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Purpose: To identify pathogenic microorganisms and microbiological risk factors causing high morbidity and mortality in immunocompromised patients requiring invasive mechanical ventilation due to pneumonia., Methods: A retrospective single-center study was performed at the intensive care unit (ICU) of the Department of Internal Medicine at Heidelberg University Hospital (Germany) including 246 consecutive patients with hematological malignancies requiring invasive mechanical ventilation due to pneumonia from 08/2004 to 07/2016. Microbiological and radiological data were collected and statistically analyzed for risk factors for ICU and 1-year mortality., Results: ICU and 1-year mortality were 63.0% (155/246) and 81.0% (196/242), respectively. Pneumonia causing pathogens were identified in 143 (58.1%) patients, multimicrobial infections were present in 51 (20.7%) patients. Fungal, bacterial and viral pathogens were detected in 89 (36.2%), 55 (22.4%) and 41 (16.7%) patients, respectively. Human herpesviruses were concomitantly reactivated in 85 (34.6%) patients. As significant microbiological risk factors for ICU mortality probable invasive Aspergillus disease with positive serum-Galactomannan (odds ratio 3.1 (1.2-8.0), p = 0.021,) and pulmonary Cytomegalovirus reactivation at intubation (odds ratio 5.3 (1.1-26.8), p = 0.043,) were identified. 1-year mortality was not significantly associated with type of infection. Of interest, 19 patients had infections with various respiratory viruses and Aspergillus spp. superinfections and experienced high ICU and 1-year mortality of 78.9% (15/19) and 89.5% (17/19), respectively., Conclusions: Patients with hematological malignancies requiring invasive mechanical ventilation due to pneumonia showed high ICU and 1-year mortality. Pulmonary Aspergillosis and pulmonary reactivation of Cytomegalovirus at intubation were significantly associated with negative outcome., (© 2024. The Author(s).)

The antibody-drug conjugate polatuzumab vedotin (pola) has recently been approved in combination with bendamustine and rituximab (pola-BR) for patients with refractory or relapsed (r/r) large B-cell lymphoma (LBCL). To investigate the efficacy of pola-BR in a real-world setting, we retrospectively analyzed 105 patients with LBCL who were treated in 26 German centers under the national compassionate use program. Fifty-four patients received pola as a salvage treatment and 51 patients were treated with pola with the intention to bridge to chimeric antigen receptor (CAR) T-cell therapy (n = 41) or allogeneic hematopoietic cell transplantation (n = 10). Notably, patients in the salvage and bridging cohort had received a median of 3 prior treatment lines. In the salvage cohort, the best overall response rate was 48.1%. The 6-month progression-free survival and overall survival (OS) was 27.7% and 49.6%, respectively. In the bridging cohort, 51.2% of patients could be successfully bridged with pola to the intended CAR T-cell therapy. The combination of pola bridging and successful CAR T-cell therapy resulted in a 6-month OS of 77.9% calculated from pola initiation. Pola vedotin-rituximab without a chemotherapy backbone demonstrated encouraging overall response rates up to 40%, highlighting both an appropriate alternative for patients unsuitable for chemotherapy and a new treatment option for bridging before leukapheresis in patients intended for CAR T-cell therapy. Furthermore, 7 of 12 patients with previous failure of CAR T-cell therapy responded to a pola-containing regimen. These findings suggest that pola may serve as effective salvage and bridging treatment of r/r LBCL patients., (© 2021 by The American Society of Hematology.)

Background: T lymphocyte collection through leukapheresis is an essential step for chimeric antigen receptor T (CAR-T) cell therapy. Timing of apheresis is challenging in heavily pretreated patients who suffer from rapid progressive disease and receive T cell impairing medication., Methods: A total of 75 unstimulated leukaphereses were analyzed including 45 aphereses in patients and 30 in healthy donors. Thereof, 41 adult patients with Non-Hodgkin's lymphoma (85%) or acute lymphoblastic leukemia (15%) underwent leukapheresis for CAR-T cell production., Results: Sufficient lymphocytes were harvested from all patients even from those with low peripheral lymphocyte counts of 0.18/nL. Only four patients required a second leukapheresis session. Leukapheresis products contained a median of 98 × 10 8 (9 - 341 × 10 8 ) total nucleated cells (TNC) with 38 × 10 8 (4 - 232 × 10 8 ) CD3+ T cells. Leukapheresis products from healthy donors as well as from patients in complete remission were characterized by high TNC and CD3+ T lymphocyte counts. CAR-T cell products could be manufactured for all but one patient., Conclusions: Sufficient yield of lymphocytes for CAR-T cell production is feasible also for patients with low peripheral blood counts. Up to 12-15 L blood volume should be processed in patients with absolute lymphocyte counts ≤ 1.0/nL.

It is a matter of debate whether myeloma patients with progressive disease (PD) after induction should receive salvage therapy or proceed directly to autologous stem cell transplantation. We performed a retrospective analysis of 1599 patients treated between 1991 and 2016 at the University Hospital of Heidelberg and other centers. Deepening of response through salvage therapy did not lead to better progression-free or overall survival (PD versus salvage therapy patients: HR  = 0.71, 95% CI [0.28, 1.80], p  = 0.5 and HR  = 0.77, 95% CI [0.30, 1.95], p  = 0.6, respectively), neither in patients treated with novel agents ( HR  = 0.66, 95% CI [0.23, 1.85], p  = 0.4 and HR  = 0.76, 95% CI [0.27, 2.15], p  = 0.6) nor older regimens ( HR  = 0.86, 95% CI [0.36, 2.07], p  = 0.7 and HR  = 0.8, 95% CI [0.34, 1.91], p  = 0.6). Therefore, primary nonresponders might benefit from a direct transplant rather than salvage induction, although the analyzed salvage therapy cohort was small ( n  = 23) and cytogenetics was not included in the multivariable analysis.

Introduction: Identification of germline mutations related to an increased cancer risk enables diagnostic, preventive, and therapeutic measures for individuals carrying the disease variant. However, recruitment of families for studies on these mutations can be challenging. Herein we present some of the obstacles that can arise during such studies. We suggest solutions for overcoming or avoiding these difficulties, enabling an efficient and ethically correct family recruitment., Patients and Methods: We describe a study on germline mutations associated with familial risk of multiple myeloma using next-generation sequencing of the whole genome. To date, the study has recruited 54 participants/16 families from different centers in Germany. It was performed at the University Hospital of Heidelberg and German Cancer Research Center., Results: We were confronted with ethical/psychological concerns of patients and family members, a large number of ineligible families, a profound time investment by the participants and the study team, incidental findings, and participants' death. We present solutions to these difficulties such as: knowledge of and adherence to the laws protecting participants' rights, an exact clarification of the inclusion and exclusion criteria, a clear division of tasks within members of the study team, a collaboration with general practitioners/oncologists and patients' support groups, a detailed and understandable informed consent including information about incidental findings, and a choice of a representative in case of participant's death., Conclusion: A successful recruitment for studies on familial cancer is challenging, yet possible. It can be facilitated by applying the previously mentioned strategies., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Premature aging of both CD4 + regulatory T (Treg) and CD4 + responder-T (Tresp) cells in patients with end-stage renal disease (ESRD) is expected to affect the success of later kidney transplantation. Both T-cell populations are released from the thymus as inducible T-cell co-stimulator-positive (ICOS + ) and ICOS - recent thymic emigrant (RTE) Treg/Tresp cells, which differ primarily in their proliferative capacities. In this study, we analysed the effect of ESRD and subsequent renal replacement therapies on the differentiation of ICOS + and ICOS - RTE Treg/Tresp cells into ICOS +  CD31 - or ICOS -  CD31 - memory Treg/Tresp cells and examined whether diverging pathways affected the suppressive activity of ICOS + and ICOS - Treg cells in co-culture with autologous Tresp cells. Compared with healthy controls, we found an increased differentiation of ICOS + RTE Treg/Tresp cells and ICOS - RTE Treg cells through CD31 + memory Treg/Tresp cells into CD31 - memory Treg/Tresp cells in ESRD and dialysis patients. In contrast, ICOS - RTE Tresp cells showed an increased differentiation via ICOS - mature naive (MN) Tresp cells into CD31 - memory Tresp cells. Thereby, the ratio of ICOS + Treg/ICOS + Tresp cells was not changed, whereas that of ICOS - Treg/ICOS - Tresp cells was significantly increased. This differentiation preserved the suppressive activity of both Treg populations in ESRD and partly in dialysis patients. After transplantation, the increased differentiation of ICOS + and ICOS - RTE Tresp cells proceeded, whereas that of ICOS + RTE Treg cells ceased and that of ICOS - RTE Treg cells switched to an increased differentiation via ICOS - MN Treg cells. Consequently, the ratios of ICOS + Treg/ICOS + Tresp cells and of ICOS - Treg/ICOS - Tresp cells decreased significantly, reducing the suppressive activity of Treg cells markedly. Our data reveal that an increased tolerance-inducing differentiation of ICOS + and ICOS - Treg cells preserves the functional activity of Treg cells in ESRD patients, but this cannot be maintained during long-term renal replacement therapy., (© 2018 John Wiley & Sons Ltd.)

Considering the unsatisfactory results of salvage therapies for patients with relapsed/refractory acute myeloid leukaemia (R/R-AML), their value before allogeneic haematopoietic stem cell transplantation (HSCT) remains questionable. However, direct allogeneic HSCT following established conditioning regimens applied in patients with R/R-AML during active disease has been equally disappointing. In this retrospective observational study, high-dose melphalan, as part of a sequential preparative regimen, followed by a total body irradiation (4 × 2 Gy)-based or a treosulfan-based dose-adapted conditioning therapy for allogeneic HSCT was administered to 292 adult patients (median age 56 years, range 17-74) with primary refractory (144 patients), secondary refractory (97 patients) or relapsed AML (51 patients). Overall survival rates at 3 years were 34%, 29% and 41%, respectively. Risk factors associated with an inferior survival were higher age, transplantation from a human leucocyte antigen-mismatched donor and high disease burden. Patients transplanted with blast infiltration <20% showed a notable survival rate of 51% at 3 years. In particular, patients with primary refractory AML showed a more favourable outcome when transplanted early during their disease course. Thus, high-dose melphalan-based sequential conditioning chemotherapy followed by an allogeneic HSCT is feasible and enables long-term remission to be achieved in a substantial proportion of patients with active R/R-AML., (© 2018 John Wiley & Sons Ltd.)

Background Aims: The immunomodulating capacity of multipotent mesenchymal stromal cells (MSCs) qualifies them as a therapeutic tool in several diseases. However, repeated transplantation with products of reproducible characteristics may be required. This could be achieved with cryopreserved aliquots of Good Manufacturing Practice (GMP)-grade MSCs. However, the impact of cryopreservation on the characteristics of GMP-MSCs is ill defined., Methods: We produced fresh and cryopreserved MSCs from human donors with a xenogen-free GMP protocol. Immunogenicity and immunomodulating capacity were tested in co-culture with putative recipient-specific peripheral blood mononuclear cells (PBMCs). Risk of malignant transformation was assessed in vitro and in vivo., Results: Cryopreservation had no impact on viability and consensus criteria of MSCs. In co-culture with PBMCs, MSCs showed low immunogenicity and suppressed mitogen-stimulated proliferation of PBMC irrespective of cryopreservation. Cytogenetic aberrations were not observed consistently in fresh and cryopreserved products, and no signs of malignant transformation occurred in functional assays. MSC products from an elderly pretreated donor showed reduced functional quality, but imminent failure of functional criteria could be detected by an increased population doubling time in early passages., Discussion: This study is the first systematic analysis on cryopreservation of xenogen-free human bone marrow-derived GMP-MSCs. The data support that cryopreservation does not alter the characteristics of the cells and thus may allow the generation of products for serial transplantation. In addition, the protocol allowed early detection of MSC products with low functional capacity., (Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Advances in our understanding of the pathophysiology of chemotherapy-induced nausea and vomiting (CINV), the identification of patient risk factors, and the development of new antiemetics have led to significant improvements in CINV prevention. With the correct use of antiemetic drugs, CINV can be prevented in the majority of patients. Extensive clinical data have been considered in the development of antiemetic treatment recommendations by reliable institutions such as the Multinational Association of Supportive Care in Cancer, the European Society of Medical Oncology and the American Society for Clinical Oncology. These guidelines are intended to enable physicians to incorporate the latest clinical research into their daily practice, considering CINV prevention as part of an optimal patient-centered approach to cancer management. Yet despite the availability of these guidelines, there is emerging evidence that implementation of treatment recommendations is suboptimal. Recently, guideline committees gave special consideration to patient-related risk factors (young, females) contributing to the emetogenic potential for patients receiving anthracycline and cyclophosphamide-based chemotherapy. As women with breast cancer represent a particularly challenging population regarding emesis control, it is especially important that treatment recommendations are followed. This review focuses on the content of the current antiemetic guidelines, addressing the importance of how these are intended to be implemented in routine clinical practice.

2-methyl-naphtho[2,3-b]furan-4,9-dione (FNQ3), a synthetic analogue of the quinone kigelinone, has demonstrated a real potential for use in the treatment of a variety of solid tumours. Unlike other quinones, such as mitomycin-C and adriamycin, the cytotoxicity of FNQ3 is often 10- to 14-fold more potent towards the tumour cells than their normal counterparts. We report, for the first time, that the drug had activity against a broad spectrum of leukaemias and multiple myeloma cells. It decreased the growth of acute myeloid leukaemia (AML) and multiple myeloma cell lines in a dose-dependent fashion (50% inhibitory concentration approximately 1.25 microg/ml against most of the leukaemia cell lines). This dose apparently initiated mitochondrial collapse as measured by depolarisation of the mitochondrial membrane. FNQ3 potentiated the differentiation of HL-60 myeloid cells in the presence of either 1alpha, 25(OH)(2) dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)] or all-trans-retinoic acid (ATRA). FNQ3 inhibited the proliferation of primary AML cells while inducing apoptosis. Eleven of 14 (79%) AML marrow samples had a prominent decrease in their clonogenic growth when cultured in the presence of the drug. In summary, this drug has growth inhibitory, apoptotic and differentiative effects against myeloid leukaemias and multiple myeloma cells. FNQ3 may represent a new therapeutic approach to these malignancies.

Fms-like tyrosine kinase 3 (FLT3) receptor mutations as internal tandem duplication (ITD) or within the kinase domain are detected in up to 35% of patients with acute myeloid leukemia (AML). N-benzoyl staurosporine (PKC412), a highly effective inhibitor of mutated FLT3 receptors, has significant antileukemic efficacy in patients with FLT3-mutated AML. Mutation screening of FLT3 exon 20 in AML patients (n = 110) revealed 2 patients with a novel mutation (Y842C) within the highly conserved activation loop of FLT3. FLT3-Y842C-transfected 32D cells showed constitutive FLT3 tyrosine phosphorylation and interleukin 3 (IL-3)-independent growth. Treatment with PKC412 led to inhibition of proliferation and apoptotic cell death. Primary AML blasts bearing FLT3-Y842C mutations showed constitutive FLT3 and signal transducer and activator of transcription 5 (STAT-5) tyrosine phosphorylation. Ex vivo PKC412 treatment of primary blasts resulted in suppression of constitutive FLT3 and STAT-5 activation and apoptotic cell death. Inspection of the FLT3 structure revealed that Y842 is the key residue in regulating the switch from the closed to the open (= active) conformation of the FLT3 activation loop. Overall, our data suggest that mutations at Y842 represent a significant new activating mutation in AML blasts. Since FLT3 tyrosine kinase inhibitors (TKIs) such as PKC412 are currently being investigated in clinical trials in AML, extended sequence analysis of FLT3 may be helpful in defining the spectrum of TKI-sensitive FLT3 mutations in AML.