Neoadjuvant irradiation of extremity soft tissue sarcoma with ions (Extrem-ion): study protocol for a randomized phase II pilot trial.

BACKGROUND: The standard of care treatment for soft tissue sarcoma of the extremities is a wide resection in combination with pre- or postoperative radiotherapy with high local control rates, sparing patients the necessity of amputation without compromising on overall survival rates. The currently preferred timing of radiotherapy is under debate. Albeit having higher rates of acute wound complications, late side effects like fibrosis, joint stiffness or edema are less frequent in preoperative compared to postoperative radiotherapy. This can be explained in smaller treatment volumes and a lower dose in the preoperative setting. Particles allow better sparing of surrounding tissues at risk, and carbon ions additionally offer biologic advantages and are preferred in less radiosensitive tumors. Hypofractionation allows for a significantly shorter treatment duration. METHODS: Extrem-ion is a prospective, randomized, monocentric phase II trial. Patients with resectable or marginally resectable, histologically confirmed soft tissue sarcoma of the extremities will be randomized between neoadjuvant proton or neoadjuvant carbon ion radiotherapy in active scanning beam application technique (39 Gy [relative biological effectiveness, RBE] in 13 fractions [5-6 fractions per week] in each arm). The primary objective is the proportion of therapies without wound healing disorder the first 120 days after surgery or discontinuation of treatment for any reason related to the treatment. The secondary endpoints of the study consist of local control, local progression-free survival, disease-free survival, overall survival, and quality of life. DISCUSSION: The aim of this study is to confirm that hypofractionated, preoperative radiotherapy is safe and feasible. The potential for reduced toxicity by the utilization of particle therapy is the rational of this trial. A subsequent randomized phase III trial will compare the hypofractionated proton and carbon ion irradiation in regards to local control. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04946357 ; Retrospectively registered June 30, 2021.

Anti-infective vaccination strategies in patients with hematologic malignancies or solid tumors-Guideline of the Infectious Diseases Working Party (AGIHO) of the German Society for Hematology and Medical Oncology (DGHO).

Infectious complications are a significant cause of morbidity and mortality in patients with malignancies specifically when receiving anticancer treatments. Prevention of infection through vaccines is an important aspect of clinical care of cancer patients. Immunocompromising effects of the underlying disease as well as of antineoplastic therapies need to be considered when devising vaccination strategies. This guideline provides clinical recommendations on vaccine use in cancer patients including autologous stem cell transplant recipients, while allogeneic stem cell transplantation is subject of a separate guideline. The document was prepared by the Infectious Diseases Working Party (AGIHO) of the German Society for Hematology and Medical Oncology (DGHO) by reviewing currently available data and applying evidence-based medicine criteria.

The influence of rituximab, high-dose therapy followed by autologous stem cell transplantation, and age in patients with primary CNS lymphoma.

For patients with diffuse large B cell lymphoma without the involvement of the CNS, the addition of rituximab to standard chemotherapy has significantly improved survival. In this single-center, retrospective analysis, a total of 81 primary CNS lymphoma (PCNSL) patients treated in our institution between 2000 and 2011 were included. Beside first-line chemotherapy with or without rituximab, we evaluated the impact of age (≤/>60 years), autologous stem cell transplantation (ASCT +/-), and other factors upon overall survival (OS) and progression-free survival (PFS). In patients treated with rituximab (n = 27), 3-year OS was 77.8 % (95 % confidence interval (CI) 62-93 %). In contrast, in patients treated without rituximab (n = 52), 3-year OS was only 39.9 % (CI 27-53 %, Fig. 1). The difference in OS was significant in the univariate (p = 0.002) as well as in the multivariate analysis (p = 0.049, hazard ratio (HR) = 0.248). Patients ≤60 years of age (n = 28) had a 3-year OS of 78.2 % (CI 63-94 %); in patients >60 years (n = 51), 3-year OS was 38.7 % (CI 25-52 %). Patients who received high-dose therapy and ASCT had a 3-year OS of 85.2 % (CI 72-99 %), and 65.1 % were alive up to the time of analysis (range 9-131 months). Without ASCT, median OS was only 16 months (CI 11-21) and 3-year OS was 35.2 % (CI 22-48 %). Age and ASCT were significantly associated with better OS in univariate (p = 0.002 and p < 0.001) as well in multivariate analysis (p = 0.004, HR = 0.023 and p = 0.001, HR = 0.014). Rituximab treatment, ASCT, and age are independent prognostic factors for OS in the first-line treatment of PCNSL.

Identification of invasive fungal diseases in immunocompromised patients by combining an Aspergillus specific PCR with a multifungal DNA-microarray from primary clinical samples.

The increasing incidence of invasive fungal diseases (IFD), most of all invasive aspergillosis (IA) in immunocompromised patients emphasises the need to improve the diagnostic tools for detection of fungal pathogens. We investigated the diagnostic performance of a multifungal DNA-microarray detecting 15 different fungi [Aspergillus, Candida, Fusarium, Mucor, Rhizopus, Scedosporium and Trichosporon species (spp.)] in addition to an Aspergillus specific polymerase chain reaction (PCR) assay. Biopsies, bronchoalveolar lavage and peripheral blood samples of 133 immunocompromised patients (pts) were investigated by a multifungal DNA-microarray as well as a nested Aspergillus specific PCR assay. Patients had proven (n = 18), probable (n = 29), possible (n = 48) and no IFD (n = 38) and were mostly under antifungal therapy at the time of sampling. The results were compared to culture, histopathology, imaging and serology, respectively. For the non-Aspergillus IFD the microarray analysis yielded in all samples a sensitivity of 64% and a specificity of 80%. Best results for the detection of all IFD were achieved by combining DNA-microarray and Aspergillus specific PCR in biopsy samples (sensitivity 79%; specificity 71%). The molecular assays in combination identify genomic DNA of fungal pathogens and may improve identification of causative pathogens of IFD and help overcoming the diagnostic uncertainty of culture and/or histopathology findings, even during antifungal therapy.

Autologous stem cell transplantation for elderly patients with newly diagnosed multiple myeloma in the era of novel agents.

BACKGROUND: High-dose therapy (HDT) with autologous stem cell transplantation (ASCT) is considered the standard of care for multiple myeloma (MM) patients <65 years. Safety and outcome of ASCT for patients >65 years is currently uncertain, especially since the introduction of novel agents for induction and maintenance therapy. Furthermore, there are no conclusive data available on risk assessment in elderly patients treated with HDT. PATIENTS AND METHODS: We retrospectively analyzed 202 patients ≥60 years with newly diagnosed MM who underwent ASCT at our institution. Patients were stratified by age into three groups (60-64, 65-69 and 70-75 years). For safety assessment, we compared data about hospitalization, hematopoetic reconstitution and early mortality. Remission before and after ASCT was analyzed according to age and application of novel agents. Event-free (EFS) and overall survival (OS) were analyzed to identify impact of age, remission before/after ASCT and maintenance therapy as well as ISS score and cytogenetic aberrations on outcome in elderly patients. RESULTS: The assessment of safety, remission before/after ASCT as well as EFS and OS showed no significant differences between the three groups (median EFS: 60-64 years: 27 months; 65-69 years: 23 months; 70-75 years: 23 months; median OS: not reached). Patients receiving novel agents as part of induction therapy achieved significantly higher nCR + CR rates than patients treated without novel agents. In Cox regression analysis, ISS and cytogenetics as well as remission after ASCT had the highest prognostic impact on EFS and OS. Maintenance therapy was associated with longer EFS in uni- and multivariate analyses. CONCLUSION: ASCT is feasible for selected patients >65 and >70 years without increased mortality. Age at transplantation has no prognostic significance on outcome after ASCT. Novel agents during induction therapy and maintenance therapy improves outcome of older patients eligible for ASCT. ISS and cytogenetic analysis should be carried out routinely for risk assessment.

Tigecycline in febrile neutropenic patients with haematological malignancies: a retrospective case documentation in four university hospitals.

OBJECTIVES: Tigecycline (TGC) is a first-in-class glycylcycline with an expanded spectrum of activity. Although TGC has not been prospectively studied in febrile neutropenia (FN), we observed that occasionally critically ill neutropenic patients unresponsive to other antibiotics were treated with TGC in our departments. The aim of our study was to analyse effectiveness and toxicity of TGC in FN. METHODS: Data of infectious episodes treated with TGC were retrospectively collected. Baseline data of patients, haematological malignancy, infection and adverse events were documented. Success was defined as defervescence (≥7 days) in the absence of any sign of persistent infection. RESULTS: Data of 35 patients with haematological malignancies and FN were evaluated. Median duration of neutropenia was 25 days (range 6-69 days). The type of infection was pneumonia in 24 patients, four microbiologically documented infections, three clinically documented infections and four with fever of unknown origin. The TGC was administered after a median of two (range 1-5) prior antibiotic regimens. Treatment was successful in 15 (43 %) patients. In patients with prolonged neutropenia (≥28 days), response was significantly lower (13 vs. 79 %; p =0.001). Eight (23 %) patients died during the fever episode. Grade 3-4 toxicity occurred in five (14 %) patients. CONCLUSION: Our results showed promising response rates to TGC and very low toxicity rates compared to the generally low response rate of third-line antibiotic therapies, indicating that TGC may be a successful alternative for salvage treatment of febrile neutropenia, but further study is needed.

Pemetrexed in patients with refractory soft tissue sarcoma: a non-comparative multicenter phase II study of the German Sarcoma Group AIO-STS 005.

BACKGROUND: This study evaluated efficacy and safety of pemetrexed in patients with refractory soft tissue sarcoma. METHODS: Patients received pemetrexed intravenously at a dose of 500 mg/m² every 21 days until progression or unacceptable toxicity. The primary endpoint was objective tumor response. RESULTS: Fourty-eight of 53 screened patients were included and received a total of 200 cycles (median 2; range 1-30). Median age was 53 years (range, 20-81). The observed toxicity profile was favorable. NCI-CTC hematologic grade 3/4 toxicity consisted of neutropenia in 13 %, anemia in 15 %, and febrile neutropenia in 4 % of patients of patients, respectively. Non-hematologic CTC grade 3/4 toxicity consisted of elevated ASAT/ALAT in 10 %, hyperglycemia in 6 %, infection with or without neutropenia in 6 %, nausea in 2 % and stomatitis in 2 % of patients. No other grade 3 toxicities and no treatment-related toxic deaths were observed. Overall response as defined by RECIST was 5 %, 16 patients experienced stable disease (40 %). The estimated 3- and 6-months progression-free rates were 33.3 % and 14.6 %, respectively. CONCLUSIONS: In patients with refractory STS, pemetrexed is well tolerated and moderately effective. The confirmed objective response rate in STS is low, however, disease stabilizations are seen in a high proportion of patients (ClinicalTrials.gov NCT00427466).

Association of transcobalamin c. 776C>G with overall survival in patients with primary central nervous system lymphoma.

BACKGROUND: Chemotherapy for primary central nervous system lymphoma (PCNSL) is based on methotrexate (MTX), which interferes with both nucleic acid synthesis and methionine metabolism. We have reported previously that genetic variants with influence on methionine metabolism are associated with MTX side effects, that is, the occurrence of white matter lesions as a sign of MTX neurotoxicity. Here, we investigated whether such variants are associated with MTX efficacy in terms of overall survival in MTX-treated PCNSL patients. METHODS: We analysed seven genetic variants influencing methionine metabolism in 68 PCNSL patients treated with systemic and facultative intraventricular MTX-based polychemotherapy (Bonn protocol). RESULTS: Median age at diagnosis was 59 years (range: 28-77), 32 patients were female. Younger age (Wald=8.9; P=0.003) and the wild-type C (CC) allele of the genotype transcobalamin c (Tc2). 776C>G (Wald=6.7; P=0.010) were associated with longer overall survival in a multivariate COX regression analysis. CONCLUSION: This observation suggests that the missense variant Tc2. 776C>G influences both neurotoxicity and efficacy of MTX in the Bonn PCNSL protocol.

Posaconazole prophylaxis in patients with acute myelogenous leukaemia--results from an observational study.

Patients with acute myelogenous leukaemia (AML) and neutropenia after chemotherapy are at high risk for life-threatening invasive fungal disease (IFD), in particular, invasive aspergillosis (IA). The aim of the study was to evaluate data on characteristics, risk factors, complications and additional antifungal treatment of patients with AML receiving posaconazole prophylaxis (PP) after chemotherapy in an actual clinical setting. A retrospective single-centre observational study on 40 patients with AML, median age 66 years, was conducted. PP 200 mg three times daily was given routinely. After 76 cycles of remission induction chemotherapy followed by PP, median duration of 31 days (range 6-61 days), no fatal case occurred. The majority of patients had at least one additional risk factor for IFD and during 32 cycles (42.1%), three risk factors were present. During 40 therapy cycles (52.6%), fever of unknown origin occurred. Pneumonia was diagnosed after 23 cycles (30.3%), thereof one case of proven IA (1.3%). PP was interrupted in 25 cycles (32.9%) and was followed by systemic antifungal therapy with different agents, with a median duration 15 days (range: 6-32 days). PP appears to be an effective and well-tolerated protection against IFD for AML patients under natural clinical conditions.

Neoadjuvant irradiation of retroperitoneal soft tissue sarcoma with ions (Retro-Ion): study protocol for a randomized phase II pilot trial.

BACKGROUND: Following surgery for soft tissue sarcoma of the retroperitoneum, the predominant pattern of failure is local recurrence, which remains the main cause of death. Radiotherapy is utilized to reduce recurrence rates but the efficacy of this strategy has not been definitely established. As treatment tolerability is more favorable with preoperative radiotherapy, normofractionated neoadjuvant treatment is the current approach. The final results of the prospective, randomized STRASS (EORTC 62092) trial, which compared the efficacy of this combined treatment to that of surgery alone, are still awaited; preliminary results presented at the 2019 ASCO Annual Meeting indicated that combined treatment is associated with better local control in patients with liposarcoma (74.5% of the cohort, 11% benefit in abdominal progression free survival after 3 years, p = 0.049). Particles allow better sparing of surrounding tissues at risk, e.g., bowel epithelium, and carbon ions additionally offer biologic advantages and are preferred in slow growing tumors. Furthermore, hypofractionation allows for a significantly shorter treatment interval with a lower risk of progression during radiotherapy. METHODS AND DESIGN: We present a prospective, randomized, monocentric phase II trial. Patients with resectable or marginally resectable, histologically confirmed soft tissue sarcoma of the retroperitoneum will be randomized between neoadjuvant proton or neoadjuvant carbon ion radiotherapy in active scanning beam application technique (39 Gy [relative biological effectiveness, RBE] in 13 fractions [5-6 fractions per week] in each arm). The primary objective is the safety and feasibility based on the proportion of grade 3-5 toxicity (CTCAE, version 5.0) in the first 12 months after surgery or discontinuation of treatment for any reason related to the treatment. Local control, local progression-free survival, disease-free survival, overall survival, and quality of life are the secondary endpoints of the study. DISCUSSION: The aim of this study is to confirm that hypofractionated, accelerated preoperative radiotherapy is safe and feasible. The rationale for the use of particle therapy is the potential for reduced toxicity. The data will lay the groundwork for a randomized phase III trial comparing hypofractionated proton and carbon ion irradiation with regard to local control. TRIAL REGISTRATION: ClinicalTrials.gov NCT04219202 . Retrospectively registered on January 6, 2020.

Forty-one recent cases of invasive zygomycosis from a global clinical registry.

BACKGROUND: Invasive zygomycosis accounts for a significant proportion of all invasive fungal diseases (IFD), but clinical data on the clinical course and treatment response are limited. PATIENTS AND METHODS: Fungiscope-A Global Rare Fungal Infection Registry is an international university-based case registry that collects data of patients with rare IFD, using a web-based electronic case form at www.fungiscope.net. RESULTS: Forty-one patients with invasive zygomycosis from central Europe and Asia were registered. The most common underlying conditions were malignancies (n = 26; 63.4%), diabetes mellitus (n = 7; 17.1%) and solid organ transplantation (n = 4; 9.8%). Diagnosis was made by culture in 28 patients (68.3%) and by histology in 26 patients (63.4%). The main sites of infection were the lungs (n = 24; 58.5%), soft tissues (n = 8; 19.5%), rhino-sinu-orbital region (n = 8; 19.5%) and brain (n = 6; 14.6%). Disseminated infection of more than one non-contiguous site was seen in six patients (14.6%). Mycocladus corymbifer was the most frequently identified species (n = 10, 24.4%). A favourable response was observed in 23 patients (56.1%). Overall survival was 51.2% (n = 21). At diagnosis, four patients (9.8%) were on continuous antifungal prophylaxis with itraconazole (n = 1; 2.4%) or posaconazole (n = 3; 7.3%). Initial targeted treatment with activity against zygomycetes was administered to 34 patients (82.9%). Liposomal amphotericin B was associated with improved response (P = 0.012) and survival rates (P = 0.004). CONCLUSIONS: Pathogen distribution and, consequently, drug susceptibility seem to vary across different geographic regions. Furthermore, protection from invasive zygomycosis for patients on posaconazole prophylaxis is not absolute. Our findings indicate that the use of liposomal amphotericin B as first-line treatment for patients diagnosed with zygomycoses merits further investigation, preferably in the form of a clinical trial.

Radiotherapy in the treatment of aggressive fibromatosis: experience from a single institution.

BACKGROUND: Desmoid-type fibromatosis is a rare, potentially locally aggressive disease. Herein we present our experience in the treatment with radiotherapy. METHODS AND MATERIALS: In total 40 patients who received 44 treatments from 2009 to 2018 at the Heidelberg University Hospital with photons (N = 28) as well as protons (N = 15) and carbon ions (N = 1) were investigated. The median age at radiotherapy was 41 years [range 8-78]. Familial adenomatous polyposis (FAP) was confirmed for nine patients and 30 had a unifocal desmoid tumor. The localizations were abdominal wall, abdominopelvic cavity, thoracic wall, extremity, head and neck and trunk. The median prescribed dose was 54 Gy/ Gy (RBE) [range 39.6-66, IQR 50-60]. Eleven treatments were performed at the time of first diagnosis; 33 at the time of progression or recurrence. Post-operative radiotherapy was performed in 17 cases. The median planning target volume was 967 ml [84-4364 ml, IQR 447-1988]. Survival analysis was performed by the Kaplan-Meier Method. RESULTS: The median follow-up time was 32 months [1-153]. At the end of the follow-up interval all patients but one were alive. The estimated local progression free survival of the treated lesion in 3 and 5 years was 76.4% and 63,8%, respectively. The progression-free survival in 3 and 5 years was 72.3 and 58.4% and the overall survival was 97.4 and 97.4%, respectively. In case of macroscopic tumor (N = 31) before radiotherapy a partial remission was observed in 12 cases (38.7%) and a complete remission in 4 cases (12.9%). Progression was observed in 13 (29.5%) cases, predominantly at the margin of the planning target volume (PTV, N = 5, 38,4%) followed by progression within the PTV (N = 4, 30.8%). In univariate analysis multifocal localization was associated with impaired progression-free survival (p = 0.013). One patient developed a grade V gastrointestinal bleeding, otherwise no acute toxicity >°III was observed. Late toxicity was depending on the localization of the desmoid tumor and was especially severe in patients with FAP and abdominopelvine desmoids including gastrointesinal fistula, perforation and abscess. CONCLUSION: Radiotherapy in the treatment of desmoids can lead to long term control. Treatment of patients with abdominopelvine desmoids should be avoided, as the risk of higher-grade complications is substantial.

Successful autologous peripheral blood stem cell transplantation in a Jehovah's Witness with multiple myeloma: review of literature and recommendations for high-dose chemotherapy without support of allogeneic blood products.

We present a case report of a successful high-dose melphalan therapy and autologous stem cell transplantation without the use of allogeneic blood product support in a 70-year-old patient suffering from multiple myeloma. Based on the experience in this case and thorough evaluation of the literature, we consider pre-transplant Hb level of 11-12 g/dl, platelet count higher than 70/nl, good WHO performance status of two and lower and informed consent as important eligibility criteria. During cytopenia recommended supportive measures include growth factor support with erythropoietin and G-CSF, p.o. iron treatment as well as prophylactic use of anti-fibrinloytic agents. Furthermore we discuss additional options that might be considered depending on the individual factors as e.g. pre-transplant collection and cryoconservation of autologous platelet concentrates. Moreover, an analysis of socio-economic issues regarding this procedure is presented. We conclude that allogeneic blood product free transplantation is a feasible procedure that can be offered to the patients belonging to distinct religious groups refusing allogeneic blood products as Jehovás Witnesses and patients presenting other contraindications for transfusions.

High-dose chemotherapy with autologous haematopoietic stem cell support for relapsed or refractory primary CNS lymphoma: a prospective multicentre trial by the German Cooperative PCNSL study group.

To investigate safety and efficacy of high-dose chemotherapy followed by autologous stem cell transplantation (HCT-ASCT) in relapsed/refractory (r/r) primary central nervous system lymphoma (PCNSL), we conducted a single-arm multicentre study for immunocompetent patients (<66 years) with PCNSL failing high-dose methotrexate)-based chemotherapy. Induction consisted of two courses of rituximab (375 mg/m2), high-dose cytarabine (2 × 3 g/m2) and thiotepa (40 mg/m2) with collection of stem cells in between. Conditioning for HCT-ASCT consisted of rituximab 375 mg/m2, carmustine 400 mg/m2 and thiotepa (4 × 5 mg/kg). Patients commenced HCT-ASCT irrespective of response after induction. Patients not achieving complete remission (CR) after HCT-ASCT received whole-brain radiotherapy. Primary end point was CR after HCT-ASCT. We enrolled 39 patients; median age and Karnofsky performance score are 57 years and 90%, respectively. About 28 patients had relapsed and 8 refractory disease. About 22 patients responded to induction and 32 patients commenced HCT-ASCT. About 22 patients (56.4%) achieved CR after HCT-ASCT. Respective 2-year progression-free survival (PFS) and overall survival (OS) rates were 46.0% (median PFS 12.4 months) and 56.4%; median OS not reached. We recorded four treatment-related deaths. Thiotepa-based HCT-ASCT is an effective treatment option in eligible patients with r/r PCNSL. Comparative studies are needed to further scrutinise the role of HCT-ASCT in the salvage setting.

Piperacillin/tazobactam vs ceftazidime in the treatment of neutropenic fever in patients with acute leukemia or following autologous peripheral blood stem cell transplantation: a prospective randomized trial.

Piperacillin/tazobactam was compared with ceftazidime for the empirical treatment of febrile neutropenia in patients with acute leukemia or following autologous peripheral blood stem cell transplantation. Owing to inclusion criteria, it was possible for the same patient to be randomized several times. A total of 219 individual patients were admitted to a prospective randomized clinical study: 24 patients were included twice. Patients (23.5%) remained afebrile. Patients who developed febrile neutropenia were randomized to receive intravenous ceftazidime (n = 74 patients, group I) or piperacillin/tazobactam (n = 87 patients, group II). Response to first-line antibiotic treatment was seen in 55% (group I) and 53% (group II). After the addition of vancomycin, a further 19% (group I) and 24% (group II) of the patients became afebrile. Causes of fever were: microbiologically documented infection in 36 and 34 patients of group I and II; Clostridium difficile in eight and 12 patients of group I and II, and fever of unknown origin in 30 and 41 patients of group I and II. One patient died in each group. Single-agent therapy with piperacillin/tazobactam is as effective as ceftazidime in the treatment of neutropenic fever and is well tolerated. Direct and indirect costs of both treatment regimes are equivalent.

Diagnosis of invasive fungal infections in haematological patients by combined use of galactomannan, 1,3-ß-D-glucan, Aspergillus PCR, multifungal DNA-microarray, and Aspergillus azole resistance PCRs in blood and bronchoalveolar lavage samples: results of a prospective multicentre study.

High mortality rates of invasive fungal disease (IFD), especially invasive aspergillosis (IA), in immunocompromised haematological patients and current diagnostic limitations require improvement of detection of fungal pathogens by defining the optimal use of biomarkers and clinical samples. Concurrent bronchoalveolar lavage (BAL) and peripheral blood samples of 99 haematological patients with suspected IFD were investigated within a multicentre prospective study. Diagnostic performance of a galactomannan (GM) enzyme immune assay (EIA), a 1,3-ß-D-glucan assay (BDG), an Aspergillus PCR, and a multifungal DNA-microarray (Chip) alone or in combination were calculated. IFD were classified as proven (n=3), probable (n=34), possible (n=33), and no IFD (n=29) according to EORTC/MSG criteria. GM, PCR, and Chip showed superior diagnostic performance in BAL than in blood, whereas specificity of BDG in BAL was poor (48% (14/29)). The combination of GM (BAL) with BDG (blood) showed sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and DOR (diagnostic odds ratio) of 92% (34/37), 93% (27/29), 94%, 90%, and 153.0, respectively. Combining GM (BAL) with PCR (BAL) showed convincing diagnostic potential for diagnosing IA with sensitivity, specificity, PPV, NPV, and DOR of 85% (17/20), 97% (28/29), 94%, 90%, and 158.7. Addition of the DNA-microarray resulted in further detection of two mucormycetes infections. In 1 out of 15 Aspergillus DNA-positive samples a triazole resistance-mediating Cyp51A mutation was found. Combination of biomarkers is superior to their sole use in diagnosing IFD, particularly IA. Integrating blood and BAL samples into a diagnostic algorithm is an advantageous approach.

High plasma basic fibroblast growth factor concentration is associated with response to thalidomide in progressive multiple myeloma.

The aim of this study was to define prognostic factors that might be predictive for response to thalidomide (Thal) in progressive multiple myeloma (n = 54). We examined the concentration of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), two potent heparin-binding mediators of angiogenesis in peripheral blood (PB; PB-VEGF and PB-bFGF) and bone marrow (BM; BM-VEGF and BM-bFGF), in combination with well-characterized predictors for response and survival to chemotherapy. After a median follow-up time of 15 months (range, 0.3-20), 29 patients (pts.) showed at least a minimal response to Thal therapy, whereas 25 pts. were nonresponsive. As shown by univariate analysis, responsive pts. had statistically significant higher concentrations of PB-bFGF (P = 0.009) and beta2-microglobulin (P = 0.03) before therapy, as well as lower hemoglobin (P = 0.008) and albumin (P = 0.02) levels, whereas no statistically significant difference was found for PB-VEGF (P = 0.93). When a multiple logistic regression analysis was performed, PB-bFGF was the only statistically significant predictor for response to therapy (P = 0.01). None of these variables was associated with a prolonged progression-free survival. In conclusion, our findings indicate that high pretreatment plasma bFGF levels in pts. with progressive multiple myeloma are associated with unfavorable parameters of response and survival but nevertheless predict for response to Thal therapy.

Successful autologous transplantation of blood stem cells mobilized with recombinant human granulocyte-macrophage colony-stimulating factor.

We investigated the effect of recombinant human granulocyte-macrophage colony-stimulating factor (rhuGM-CSF) on the pool of circulating hemopoietic progenitor cells in 11 patients with hematological malignancies of nonmyeloid origin and 1 patient with sarcoma. These patients were eligible for autologous blood stem cell transplantation rather than autologous bone marrow transplantation because sufficient marrow aspirates could not be performed due to damage at the usual sites of bone marrow harvest by previous chemo- and/or radiotherapy. Recombinant human GM-CSF was given as continuous i.v. infusion via central venous line for a median time of 11.5 days (range 5-22 days), during which a median number of six aphereses were performed. In comparison to the pretreatment level the median increase in the number of granulocyte-macrophage colony-forming units (CFU-GM)/ml of peripheral blood was 8.5-fold. In all 12 patients a median decrease of the platelet count of 21% (range 7%-67%) was observed during rhuGM-CSF treatment prior to the start of the apheresis procedures. Six patients were treated with a myeloablative conditioning therapy consisting of total body irradiation and/or high-dose polychemotherapy followed by autografting with blood stem cells. Five of them achieved a sustained engraftment. Recombinant human GM-CSF proved to be highly efficient in increasing the number of circulating progenitor cells in these patients with severely compromised hemopoiesis. Blood stem cells harvested under a rhuGM-CSF treatment are capable of restoring hemopoiesis in man after a myeloablative pretransplant therapy.

Autologous and allogeneic stem cell transplantation in multiple myeloma.

Multiple myeloma is still an incurable disease. The standard conventional chemotherapy comprises melphalan and prednisone (MP). Combination chemotherapy regimens could not improve the median survival of 36 months observed with MP. In the French IFM90 study, HD therapy with TBI plus melphalan 140 mg/m2 was shown to prolong overall survival and progression-free survival compared to conventional treatment. Nonetheless, most patients eventually succumb due to disease progression. Allogeneic transplantation may induce long-term remissions and even cure, but is hampered by a high transplantation-related mortality (TRM). Currently, efforts are made to reduce this TRM and to evaluate the graft-versus-myeloma effect.

Recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) subsequent to chemotherapy improves collection of blood stem cells for autografting in patients not eligible for bone marrow harvest.

Fourteen patients with relapsed Hodgkin's disease responded to a salvage therapy with Dexa-BEAM (dexamethasone, BCNU, etoposide, Ara-C and melphalan). In seven patients a continuous i.v. infusion with recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) was started subsequent to Dexa-BEAM (+rhGM-CSF) while the other seven patients received no hemopoietic growth factor (-rhGM-CSF). It was our objective to study the impact of rhGM-CSF on the collection of blood-derived hemopoietic stem cells in patients with extensive prior chemo- and radiotherapy not eligible for marrow harvest. Compared to baseline, we observed a significant increase of colony-forming units granulocyte-macrophage (CFU-GM) in the peripheral blood of patients receiving rhGM-CSF (p less than 0.05). On average, the yield of total nucleated cells and CFU-GM collected per single leukapheresis was 2.2 and 2.4-fold higher in the rhGM-CSF-treated patients respectively (p less than 0.05). With rhGM-CSF the interval from the start of chemotherapy to the end of blood stem cell collection could be reduced by 6 days (p less than 0.05). Following the CBV pretransplant regimen (cyclophosphamide, BCNU, etoposide), the reinfusion of rhGM-CSF-exposed stem cells resulted in a shorter time of leukocyte recovery (p less than 0.05). The number of CFU-GM/kg body weight transplanted was found to be predictive for the time of neutrophil recovery (p less than 0.05). In patients with bone marrow hypoplasia or fibrosis, rhGM-CSF as part of an effective salvage therapy improves the collection of blood stem cells that are capable of restoring hemopoiesis after high-dose pretransplant therapy.