Reinhard Andreesen

University Hospital Regensburg | Uni Regensburg

Introduction: The diagnosis of cancer leads to high levels of emotional distress in many patients. Quality of life is an important therapeutic goal in this context. A quality-of-life guide was implemented in the oncological day clinic (ICT) at the University Hospital of Regensburg (UKR) in order to individually support outpatients, help them with...

Malignant transformation is frequently associated with disease-specific epigenetic alterations, but the underlying mechanisms and pathophysiological consequences remain poorly understood. Here, we used global comparative DNA methylation profiling at CG-rich regions of 27 acute myeloid leukemia (AML) samples to select a subset of aberrantly methylat...

Two consecutive multi-center phase II trials were designed to prove the hypothesis, whether therapeutic modeling of tumor-associated inflammatory processes could result in improved tumor response. Therapy in both trials consisted of low-dose capecitabine 1g/m2 twice daily p.o. for 14 days, every 3 weeks, day 1+, and rofecoxib 25 mg daily p.o., day...

Systemic therapy for advanced hepatocellular carcinoma (HCC) is still challenging. A biomodulatory therapy approach targeting the communicative infrastructure of HCC, including metronomic low-dose chemotherapy with capecitabine, pioglitazone and rofecoxib, has been evaluated in patients with non-curative HCC. Altogether 38 patients were evaluable i...

Introduction: Surveys state a widespread use of complementary and alternative medicine (CAM) in patients with malignant diseases. CAM methods might potentially interfere with the metabolization of tumor-specific therapy. However, there is little communication about CAM use in hematology/oncology patients between patients, CAM providers, and oncolo...

The strong link between T-cell metabolism and effector functions is well characterized in the murine system but hardly investigated in human T cells. Therefore, we analyzed glycolytic and mitochondrial activity in correlation to function in activated human CD4 and CD8 T cells. Glycolysis was barely detectable upon stimulation but accelerated beyond...

Therapeutic options for patients with castration-resistant prostate cancer (CRPC) remain limited. In a multicenter, Phase II study, 65 patients with histologically confirmed CRPC received a biomodulatory regimen during the six-month core study. Treatment comprised daily doses of imatinib mesylate, pioglitazone, etoricoxib, treosulfan and dexamethas...

Background: Although advance care planning and the completion of advance directives (ADs) are important tools to avoid unwanted aggressive care once patients have lost their decision-making capacity, only a minority of cancer patients are admitted with completed ADs, and little is known about patients' wishes regarding AD consultations. Methods:...

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neuronal disease resulting in a loss of the upper and lower motor neurons and subsequent death within three to four years after diagnosis. Mouse models and preliminary human exposure data suggest that the treatment with granulocyte-colony stimulating factor (G-CSF) has neuro-protective ef...

CD4(+)CD25(+)FOXP3(+) human regulatory T cells (Tregs) are essential for self-tolerance and immune homeostasis. Here, we describe the promoterome of CD4(+)CD25(high)CD45RA(+) naïve and CD4(+)CD25(high)CD45RA(-) memory Tregs and their CD25(-) conventional T-cell (Tconv) counterparts both before and after in vitro expansion by cap analysis of gene ex...

Key Points In-depth regulome analysis of human monocyte subsets, including transcription and enhancer profiling. Description of metabolomic differences in human monocyte subsets.

Eosinophilia after allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been associated with the development of acute and chronic graft-versus-host disease (cGVHD). However, a limited number of studies have investigated the course of eosinophil counts in relation to the onset of cGVHD. In this study, the course of relative eosinophil...

Next-generation sequencing of the hypervariable V3 region of the 16s rRNA gene isolated from serial stool specimens that had been collected from 31 patients receiving allogeneic stem cell transplantation was performed to elucidate variations in the composition of the intestinal microbiome in the course of allogeneic SCT. Metagenomic analysis was co...

Background and aim. We recently described novel COX-independent effects of the non-steroidal inflammatory drug (NSAID) diclofenac, which significantly diminished MYC expression and glucose metabolism in tumor cells in vitro and in vivo. It is well known that the accelerated glucose metabolism in tumor cells leads to lactic acid export and subsequen...

While current treatment of acute myeloid leukemia is characterized by high response rates, patients' long-term outcome is still disappointing, due to frequent relapse and ineligibility of the often elderly patients for stem cell transplantation approaches. Considerable efforts have, thus, been made to incorporate immunotherapeutic approaches in the...

Up to now, systemically pretreated multi-systems Langerhans cell histiocytosis has been an incurable disease, and therapeutic options for patients have been limited. Acknowledging the fact that the continuous production of pro-inflammatory cytokines contributes to the resistance to commonly used agents, we hypothesized that a multi-targeted approac...

With a median survival period of approximately 19 months, therapeutic options for patients with castration-resistant prostate cancer (CRPC) remain limited. In a multicenter phase II trial, 65 patients with histologically confirmed CRPC continuously received a biomodulatory regimen during the 6-month core period for redirecting tumor-promoting norma...

Non-steroidal anti-inflammatory drugs such as diclofenac exhibit potent anticancer effects. Up to now these effects were mainly attributed to its classical role as COX-inhibitor. Here we show novel COX-independent effects of diclofenac. Diclofenac significantly diminished MYC expression and modulated glucose metabolism resulting in impaired melanom...

Gemcitabine inhibits proliferation and lactate of the melanoma cell line Mellm. (TIF)

Diclofenac inhibits MCT1 , GLUT1 and LDHA mRNA expression in Mellm. (TIF)

Densitometric analyses of MYC protein expression as a function of diclofenac concentration in Mellm, PC3 and U937 after 24 h. (TIF)

Accumulation of diclofenac and lactate in U937. (TIF)

Background Cytosine methylation is a frequent epigenetic modification restricting the activity of gene regulatory elements. Whereas DNA methylation patterns are generally inherited during replication, both embryonic and somatic differentiation processes require the removal of cytosine methylation at specific gene loci to activate lineage-restricted...

5029 Introduction Therapeutic options for patients (pts) with second progression of multiple myeloma (MM) are limited, as patients have already received novel targeted therapy approaches at this stage, i. e. bortezomib and lenalidomide. Acknowledging that continuous production of pro-inflammatory cytokines contributes to resistance towards the age...

SCI-50 A dysregulated interaction of the intestinal microbiome with the patient's innate and adaptive immune response seems to contribute to both inflammatory bowel disease (IBD) and intestinal graft-versus-host disease (GVHD). In IBD, polymorphisms within genes involved in antibacterial defense have been identified as genetic risk factors, such as...

In this retrospective analysis, 30 patients with acute GVHD (aGVHD) and 32 patients with chronic GVHD (cGVHD) treated with extracorporeal photopheresis (ECP) performed by the COBE Spectra System were evaluated. After 3 months of ECP treatment, a CR and PR were observed in 9 (30%) and 6 (20%) patients with aGVHD and in 2 (6%) and 12 (38%) patients w...

Cellular differentiation is orchestrated by lineage-specific transcription factors and associated with cell type-specific epigenetic signatures. In the present study, we used stage-specific, epigenetic "fingerprints" to deduce key transcriptional regulators of the human monocytic differentiation process. We globally mapped the distribution of epige...

The intensity of chemotherapy and need for additional radiotherapy in patients with advanced stage Hodgkin's lymphoma has been unclear. We did a prospective randomised clinical trial comparing two reduced-intensity chemotherapy variants with our previous standard regimen. Chemotherapy was followed by PET-guided radiotherapy. In this parallel group,...

Wir berichten über eine 72-jährige Patientin mit multiplem Myelom und trophischen Störungen (Alopezie, Nagel- und Hautveränderungen). Aus einer Hautbiopsie konnte die Diagnose einer AL-Amyloidose gestellt werden. Bei Nachweis eines multiplen Myeloms im Stadium I und nach Diagnosestellung der AL-Amyloidose mit Hautbefall und trophischen Störungen, s...

Clinical progression of cancer patients is often observed despite the presence of tumor-reactive T cells. Co-inhibitory ligands of the B7 superfamily have been postulated to play a part in this tumor-immune escape. One of these molecules, PD-L1 (B7-H1, CD274), is widely expressed on tumor cells and has been shown to mediate T-cell inhibition. Howev...

Bone Marrow Transplantation is a high quality, peer-reviewed journal covering all aspects of clinical and basic haemopoietic stem cell transplantation.

We report on a 72-year-old female patient with multiple myeloma who presented with alopecia and eye-catching alterations of the skin and the nails. A biopsy of the skin could confirm the diagnosis of immunoglobulin light chain (AL) amyloidosis, which was also suspected of having affected other organs. After six cycles of a cytoreductive therapy wit...

CD4(+)CD25(+)FOXP3(+) regulatory T cells (Treg) are pivotal for peripheral self-tolerance. They prevent immune responses to auto- and alloantigens and are thus under close scrutiny as cellular therapeutics for autoimmune diseases and the prevention or treatment of alloresponses after organ or stem cell transplantation. We previously showed that hum...

Combination of standard chemotherapy with rituximab led to improved disease control in patients with B cell lymphoma in clinical trials. We wanted to know if a similar benefit could be demonstrated in the routine data of a regional population-based cancer registry. We searched the registry of the Regensburg Tumor Center for B cell non-Hodgkin lymph...

Induction of indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme in tryptophan degradation along the kynurenine pathway, acts as a potent immunoregulatory loop. To address its role in human allogeneic stem cell transplantation, we measured major tryptophan metabolites, such as quinolinic acid and kynurenine, in serial urine specimens from 5...

2987 Acute graft-versus-host disease (GVHD) is a frequent complication after allogeneic bone marrow transplantation (BMT). We previously showed that the adoptive transfer of donor-type CD4+CD25+ regulatory T cells (Treg) at the time of BMT prevents acute GVHD in murine models. However, the therapeutic potential of donor-derived Treg cells for the t...

2976 Graft-versus-host disease (GVHD) and infectious complications are main causes of non-relapse mortality after allogeneic stem cell transplantation (SCT). Impaired immune function after SCT is usually attributed to the immunosuppressive medication applied for GVHD prophylaxis or therapy. Using a major histocompatibility complex (MHC)–mismatched...

General out-patient palliative care (GOPC) must be integrated into the care of patients with life-limiting diseases. Aim of the study was to evaluate experiences of general practitioners concerning advance directives and palliative emergency sheets. A self-provided survey was mailed to all general practitioners in Regensburg (cross-sectional study)...

Limited data are available on immunologic responses to primary pandemic H1N1 (2009) vaccination in recipients of allogeneic hematopoietic stem cell transplantation (HSCT) recipients. In 2009 serologic responses to either pandemic H1N1 (2009) vaccine (n = 36) or pandemic H1N1 (2009) infection (n = 2) were studied in 38 HSCT recipients. Responses wer...

4599 Background: Therapeutic options for pts with CRPC are still limited. Continuous production and release of pro-inflammatory cytokines may account for its resistance towards cytotoxic drugs. Therefore, a phase II study was implemented in pts with CRPC to assess tumor response to combined biomodulatory agents. Primary objective was the PSA-respon...

Depletion of host Langerhans cells (LCs) prevents cutaneous graft-versus-host disease (GvHD) in mice. We analyzed whether UVB irradiation is tolerated during the course of human allogeneic hematopoietic cell transplantation and whether depletion of LCs by broadband UVB could improve GvHD outcome. A total of 17 patients received six whole-body UVB i...

We enrolled 45 patients with metastatic renal cell carcinoma (RCC) at a progressive disease between March 2003 and April 2008 to assess the impact of an anti-inflammatory treatment regime in combination with metronomic low-dose chemotherapy. 42% of the patients had been systemically pre-treated. Therapy consisted of etoricoxib 60 mg daily plus piog...

Many tumor cells are characterized by a dysregulated glucose metabolism associated with increased glycolysis in the presence of oxygen ("Warburg Effect"). Here, we analyzed for the first time a possible link between glucose metabolism and immune cell infiltration in renal cell carcinoma (RCC). RCC specimens revealed a highly significant increase in...

Bone Marrow Transplantation is a high quality, peer-reviewed journal covering all aspects of clinical and basic haemopoietic stem cell transplantation.

The adoptive transfer of in vitro expanded Treg is a promising treatment option for autoimmune as well as alloantigen-induced diseases. Yet, concerns about the phenotypic and functional stability of Tregs upon in vitro culture command both careful selection of the starting population and thorough characterization of the final cell product. Recently...

Pulmonary invasive fungal infections (IFI) are well-recognized complications with high morbidity and mortality in patients with hematologic malignancies. Aerosolized liposomal amphotericin B (lipAmB) was evaluated as an antifungal prophylaxis in patients with an expected neutropenia of more than 10 days due to intensive chemotherapy or stem cell tr...

N.A. Kittan, F. Beier, K. Kurz, H.H. Niller, L. Egger, W. Jilg, R. Andreesen, E. Holler, G.C. Hildebrandt. Isolated cerebral manifestation of Epstein–Barr virus‐associated post‐transplant lymphoproliferative disorder after allogeneic hematopoietic stem cell transplantation: a case of clinical and diagnostic challenges. Transpl Infect Dis 2011: 13:...

Acute graft-vs.-host disease (aGVHD) is a major complication after allogeneic bone marrow transplantation (allo-BMT) that is characterized by high morbidity and mortality. Systemic treatment with steroids has been the mainstay of first-line therapy of aGVHD, although controlled experimental data in this context are limited. Using a haploidentical m...

Invasive fungal infections (IFI) are major causes of death in high-risk haematological patients receiving induction therapy for acute leukaemia or intensified immunosuppression due to acute or chronic graft-vs.-host disease (GvHD) following allogeneic stem cell transplantation (SCT). Recently, two randomised studies showed the efficacy of a posacon...

The present multi-center phase II study was designed to support the hypothesis that networking agents, which bind to ubiquitous accessible targets in metastatic castration-refractory prostate cancer (CRPC) may counteract neoplasia-specific aberrant cellular functions, thereby mediating PSA response (primary endpoint). Patients with metastatic CRPC...

We report the case of a 53-year-old female patient with refractory acute myeloid leukemia developing a necrotic, soft tissue abscess on the right forearm caused by Scedosporium apiospermum during prolonged severe neutropenia (absolute white blood cell count <500/μL for 49 days). In the context of the severely immunocompromised state of the patient...

2498 CpG islands show frequent and often disease-specific epigenetic alterations during malignant transformation, however, the underlying mechanisms are poorly understood. We used methyl-CpG immunoprecipitation (MCIp) to generate comparative DNA methylation profiles of 30 patients with acute myeloid leukemia for human CpG islands across the genome....

3875 The differentiation of human macrophages is accompanied by distinctive phenotypical changes and generally proceeds in the absence of proliferation. The molecular events governing this process are still poorly understood. Using ChIP-Seq technology we studied epigenetic changes as well as alterations in transcription factor occupancy during huma...

Under inflammatory conditions, the pleiotropic cytokine interleukin-10 (IL-10) is released in many tissues. It mediates anti-inflammatory effects in particular by inhibiting the release of T helper type 1 (Th1) cytokines. In con- trast, we show here that NK cell cytotoxicity against autologous macrophages is elevated if both cell types are cultured...

GVHD is a common complication in patients after allo-SCT. Early detection is important because early therapy may improve the outcome. We evaluated contrast-enhanced ultrasound (CEUS) in patients with GVHD to assess typical imaging features. CEUS was performed in nine patients with histologically proven GVHD. As a control four healthy volunteers and...

Prostate cancer, the most frequently diagnosed neoplasia in men, represents a therapeutic challenge throughout all disease stages. Initial therapy of metastatic prostate cancer consists of androgen ablation, either by drugs (LHRH agonists) or by surgery (bilateral orchiectomy), and responses can be observed in up to 85% of patients.

Peroxisome proliferator-activated receptor-gamma and cyclooxygenase-2 are ­frequently overexpressed on cholangiocarcinoma (CC) cells and adjacent stroma cells, and might be potential therapeutic targets. A pilot phase II trial was started to analyze the activity of angiostatically scheduled chemotherapy, capecitabine 2 × 1 g/m2from day 15 to 28 eve...

The present multi-center phase II study was designed to support the hypothesis that networking agents which bind to ubiquitous accessible targets in metastatic castration-resistent prostate cancer (CRPC) may counteract neoplasia-specific aberrant cellular functions, thereby mediating PSA response. Patients with metastatic CRPC received low-dose che...

In mammals, the dynamics of DNA methylation, in particular the regulated, active removal of cytosine methylation, has remained a mystery, partly due to the lack of appropriate model systems to study DNA demethylation. Previous work has largely focused on proliferating cell types that are mitotically arrested using pharmacological inhibitors to dist...

Supplementary methods, additional results, description of supplementary tables, and supplementary figures.

Oligonucleotide sequences used for quantitative PCR, cloning, and electrophoretic mobility shift assay.

Oligonucleotides for bisulfite amplicon generation. Genomic locations and oligonucleotides for EpiTYPER bisulfite amplicons.

MassARRAY EpiTYPER results. EpiTYPER methylation ratios of individual CpG units in 46 amplicons covering 26 distinct genomic locations are given for all samples of different donors along with mean values for d7 macrophages (MAC), monocytes (MO), dendritic cells (DC) at day 7 or 51 h and data for unmethylated, 33%, 66% and 100% methylated control DN...

The syndrome of inappropriate antidiuresis is the most common cause of euvolemic hypo-osmolality. This syndrome is associated with a wide variety of diseases. However, its most frequent causes are related to malignancies, especially lung cancer. In this case report, we describe an unknown association of the syndrome of inappropriate antidiuresis wi...

The anti-diabetic thiazolidinedione compound pioglitazone, a peroxisome proliferator-activated receptor-gamma agonist, and selective cyclooxygenase-2 inhibitors are clinically used in patients with advanced malignancies. Several previously published in vivo and in vitro studies showed growth inhibitory effects on different cancer cell lines. Howeve...

Adoptive cell transfer (ACT), either using rapidly expanded tumor infiltrating lymphocytes or T-cell receptor transduced peripheral blood lymphocytes, can be considered one of the most promising approaches in cancer immunotherapy. ACT results in the repopulation of the host with high frequencies of tumor-specific T cells; however, optimal function...

Aberrant DNA methylation at CpG islands is thought to contribute to cancer initiation and progression, but mechanisms that establish and maintain DNA methylation status during tumorigenesis or normal development remain poorly understood. In this study, we used methyl-CpG immunoprecipitation to generate comparative DNA methylation profiles of health...

High concentrations of lactic acid (LA) are found under various pathophysiological conditions and are accompanied by an acidification of the environment. To study the impact of LA on TNF secretion, human LPS-stimulated monocytes were cultured with or without LA or the corresponding pH control. TNF secretion was significantly suppressed by low conce...

Pro-inflammatory and dendritic cell-activating properties of macrophage migration inhibitory factor (MIF) suggest a potentially important role for MIF in alloantigen-specific immune responses after allogeneic stem cell transplantation (allo-SCT). We tested whether MIF −173 G/C gene polymorphism of donor or patient had impacts on the outcomes after...

2259 Poster Board II-236 The modified lung function score (LFS), which combines changes in forced expiratory volume in the first second (FEV1) and the capacity of the lung for carbon monoxide adjusted for haemoglobin level (cDLCO), has been proposed by the NIH consensus project on criteria for clinical trials in chronic graft versus host disease (c...

1155 Poster Board I-177 Introduction A genome wide association scan of DNA polymorphisms identified association of a threonine-to-alanine substitution (T300A) in the autophagy-related 16-like gene ATG16 L1 as a new genetic risk factor of Crohn's disease. As our group had previously reported SNPs of another innate immunity receptor important in Cro...

4958 Introduction Therapeutic options for patients with refractory and multifold pretreated multiple myeloma (MM) are limited, as patients have already received the novel targeted therapy approaches at this stage. Continuous production and release of pro-inflammatory cytokines may account for its resistance towards cytotoxic agents. Therefore, a m...

Adoptive transfer of naïve CD8(+) T cells into lymphopenic recipients results both in spontaneous proliferation and in partial activation of T cells, a phenomenon termed homeostatic proliferation (HP). HP of CD8(+) T cells is dependent on host IL-7, IL-15, and MHC-class I and has been shown to prevent T-cell tolerance, reverse T-cell anergy and sup...

Nucleotide-binding oligomerization domain 2/caspase recruitment domain 15 (NOD2/CARD15) polymorphisms have been identified as risk factors of both Crohn's disease and graft-versus-host disease (GVHD) following allogeneic stem cell transplantation. However, the role of these receptors of innate immunity in the pathophysiology of gastrointestinal GVH...

Acute graft-versus-host disease (aGVHD) is a major complication after allogeneic bone marrow transplantation (allo-BMT), and infiltration of donor leukocytes into aGVHD target organs is partially orchestrated by chemokines. Using a murine BMT model, the expression of 30 chemokines or chemokine receptors in the lung, liver, gut and tongue was analyz...

DNA methylation participates in establishing and maintaining chromatin structures and regulates gene transcription during mammalian development and cellular differentiation. With few exceptions, research thus far has focused on gene promoters, and little is known about the extent, functional relevance, and regulation of cell type-specific DNA methy...

Venous thromboembolism is a frequent complication in cancer patients and represents an important cause of morbidity and mortality. The risk of thrombosis depends on the specific type of malignancy and the presence of distant metastases. Furthermore, chemotherapeutic regimens and hormonal therapy as well as surgery and hospitalization are associated...

e15584 Background: An angiostatic approach was used to assess the impact of anti-inflammatory therapy in combination with metronomic low-dose chemotherapy. Methods: A randomized multi-institutional phase II trial was designed to select metronomic chemotherapy (arm A: capecitabine 1 g orally twice daily for 14 days with one week break until tumor pr...

Zusammenfassung Das Auftreten eines thromboembolischen Ereignisses ist eine häufige und schwerwiegende Komplikation bei Tumorpatienten und stellt eine wichtige Ursache für Morbidität und Mortalität in diesem Patientengut dar. Als Hauptrisikofaktoren für eine Thromboembolie werden neben der Tumorentität und dem Tumorstadium die Hormon- und Chemother...

Pulmonary graft-versus-host disease (pGVHD) is a major complication after allogeneic bone marrow transplantation (BMT), which involves donor leukocyte migration into the lung along chemokine gradients, leading to pulmonary dysfunction and respiratory insufficiency. As broad spectrum chemokine inhibitor (BSCI) NR58-3.14.3 suppresses leukocyte migrat...

The adoptive transfer of CD4(+)CD25(+) natural regulatory T cells (Treg) is a promising strategy for the treatment of autoimmune diseases and the prevention of alloresponses after transplantation. Clinical trials exploring this strategy require efficient in vitro expansion of this rare cell population. Protocols developed thus far rely on high-grad...

Natural CD4+CD25+ regulatory T cells (Treg) contribute to tolerance induction after transplantation. We previously showed that the adoptive transfer of donor-derived Treg cells prevents lethal graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT) in murine disease models. In contrast, host-type Treg cells failed to pro...

Introduction: Combination of standard chemotherapy with Rituximab led to improved disease control in pts. with B-cell lymphoma and a clearcut survival benefit in diffuse large B cell lymphoma (DLBCL) in a multitude of clinical trials. We wanted to know, if a similar benefit could be demonstrated in the routine follow-up data of the regional populat...

In murine disease models, the adoptive transfer of donor CD4+CD25+ regulatory T cells (Treg) prevents lethal graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation. We recently described methods for the isolation and in vitro expansion of human Treg from adult peripheral blood and found that only CD45RA+ but not CD45RA− CD4+C...

A successful stem cell harvest is a prerequisite for peripheral blood SCT. We investigated the number of CD34(+) cells mobilized, the number of leukaphereses needed and the expenses of treatment for 28 patients with multiple myeloma randomly assigned to receive either G-CSF alone or G-CSF+EPO for stem cell mobilization after chemotherapy with ifosf...

Previous studies from our group indicated a role of SNPs within the innate immunity receptor NOD2/CARD15 as a risk factor for GvHD and treatment-related mortality allogeneic stem cell transplantation from HLA-identical siblings. We now extended these studies to assess the role of NOD2/CARD15 SNPs in 342 unrelated donor transplants. Overall, presenc...