Fludarabine, cyclophosphamide, antithymocyte globulin, with or without low dose total body irradiation, for alternative donor transplants, in acquired severe aplastic anemia: a retrospective study from the EBMT-SAA working party

Background

We analyzed the outcome of 100 patients with acquired severe aplastic anemia undergoing an alternative donor transplant, after immune suppressive therapy had failed.

Design and Methods

As a conditioning regimen, patients received either a combination of fludarabine, cyclophosphamide, and antithymocyte globulin (n=52, median age 13 years) or this combination with the addition of low dose (2 Gy) total body irradiation (n=48, median age 27 years).

Results

With a median follow-up of 1665 and 765 days, the actuarial 5-year survival was 73% for the group that received fludarabine, cyclophosphamide, and antithymocyte globulin and 79% for the group given the conditioning regimen including total body irradiation. Acute graft-versus-host disease grade III–IV was seen in 18% and 7% of the groups, respectively. Graft failure was seen in 17 patients with an overall cumulative incidence of 17% in patients receiving conditioning with or without total body irradiation: 9 of these 17 patients survive in the long-term. The most significant predictor of survival was the interval between diagnosis and transplantation, with 5-year survival rates of 87% and 55% for patients grafted within 2 years of diagnosis and more than 2 years after diagnosis, respectively (P=0.0004). Major causes of death were graft failure (n=7), post-transplant-lymphoproliferative-disease (n=4) and graft-versus-host disease (n=4).

Conclusions

This study confirms positive results of alternative donor transplants in patients with severe aplastic anemia, the best outcomes being achieved in patients grafted within 2 years of diagnosis. Prevention of rejection and Epstein-Barr virus reactivation may further improve these results.     

Analysis of aluminium content and iron homeostasis in nipple aspirate fluids from healthy women and breast cancer-affected patients

Aluminium is not a physiological component of the breast but has been measured recently in human breast tissues and breast cyst fluids at levels above those found in blood serum or milk. Since the presence of aluminium can lead to iron dyshomeostasis, levels of aluminium and iron‐binding proteins (ferritin, transferrin) were measured in nipple aspirate fluid (NAF), a fluid present in the breast duct tree and mirroring the breast microenvironment. NAFs were collected noninvasively from healthy women (NoCancer; n = 16) and breast cancer‐affected women (Cancer; n = 19), and compared with levels in serum (n = 15) and milk (n = 45) from healthy subjects. The mean level of aluminium, measured by ICP‐mass spectrometry, was significantly higher in Cancer NAF (268.4 ± 28.1 μg l^?1; n = 19) than in NoCancer NAF (131.3 ± 9.6 μg l^?1; n = 16; P < 0.0001). The mean level of ferritin, measured through immunoassay, was also found to be higher in Cancer NAF (280.0 ± 32.3 μg l^?1) than in NoCancer NAF (55.5 ± 7.2 μg l^?1), and furthermore, a positive correlation was found between levels of aluminium and ferritin in the Cancer NAF (correlation coefficient R = 0.94, P < 0.001). These results may suggest a role for raised levels of aluminium and modulation of proteins that regulate iron homeostasis as biomarkers for identification of women at higher risk of developing breast cancer. The reasons for the high levels of aluminium in NAF remain unknown but possibilities include either exposure to aluminium‐based antiperspirant salts in the adjacent underarm area and/or preferential accumulation of aluminium by breast tissues. Copyright © 2011 John Wiley & Sons, Ltd.     

Aripiprazole versus haloperidol in combination with clozapine for treatment-resistant schizophrenia in routine clinical care: a randomized, controlled trial

This multisite study was conducted to compare the efficacy and tolerability of combination treatment with clozapine plus aripiprazole versus combination treatment with clozapine plus haloperidol in patients with schizophrenia who do not have an optimal response to clozapine. Patients continued to take clozapine and were randomly assigned to receive daily augmentation with aripiprazole or haloperidol. Physicians prescribed the allocated treatments according to usual clinical care. Withdrawal from allocated treatment within 3 months was the primary outcome. Secondary outcomes included severity of symptoms on the Brief Psychiatric Rating Scale and antipsychotic subjective tolerability on the Liverpool University Neuroleptic Side Effect Rating Scale. A total of 106 patients with schizophrenia were randomly assigned to treatment. After 3 months, we found no difference in the proportion of patients who discontinued treatment between the aripiprazole and haloperidol groups (13.2% vs 15.1%, P = 0.780). The 3-month change of the Brief Psychiatric Rating Scale total score was similar in the aripiprazole and haloperidol groups (-5.9 vs -4.4 points, P = 0.523), whereas the 3-month decrease of the Liverpool University Neuroleptic Side Effect Rating Scale total score was significantly higher in the aripiprazole group than in the haloperidol group (-7.4 vs -2.0 points, P = 0.006). These results suggest that augmentation of clozapine with aripiprazole offers no benefit with regard to treatment withdrawal and overall symptoms in schizophrenia compared with augmentation with haloperidol. However, an advantage in the perception of adverse effects with aripiprazole treatment may be meaningful for patients.     

Anxiety-like behaviour in mice exposed to tannery wastewater: The effect of photoelectrooxidation treatment

The leather industry is a major producer of wastewaters and releases large quantities of many different chemical agents used in hide processing into the environment. Since the central nervous system is sensitive to many different contaminants, our aim was to investigate the neurobehavioral effects of exposure of mice to tannery effluents using animal models of depression and anxiety, namely forced swim and elevated plus-maze. In order to propose a clean technology for the treatment of this effluent, we also investigated the exposure of mice to effluents treated by photoelectrooxidation process (PEO). Adult male Swiss albino mice (CF1 strain) were given free access to water bottles containing an effluent treated by a tannery (non-PEO) or PEO-treated tannery wastewater (0.1 and 1% in drinking water). Exposure to tannery wastewater induced behavioural changes in the mice in elevated plus-maze. Exposure to non-PEO 1% decreased the percentage of time spent in the open arms, indicating anxiety-like behaviour. Exposure to tannery wastewater did not alter immobility time in the forced swim test, suggesting that tannery effluents did not induce depression-like behaviour in the mice. These behavioural data suggest that non-PEO tannery effluent has an anxiogenic effect, whereas PEO-treated tannery effluents do not alter anxiety levels.     

CB1 and CB2 receptor agonists promote analgesia through synergy in a murine model of tumor pain

In light of the adverse side-effects of opioids, cannabinoid receptor agonists may provide an effective alternative for the treatment of cancer pain. This study examined the potency and efficacy of synthetic CB1 and CB2 receptor agonists in a murine model of tumor pain. Intraplantar injection of the CB1 receptor agonist arachidonylcyclopropylamide (ED(50) of 18.4 μg) reduced tumor-related mechanical hyperalgesia by activation of peripheral CB1 but not CB2 receptors. Similar injection of the CB2 receptor agonist AM1241 (ED50 of 19.5 μg) reduced mechanical hyperalgesia by activation of peripheral CB2 but not CB1 receptors. Both agonists had an efficacy comparable with that of morphine (intraplantar), but their analgesic effects were independent of opioid receptors. Isobolographic analysis of the coinjection of arachidonylcyclopropylamide and AM1241 determined that the CB1 and CB2 receptor agonists interacted synergistically to reduce mechanical hyperalgesia in the tumor-bearing paw. These data extend our previous findings that the peripheral cannabinoid receptors are a promising target for the management of cancer pain and mixed cannabinoid receptor agonists may have a therapeutic advantage over selective agonists.     

In vitro approach to assess the potential for risk of idiosyncratic adverse reactions caused by candidate drugs

Idiosyncratic adverse drug reactions (IADRs) in humans can result in a broad range of clinically significant toxicities leading to attrition during drug development as well as postlicensing withdrawal or labeling. IADRs arise from both drug and patient related mechanisms and risk factors. Drug related risk factors, resulting from parent compound or metabolites, may involve multiple contributory mechanisms including organelle toxicity, effects related to compound disposition, and/or immune activation. In the current study, we evaluate an in vitro approach, which explored both cellular effects and covalent binding (CVB) to assess IADR risks for drug candidates using 36 drugs which caused different patterns and severities of IADRs in humans. The cellular effects were tested in an in vitro Panel of five assays which quantified (1) toxicity to THLE cells (SV40 T-antigen-immortalized human liver epithelial cells), which do not express P450s, (2) toxicity to a THLE cell line which selectively expresses P450 3A4, (3) cytotoxicity in HepG2 cells in glucose and galactose media, which is indicative of mitochondrial injury, (4) inhibition of the human bile salt export pump, BSEP, and (5) inhibition of the rat multidrug resistance associated protein 2, Mrp2. In addition, the CVB Burden was estimated by determining the CVB of radiolabeled compound to human hepatocytes and factoring in both the maximum prescribed daily dose and the fraction of metabolism leading to CVB. Combining the aggregated results from the in vitro Panel assays with the CVB Burden data discriminated, with high specificity (78%) and sensitivity (100%), between 27 drugs, which had severe or marked IADR concern, and 9 drugs, which had low IADR concern, we propose that this integrated approach has the potential to enable selection of drug candidates with reduced propensity to cause IADRs in humans.