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Biomedical subjects

Hermann Einsele

Publications and source records attributed to Hermann Einsele.

At least 37 records · Page 2Linked to original sources
PubMed2005

Duplication of chromosome arms 9q and 11q: evidence for a novel, 14q32 translocation-independent pathogenetic pathway in multiple myeloma.

14q32 translocations [t(14q)] represent critical but not universal events in multiple myeloma (MM). Gains of chromosome arms 1q, 9q, and 11q (+1q, +9q, and +11q) have recently been identified as frequent aberrations in this disease, but their pathogenetic significance remains unclear. We studied a series of 108 MM patients using fluorescence in situ hybridization and DNA probes mapping to chromosome bands 1q21, 9q34, 11q25, 13q14, and 14q32. Three subsets of tumors were defined: (1) MM+/+ (detection of +9q and +11q; 43.5% of cases), (2) MM+/- (+9q or +11q; 21.3%), and (3) MM-/- (neither +9q nor +11q; 35.2%). The incidence of t(14q) was significantly different in these subgroups: 23% in MM+/+, 56% in MM+/-, and 89% in MM-/-. Deletion of 13q (13q-) also was significantly less frequent in MM+/+ (23%) than in MM+/- and MM-/- (36% and 63%, respectively). The nonrandom distribution of chromosomal aberrations in the present series of MM tumors points to a novel, 14q32 translocation-independent pathogenetic pathway in plasma cell neoplasms.

Chromosome Aberrations↗
PubMed2005

Significance of the "halo" sign for progression and regression of nodular pulmonary amyloidosis: radiographic-pathological correlation (2005:6b).

We describe a case of a systemic amyloidosis of kappa-AL type, presenting at CT as focal lung parenchymal nodules or areas of consolidation with or without a halo,showing different sizes and morphologic kinetics at follow-up. Lesions accompanied by a halo revealed faster progression and earlier response to chemotherapy with almost complete resolution after high dose therapy with a cytostatic alkylating agent(Melphalan) and autologous peripheral stem cell transplantation than their counterparts without a halo. Amyloid deposition was histologically confirmed, and severe inflammatory activity was found in and at the margins of the amyloidomas, the latter correlating in CT with the halo sign. In our case, this sign had a high prediction for growth kinetics and response to therapy of pulmonary amyloid.

Amyloid↗
PubMed2005

Infectious pulmonary complications after stem cell transplantation or chemotherapy: diagnostic yield of bronchoalveolar lavage.

Hematologic patients are at high risk for infectious pulmonary complications after stem cell transplantation (SCT) or chemotherapy. The aim of this study was to detect the range of pulmonary pathogens in these patients, analyzing 95 bronchoalveolar lavage (BAL) samples with classic and molecular (polymerase chain reaction [PCR]) detection methods. Human cytomegalovirus (HCMV) was detected in 33, herpes simplex virus in 21, human herpesvirus 6 in 24, and other viruses in 16 samples. Aspergillus species were detected in 19, Candida species in 25, and Gram-positive bacteria in 29 samples. The additional use of PCR detection methods increased the diagnostic yield from 56% to 73%, especially concerning viral and fungal infections in BAL samples. No infectious agent was detected in 26 samples. Interestingly, a high incidence of polymicrobial infections (50/95) was detected, dominated by HCMV co-infections, especially after allogeneic SCT. Within 3 years of follow-up, a poor outcome of co-infections of Aspergillus species with HCMV in 9 of 10 cases could be documented, whereas only 7 of 20 patients died with noninfectious BAL results. Herpesviruses, fungi, and Gram-positive bacteria were detected most frequently, and in 53%, polymicrobial infections were diagnosed.

Adult↗
PubMed2005

Empirical antimicrobial monotherapy in patients after high-dose chemotherapy and autologous stem cell transplantation: a randomised, multicentre trial.

We report on 232 patients undergoing autologous haematopoietic stem cell transplantation (ASCT) entered into a multicentre, randomised trial comparing the efficacy and tolerability of meropenem (MPM) with that of piperacillin/tazobactam (P/T) as empirical antimicrobial first-line therapy for febrile neutropenia. In 27.6% of patients in the MPM group and 22.4% in the P/T group, therapy was initially supplemented with a glycopeptide for venous catheter infection or bacteraemia because of coagulase-negative staphylococci. Complete response rate after 72 h was 63.8% in the MPM group and 49.6% in the P/T group (P = 0.034). Overall complete response rate after treatment modification was 94.0% in the MPM group and 93.1% in the P/T group. Median time to defervescence was 2 d in the MPM group and 3 d in the P/T group. The most frequently isolated pathogens were Gram-positive cocci. Treatment was well tolerated in both groups. One patient (0.4%) died from infection. Empirical first-line therapy with MPM as well as with P/T is safe and effective in febrile episodes emerging after ASCT. Higher response rates to primary treatment can be achieved with MPM.

Adolescent↗
PubMed2005

Mucormycoses in patients with hematologic malignancies: an emerging fungal infection.

BACKGROUND AND OBJECTIVES: Mucormycoses are seen with an increasing incidence in immunocompromised patients. Most common presentations are rhinocerebral and pulmonary. We here report the experience of a single center with mucormycoses in patients with hematologic malignancies. RESULTS: Mucormycoses were diagnosed in six patients, (median age of 52 years; range, 26-74) treated between 2001-2004. Diagnoses included acute myeloid leukemia (AML) (n=3), acute lymphoblastic leukemia (n=1), chronic lymphocytic leukemia (n=1) and multiple myeloma (n=1). Mucormycosis was diagnosed in the neutropenic state following allogeneic hematopoietic cell transplantation (n=3) or intense chemotherapy (n=3). Sites of infections were rhinocerebral, facial and pulmonary involvement in one patient each and disseminated mucormycosis in three patients. The diagnosis was established by computed tomography followed by surgical interventions and histological diagnosis in 4 patients and post-mortem in two patients. Species identified were Rhizopus (n=3), Rhizomucor (n=2) and Absidia (n=1). Treatment responses were best if surgical resection was followed by aggressive antifungal chemotherapy. Five of six 6 patients died, all of complications of mucormycosis or their underlying disease. Only one patient with facial mucormycosis is still alive. CONCLUSIONS: This experience demonstrates that patient with mucormycoses have a high mortality rate and early recognition followed by aggressive surgical debridement, high dose antifungal therapy and attempts to correct the underlying immunocompromised state are crucial in the treatment of this fatal infection.

Adult↗
PubMed2004

Myeloma cell contamination of peripheral blood stem-cell grafts can predict the outcome in multiple myeloma patients after high-dose chemotherapy and autologous stem-cell transplantation.

PURPOSE: High-dose chemotherapy with hematopoietic stem-cell rescue is increasingly being used in the treatment of multiple myeloma. Bone marrow and also peripheral blood stem-cell (PBSC) grafts contain measurable quantities of plasma cells, the biological significance of which is unknown. METHODS: Patients with multiple myeloma were mobilized with chemotherapy and filgrastim. The number of CD38++/CD138+ cells/kg in the grafts for autologous transplantation was determined by flow cytometry. Patients were stratified into two groups (threshold 4.5 x 10(5) plasma cells kg(-1)) of reinfused plasma cells in the first autologous graft. RESULTS: The median statistical progression-free survival was 14 months (4-34 months) in the high-contamination group (>4.5 x 10(5) plasma cells kg(-1)) compared to 26 months (4-43 months) in the low-contamination group (<4.5 x 10(5) plasma cells kg(-1), P =0.0096). Patients with 13q deletion were more frequently found to have a high contamination of the stem-cell graft with malignant plasma cells. CONCLUSIONS: Patients with graft contamination of more than 4.5 x 10(5) plasma cells kg(-1) had a high risk of early disease progression after high-dose chemotherapy. In vivo tumor cell purging prior to mobilization chemotherapy might be one strategy to improve the time to progression of high-risk patients.

Adult↗
PubMed2004

Early detection of Toxoplasma infection by molecular monitoring of Toxoplasma gondii in peripheral blood samples after allogeneic stem cell transplantation.

BACKGROUND: Isolated case reports have shown that recipients of allogeneic hematopoietic stem cell transplants (HSCTs) who develop toxoplasmosis may have circulating Toxoplasma gondii DNA in peripheral blood before the onset of clinical symptoms. METHODS: We prospectively studied 106 T. gondii-seropositive adult recipients of HSCTs for the incidence of reactivation of toxoplasmosis in the first 6 months after transplantation. Toxoplasmosis infection (TI) was defined by a positive result of polymerase chain reaction (PCR) of peripheral blood specimens, whereas toxoplasmosis disease (TD) was defined as an invasive infection. RESULTS: The incidence of TI was 16% (95% confidence interval [CI], 8%-21%), whereas the incidence of TD was 6% (95% CI, 1%-10%). In the 16 patients with TI, the incidence of disease was 38%, whereas it was 0% in patients without TI (P<.0001). In most patients, the onset of TD or treatment for TI was preceded by an increase in the parasite load in peripheral blood samples, as determined by quantitative PCR. CONCLUSIONS: Toxoplasmosis occurs more commonly after HSCT than has previously been suggested, and routine PCR testing of peripheral blood specimens may be an appropriate tool for guiding preemptive therapy in patients at very high risk of developing invasive disease.

Adult↗
PubMed2004

Responsiveness to G-CSF before leukopenia predicts defense to infection in high-dose chemotherapy recipients.

An active assessment of the host capacity to prevent infection during myelosuppression should be beneficial in patients receiving high-dose chemotherapy. A single dose of granulocyte colony-stimulating factor (G-CSF) (5 microg/kg) was given to 57 patients with multiple myeloma early after the completion of 85 high-dose chemotherapy (melphalan 200 mg/m2) courses. This provoked a highly variable white blood cell (WBC) peak after 12 to 14 hours. The median WBC count was 21,000/microL (range, 6400-60,600/microL) after a first high-dose therapy (n = 50) and 13,500/microL (range, 4700-24,800/microL) after a second high-dose therapy (n = 35). The responsiveness to single G-CSF was associated with the risk of infection during subsequent cytopenia (P =.003). This association was significant after adjustment for neutropenia duration. Notably, the result of testing G-CSF responsiveness was opportunely available before the onset of leukopenia, and G-CSF responsiveness was more informative than neutropenia duration regarding the risk of infection. Furthermore, there was an association between the responsiveness to G-CSF and stem cell engraftment (P <.005), which remained significant after adjustment for the number of transplanted CD34+ cells. Our results show for the first time that G-CSF potentially could be used for an early in vivo assessment of defense to infection in recipients of high-dose chemotherapy.

Adult↗
PubMed2004

Fatal immune-mediated pancytopenia and a TRALI-like syndrome associated with high titers of recipient-type antibodies against donor-derived peripheral blood cells after allogeneic bone marrow transplantation following dose reduced conditioning.

Pancytopenia occurring after bone marrow transplantation is a rare complication. A 47 year old patient with progression of multiple myeloma after standard therapy received an allogeneic marrow graft from a matched unrelated donor. The non-myeloablative conditioning regimen consisted of fludarabine, cyclophosphamide, rabbit anti-thymocyte globulin and total body irradiation. GVHD prophylaxis consisted of cyclosporine. Neutrophil engraftment was as expected and the patient was discharged without signs of acute GvHD. On day +34 the patient presented with clinical and laboratory findings consistent with severe pancytopenia. Antibodies against red cells, platelets, lymphocytes and granulocytes were detected in extremely high titers. Immune-mediated pancytopenia was refractory on multiple immunosuppressive treatment strategies. Proliferation of polyclonal plasma cells of recipient-type that was documented postmortem, was most likely responsible for excessive antibody formation.

Anemia, Hemolytic, Autoimmune↗
PubMed2004

Identification of new Th peptides from the cytomegalovirus protein pp65 to design a peptide library for generation of CD4 T cell lines for cellular immunoreconstitution.

CD8 and CD4 lymphocytes control cytomegalovirus (CMV) infection in immunocompetent individuals, while patients with defective cellular immunity are prone to endogenous reactivation of latent CMV or, like seronegative subjects, prone to primary infection. Administration of CMV-specific CD8 lymphocytes was beneficial for immunocompromised hemopoietic stem cell (HSC) graft recipients. Since CD4 cells contribute to expansion of cytotoxic T lymphocytes (CTL), we defined new T(h) peptides on the immunodominant protein pp65 recognized by CD4 cells from HLA-typed subjects, in the perspective of complementing CTL administration with CMV-specific T(h) cells. Screening by ELISPOT on CD4 and CD8 subsets using overlapping peptides identified 10 novel CD4 peptides. To simplify procedures to generate T cell lines, we used a CD4 peptide library for T cell stimulation instead of ill-defined viral lysates, without the requirement of dendritic cells. This library stimulated CMV-specific CD4 cells. In fact, peptide-induced CD4 cells responded to pp65 and to the viral lysate. These cells were also devoid of alloreactivity after one stimulation cycle. Since Good Manufacturing Procedure-grade peptides can be synthesized, culture conditions are simplified and alloreactivity is rapidly lost, these procedures based on peptide stimulation can facilitate implementation of adoptive reconstitution of CD4 responses in immunocompromised patients also in the case when the HSC allodonor is available for generation of the T cell line.

Adolescent↗
PubMed2004

Deletion of chromosome band 13q14 as detected by fluorescence in situ hybridization is a prognostic factor in patients with multiple myeloma who are receiving allogeneic dose-reduced stem cell transplantation.

We investigated in a retrospective multicenter study the impact of chromosome arm 13q deletion (13q-) as detected by fluorescence in situ hybridization (FISH) on outcome after dose-reduced allografting in patients with multiple myeloma. In 68 of 140 patients, data on chromosome 13q status were available. Most patients included had advanced myeloma. At 2 years, patients with 13q deletion (n = 31) had a shorter event-free (18% vs 42%; P =.05) and overall survival (18% vs 67%; P =.03) than patients without 13q- (n = 37). Patients with 13q- experienced a higher relapse rate (77% vs 44%; P <.001) but a similar incidence of transplantation-related mortality at one year (24% vs 18%). In a multivariate analysis, 13q- remained a significant risk factor for a higher relapse rate (hazard ratio [HR], 3.28; 95% confidence interval [CI], 1.31-8.24; P =.01) and a shorter event-free survival (HR, 1.94; 95% CI, 1.03-3.67; P =.04). Concerning overall survival, 2 or more cycles of prior high-dose chemotherapy were associated with a significantly higher probability of death (HR, 2.48; 95% CI, 1.19-5.17; P =.02), while patients with deletion 13q had a nearly 2 times higher risk of death (HR, 1.94; 95% CI, 0.95-3.98; P =.07) after dose-reduced allogeneic stem cell transplantation.

Adult↗
PubMed2004

Isolation and expansion of human adenovirus-specific CD4+ and CD8+ T cells according to IFN-gamma secretion for adjuvant immunotherapy.

OBJECTIVE: In patients with lymphopenia following allogeneic stem cell transplantation adenovirus (ADV) infection is associated with high morbidity and mortality despite aggressive antiviral drug therapy. Virus-specific T cells seem to be essential for virus elimination. The aim of this study was to isolate and expand donor-derived human ADV-specific T lymphocytes for adoptive transfer of sufficient cell numbers to restore protective immunity after allogeneic stem cell transplantation. MATERIALS AND METHODS: A clinical-grade strategy to generate ADV-specific T cells using the interferon-gamma (IFN-gamma) secretion assay, followed by expansion to numbers sufficient for clinical application with interleukin-2 (IL-2) and feeder cell stimulation, is described. RESULTS: A mean number of 3.4 x 10(6) (+/-3 SD) ADV antigen-specific T lymphocytes were isolated from 0.1 to 2 x 10(9) mononuclear cells from peripheral blood (n=5) or leukapheresis products (n=6). Characterization of ADV-specific T cells after isolation revealed a mean purity of 85.1% (+/-12% SD) using antigen-specific intracellular cytokine staining. Isolated cells were expanded ex vivo for a median of 18 days (range 7-29 days; n=5) to greater than 10(8) total cells using IL-2 and autologous feeder cell stimulation. ADV-specific response to adenovirus antigen was confirmed in the generated T cell lines, using intracellular cytokine staining, IFN-gamma Elispot assay, and (3)H-thymidine uptake. Generated T-cell lines showed specific killing of ADV-infected B-LCL (n=4). Alloreactive proliferation of generated T-cell lines in mixed lymphocyte cultures was significantly reduced when compared to unmanipulated PBMCs. CONCLUSION: Generation of adenovirus-specific T cells in a simple and rapid clinical-grade protocol was established, using IFN-gamma secretion assay with short expansion times, leading to sufficient numbers of ADV-specific T cells that can be used for adoptive immunotherapy.

Adenoviridae Infections↗
PubMed2004

CMV-specific immunotherapy.

Considerable progress has been made in our understanding of the immunobiology of infections in immunocompromised hosts. Insights derived from animal model and human studies have provided the rationale to investigate immunotherapy with alphabeta+ T cells to restore responses considered essential for protective immunity to cytomegalovirus infection. Future studies will address the role of adoptive immunotherapy using different immunoeffector cell populations to improve control of virus infection. The use of genetically modified T cells has already been evaluated clinically and offers the potential for improving safety and efficacy and removing obstacles to successful immunotherapy. Although these studies are in the early stages and present considerable technical challenges, the results suggest that cellular immunotherapy will be a fruitful area for investigation in future years.

Adoptive Transfer↗
PubMed2004

Clinical aspects of CMV infection after stem cell transplantation.

Cytomegalovirus (CMV) infection is one of the most important infectious complications after stem cell transplantation (SCT). Major improvements in the management of CMV infection have been achieved during the last decade, including the introduction of safe blood product support for CMV-seronegative patients, the development of early pre-emptive antiviral therapy based on sensitive diagnostic tests, and antiviral prophylaxis. With the better control of CMV infection during the first 100 days after allogeneic SCT an increase in the incidence of CMV infection and disease after day 100 after transplantation was observed. New methods that allow for the reconstitution of CMV-specific immune responses such as adoptive T-cell therapy are promising tools that might help to improve the management of late CMV infection and disease.

Antiviral Agents↗
PubMed2004

Transplantation of a combination of CD133+ and CD34+ selected progenitor cells from alternative donors.

Positive selected haematopoietic stem cells are increasingly used for allogeneic transplantation with the CD34 antigen employed in most separation techniques. However, the recently described pentaspan molecule CD133 appears to be a marker of more primitive haematopoietic progenitors. Here we report our experience with a new CD133-based selection method in 10 paediatric patients with matched unrelated (n = 2) or mismatched-related donors (n = 8). These patients received a combination of stem cells (median = 29.3 x 10(6)/kg), selected with either anti-CD34 or anti-CD133 coated microbeads. The proportion of CD133+ selected cells was gradually increased from patient to patient from 10% to 100%. Comparison of CD133+ and CD34+ separation procedures revealed similar purity and recovery of target populations but a lower depletion of T cells by CD133+ selection (3.7 log vs. 4.1 log, P < 0.001). Both separation procedures produced >90% CD34+/CD133+ double positive target cells. Engraftment occurred in all patients (sustained primary, n = 8; after reconditioning, n = 2). No primary acute graft versus host disease (GvHD) >/= grade II or chronic GvHD was observed. The patients showed a rapid platelet recovery (median time to independence from substitution = 13.5 d), whereas T cell regeneration was variable. Five patients are alive with a median follow-up of 10 months. Our data demonstrates the feasibility of CD133+ selection for transplantation from alternative donors and encourages further trials with total CD133+ separated grafts.

AC133 Antigen↗
PubMed2004

Aspergillus fumigatus antigens activate innate immune cells via toll-like receptors 2 and 4.

Invasive aspergillosis (IA) is a leading cause of mortality in haematological patients. Appropriate activation of the innate immune system is crucial for the successful clearance of IA. Therefore, we studied the Aspergillus fumigatus-mediated activation of human granulocytes and monocyte-derived immature dendritic cells (DCs), as well as murine bone marrow-derived DCs (BMDCs) from wild type, toll-like receptor (TLR)4-deficient, TLR2 knockout, and TLR2/TLR4 double deficient mice. Aspergillus fumigatus antigens induced the activation and maturation of immature DCs as characterized by CD83 expression, upregulation of major histocompatibility complex and co-stimulatory molecules. Moreover, fungal antigens enhanced the phagocytosis and production of interleukin (IL)-8 in granulocytes. The release of IL-12 by BMDCs in response to A. fumigatus antigens was dependent on the expression of TLR2, whereas the release of IL-6 was dependent on the expression of functional TLR4 molecules. The protein precipitate of A. fumigatus supernatant provided strong stimulation of DCs and granulocytes, indicating that a factor secreted by A. fumigatus might activate innate immune cells. In conclusion, A. fumigatus antigens induced the activation of DCs and granulocytes. Our results indicated that this activation was mediated via TLR2 and TLR4. Future studies are needed to assess the clinical impact of these findings in patients at high risk for IA.

Animals↗