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Purpose: The detection of galactomannan in serum is a cornerstone for the diagnosis of invasive fungal disease (IFD). Because a delay in treatment initiation is associated with a poor outcome, the results have to be available promptly. However, due to methodological and economic reasons, the test frequencies of the commonly used galactomannan assays vary between daily to weekly, meaning that results may be available too late to be clinically useful. The novel Aspergillus lateral-flow device ( Aspergillus-LFD) is a rapid test that may overcome these limitations. Methods: We compared the diagnostic performance of the Aspergillus-LFD and the Platelia ®Aspergillus EIA (GM-EIA) in serum from 101 patients during and after allogeneic haematopoietic stem cell transplantation (HSCT). Clinical data and sera were collected prospectively and patients classified according to the European Organisation for Research and Treatment of Cancer (EORTC)/Mycoses Study Group (MSG) 2008 guidelines. Results: By the end of hospitalisation, one proven, nine probable and 20 possible cases of IFD were identified. Depending on the number of positive serum samples required for test positivity, the sensitivities, specificities and diagnostic odds ratios in patients with proven and probable IFD were as follows. One positive serum required: Aspergillus-LFD 40.0 %, 86.8 % and 3.03; GM-EIA 40.0 %, 89.0 % and 3.64. Two positive sera required: Aspergillus-LFD 20.0 %, 97.8 % and 11.13; GM-EIA 30.0 %, 98.9 % and 38.57. Although the GM-EIA was positive in a higher percentage of samples, this did not result in an earlier diagnosis. Conclusions: If used as a screening test (one positive serum required for test positivity) or to rule out IFD, the Aspergillus-LFD has shown a comparable diagnostic performance to the GM-EIA. However, if the results have to be confirmed by a second positive serum, the GM-EIA exhibited superior sensitivity. In terms of practicability, the Aspergillus-LFD has demonstrated to be a quick (15 min) and easy-to-use test for single-patient detection of Aspergillus antigens. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic cell transplantation (allo-HCT) of older or patients with comorbidities has become possible due to new regimens for reduced-intensity conditioning. The use of fludarabine, carmustine and melphalan as the preparative regimen (FBM) reduces toxicity while providing substantial anti-leukemic activity. Chronic GVHD (cGVHD) of the lung or bronchiolitis obliterans syndrome (BOS) remains a serious non-infectious complication contributing to treatment-related morbidity. We conducted a retrospective analysis of 259 patients (median age: 61.5, range: 24-76 years) transplanted after FBM conditioning to identify and characterize clinical risk factors for developing BOS. The cumulative incidence rate of BOS was 4.2% (95% confidence interval (CI): 2.4-7.6%) at 1 year and 8.5% (95% CI: 5.6-12.9%) at 5 years after allo-HCT with a median follow-up of 36.5 (range: 3-136) months. In multivariate analysis, age <55 years at allo-HCT (who received 25% higher carmustin-dose in preparative regimen), pulmonary complications after allo-HCT and GVHD prophylaxis without in-vivo T-cell depletion (cyclosporine-A/ATG or cyclosporine-A/alemtuzumab) were associated with BOS. We observed no significant differences in clinical variables such as smoking or lung diseases before allo-HCT. In contrast to cGVHD affecting other organs, BOS showed no impact on overall survival. In conclusion, we identified risk factors associated with developing BOS after conditioning with a reduced toxicity protocol. [ABSTRACT FROM AUTHOR]

A second allograft was offered to 58 relapsed AML patients after conditioning with fludarabine 90-150 mg/m2 and thiotepa 15 mg/kg, in most cases with active disease. Median age was 53 years (range 23-69), median time to relapse after the first allo-SCT was 326 (47-2189) days and median follow-up was 6.7 years. GVHD prophylaxis consisted mainly of CsA and alemtuzumab. Response rates at 1 month were CR in 50 and persistent disease in 3/53 evaluable patients. At 3 years, the relapse incidence (95% confidence interval) was 56 (45-71)%, the TRM 31 (21-46)%, the OS rate was 18 (9-29)% and the EFS rate was 13 (5-23)%. OS improved with younger patient age, longer relapse-free interval after the first allo-SCT and the development of chronic GVHD. Patients 65 years old who relapsed >12 months after the first allograft (n=20) had a 3-year OS rate of 41 (19-62)%. Conventional cytogenetics and FLT3 mutation status did not affect outcome. Our regimen is feasible and provides at least for a subgroup of patients with AML recurrence after allo-SCT a reasonable therapeutic option in an otherwise fatal situation. Further modifications and a better understanding of the underlying biology could help lower the risk of relapse. [ABSTRACT FROM AUTHOR]

There are few longitudinal data on nutritional status and body composition of patients undergoing allogeneic hematopoietic cell transplantation (alloHCT). We assessed nutritional status of 105 patients before alloHCT and its course during the early post-transplant period to day +30 and day +100 via weight history, body mass index (BMI) normalized for gender and age, Subjective Global Assessment, phase angle normalized for gender, age, and BMI, and fat-free and body fat masses. Furthermore, we present a multivariate regression model investigating the impact of factors on body weight. At admission, 23.8% reported significant weight losses (>5%) in the previous 6 months, and we noted 31.5% with abnormal age- and sex-adjusted BMI values (10th, 90th percentiles). BMI decreased significantly (P<0.0001) in both periods by 11% in total, meaning a weight loss of 8.6±5.7 kg. Simultaneously, the patients experienced significant losses (P<0.0001) of both fat-free and body fat masses. Multivariate regression model revealed clinically relevant acute GVHD (parameter estimate 1.43; P=0.02) and moderate/severe anorexia (parameter estimate 1.07; P=0.058) as independent factors influencing early weight loss. In conclusion, our results show a significant deterioration in nutritional status during the early post-transplant period. Predominant alloHCT-associated complications such as anorexia and acute GVHD became evident as significant factors influencing nutritional status. [ABSTRACT FROM AUTHOR]

Chemotherapy and/or radiotherapy used as conditioning regimens before autologous or allogeneic haematopoietic cell transplantations (HCTs) cause neutropenia, which is the main reason for bloodstream infections. Autologous HCTs are considered to be superior to allogeneic HCTs in terms of infection outcome. A previous analysis suggested that patients with allogeneic HCTs are exposed to a reduced infection hazard and that an unfavourable infection outcome of allogeneic HCTs may be mediated through prolonged neutropenia. Therefore, we investigated whether allogeneic HCTs initially lead to fewer infections. We evaluated data from a prospective non-randomized multi-centre cohort study, with a total of 1616 patients. Of these, 703 patients received autologous and 913 patients received allogeneic HCTs from January 2000 to June 2004. The retrospective analysis used simultaneous confidence bands for the cumulative infection probability in the presence of competing risks. Patients with allogeneic HCTs experienced fewer infections during the early phase of neutropenia. As patients with autologous HCTs are not necessarily subject to antibiotic prophylaxis, a future study should investigate this policy. A limitation of the analysis is that it did not find the effect of crossing cumulative infection probabilities to be significant. [ABSTRACT FROM AUTHOR]

Background Despite advances in immunosuppressive therapy, up to 10% of patients with severe Crohn's disease ( CD) remain refractory to conventional treatment. Limited evidence from pilot trials suggests that high-dose immunosuppression and autologous peripheral blood stem cell transplantation (auto PBSCT) may induce remission in these patients, but there is substantial controversy regarding the safety and efficacy of this approach. Aim To address this issue, a monocentre phase I/ II trial of auto PBSCT was performed in patients with refractory CD in our hospital. Methods Here, we report on the outcome of 12 patients with refractory CD treated with auto PBSCT. Briefly, CD34+-selected PBSCs were harvested after mobilisation therapy with cyclophosphamide and granulocyte-colony stimulating factor. Later, immunoablative conditioning therapy with high-dose cyclophosphamide followed by auto PBSCT was applied and clinical and endoscopic responses were analysed after a mean follow-up of 3.1 years (range 0.5-10.3 years). Results PBSC harvest following mobilisation chemotherapy was successful in 11/12 patients and resulted in a clinical and endoscopic improvement in 7/12 patients. Subsequent conditioning and auto PBSCT were performed in nine patients and were relatively well tolerated. Among those, five patients achieved a clinical and endoscopic remission within 6 months after auto PBSCT. However, relapses occurred in 7/9 patients during follow-up, but disease activity could be controlled by low-dose corticosteroids and conventional immunosuppressive therapy. Conclusion Immunoablation by cyclophosphamide and autologous peripheral blood stem cell transplantation is safe and effective to induce remission of refractory Crohn's disease, and should be further evaluated in randomised controlled trials. [ABSTRACT FROM AUTHOR]

Hypovitaminosis D (<30 ng/ml) is highly prevalent in allogeneic hematopoietic cell transplantation (alloHCT), but the relevance of influencing factors for serum 25-hydroxyvitamin D(3) [25(OH)D(3)] status in adult patients remains unknown. We are the first to have prospectively assessed 25(OH)D(3) status and its influencing factors in 102 patients before and at days +30 and +100 after alloHCT. Among others, we evaluated age, gender, weight, fat mass, season, sun exposure habits, and dietary and supplemental vitamin D intake as factors potentially influencing baseline vitamin D status in uni- and multivariate linear regression analysis. Furthermore, we investigated the impact of changes in fat mass, duration of parenteral nutrition, and acute graft-versus-host disease (aGVHD) on the course of serum 25(OH)D(3). Baseline 25(OH)D(3) concentrations were 16.4 ± 8.9 ng/ml, revealing that the majority (89%) had concentrations beneath the normal range. In multivariate linear regression model, only higher body fat mass remained an independent risk factor for reduced baseline 25(OH)D(3) concentrations (P = 0.007). In the early post-transplant period, 25(OH)D(3) status remained low, revealing a tendency to further deterioration, especially in patients with corticosteroid-treated aGVHD (≥II). Reduced vitamin D status was very common in these patients before and after alloHCT, whereby the most important influencing factors, namely season and dietary factors seem to have little impact. Our findings suggest that monitoring and if necessary, correcting vitamin D status may be indicated at regular intervals before alloHCT and during long-term follow-up. Further investigations of these patients' vitamin D requirements are needed, especially if they are on long-term corticosteroids. [ABSTRACT FROM AUTHOR]

The benefit of survival at the expense of new GVHD after DLI for acute leukemia following human allogeneic hematopoietic cell transplantation (allo-HCT) remains a matter of controversy. The detection of biological markers predicting this outcome would be an enormous breakthrough. The purpose of this study was the analysis of CT60 single-nucleotide polymorphism (SNP) of the CTLA-4 T-regulatory gene as a surrogate marker for DLI outcome in this difficult setting. Using Pyrosequencing, we genotyped the alleles of the CT60 SNP of 79 DLI donors and correlated them with the post-DLI outcome of their matching recipients. The presence of a donor 'AA' or 'AG' CT60 genotype vs a 'GG' genotype was an independent factor for remaining in complete chimerism/remission post-DLI (odds ratio (OR) 2.61 vs 0.42, respectively, P=0.05). Further, in cases with evident post-DLI allo-reactivity the importance of an 'AA' or 'AG' vs a 'GG' genotype gained significance for ongoing complete chimerism (OR 4.35 vs 0.32, P=0.03). Neither alterations in cumulative DLI dose nor any other clinical parameter significantly weakened the importance of CT60 SNP. Our results provide evidence for the necessity of genotyping CT60 SNP prior to DLI administration in patients with acute leukemia. [ABSTRACT FROM AUTHOR]

Diagnosis of acute intestinal GVHD (aGVHD) following allogeneic hematopoietic cell transplantation is based on clinical symptoms and histological lesions. This retrospective analysis aimed to validate the 'Freiburg Criteria' for the endoscopic grading of intestinal aGVHD. Grade 1: no clear-cut criteria; grade 2: spotted erythema; grade 3: aphthous lesions; and grade 4: confluent defects, ulcers, denudation of the mucosa. Having excluded patients with infectious diarrhea, we evaluated 175 consecutive patients between January 2001 and June 2009. Setting a cutoff between grade 1 (no change in therapy) and grade 2 (intensification of immunosuppression), macroscopy had a sensitivity of 89.2% (95% confidence interval (CI): 80.4-94.9%), a specificity of 79.4% (95% CI: 69.6-87.1%), a positive-predictive value of 79.6% (95% CI: 70.0-87.2%) and a negative-predictive value of 89.0% (95% CI: 80.2-94.9%). In all, 20% of patients with aGVHD in the lower gastrointestinal tract (GIT) had lesions only in the terminal ileum. In all patients with aGVHD 2 of the upper GIT, typical lesions were also found in the lower GIT. Ileo-colonoscopy showed the highest diagnostic yield for aGVHD. In conclusion, the 'Freiburg Criteria' for macroscopic diagnosis of intestinal aGVHD provide high accuracy for identifying aGVHD 2. [ABSTRACT FROM AUTHOR]

To evaluate safety and efficacy of donor lymphocyte infusions (DLI), derived from frozen aliquots of the original G-CSF-stimulated graft after allogeneic PBSCT from unrelated donors, data of 121 patients with hematological malignancies treated with DLIs were retrospectively analyzed. Indications for PBSCT were AML/myelodysplastic syndrome (n=63/8), ALL (n=17), lymphoma (n=13), multiple myeloma (n=10) and myeloproliferative syndrome (n=10). Reasons for DLI were hematological relapse (n=81), molecular and/or cytogenetic relapse (n=5), mixed chimerism (n=22) and prophylactic DLI in high-risk patients (n=13). DLIs were well tolerated with no acute adverse reactions. DLI-induced acute-type GvHD (aGvHD) was observed in 19 patients and chronic-type GvHD (cGvHD) developed in 14 patients. Three patients died of GvHD complications. DLI induced CR, complete chimerism or PR in 34 patients; 24 patients had stable disease, 50 patients progressed and 13 patients were not evaluable for response. Objective response was more obvious for molecular relapse (5/5) or mixed chimerism (14/22) compared with hematological relapse (13/81). Median survival after first DLI was 10.4 months (95% confidence interval: 4.4-26.0). Cryopreserved G-CSF-stimulated DLI, derived from allogeneic grafts are safe and immunoreactive, and can be applied early in case of mixed chimerism and molecular or cytogenetic relapse. [ABSTRACT FROM AUTHOR]

This consensus statement established under the auspices of the German working group on BM and blood stem cell transplantation (DAG-KBT), the German Society of Hematology and Oncology (DGHO), the Austrian Stem Cell Transplant Working Group, the Swiss Blood Stem Cell Transplantation Group (SBST) and the German-Austrian Pediatric Working Group on SCT (Päd-Ag-KBT) summarizes current evidence for diagnosis, immunosuppressive and supportive therapy to provide practical guidelines for the care and treatment of patients with pulmonary manifestations of chronic GVHD (cGVHD). Pulmonary cGVHD can present with obstructive and/or restrictive changes. Disease severity ranges from subclinical pulmonary function test (PFT) impairment to respiratory insufficiency with bronchiolitis obliterans being the only pulmonary complication currently considered diagnostic of cGVHD. Early diagnosis may improve clinical outcome, and regular post-transplant follow-up PFTs are recommended. Diagnostic work-up includes high-resolution computed tomography, bronchoalveolar lavage and histology. Topical treatment is based on inhalative steroids plus beta-agonists. Early addition of azithromycin is suggested. Systemic first-line treatment consists of corticosteroids plus, if any, continuation of other immunosuppressive therapy. Second-line therapy and beyond includes extracorporeal photopheresis, mammalian target of rapamycin inhibitors, mycophenolate, etanercept, imatinib and TLI, but efficacy is limited. Clinical trials are urgently needed to improve understanding and treatment of this deleterious complication. [ABSTRACT FROM AUTHOR]

WUENSCH A., GOELZ T., BERTZ H., WIRSCHING M. & FRITZSCHE K. (2010) European Journal of Cancer Care 20, 570-576 Disclosing information about randomised controlled trials in oncology: training concept and evaluation of an individualised communication skills training for physicians COM-ON-rct When physicians disclose information about randomised controlled trials, they have to balance the requirements of conducting high standard research and the respect for patients' rights. Physicians need training in this difficult matter. An individualised communication skills training (CST) about randomised controlled trials for oncologists has been developed. The aim of this publication is to describe the concept of our CST and present data of evaluation by the participants: First, a theoretical introduction about a communication model and important ethical and legal issues was presented. Individual learning goals of participants were then derived through video assessment with actor-patients. The learning goals were the basis for practicing in role play. Individual coaching helped physicians to transfer the made experience into their daily work. Forty physicians have been trained. The acceptance of the training concept was assessed by a questionnaire consisting of 14 items and using a 6-point scale from 1 (very best) to 6 (very bad): the individualised CST was highly accepted (mean = 1.33). Practicing with actor-patients (mean = 1.4), providing constructive feedback (mean = 1.3) and assessing individual learning goals (mean = 1.85) were seen as helpful. Our CST trains physicians to realise best research standards and incorporate patients' rights. [ABSTRACT FROM AUTHOR]

Background/Objectives:Mushrooms contain very little or any vitamin D2 but are abundant in ergosterol, which can be converted into vitamin D2 by ultraviolet (UV) irradiation. Our objective was to investigate the bioavailability of vitamin D2 from vitamin D2-enhanced mushrooms by UV-B in humans, and comparing it with a vitamin D2 supplement.Subjects/Methods:Fresh mushrooms were irradiated with an UV-B dose of 1.5 J/cm2, increasing vitamin D2 content from <1 to 491 μg/100 g and made to an experimental soup. In this 5-week, single-blinded, randomized, placebo-controlled trial, 26 young subjects with serum 25-hydroxyvitamin D (25OHD) 50 nmol/l were randomly assigned into three groups ((a) mushroom, (b) supplement and (c) placebo). They received during winter (a) 28 000 IU (700 μg) vitamin D2 via the experimental soup, or (b) 28 000 IU vitamin D2 via a supplement or (c) placebo, respectively.Results:After 2 weeks, serum 25OHD was significantly higher in the mushroom than in the placebo group (P=0.001). The serum 25OHD concentrations in the mushroom and supplement groups rose significantly and similarly over the study period by 3.9 nmol/l (95% confidence interval (95% CI): 2.9, 4.8) and by 4.7 nmol/l per week (95% CI: 3.8, 5.7), respectively.Conclusions:We are the first to demonstrate in humans that the bioavailability of vitamin D2 from vitamin D2-enhanced button mushrooms via UV-B irradiation was effective in improving vitamin D status and not different to a vitamin D2 supplement. This trial was registered at http://germanctr.de as DRKS00000195. [ABSTRACT FROM AUTHOR]

Summary Supportive therapy plays a central role in the management of cutaneous and musculoskeletal manifestations of chronic graft-versus-host disease (cGVHD), either alone or in combination with systemic approaches. We present results from the German-Austrian-Swiss Consensus Conference on clinical practice in cGVHD, held in Regensburg, Germany, in November 2009. The intention was to achieve a consensus on current evidence-based treatment options as well as to provide guidelines for daily clinical practice. Skin is the most common organ involved in cGVHD. Its clinical presentation varies considerably. Patients may have pruritus, rash, pain, dyspigmentation and fibrotic or sclerodermatous lesions, often leading to contractures. Treatment options for supportive therapy in cutaneous cGVHD include topical therapies such as topical steroids and topical calcineurin inhibitors, as well as phototherapy and physiotherapy. The most relevant manifestation in musculoskeletal cGVHD is fasciitis which must be distinguished from sclerodermatous skin cGVHD. Physiotherapy is the mainstay of supportive treatment in fasciitis in cGVHD. Successful therapy of cutaneous and musculoskeletal cGVHD depends on interdisciplinary management to improve patients' quality of life. [ABSTRACT FROM AUTHOR]

Background Ethically, informed consent regarding randomised controlled trials (RCTs) should beunderstandable to patients. The patients can then give free consent or decline to participate in a RCT. Little is known about what patients really understand in consultations about RCTs. Methods Cancer patients who were asked to participate in a randomised trial were surveyed using a semistandardised interview developed by the authors. The interview addresses understanding, satisfaction and needs of the patients. The sample included eight patients who participated in a trial and two who declined. The data were analysed on the basis of Mayring's qualitative analysis. Results Patients' understanding of informed consent was less developed than anticipated, especially concerning key elements such as randomisation, content and procedure of RCTs. Analysing the result about satisfaction of the patients, most of the patients described their consultations as hectic and without advance notice. Health limitations due to cancer played a decisive role. However, most of the patients perceived their physician to be sympathetic. Analysing the needs of patients, they ask for a clear informed consent consultation with enough time and adequate advance notice. Conclusion This study fills an important empirical research gap of what is ethically demanded in an RCT consultation and what is really understood by patients. The qualitative approach enabled us to obtain new results about cancer patients' understanding of informed consent, to clarify patients' needs and to develop new ideas to optimise the informed consent. [ABSTRACT FROM AUTHOR]

There are limited data on the comparison of unrelated vs related peripheral blood-derived hematopoietic cell transplantation (HCT) in patients with AML and its implications in high-risk patients. In this single-center retrospective study, we report on a total of 92 consecutive patients with AML (n=87) or myelodysplastic syndrome (MDS; n=5), who were treated between 1996 and 2006 with a uniform preparative regimen of BU and CY and peripheral blood-derived HCT from related (n=46) or unrelated donors (n=46). At transplantation, 45 patients were in CR, 11 were untreated and 36 had relapsed or refractory disease. Median follow-up was 864 days after transplant (range 24–3798). At 5 years after HCT, cumulative incidences for relapse (32% of all patients) and nonrelapse mortality (NRM; 17%) were low. The 5-year relapse-free survival (RFS) and OS rates were 36 and 45% for related and 47 and 57% for unrelated patients, respectively (RFS P=0.43; OS P=0.28). High-risk patients with an unfavorable remission status before HCT benefited more from unrelated HCT than related HCT, showing a significantly better 5-year RFS of 46% (95% confidence interval (CI) 27–65) vs 22% (95% CI 4–40) (P=0.04). Unrelated HCT benefited high-risk AML patients with an unfavorable remission status better than related HCT. [ABSTRACT FROM AUTHOR]

Background Graft-versus-host disease (GvHD) occurs frequently after haematopoietic cell transplantation (HCT). Mucocutaneous lesions of GvHD may mimic bullous autoimmune dermatoses, and 10 cases of concurrent GvHD and a bullous autoimmune disease have been reported in the literature. Objective To determine the frequency of circulating antibodies to the cutaneous basement membrane zone (BMZ) in HCT patients with GvHD in comparison with HCT patients without GvHD, psoriasis patients and healthy controls. Subjects and methods We examined 42 patients with chronic GvHD, 18 HCT patients without GvHD, 11 psoriasis patients and 40 healthy controls, prospectively. Sera were tested by indirect immunofluorescence (IIF) on salt-split skin, NC16a-ELISA and immunoblot using keratinocyte extracts. Univariate statistical analyses and logistic regression were performed to assess possible correlations of graft and patient characteristics with the presence of BMZ antibodies. Results Circulating basement membrane zone (BMZ) antibodies were detected in 10/42 (24%) GvHD sera by immunoblot, but not in any of the HCT sera from patients without GvHD (0/18; 0%). The antibodies targeted collagen VII, BP230, collagen XVII/BP180 or p200/laminin γ1. Clinically manifest bullous autoimmune dermatoses (bullous pemphigoid or epidermolysis bullosa acquisita) were found in two GvHD patients. 1/11 (9%) psoriasis sera and 1/40 (2.4%) healthy control sera reacted with collagen XVII or BP230, respectively. Conclusions Circulating BMZ antibodies are significantly associated with chronic GvHD in contrast to uncomplicated HCT. Recurrent mucocutaneous lesions in chronic inflammatory skin disorders may liberate antigens, which may lead to production of BMZ antibodies, particularly in the context of GvHD-mediated reduced self-tolerance. [ABSTRACT FROM AUTHOR]

We have piloted a low-dose schedule of 5-azacytidine followed by donor lymphocyte infusions (DLIs) in patients with relapse of AML or chronic myelomonocytic leukemia (CMMoL) after allografting. Of the 26 patients (median age 62 years, range 28–75) with relapsed AML (n=24) or CMMoL (n=2), 11 (42%) had poor-risk cytogenetics. Twenty-three patients had received fludarabine-based reduced-toxicity conditioning regimens, and three had received conventional myeloablative conditioning. Patients received 5-azacytidine s.c., at a total daily dose of 100 mg, on days 1–3, to be followed by DLI on day 10, with the next course of treatment to be started on day 22. A total of 60 courses of 5-azacytidine were administered, with a median of 2 courses (range: 1–10). In 44 courses, 5-azacytidine was followed by DLI, and thus 19/26 (73%) patients received at least one course of this combined treatment. Clinically relevant neutropenic infections not associated with progressive disease developed in four patients, one of them succumbing to sepsis. Only two patients developed de novo acute GvHD after the combination of 5-azacytidine and DLI. Overall, 66% of the patients benefited from this treatment, with continued CRs achieved in 4 (16%) patients, lasting a median of 525 days (range: 450+ to 820+), and a 50% rate of temporary disease control with stable mixed chimerism (median duration 72 days). The median survival from the start of 5-azacytidine treatment was 136 days (range: 23 to 873+), with an estimated 2-year survival probability of 16%. In conclusion, this non-intensive outpatient regimen of 5-azacytidine followed by DLI is feasible, with a very low aGVHD rate. Objective responses, including continuous complete donor chimerism, occurred also in patients with poor-risk cytogenetics. [ABSTRACT FROM AUTHOR]

We hypothesized that chronic tissue stress due to interaction of alloreactive donor cells with host epithelium after allogeneic hematopoietic cell transplantation (allo-HCT) may cause genomic alterations. We therefore analyzed 176 buccal samples obtained from 71 unselected allotransplanted patients for microsatellite instability (MSI). MSI was observed in 52% of allotransplanted patients but never in 31 healthy or autotransplanted controls. The patient age, the donor age, a female-to-male transplantation and a low number of CD34+ cells in the graft were significantly correlated with genomic instability. There was a trend for increasing risk of MSI for patients who experienced severe graft-vs-host disease. Secondary malignancy was diagnosed in five (14%) of the MSI+ and only in one (3%) MSI− patient. In an in vitro model of mutation analysis we found significant induction of frameshift mutations and DNA strand breaks in HaCaT keratinocytes co-cultured with mixed lymphocyte cultures (MLCs) but not after their exposure to interferon-γ, tumor necrosis factor-α, transforming growth factor-β (TGF-β), MLC supernatant, peripheral blood mononuclear cells (PBMCs) or phytohemagglutinin-stimulated PBMC. A reactive oxygen species-mediated mechanism is implicated. The in vivo and in vitro data of our study show that alloreactions after allo-HCT may induce genomic alterations in epithelium. Progress in understanding DNA damage and repair after allo-HCT can potentially provide molecular biomarkers and therapeutic targets. [ABSTRACT FROM AUTHOR]

Earlier reports have shown a high mortality of invasive infection due to vancomycin-resistant Enterococcus faecium (VREF). Most of these studies have been conducted in US hospitals prior to the advent of newer VREF-active antimicrobials, and the reported poor outcomes have been explained by the limited choices for effective antimicrobial therapy. A total of 25 cases of invasive VREF infection were seen during an outbreak in a tertiary care hospital. Patient characteristics and outcomes were evaluated by a structured retrospective chart review and descriptive analysis. Severe underlying diseases such as leukemia not in remission (86%) were highly prevalent among patients with invasive VREF infection. Fifty-two percent of underlying diseases and/or comorbidities were considered according to the McCabe classification as rapidly fatal. Most patients had received high-dose cytotoxic chemotherapy, and many were neutropenic at the onset of VREF infection. Concomitant infection due to other organisms was found in 48% of the patients. All patients had received extensive antibiotic treatment prior to the onset of VREF infection. Resistance to linezolid was observed in four cases. Overall survival at day 30 was 48%. Four deaths were considered to be directly related to VREF infection. Invasive VREF infection during this outbreak was confined to patients with severe underlying comorbidity. The mortality of VREF infection remained high, despite treatment with newer VREF-active antibiotics such as linezolid and quinupristin–dalfopristin. [ABSTRACT FROM AUTHOR]

Novel, non-intensive treatment options in older MDS/AML patients planned for allografting, with the goal of down-staging the underlying disease and bridging time to transplantation, are presently being developed. 5-azacytidine and decitabine (DAC) are of particular interest, as they can be given repetitively, with very limited non-hematologic toxicity and result in responses both in MDS and AML even at low doses. We describe 15 consecutive patients (median age 69 years, range 60–75 years) with MDS (n=10) or AML (n=5) who all received first-line treatment with DAC and subsequent allografting (from sibling donor in four patients, unrelated donor in 11) after reduced-intensity conditioning with the FBM regimen. Successful engraftment was attained in 14/15 patients, all of whom achieved a CR, with a median duration of 5 months (range 1+ to 51+). Six of these 14 patients are alive (4 with complete donor chimerism), 8 have died either from relapse (n=4) or treatment-related complications while in CR (n=4). We conclude that allografting after low-dose DAC and subsequent conditioning with FBM is feasible, with no unexpected toxicities and appears as a valid alternative to standard chemotherapy (‘InDACtion instead of induction’) in elderly patients with MDS/AML. [ABSTRACT FROM AUTHOR]

We present a phase II study of fludarabine 5 × 30 mg/m2, thiotepa 3 × 5 mg/kg as preparative regimen specifically for allogeneic second haematopoietic stem cell transplantation (HCT) after failure of previous HCT. Forty-nine patients (median age 52 years, range 27–68) received an allogeneic second HCT after failed autologous (n=29) or allogeneic (n=20) HCT. Diagnoses were AML (n=18), ALL (n=3), multiple myeloma (n=11), lymphoma (n=16) and CML (n=1). GVHD prophylaxis consisted of CYA and mainly low dose alemtuzumab (40 mg). The median follow-up for patients alive is 528 days (range 217–1344). In 43 of 49 (88%) evaluable patients response rates were CR=19, PR=14 and SD=10 at one month. At one year, the probability (95% confidence interval) of relapse is 55.1 (38.2–72)% and the nonrelapse mortality (NRM) is 29 (14.2–44.4)%. Estimated survival at one year is 42.6 (28.7–56.6)% and event free survival is 38.1 (24.4–51.8)%. Survival was significantly better for patients experiencing relapse beyond one year, than for patients relapsing within one year from first transplantation (51.2 (33.5–68.9)% vs 27 (7–48.5)%; P=0.013). We conclude that this regimen is feasible and well tolerated for allogeneic second HCT.Bone Marrow Transplantation (2008) 41, 845–850; doi:10.1038/sj.bmt.1705989; published online 21 January 2008 [ABSTRACT FROM AUTHOR]

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Here we investigated the influence of parameters known before hematopoietic stem cell transplantation (HSCT) as well as the relevance of graft-versus-host disease (GvHD) and cytomegalovirus (CMV) reactivation on post transplant lymphocyte reconstitution in 148 patients treated in our institution between 1996 and 2003. Median patient age was 42 (19–68) years, HSCT followed standard high dose (n=91) or reduced-intensity conditioning regimens (n=57) with bone marrow (BM, n=67) or peripheral blood stem cells (PBSC, n=81) from related (n=71) or unrelated (n=77) donors. In the first months, we observed a partially faster reconstitution of CD3+4+, CD3+8+ and CD4+45RA+ T cells in patients following peripheral blood stem cell transplantation when compared to bone marrow transplantation. Prolonged CD3+4+ and CD4+45RA+ lymphopenia was noted after unrelated donor HSCT and GvHD prophylaxis containing anti-T-lymphocyte globulin. Lymphocyte subset counts in patients older than the median age were comparable to those in patients transplanted at a younger age and not influenced by the conditioning regimen. CD3+8+ T cell reconstitution was strongly correlated with CMV reactivation, but not significantly affected by CMV serostatus before HSCT. Incidence or extent of GvHD did not significantly influence lymphocyte reconstitution. Therefore, the source of graft is the most predictive parameter in early lymphocyte reconstitution, but the differences in lymphocyte recovery completely resolved within the first year after HSCT.Bone Marrow Transplantation (2007) 39, 613–622. doi:10.1038/sj.bmt.1705648; published online 26 March 2007 [ABSTRACT FROM AUTHOR]

The purpose of this study was to analyse risk factors for blood stream infection (BSI) and pneumonia in neutropenic patients who have undergone peripheral blood stem-cell transplantation (PBSCT). Data were taken from the ONKO-KISS multicenter surveillance project. Infections were identified using CDC definitions (laboratory-confirmed BSI) and modified criteria for pneumonia in neutropenic patients. The multivariate analysis was performed using the Fine–Gray regression model for the cumulative incidences of the competing events ‘infection’, ‘death’ and ‘end of neutropenia’. The risk factors investigated were: sex, age, underlying disease and type of transplant. From January 2000 to June 2004, a total of 1699 patients in 20 hospitals were investigated. In the multivariate analysis, male patients had a significantly higher risk of acquiring BSI than female patients (P=0.002). The risk of acquiring BSI is highest in patients with advanced acute myeloid leukaemia (AML). In the univariate and multivariate analysis, unrelated donor allogeneic transplantation constituted a risk factor for pneumonia (P=0.012). ONKO-KISS provides reference data on the incidence of pneumonia and BSI. The increased risk for BSI in males and patients with advanced AML, and the increased risk for pneumonia in unrelated donor allogeneic PBSCT patients should be targeted to prevent infections in these higher risk groups.Bone Marrow Transplantation (2007) 39, 173–178. doi:10.1038/sj.bmt.1705561 [ABSTRACT FROM AUTHOR]

An allogeneic stem cell transplant recipient developed pulmonary infiltrates and Aspergillus antigenemia during prophylactic low–dose liposomal amphotericin B. No response to therapy was observed after increasing the dose of liposomal amphotericin B and addition of caspofungin, and breakthrough candidemia developed. Therapy switch to voriconazole did not prevent the development of lethal septic shock. Shortly before death, Scopulariopsis brevicaulis was cultured from bronchial secretions, and positive blood cultures demonstrated persistent candidemia due to Debaryomyces hansenii, teleomorph of Candida famata. [ABSTRACT FROM AUTHOR]

Both conventional chimerism analysis (CCA) and lineage-specific chimerism analysis (LCA) have potential pitfalls as diagnostic means for the detection of minimal residual disease after allogeneic hematopoietic cell transplantation (aHCT). Therefore, the present study examines the results of both methods in order to determine how predictive consecutive evaluations were, with respect to the risk that the patient would relapse during post-transplant follow-up and with respect to responsiveness to immunomodulatory treatment. A total of 168 individuals with acute myeloid leukemia (AML) (n=137) and myelo dysplastic syndrome (n=31) were investigated with CCA and LCA at mean intervals of 24 days (range: 11-116). The median follow-up after myeloablative aHCT was 22 months (range: 4-49). Of 168 patients, 65 experienced a clinical relapse after aHCT. CCA and LCA were comparatively sensitive and specific for relapse at the intervals of chimerism testing employed in this study. Of 32 patients, 10 who were offered donor lymphocyte infusions (DLI) treatment for increasing (n=29) or stable (n=3) mixed chimerism (MC) achieved at least transitory CC. The observation that all patients with increasing MC relapsed despite DLI treatment (54%) or withdrawal of immune suppression (24%) indicates that novel strategies to deal with rapidly evolving relapse in AML patients, such as shortening of chimerism monitoring intervals, need to be evaluated.Leukemia (2005) 19, 814-821. doi:10.1038/sj.leu.2403719 Published online 17 March 2005 [ABSTRACT FROM AUTHOR]

For surveillance of nosocomial bloodstream infections (BSIs) and pneumonia during neutropenia in adult patients who have undergone bone marrow transplantation (BMT) or peripheral blood stem cell transplantation (PBS CT), a multicenter study-the Hospital Infection Surveillance System for Patients with Hematologic/ Oncologic Malignancies (ONKO-KISS)-was initiated in Germany in 2000. Nosocomial infections were identified in neutropenic patients by means of Centers for Disease Control and Prevention definitions for laboratory-confirmed BSI and modified criteria for pneumonia. During the first 38-month period of the study (i.e., through December 2003), a total of 1899 patients associated with 28,273 neutropenic days were investigated. Of these, 1173 (62%) had undergone allogeneic and 726 (38%) had undergone autologous BMT or PBSCT. The mean duration of neutropenia was 14.9 days (9.6 and 18.1 days after autologous and allogeneic transplantation, respectively). Overall, 395 BSIs and 168 cases of pneumonia were identified. The pooled mean site-specific incidence density per 1000 neutropenic days was 14.0 for BSI (12.4 and 18.9 for the allogeneic and autologous transplantation groups, respectively) and 5.9 for pneumonia (6.1 and 5.6 in the allogeneic and autologous transplantation groups, respectively). After allogeneic transplantation, 22.4 BSIs per 100 patients and 11.0 cases of pneumonia per 100 patients occurred, whereas 18.2 BSIs per 100 patients and 5.4 cases of pneumonia per 100 patients occurred after autologous transplantation. The majority (57%) of pathogens associated with BSI were coagulase-negative staphylococci. The ongoing ONKO-KISS project provides unprecedented reference data about the incidence of pneumonia and sepsis among BMT recipients and PBSCT recipients in Germany. These data will be used for further evaluation of the impact of hygiene measures and therapeutic regimens for these patients. [ABSTRACT FROM AUTHOR]

Summary:Risk-adapted treatment of multiple myeloma (MM) includes autologous (auto-) and allogeneic (allo-) hematopoietic stem cell transplantation (HSCT). Case reports on extramedullary (EM) compared to bone marrow (BM) relapse after HSCT suggest a dismal prognosis. We compared the outcome of 78 MM patients relapsing after auto- (group A: n=53) or allo- (group B: n=25) HSCT, stratified into BM (64 patients) vs EM (14 patients) relapse. The relapse-specific groups were also compared with respect to risk factors, including age,ß2-microglobulin, pretreatment, cytogenetics and stage. EM relapse sites were lungs (5), soft tissue (4), pericardium (2), bone (1), skin (1) and CNS (1). As of May 2004, the overall (OS) and progression-free (PFS) survival after HSCT in patients relapsing from EM sites was not significantly different from BM relapse patients, both after auto- and allo-HSCT. Although MM patients relapsing from EM sites after allo-HSCT used to be regarded as having few therapeutic options, we observed encouraging responses to donor lymphocyte infusions (DLI). Treatment responses to DLIs were observed in 5/9 (56%) BM relapse patients, and in 3/4 (75%) EM relapse patients. These observations suggest that EM relapse after HSCT is common and needs an individualized diagnostic and therapeutic approach in MM during clinical follow-up after HSCT.Bone Marrow Transplantation (2004) 34, 1057-1065. doi:10.1038/sj.bmt.1704713 Published online 1 November 2004 [ABSTRACT FROM AUTHOR]