Axel Glasmacher

University of South Florida, Tampa, FL, United States

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Publications (70)348.42 Total impact

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    ABSTRACT: Bisphosphonates are specific inhibitors of osteoclastic activity and used in the treatment of patients with multiple myeloma (MM). While bisphosphonates are shown to be effective in reducing vertebral fractures and pain, their role in improving overall survival (OS) remains unclear. This is an update of a Cochrane review first published in 2002 and previously updated in 2010. To assess the evidence related to benefits and harms associated with use of various types of bisphosphonates (aminobisphosphonates versus nonamino bisphosphonates) in the management of patients with MM. Our primary objective was to determine whether adding bisphosphonates to standard therapy in MM improves OS and progression-free survival (PFS), and decreases skeletal-related morbidity. Our secondary objectives were to determine the effects of bisphosphonates on pain, quality of life, incidence of hypercalcemia, incidence of bisphosphonate-related gastrointestinal toxicities, osteonecrosis of jaw and hypocalcemia. We searched MEDLINE, LILACS, EMBASE (December 2009 to October 2011) and the Cochrane Controlled Trials Register (all years, latest Issue September 2011) to identify all randomized trials in MM up to October 2011 using a combination of text and MeSH terms. We also handsearched relevant meeting proceedings (December 2009 to October 2011). Any randomized controlled trial (RCT) assessing the role of bisphosphonates and observational studies or case reports examining bisphosphonate-related osteonecrosis of the jaw in patients with MM were eligible for inclusion. Two review authors extracted the data. Data were pooled and reported as hazard ratio (HR) or risk ratio (RR) under a random-effects model. Statistical heterogeneity was explored using metaregression. In this update, we included 2 studies (2464 patients) that were not part of our last Cochrane review published in 2010. In this review we included 16 RCTs comparing bisphosphonates with either placebo or no treatment and 4 RCTs with a different bisphosphonate as a comparator. The 20 included RCTs enrolled 6692 patients. Overall methodological quality of reporting was moderate. Thirty per cent (6/20) of trials reported the method of generating the randomization sequence. Forty per cent (8/20) of trials had adequate allocation concealment. Withdrawals and dropouts were described in 60% (12/20) of trials. Pooled results showed no direct effect of bisphosphonates on OS compared with placebo or no treatment (HR 0.96, 95% CI 0.82 to 1.13; P = 0.64). However, there was a statistically significant heterogeneity among the included RCTs (I(2) = 55%, P = 0.01) for OS. To explain this heterogeneity we performed a metaregression assessing the relationship between bisphosphonate potency and improvement in OS, which found indicating an OS benefit with zoledronate (P = 0.058). This provided a further rationale for performing network meta-analyses of the various types of bisphosphonates that were not compared head to head in RCTs. Results from network meta-analyses showed superior OS with zoledronate compared with etidronate (HR 0.43, 95% CI 0.16 to 0.86) and placebo (HR 0.61, 95% CI 0.28 to 0.98). However, there was no difference between zoledronate and other bisphosphonates. Pooled analysis did not demonstrate a beneficial effect of bisphosphonates compared with placebo or no treatment in improving PFS (HR 0.70, 95% CI 0.41 to 1.19; P = 0.18) There was no heterogeneity among trials reporting PFS estimates (I(2) = 35%, P = 0.20).Pooled analysis demonstrated a beneficial effect of bisphosphonates compared with placebo or no treatment on prevention of pathological vertebral fractures (RR 0.74, 95% CI 0.62 to 0.89; I(2) = 7%), skeletal-related events (SRE) (RR 0.80, 95% CI 0.72 to 0.89; I(2) = 2%) and amelioration of pain (RR 0.75, 95% CI 0.60 to 0.95; I(2) = 63%). The network meta-analysis did not show any difference in the incidence of osteonecrosis of the jaw (5 RCTs, 3198 patients) between bisphosphonates. Rates of osteonecrosis of the jaw in observational studies (9 studies, 1400 patients) ranged from 0% to 51%. The pooled results (6 RCTs, 1689 patients) showed no statistically significant increase in frequency of gastrointestinal symptoms with the use of bisphosphonates compared with placebo or no treatment (RR 1.23, 95% CI 0.95 to 1.60; P = 0.11).The pooled results (3 RCTs, 1002 patients) showed no statistically significant increase in frequency of hypocalcemia with the use of bisphosphonates compared with placebo or no treatment (RR 2.19, 95% CI 0.49 to 9.74). The network meta-analysis did not show any differences in the incidence of hypocalcemia, renal dysfunction and gastrointestinal toxicity between the bisphosphonates used. Use of bisphosphonates in patients with MM reduces pathological vertebral fractures, SREs and pain. Assuming a baseline risk of 20% to 50% for vertebral fracture without treatment, between 8 and 20 MM patients should be treated to prevent vertebral fracture(s) in one patient. Assuming a baseline risk of 31% to 76% for pain amelioration without treatment, between 5 and 13 MM patients should be treated to reduce pain in one patient. With a baseline risk of 35% to 86% for SREs without treatment, between 6 and 15 MM patients should be treated to prevent SRE(s) in one patient. Overall, there were no significant adverse effects associated with the administration of bisphosphonates identified in the included RCTs. We found no evidence of superiority of any specific aminobisphosphonate (zoledronate, pamidronate or ibandronate) or nonaminobisphosphonate (etidronate or clodronate) for any outcome. However, zoledronate appears to be superior to placebo and etidronate in improving OS.
    Cochrane database of systematic reviews (Online) 01/2012; 5:CD003188. · 5.70 Impact Factor
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    ABSTRACT: Thalidomide has potent antimyeloma activity, but no prospective, randomized controlled trial has evaluated thalidomide monotherapy in patients with relapsed/refractory multiple myeloma. We conducted an international, randomized, open-label, four-arm, phase III trial to compare three different doses of thalidomide (100, 200, or 400 mg/day) with standard dexamethasone in patients who had received one to three prior therapies. The primary end-point was time to progression. In the intent-to-treat population (N=499), the median time to progression was 6.1, 7.0, 7.6, and 9.1 months in patients treated with dexamethasone, and thalidomide 100, 200, and 400 mg/day, respectively; the difference between treatment groups was not statistically significant. In the per-protocol population (n=465), the median time to progression was 6.0, 7.0, 8.0, and 9.1 months, respectively. In patients who had received two or three prior therapies, thalidomide significantly prolonged the time to progression at all dose levels compared to the result achieved with dexamethasone. Response rates and median survival were similar in all treatment groups, but the median duration of response was significantly longer in all thalidomide groups than in the dexamethasone group. Adverse events reported in the thalidomide groups, such as fatigue, constipation and neuropathy, confirmed the known safety profile of thalidomide. Although thalidomide was not superior to dexamethasone in this randomized trial, thalidomide monotherapy may be considered an effective salvage therapy option for patients with relapsed/refractory multiple myeloma, particularly those with a good prognosis and those who have received two or three prior therapies. The recommended starting dose of thalidomide monotherapy is 400 mg/day, which can be rapidly reduced for patients who do not tolerate this treatment. (Clinical trial registration number: NCT00452569).
    Haematologica 12/2011; 97(5):784-91. · 5.94 Impact Factor
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    ABSTRACT: Antifungal prophylaxis for allogeneic haematopoietic stem-cell transplant (alloHCT) recipients should prevent invasive mould and yeast infections (IFIs) and be well tolerated. This prospective, randomized, open-label, multicentre study compared the efficacy and safety of voriconazole (234 patients) versus itraconazole (255 patients) in alloHCT recipients. The primary composite endpoint, success of prophylaxis, incorporated ability to tolerate study drug for ≥ 100 d (with ≤ 14 d interruption) with survival to day 180 without proven/probable IFI. Success of prophylaxis was significantly higher with voriconazole than itraconazole (48·7% vs. 33·2%, P < 0·01); more voriconazole patients tolerated prophylaxis for 100 d (53·6% vs. 39·0%, P < 0·01; median total duration 96 vs. 68 d). The most common (>10%) treatment-related adverse events were vomiting (16·6%), nausea (15·8%) and diarrhoea (10·4%) for itraconazole, and hepatotoxicity/liver function abnormality (12·9%) for voriconazole. More itraconazole patients received other systemic antifungals (41·9% vs. 29·9%, P < 0·01). There was no difference in incidence of proven/probable IFI (1·3% vs. 2·1%) or survival to day 180 (81·9% vs. 80·9%) for voriconazole and itraconazole respectively. Voriconazole was superior to itraconazole as antifungal prophylaxis after alloHCT, based on differences in the primary composite endpoint. Voriconazole could be given for significantly longer durations, with less need for other systemic antifungals.
    British Journal of Haematology 08/2011; 155(3):318-27. · 4.94 Impact Factor
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    ABSTRACT: Invasive Candida infections are important causes of morbidity and mortality in immunocompromised and hospitalised patients. This article provides the joint recommendations of the German-speaking Mycological Society (Deutschsprachige Mykologische Gesellschaft, DMyKG) and the Paul-Ehrlich-Society for Chemotherapy (PEG) for diagnosis and treatment of invasive and superficial Candida infections. The recommendations are based on published results of clinical trials, case-series and expert opinion using the evidence criteria set forth by the Infectious Diseases Society of America (IDSA). Key recommendations are summarised here: The cornerstone of diagnosis remains the detection of the organism by culture with identification of the isolate at the species level; in vitro susceptibility testing is mandatory for invasive isolates. Options for initial therapy of candidaemia and other invasive Candida infections in non-granulocytopenic patients include fluconazole or one of the three approved echinocandin compounds; liposomal amphotericin B and voriconazole are secondary alternatives because of their less favourable pharmacological properties. In granulocytopenic patients, an echinocandin or liposomal amphotericin B is recommended as initial therapy based on the fungicidal mode of action. Indwelling central venous catheters serve as a main source of infection independent of the pathogenesis of candidaemia in the individual patients and should be removed whenever feasible. Pre-existing immunosuppressive treatment, particularly by glucocorticosteroids, ought to be discontinued, if feasible, or reduced. The duration of treatment for uncomplicated candidaemia is 14 days following the first negative blood culture and resolution of all associated symptoms and findings. Ophthalmoscopy is recommended prior to the discontinuation of antifungal chemotherapy to rule out endophthalmitis or chorioretinitis. Beyond these key recommendations, this article provides detailed recommendations for specific disease entities, for antifungal treatment in paediatric patients as well as a comprehensive discussion of epidemiology, clinical presentation and emerging diagnostic options of invasive and superficial Candida infections.
    Mycoses 07/2011; 54(4):279-310. · 1.28 Impact Factor
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    ABSTRACT: Introduction of lenalidomide has expanded the therapeutic options for refractory and recurrent multiple myeloma (MM) patients. However, the application of the approved doses may be difficult in some patients due to adverse effects. Therefore, we evaluated the efficacy and safety of lenalidomide in 10 patients with relapsed and refractory MM who received a reduced dose due to leukopenia (4), polyneuropathy (1), muscle cramps (1), thrombocytopenia (1), renal insufficiency (1), at the request of patient (1), as continuous therapy (1), either from the beginning (2) or during treatment (8). They received lenalidomide at a mean (median) daily dose of 14 (15) mg/d once a day (days 1-21 every 28 days) in combination with dexamethasone at a mean (median) dose of 17.6 (28) mg per day (4-40 mg) on days 1-4, 9-12 and 17-20. Mean (median) duration of treatment with lenalidomide was 15.1 (15) months. Partial response or better was reported in seven and minimal response or better was reported in eight patients. Mean (median) values for time-to-progression (TTP) and for progression-free survival (PFS) were 8.7 (4) months. Mean overall survival (OS) has not been reached, all patients are still alive. In conclusion, dose-reduced lenalidomide is an effective and well tolerated treatment for patients with recurrent or refractory MM who cannot tolerate full doses.
    German medical science : GMS e-journal 01/2011; 9:Doc26.
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    ABSTRACT: Invasive fungal infections (IFIs) contribute significantly to mortality and morbidity in patients receiving myelosuppressive chemotherapy for haematological malignancies. The present study investigates the overall survival (OS), infection-related mortality and changes in treatment of IFIs in our department from 1995 until 2006. Outcomes of all chemotherapy courses were retrospectively evaluated using a standard questionnaire. Modified EORTC/MSG criteria for IFIs were applied: a positive PCR result for Aspergillus spp. in bronchoalveolar lavage was also defined as probable IFI. In total, 1693 chemotherapy courses in 592 patients were evaluated. Sixty-three percent of chemotherapy courses were given to treat acute myeloid leukaemia, with the rest for acute lymphoblastic leukaemia or aggressive lymphoma. IFIs were observed in 139/592 patients [23.5%, 95% confidence interval (CI) 20%-27%] and in 149/1693 courses (8.8%, 95% CI 8%-10%). IFI-related mortality was 56.9% in 1995-2001 and 28.6% in 2002-06, P < 0.001. Accordingly, median OS in patients with IFI increased: 54 days (95% CI 26-82 days) in 1995-2001 versus 229 days (95% CI 35-423 days) in 2002-06, P = 0.001. By multivariate analysis, factors predictive for better OS were controlled disease after chemotherapy [hazard ratio (HR) 0.228, P < 0.001], possible IFI (in contrast to proven/probable IFI, HR 0.537, P = 0.005), age <60 years (HR 0.583, P = 0.008), time period 2002-06 (HR 0.612, P = 0.021) and use of novel antifungals (HR 0.589, P = 0.033). Compared with 1995-2001, IFI-related mortality decreased and OS in patients with IFI increased significantly in recent years. Improved OS was associated with controlled haematological disease, certainty of IFI diagnosis (possible), younger age, time period 2002-06 and the use of novel antifungals.
    Journal of Antimicrobial Chemotherapy 04/2010; 65(4):761-8. · 5.34 Impact Factor
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    ABSTRACT: In primary central nervous system lymphoma (PCNSL), 2 international prognostic scores have been developed to estimate the outcome according to certain "prognostic groups". However, these scores do not predict the individual course of a single patient under therapy. In this analysis, we addressed the question of whether early tumor remission in patients still under therapy, according to magnetic resonance imaging (MRI) criteria, helps to predict long-term outcome. Eighty-eight patients treated with 6 polychemotherapy cycles within a pilot/phase II trial underwent MRI scanning within 72 hours prior to initiation of therapy, after the second chemotherapy cycle, and after completion of chemotherapy. Response was assessed by contrast-enhanced MRI of the brain according to the Macdonald criteria. Median follow-up was 42 months (range, 0-124 months). Patients achieving a complete radiographic response after 2 courses of chemotherapy (n = 18) had a significantly longer median overall survival (OS) (not reached) and median time-to-treatment failure (TTF) (not reached) than patients with complete response (CR) after termination of treatment but with only a partial response after the second cycle (n = 24) (OS: 55 months; TTF: 32 months) (P < .01). Early complete tumor response assessed by MRI after the second of sixth scheduled chemotherapy cycles was highly predictive for both OS and TTF in patients with PCNSL treated in this series.
    Neuro-Oncology 02/2010; 12(7):720-4. · 6.18 Impact Factor
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    ABSTRACT: Bisphosphonates are specific inhibitors of osteoclastic activity and are currently used as supportive therapy for multiple myeloma (MM). However, the exact clinical role of bisphosphonates in MM remains unclear. This update of the first review published in 2002. We have also analyzed observational studies targeting osteonecrosis of jaw (ONJ). We searched the literature using the methods outlined in the previous review. We also searched observational studies or case reports examining ONJ. We selected RCTs with a parallel design related to the use of bisphosphonate in myeloma. We also selected observational studies or case reports examining bisphosphonates related to ONJ. We have reported pooled data using either hazard ratio or risk ratio and, when appropriate, as absolute risk reduction and the number needed to treat to prevent or to cause a pathological event. We have assessed statistical heterogeneity and reported I(2) statistic. This review includes 17 trials with 1520 patients analyzed in bisphosphonates groups, and 1490 analyzed in control groups. In comparison with placebo/no treatment, the pooled analysis demonstrated the beneficial effect of bisphosphonates on prevention of pathological vertebral fractures (RR= 0.74 (95% CI: 0.62 to 0.89), P = 0.001), total skeletal related events (SREs) (RR= 0.80 (95% CI: 0.72 to 0.89), P < 0.0001) and on amelioration of pain (RR = 0.75 (95% CI: 0.60 to 0.95), P = 0.01). We found no significant effect of bisphosphonates on overall survival (OS), progression-free survival (PFS), hypercalcemia or on the reduction of non-vertebral fractures. The indirect meta-analyses did not find the superiority of any particular type of bisphosphonate over others. Only two RCTs reported ONJ. The identified observational studies suggested that ONJ may be a common event (range: 0% to 51%). Adding bisphosphonates to the treatment of MM reduces pathological vertebral fractures, SREs and pain but not mortality. Assuming the baseline risk of 20% to 50% for vertebral fracture without treatment, we estimate that between eight and 20 MM patients should be treated to prevent vertebral fracture(s) in one patient. Assuming the baseline risk of 31% to 76% for pain amelioration without treatment, we estimate that between five to 13 MM patients should be treated to reduce pain in one patient. Also, with the baseline risk of 35% to 86% for SREs without treatment, we estimate that between six and 15 MM patients should be treated to prevent SRE(s) in one patient. No bisphoshphonate appears to be superior to others.
    Cochrane database of systematic reviews (Online) 01/2010; · 5.70 Impact Factor
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    ABSTRACT: Abstract 3028 BackgroundBisphosphonates are used as supportive therapy for patients with multiple myeloma (MM) to prevent bone destruction. There are multiple types of bisphosphonates. Currently, which bisphosphonate is superior to others in the treatment of patients with MM is not known. There are only three randomized controlled trials (RCTs) which employed head to head comparison of bisphsophonates in patients with MM. We performed indirect meta analysis of various bisphohsphonates and did not find the superiority of any particular type of bisphosphonate over others (Mhaskar et al Cochrane Database Syst Rev. 2010 Mar 17;3). In June 2010, Morgan et al published largest RCT to date involving 1960 MM patients employing head to head comparison of zoledronate and clodronate (Morgan et al J Clin Oncol, 2010. 28(15_suppl): p. 8021). Hence, the aim of this analysis is to assess if any specific type of bisphosphonate is superior to others incorporating data from this RCT. MethodsWe extracted data regarding overall survival (OS), progression free survival (PFS), skeletal related events (SREs), and grade III-IV treatment related harms. Superiority of bisphosphonates was assessed by the mixed treatment comparison (MTC) as described by Lu and Ades (Lu et al. Stat Med, 2004. 23(20): p.3105-24). The fixed and random effects MTC models were compared using the deviance information criterion. Network consistency was checked using the back-calculation method. Since there was no evidence suggesting the superiority of random effects model we have reported fixed effects model estimates. ResultsEighteen RCTs were included enrolling 4,970 patients. For the outcome of OS the pooled analysis demonstrated a beneficial effect of zoledronate in comparison with clodronate [HR = 0.83 (95% CI: 0.73 to 0.94)] and etidronate [HR = 0.48 (95% CI: 0.31 to 0.71)]. However, there was no evidence that zoledronate was superior to pamidronate [HR = 0.84 (95% CI: 0.61 to 1.13)], or ibandronate [HR = 0.70 (95% CI: 0.42 to 1.11)] for the outcome of OS. Zoledronate was superior to clodronate [HR = 0.88 (95% CI: 0.78 to 0.99)] for the outcome PFS. Zoledronate was also superior to clodronate [HR = 0.75 (95% CI: 0.64 to 0.88)], pamidronate [HR = 0.65 (95% CI: 0.42 to 0.95)], and ibandronate [HR = 0.44 (95% CI: 0.26 to 0.72)] for the outcome of SREs. There were no significant adverse effects associated with the administration of bisphosphonates. Only three RCTs reported the incidence of osteonecrosis of jaw (ONJ). The incidence of ONJ was higher in zoledronate [OR: 12.03 (95% CI: 3.68 to 39.26)] compared to clodronate. We also identified 7 observational studies evaluating 1068 patients for ONJ. These studies suggest that ONJ may be a common event (range: 0%- 51%). ConclusionThe results demonstrate a beneficial effect of zoledronate on OS compared to clodronate and etidronate. Similarly, zoledronate was superior to clodronate in improving PFS. zoledronate is superior to clodronate, pamidronate and ibandronate in prevention of SREs in patients with MM. In the context of MTC uncertainty analysis, zoledronate ranked as the best treatment followed by clodronate and pamidronate. These finding underscore the need for RCT with head to head comparison of zoledronate and pamidronate for their efficacy and safety in MM patients. View this table: T1500400T1 Table 1 DisclosuresNo relevant conflicts of interest to declare.
    ASH Annual Meeting Abstracts. 01/2010; 116(21):3028-.
  • Biology of Blood and Marrow Transplantation - BIOL BLOOD MARROW TRANSPLANT. 01/2010; 16(2).
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    ABSTRACT: There is limited understanding of the dysregulation of the innate immune system in multiple myeloma (MM). We analysed the expression of the activating receptor NKG2D on NK cells and T cells of MM patients and investigated the impact of soluble versus membrane-bound NKG2D ligands on the expression of NKG2D. NKG2D expression on NK cells and CD8+ alphabeta T cells from patients with MM or monoclonal gammopathy of uncertain significance and healthy controls was examined flow-cytometrically. Sera from patients and controls were analysed for soluble NKG2D ligands (sNKG2D ligands). Significantly fewer NK cells and CD8+ alphabeta T cells from patients expressed NKG2D compared to healthy controls (NK cells: median 54% interquartile range (IQR) 32-68 versus 71% IQR 44-82%, P = 0.017, CD8+ alphabeta T cells: median 63% IQR 52-81 versus 77% IQR 71-90%, P = 0.018). The sNKG2D ligand sMICA was increased in patients [median 175 (IQR 87-295) pg/ml] versus controls [median 80 (IQR 32-129) pg/ml, P < 0.001], but levels of sMICA did not correlate with NKG2D expression on effector cells. To elucidate the mechanism of NKG2D down-regulation, we incubated lymphocytes from healthy donors in the presence of sNKG2D ligands or in co-culture with MM cell lines. sNKG2D ligands in clinically relevant concentrations did not down-regulate NKG2D expression, but co-culture of effector cells with myeloma cells with high surface expression of NKG2D ligands reduced NKG2D expression significantly. These results indicate that MM is associated with a significant reduction in NKG2D expression which may be contact-mediated rather than caused by soluble NKG2D ligands.
    Cancer Immunology and Immunotherapy 12/2009; 59(6):829-39. · 3.64 Impact Factor
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    ABSTRACT: Infection is the main treatment-related cause of mortality in cancer patients. Rapid and accurate diagnosis to facilitate specific therapy of febrile neutropenia is therefore urgently warranted. Here, we evaluated a commercial PCR-based kit to detect the DNA of 20 different pathogens (SeptiFast) in the setting of febrile neutropenia after chemotherapy. Seven hundred eighty-four serum samples of 119 febrile neutropenic episodes (FNEs) in 70 patients with hematological malignancies were analyzed and compared with clinical, microbiological, and biochemical findings. In the antibiotic-naïve setting, bacteremia was diagnosed in 34 FNEs and 11 of them yielded the same result in the PCR. Seventy-three FNEs were negative in both systems, leading to an overall agreement in 84 of 119 FNEs (71%). During antibiotic therapy, positivity in blood culture occurred only in 3% of cases, but the PCR yielded a positive result in 15% of cases. In six cases the PCR during antibiotic treatment detected a new pathogen repetitively; this was accompanied by a significant rise in procalcitonin levels, suggestive of a true detection of infection. All patients with probable invasive fungal infection (IFI; n = 3) according to the standards of the European Organization for Research and Treatment of Cancer had a positive PCR result for Aspergillus fumigatus; in contrast there was only one positive result for Aspergillus fumigatus in an episode without signs and symptoms of IFI. Our results demonstrate that the SeptiFast kit cannot replace blood cultures in the diagnostic workup of FNEs. However, it might be helpful in situations where blood cultures remain negative (e.g., during antimicrobial therapy or in IFI).
    Journal of clinical microbiology 08/2009; 47(8):2405-10. · 4.16 Impact Factor
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    ABSTRACT: To evaluate long-term progression-free survival and overall survival, quality of life, and cognitive function in primary central nervous system lymphoma after systemic and intraventricular chemotherapy without radiotherapy. A long-term follow-up was conducted on surviving primary central nervous system lymphoma patients having been enrolled in a pilot/phase II trial between September 1995 and December 2001. Initially, 65 patients (median age, 62 years) had been treated with systemic and intraventricular chemotherapy without radiotherapy. All living patients were contacted, and a neurological examination, comprehensive neuropsychological testing, quality-of-life assessment, and imaging were performed. Twenty-one of all 65 patients (32 %) and 17 of 30 patients 60 years or younger (57%), respectively, were still alive at median follow-up of 100 months (range, 77-149 months). Nineteen of 21 patients completed all investigations; 1 was lost to follow-up. In three patients, an exclusively extraneural relapse of a high-grade non-Hodgkin's lymphoma was diagnosed after 9, 31, and 40 months, respectively. All of them experienced complete remission to high dose. Neither late neurotoxicity nor compromise of quality of life was found in any of the patients examined. Primary polychemotherapy based on high-dose methotrexate (MTX) and cytarabine (Ara-C) is highly efficient in treatment of primary central nervous system lymphoma. About half of patients 60 years or younger can obviously be cured with this regimen without long-term neurotoxic sequelae or quality-of-life compromise.
    Annals of Neurology 08/2009; 67(2):182-9. · 11.19 Impact Factor
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    ABSTRACT: We conducted a phase 1/2 trial combining lenalidomide (R) with adriamycin (A) and dexamethasone (D) for relapsed and relapsed-refractory myeloma to determine tolerability and efficacy of this novel regimen, RAD, delivered for six 28-day cycles. A total of 69 intensively pretreated patients with a median age of 65 years (range, 46-77 years) were enrolled. Using pegfilgrastim (G), the maximum tolerated dose (MTD) was formally not reached at the highest dose level (R, 25 mg on days 1-21; A, 9 mg/m(2) intravenously on days 1-4; and D, 40 mg on days 1-4 and 17-20; dose level 5+G), which was then used to determine efficacy. Grades 3/4 neutropenia and thrombocytopenia were seen in 48% and 38% of patients, respectively. Thromboembolic events occurred in 4.5% and severe infections in 10.5% of patients. On an intent-to treat analysis, overall response rate (ORR) was 73% for the whole study and 77% including 74% complete response (CR) plus very good partial response (VGPR) for dose level 5+G. Response rates and progression-free survival did not differ between relapsed and relapsed-refractory patients. Deletion of chromosome 17p and elevated beta(2)-microglobulin were associated with significantly inferior response and shortened time to progression. In conclusion, RAD induces substantial and durable remission with an acceptable toxicity profile in patients with relapsed and relapsed-refractory myeloma. This trial was registered at www.ClinicalTrials.gov as no. NCT00306813.
    Blood 02/2009; 113(18):4137-43. · 9.78 Impact Factor
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    ABSTRACT: Evidence bearing on the efficacy of tandem autologous hematopoietic transplant (AHCT) vs a single AHCT in patients with multiple myeloma (MM) is conflicting. We performed a systematic review and meta-analysis to synthesize the existing evidence related to the effectiveness of tandem vs single AHCT in patients with MM. We searched Medline, conference proceedings, and bibliographies of retrieved articles and contacted experts in the field to identify randomized controlled trials (RCTs) reported in any language that compared tandem with single AHCT in patients with MM through March 31, 2008. Endpoints were overall survival (OS), event-free survival (EFS), response rate, and treatment-related mortality (TRM). Data were pooled under a random-effects model. Six RCTs enrolling 1803 patients met the inclusion criteria. Patients treated with tandem AHCT did not have better OS (hazard ratio [HR] for mortality for patients treated with tandem transplant vs single transplant = 0.94; 95% confidence interval [CI] = 0.77 to 1.14) or EFS (HR = 0.86; 95% CI = 0.70 to 1.05). Response rate was statistically significantly better with tandem AHCT (risk ratio = 0.79, 95% CI = 0.67 to 0.93), but with a statistically significant increase in TRM (risk ratio = 1.71, 95% CI = 1.05 to 2.79). There was statistically significant heterogeneity among RCTs for OS and EFS. In previously untreated MM patients, use of tandem AHCT did not result in improved OS or EFS. We conclude that tandem AHCT is associated with improved response rates but at risk of clinically significant increase in TRM.
    CancerSpectrum Knowledge Environment 02/2009; 101(2):100-6. · 14.07 Impact Factor
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    ABSTRACT: Abstract 3858 Poster Board III-794 BackgroundBisphosphonates are currently used as supportive therapy for multiple myeloma (MM). In 2001 we conducted a Cochrane systematic review (SR) showing that Bisphosphonates reduce vertebral fractures and pain but have no effect on other important outcomes. Here we report an update of that SR. MethodsA comprehensive literature search of MEDLINE, EMBASE, LILACS, Cochrane database of randomized controlled trials (RCTs) and www.clinicaltrials.gov and meetings abstracts from American Society of Clinical Oncology, American Society of Hematology and European Hematology Association was undertaken to identify all phase III RCTs published until January 2009. We extracted data regarding overall survival (OS), progression free survival (PFS), vertebral and non vertebral fractures, skeletal related events (SREs), pain, hypercalcemia, grade III-IV treatment related harms. The time to event data and dichotomous data were pooled under the random effects model as hazard ratios (HR) and risk ratios (RR) respectively. Heterogeneity was assessed using the chi square test and I2 statistic. Indirect comparison of various bisphosphonates was conducted according to the methods developed by Bucher and Glenny et al and were extended to calculate HR/RR. ResultsSeventeen RCTs were included enrolling 3,010 patients. In comparison with placebo / no treatment, the pooled analysis demonstrated a beneficial effect of bisphosphonates on prevention of pathological vertebral fractures (7 RCTs, 1116 patients) [RR= 0.74 (95% CI: 0.62 to 0.89), P = 0.001], SREs (6 RCTs, 1334 patients) [RR= 0.81 (95% CI: 0.72 to 0.92), P = 0.001] and on amelioration of pain (8 RCTs, 1281 patients) [RR = 0.75 (95% CI: 0.60 to 0.95), P = 0.01]. We found no significant effect of bisphosphonates on OS, PFS, hypercalcemia or on the reduction of non-vertebral fractures. There was statistically significant heterogeneity for OS and pain endpoints. The heterogeneity for the outcome of pain could be explained by the variation in the pain scales used to measure pain. However, we also found that the beneficial effect of bisphosphonates on pain reduction was greater in patients who were asymptomatic at the start of treatment [RR= 0.28 (95% CI: 0.12 to 0.67)] compared to symptomatic patients [RR= 0.83 (95% CI: 0.69 to 1.00)] (Test of interaction: p = 0.005). The heterogeneity for OS was attributed to one RCT with unrealistic treatment effects ("an outlier effect"). Results of indirect meta analysis were consistent with the results from direct comparisons for the outcomes of vertebral fractures, SREs and pain. The indirect meta analyses did not find the superiority of any particular type of bisphosphonate over others. There were no significant adverse effects associated with the administration of bisphosphonates. In fact, only two RCTs reported osteonecrosis of jaw (ONJ). We also identified 7 observational trials evaluating 1068 patients for ONJ. These studies suggest that ONJ may be a common event (range: 0%- 51%). Since ONJ was only sporadically reported in RCTs the results from observational studies may be an overestimate due to their non-controlled design. ConclusionAdding bisphosphonates to the treatment of MM reduces pathological vertebral fractures, SREs and pain but - from the published evidence - not mortality. Assuming the baseline risk of 20%-50% for vertebral fracture without treatment, we estimate that between 8 - 20 MM patients should be treated to prevent vertebral fracture(s) in one patient. Similarly, assuming the baseline risk of 31%-76% for pain amelioration without treatment, we estimate that between 5 - 13 MM patients should be treated to reduce pain in one patient. Also, with the baseline risk of 35%-86% for SREs without treatment, we estimate that between 6 - 15 MM patients should be treated to prevent SRE(s) in one patient. No bisphosphonate appears to be superior to others. DisclosuresGlasmacher: Celgene: Employment, Equity Ownership.
    ASH Annual Meeting Abstracts. 01/2009; 114(22):3858-.
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    ABSTRACT: Thalidomide monotherapy in relapsed/refractory multiple myeloma (MM) has a response rate of 30%. The combination of thalidomide with dexamethasone (Thal/Dex) is expected to improve responses, but it is unknown if the combination increases the rate of adverse events. Here, we conducted a systematic review of studies evaluating Thal/Dex in relapsed/refractory MM. Twelve studies were included, comprising 451 patients. The response rate (CR and PR) was 46% (95% CI 42-51%). Therapy-related toxicity was comparable to thalidomide monotherapy and included somnolence (26%, 95% CI 22-31%), constipation (37%, 95% CI 32-42%) and peripheral neuropathy (27%, 95% CI 23-32%). Only venous thromboembolism appeared to occur more often with Thal/Dex (5%, 95% CI 3-8%). Thus, using Thal/Dex results in an improved response rate in relapsed/refractory MM, with a toxicity rate comparable to thalidomide monotherapy.
    European Journal Of Haematology 10/2008; 81(4):247-52. · 2.55 Impact Factor
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    ABSTRACT: A systemic and intraventricular polychemotherapy regimen (the Bonn protocol) without radiotherapy resulted in durable responses in 75% of patients <60 years with primary CNS lymphoma (PCNSL), but was complicated by a high rate of Ommaya reservoir infections. Here, the efficacy and toxicity of this regimen without intraventricular treatment was evaluated in PCNSL. From August 2003 to November 2005, 18 patients with PCNSL <60 years (median age, 53 years) were treated in a phase II trial with a high-dose methotrexate (MTX; cycles 1, 2, 4 and 5) and cytarabine (Ara-C; cycles 3 and 6) based systemic therapy including dexamethasone, vinca-alkaloids, ifosfamide and cyclophosphamide. Study accrual was prematurely stopped in November 2005 due to a high rate of early relapses. Seventeen of 18 patients were assessable for response: nine (53%) achieved complete response (CR), two (12%) complete response/unconfirmed (CRu) and two (12%) partial response (PR); four (24%) showed progressive disease (PD). One treatment was stopped due to toxicity. Median follow-up was 23 months, median response duration was only 10 months in responding patients, and median time to treatment failure (TTF) was 8 months in the whole group. Median overall survival (OS) has not been reached. Systemic toxicity was mainly hematologic. In PCNSL patients <60 years, polychemotherapy without intraventricular treatment results in a high response rate, but is associated with early relapses in the majority of cases. This is in contrast to the results achieved with the same protocol but with intraventricular treatment.
    Journal of Neuro-Oncology 10/2008; 91(3):299-305. · 3.12 Impact Factor
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    ABSTRACT: Methotrexate (MTX) is an important anticancer drug and the most efficient chemotherapy component in primary CNS lymphoma (PCNSL). A typical side effect of intravenous high-dose MTX is the occurrence of confluent CNS white matter changes (WMC). Because MTX directly interferes with methionine metabolism, we analyzed the impact of genetic variants of methionine metabolism on the occurrence of WMC as a model of MTX toxicity. In a retrospective analysis of 68 PCNSL patients treated with MTX-based polychemotherapy with (n = 42) or without (n = 26) intraventricular treatment, 10 genetic variants influencing methionine metabolism were analyzed. Pearson's chi(2) test and multinominal regression analysis were used to define the relevance of these genetic variants for the occurrence of WMC. In this patient sample, the occurrence of WMC was significantly predicted by the TT genotype of methylenetetrahydrofolate reductase c.677C>T (chi(2) = 8.67; p = 0.013; df = 2), the AA genotype of methylenetetrahydrofolate reductase c.1298A>C (chi(2) = 13.5; p = 0.001; df = 2), and the GG genotype of transcobalamin 2 c.776C>G (chi(2) = 19.73; p < 0.001), in addition to male gender (chi(2) = 11.95; p = 0.001). These data strengthen the hypothesis that MTX effects are influenced by methionine metabolism, which may offer new strategies to improve MTX-based therapies.
    Neuro-Oncology 09/2008; 11(1):2-8. · 6.18 Impact Factor
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    ABSTRACT: As antifungal agents are frequently used in hematology and oncology, economic data on the empirical therapy of suspected systemic fungal infection are pivotal. Data were analyzed according to: (1) the rate of nephrotoxicity related to treatment with caspofungin in comparison to liposomal amphotericin B (L-AmB) from a randomized clinical trial, (2) the effect of nephrotoxicity on length of hospital stay from a European observational study, and (3) an example of total bottom-up cost in a department of hematology in Germany. All estimates include 95% confidence intervals (CI) using two-stage Monte Carlo simulation on binominal and Gaussian random variables from separate studies with comparable populations. Overall, 8.9 (95% CI 5.9-12.1) fewer patients (of 100 randomized) experienced worsening of renal function with caspofungin vs L-AmB, giving a number needed to treat for one patient to be harmed by L-AmB of 12 (95% CI 8-17). This was estimated to translate into 5.3 extra days in hospital (95% CI 1.6-9.1) per event or 0.48 days (95% CI 0.14-0.88) worth 298 euro (95% CI 89-554) per patient receiving L-AmB rather than caspofungin. From the hospital perspective, use of caspofungin was estimated to be cost-neutral compared to L-AmB at a per diem total hospital cost of 428 euro with, and 1284 euro without, consideration of supplementary reimbursement (Zusatzentgelt) of both L-AmB and caspofungin. The data presented in this scenario show that use of caspofungin in hematology-oncology departments in Germany results in shorter hospital stays and is at least cost-neutral compared to use of L-AmB.
    Annals of Hematology 05/2008; 87(4):311-9. · 2.87 Impact Factor

Publication Stats

2k Citations
348.42 Total Impact Points

Institutions

  • 2010–2012
    • University of South Florida
      • Center for Evidence Based Medicine and Health Outcomes Research
      Tampa, FL, United States
  • 2011
    • University Hospitals Bristol NHS Foundation Trust
      Bristol, England, United Kingdom
  • 2001–2011
    • University of Bonn
      • • Medizinische Klinik und Poliklinik II
      • • Medizinische Klinik und Poliklinik I
      Bonn, North Rhine-Westphalia, Germany
  • 2008–2010
    • University of Bonn - Medical Center
      Bonn, North Rhine-Westphalia, Germany
    • Ruhr-Universität Bochum
      Bochum, North Rhine-Westphalia, Germany
  • 2009
    • Moffitt Cancer Center
      • Department of Health Outcomes and Behavior (HOB)
      Tampa, FL, United States
  • 2005
    • Royal Free London NHS Foundation Trust
      • Department of Haematology
      Londinium, England, United Kingdom
    • Ernst von Bergmann Klinikum Potsdam
      Potsdam, Brandenburg, Germany
  • 2004
    • World Health Organization WHO
      Genève, Geneva, Switzerland
  • 2002
    • University of Birmingham
      Birmingham, England, United Kingdom