infections using gender specific approaches for women IDUs incarcerated in Spanish prisons.
Adult↗
Allogeneic whole-cell vaccine: a phase I/II study in men with hormone-refractory prostate cancer.
OBJECTIVE: To establish the safety and toxicity of an allogeneic human tumour cell vaccine in patients with hormone-refractory prostate cancer, and to determine any biochemical, immunological or clinical response to vaccination. PATIENTS AND METHODS: Sixty patients with hormone-refractory prostate cancer were recruited and randomly allocated into four equal groups. Three cell lines (from a bank of four) were administered initially every 2 weeks and then monthly, in conjunction with the immunostimulant Mycobacterium vaccae (SRL-172), each group receiving a different combination of the four cell lines. The patients' serum prostate-specific antigen (PSA) levels were monitored regularly, and the immune response to the vaccine measured using nonspecific intracellular cytokines and specific humoral and cell-mediated assays. RESULTS: The vaccine was safe and well tolerated with no major side-effects. Whilst several patients had a decline in PSA from the entry level, there was no significant decrease that could be attributed solely to the vaccine. However, the immunological data were more encouraging, with several patients from each arm of the trial having an increase in cytokine production, increases in specific antibodies and evidence of T-cell proliferation in response to the vaccinations. CONCLUSION: The failure of the vaccine to produce a PSA response in the patients in the trial is not surprising considering the stage of the disease. The high PSA levels on entry indicate that the burden of disease was probably high and thus this was an extremely challenging group of patients in which to try and elicit a response through immunotherapy. However, the immunological evidence of a response to the vaccine was encouraging and suggests that further exploration of immunotherapy in less advanced disease may yield more encouraging clinical responses.
Aged↗
Immune defence against HIV-1 infection in HIV-1-exposed seronegative persons.
Rare individuals who are repeatedly exposed to HIV-1 through unprotected sexual contact fail to acquire HIV-1 infection. These persons represent a unique study population to evaluate mechanisms by which HIV-1 replication is either prevented or controlled. We followed longitudinally a group of healthy HIV-1 seronegative persons each reporting repeated high-risk sexual activities with their HIV-1-infected partner at enrollment. The volunteers were primarily (90%) male homosexuals, maintaining high risk activities with their known infected partner (45%) or multiple other partners (61%). We evaluated the quantity and specificity of HIV-1-specific T cells in 31 exposed seronegatives (ES) using a IFN-gamma ELISPOT assay to enumerate T cells recognizing epitopes within HIV-1 Env, Gag, Pol and Nef. PBMC from only three of the 31 volunteers demonstrated ex vivo HIV-1-specific IFN-gamma secretion, in contrast to nearly 30% exhibiting cytolytic responses in previous studies. These findings suggest that if T cell responses in ES are induced by HIV-1 exposure, the frequency is at low levels in most of them, and below the level of detection using the ELISPOT assay. Alternative approaches to improve the sensitivity of detection may include use of dendritic cells as antigen-presenting cells in the ex vivo assay and more careful definition of the risk behavior and extent of HIV-1 exposure in conjunction with the evaluation of T cell responses.
CD8-Positive T-Lymphocytes↗
Mitochondrial membrane sensitivity to depolarization in acute myeloblastic leukemia is associated with spontaneous in vitro apoptosis, wild-type TP53, and vicinal thiol/disulfide status.
Nonresponse to remission-induction chemotherapy, which remains a major problem in acute myeloblastic leukemia (AML), has been linked to cellular resistance to apoptosis. Because the apoptosis induced by chemotherapeutic drugs is mediated by loss of mitochondrial transmembrane potential (MTP), it was postulated that sensitivity to mitochondrial membrane depolarization might be heterogeneous in AML. Using the uncoupling agent carbonyl cyanide m-chlorophenylhydrazone (mClCCP), the mitochondrial membrane sensitivity to depolarization (mClCCP concentrations that inhibit 50% of the transmembrane potential [IC(50)]) in AML blasts was measured and demonstrated marked interclonal heterogeneity, with the existence of comparatively sensitive (median mClCCP IC(50), 4 microM) and resistant (median mClCCP IC(50), 10 microM) clones. Furthermore, the mClCCP IC(50) was inversely associated with spontaneous in vitro apoptosis (P =.001). It was high in cases with mutant TP53 and correlated with the total cellular level of the multidrug resistance-associated protein (P =.019) but not of bcl-2, bax, or bcl-x. It was also found that the dithiol oxidant diamide, in contrast to the monovalent thiol oxidant diethyl maleate, increased the sensitivity of mitochondrial membranes to mClCCP. To confirm that TP53 directly affects MTP in leukemic cells and to establish the role of vicinal thiol oxidation in the TP53-dependent pathway, CEM 4G5 leukemia cells with forced, temperature-dependent expression of TP53 were studied. Monobromobimane, which inhibits mitochondrial membrane depolarization by preventing dithiol cross-linking, inhibited depolarization and apoptosis in 4G5 cells. It was concluded that in leukemia, TP53 and vicinal thiol/disulfide status are determinants of mitochondrial membrane sensitivity to depolarization, which is in turn associated with spontaneous apoptosis.
Apoptosis↗
Respiratory virus infections after stem cell transplantation: a prospective study from the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation.
Community-acquired respiratory virus infections are a cause of mortality after stem cell transplantation (SCT). A prospective study was performed at 37 centers to determine their frequency and importance. Additional cases were also collected to allow the analysis of risk factors for severe infection. Forty episodes were collected in the prospective study and 53 additional episodes through subsequent case collection. The frequency of documented respiratory virus infections was 3.5% among 819 allogeneic and 0.4% among 1154 autologous SCT patients transplanted during the study period. The frequency of lower respiratory tract infections (LRTI) was 2.1% among allogeneic and 0.2% among autologous SCT patients. The mortality within 28 days from diagnosis of a respiratory viral infection was 1.1% among allogeneic SCT while no autologous SCT patient died. The deaths of five patients (0.6%) were directly attributed to a respiratory virus infection (three RSV; two influenza A). On multivariate analysis, lymphocytopenia increased the risk for LRTI (P = 0.008). Lymphocytopenia was also a significant risk factor for LRTI in patients with RSV infections. The overall mortality in RSV infection was 30.4% and the direct RSV-associated mortality was 17.4%. For influenza A virus infection, the corresponding percentages were 23.0% and 15.3%. This prospective study supports the fact that community-acquired respiratory virus infections cause transplant-related mortality after SCT.
Adolescent↗
Women's health after plastic surgery.
BACKGROUND: Allegations that exposure to endogenous silicone, especially related to breast implants, might be causally related to connective tissue disease originated from case studies. More recent comparative studies have implied no such increased risk. The aims of the present study were to compare the prevalence and/or incidence of autoimmune and connective tissue disorders in a population-based cohort of female Sydney residents stratified by augmentation mammoplasty status. METHODS: In this population-based retrospective cohort study, the health status of female Sydney residents who had augmentation mammoplasty for cosmetic reasons between 1979 and 1983 was compared with that of female Sydney residents who had non-silicone-associated plastic surgery over the same period. Both groups were matched for age (+/- 5 years), year of plastic surgery (+/- 2 years), plastic surgeon, anaesthetist and mode of anaesthesia. Outcome measures comprised rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, sicca symptoms polymyositis/ dermatomyositis, connective tissue disease overlap, digital vasospasm, abnormal nailfold capillaroscopy, elevated antinuclear antibody titre, carpal tunnel syndrome, tendonitis, osteoarthritis, psoriatic arthritis, livedo reticularis, thyroid disease, multiple sclerosis, axillary lymphadenopathy, fibromyalgia and breast carcinoma. RESULTS: There was no difference in the occurrence of connective tissue diseases or connective tissue disease-related parameters, thyroid disorders, fibromyalgia or multiple sclerosis between cohorts. However, axillary adenopathy and low titre positive antinuclear antibody (ANA) occurred with a significantly greater frequency in the exposed cohort (odds ratio (OR) = 3.50, 95% confidence interval (CI) = 2.10-5.84 and OR = 1.29, 95% CI = 1.03-1.62, respectively). Axillary adenopathy correlated with capsular contracture (relative risk (RR) = 2.07, 95% CI = 1.22-3.51) and also the self-reported development of digital vasospasm (RR = 3.20, 95% CI = 1.46-7.03) after breast augmentation. CONCLUSIONS: No association was found between augmentation mammoplasty exposure and various connective tissue diseases and/or their related features. However, axillary adenopathy and low titre ANA were detected more frequently in the exposed cohort. Women with axillary adenopathy were more likely to have breast capsular contracture and report digital vasospasm post-dating surgery. Given comparable frequencies of higher titre ANA of both cohorts, the finding of elevations of low titre ANA is of dubious clinical significance.
Adult↗
P-glycoprotein plays a drug-efflux-independent role in augmenting cell survival in acute myeloblastic leukemia and is associated with modulation of a sphingomyelin-ceramide apoptotic pathway.
P-glycoprotein (pgp), which is the product of the MDR1 (multidrug resistance-1) gene, has an established role as a mediator of cytotoxic drug resistance in acute myeloid leukemia (AML). To study the role of pgp in mediating apoptosis resistance in AML cells deprived of serum and growth factors, apoptosis was quantified by flow cytometry using uptake of the dye 7-amino-actinomycin D (7-AAD) alongside low forward scatter. In pgp+ve primary AML samples, there was a significant increase in apoptosis in the presence of the pgp-specific antibody UIC2 (mean increase: 58%; range: 11%-95%; P <. 05). Likewise, apoptosis in growth factor-deprived TF1 cells cultured for 30 hours increased 2.5-fold in the presence of 25 microg/mL UIC2. The pgp reversal agent PSC-833 (1 micromol/L) augmented in vitro apoptosis by a median of 52% in pgp+ve patient samples and to a comparable degree in 6 pgp-ve samples. To determine whether the sphingomyelin-ceramide (SM-ceramide) pathway of apoptosis occurs in AML blasts in response to cytotoxic drugs, cells were incubated with daunorubicin at the patient-specific IC(30) (the concentration of daunorubicin that caused apoptotic cell death in 30% of cells) in the presence of the ceramide synthase inhibitor fumonisin B1, which inhibited apoptosis by 18%-81% (median: 40%). Exogenous SM failed to augment apoptosis induced by growth factor withdrawal in pgp+ve TF1 cells and was significantly more effective at augmenting apoptosis in pgp-ve patient blasts (median increase in cell death: 33%; range: 19%-88%) than in pgp+ve samples (median: 7%; range: 0%-27%; P =.028). Cellular accumulation of exogenous SM was associated with apoptosis and also occurred in nonapoptotic patient cells treated with PSC-833. However, this effect was not seen following treatment with the UIC2 antibody. These results indicate that pgp is able to exert a protective effect on AML cell viability and that this is associated with a reduced effect of exogenous SM on apoptosis. The pgp reversal agent PSC-833 acts, at least in part, by a pgp independent mechanism to alter SM distribution and to augment apoptosis induced in AML cells by serum and growth factor withdrawal. (Blood. 2000;95:2897-2904)
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Allogeneic haemopoietic stem cell transplantation for multiple myeloma or plasma cell leukaemia using fractionated total body radiation and high-dose melphalan conditioning.
We have evaluated the outcome of allogeneic haemopoietic stem cell transplantation for multiple myeloma using a conditioning regimen comprising fractionated total body irradiation and high-dose melphalan (110 mg/m2). The study comprised 25 patients (median age 49 years) who had been transplanted by either bone marrow (n = 13) or G-CSF mobilized peripheral blood stem cells (n = 12). Overall transplant-related mortality was 30% but was lower for patients < 50 years of age at transplant (21%). The main cause of treatment-related mortality was viral infection. Of the 19 patients evaluable post-transplant, 17 have so far achieved complete remissions. Currently, with a median follow-up of 3.4 years, 18 out of 25 patients are alive, of whom 15 are in continuing complete remission (CR) and 2 in second remission after suffering localized relapses, which were treated with radiotherapy and donor leucocyte infusions. Patients transplanted after 1 line of previous therapy, < 50 years of age and receiving peripheral blood stem cells (PBSC) rather than bone marrow (BM) had a superior outcome, although there was no statistically significant factor. We conclude that allogeneic transplantation should be considered as a potentially curative option for younger patients with myeloma and that the regimen using fractionated total body irradiation and melphalan has a high CR rate and a relatively low risk of treatment-related mortality, particularly in younger patients.
Adult↗
Reducing errors by increasing legibility.
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Adverse Drug Reaction Reporting Systems↗