Nikolas Von BubnoffUniversity Medical Center Freiburg · Department of Internal Medicine
Nikolas Von Bubnoff
MD
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258
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Introduction
Publications
Publications (258)
Tenosynovial giant cell tumor (TGCT) is a rare type of tumor that originates from the synovium of joints and tendon sheaths. It is characterized by recurring genetic abnormalities, often involving the CSF1 gene. Common symptoms include pain and swelling, which are not specific to TGCT, so MRI and a pathological biopsy are needed for an accurate dia...
Despite major advances in molecular profiling and classification of primary brain tumors, personalized treatment remains limited for most patients. Here, we explored the feasibility of individual molecular profiling and the efficacy of biomarker-guided therapy for adult patients with primary brain cancers in the real-world setting within the molecu...
Leukemia represents a diverse group of hematopoietic neoplasms that can be classified into different subtypes based on the molecular aberration in the affected cell population. Identification of these molecular classification is required to identify specific targeted therapeutic approaches for each leukemic subtype. In general, targeted therapy app...
Expression of CD2, CD25 and/or CD30 in extracutaneous mast cells (MC) is a minor diagnostic criterion for systemic mastocytosis (SM) in the classification of the World Health Organization and International Consensus Classification. So far, it remains unknown whether expression of these antigens on MC is of prognostic significance in SM. We performe...
Background
Ruxolitinib has been approved by the US FDA for the treatment of myeloproliferative neoplasms such as polycythemia vera and primary myelofibrosis. Ruxolitinib will remain a main stay in the treatment of MPN patients due to its effective therapeutic benefits. However, there have been instances of ruxolitinib resistance in MPN patients. As...
Primary renal manifestations of diffuse large B-cell lymphoma (PR-DLBCL) represent an exceptionally rare variant of the most common type of non-Hodgkin lymphoma (NHL). Insights into PR-DLBCL pathogenesis have been limited to small case series and methodologically limited approaches. The mechanisms driving lymphomagenesis within an organ lacking an...
Development of Janus-kinase (JAK) inhibitors has revolutionized the therapeutic landscape for patients with myeloproliferative neoplasia (MPN). Following approval of the first JAK1/2-inhibitor Ruxolitinib, symptoms of this inflammatory disease, characterized by splenomegaly, release of inflammatory cytokines and appearance of thrombosis, could be e...
We report a case of a long-term surviving patient with EML4/ALK translocated non–small cell adenocarcinoma of the lung in UICC8 stage IVA. During recurrence under continuous crizotinib therapy, a hitherto insufficiently characterized missense mutation in the ALK gene (Arg1181His) was identified through targeted sequencing. The aforementioned EML4/A...
Background
AML is a rare hematological malignancy still associated with poor prognosis. 5% of de novo AML and 30% of core binding factor (CBF) AML (translocation t(8;21)(q22;q22) or invasion (16)(p13;q22)), respectively, harbor activating c-Kit (CD117) mutations leading to an adverse clinical outcome. Posttranslational protein modifications, especi...
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) constitutes a rare and aggressive malignancy originating from plasmacytoid dendritic cells (pDCs) with a primarily cutaneous tropism followed by dissemination to the bone marrow and other organs. We conducted a genome-wide analysis of the tumor methylome in an extended cohort of 45 BPDCN patients...
Certain laboratory abnormalities correlate with subvariants of systemic mastocytosis (SM) and are often prognostically relevant. To assess the diagnostic and prognostic value of individual serum chemistry parameters in SM, 2607 patients enrolled within the European Competence Network on Mastocytosis (ECNM) and 575 patients enrolled within the Germa...
Simple Summary
Myelofibrosis is a rare bone marrow disorder, leading to an increasing failure to generate healthy blood cells. Defining clinical prognosis scores for rare diseases is difficult, as sufficient numbers of patients for score validation are difficult to obtain. The current study investigates the utility of the TriNetX database, containi...
Introduction: In classical Hodgkin-lymphoma (cHL), only a few cases recur, and only a limited fraction of patients is primary-refractory to standard-polychemotherapy. Underlying genomic features of unfavorable clinical courses remain sparsely characterized. Here, we investigated the genomic characteristics of primary-refractory/relapsed cHL in cont...
Background
Extracellular vesicles (EVs), including microvesicles, hold promise for the management of bladder urothelial carcinoma (BLCA), particularly because of their utility in identifying therapeutic targets and their diagnostic potential using easily accessible urine samples. Among the transmembrane glycoproteins highly enriched in cancer-deriv...
Introduction
Pancreatic acinar cell carcinomas are rare malignant neoplasms. High‐quality evidence about the best treatment strategy is lacking. We present the case of a 52‐year‐old male with a BRAF V600E ‐mutated PACC who experienced a complete remission after chemotherapy with BRAF‐/MEK‐inhibitors.
Case
The patient presented with upper abdomen p...
Ruxolitinib has been approved by FDA for the treatment of myeloproliferative neoplasms such as polycythemia vera and idiopathic myelofibrosis. Although ruxolitinib has been in the clinic for more than ten years, surprisingly, no JAK2 drug resistant mutations have been identified in patients. At the moment, it is not clear whether the absence of JAK...
Tyrosine‐protein kinase (janus kinase; JAK)–signal transducer and activator of transcription (STAT) signaling plays a pivotal role in the development of myeloproliferative neoplasms (MPNs). Treatment with the potent JAK1/JAK2‐specific inhibitor, ruxolitinib, significantly reduces tumor burden; however, ruxolitinib treatment does not fully eradicate...
Introduction: Polycythemia vera (PV) is characterized by trilineage blood cell expansion, PV-associated symptoms, and the risk of thromboembolic complications, progression to post-PV myelofibrosis, and acute leukemia. Cytoreductive treatment with hydroxyurea (HU) or ropeginterferon-alpha is approved in EU for the treatment of high-risk patients (pt...
Background and Objectives
Medical advances in treatment of hematologic malignancies have led to improved survival. However, aggressive treatments come with the potential of significant side effects that can affect quality-adjusted life years. During treatment, physical activities are markedly reduced and immobility and psychologic burden, especiall...
Introduction: The tumor suppressor p53 ( TP53) maintains genomic integrity, and nearly 50% of cancers are characterized by a loss or mutation in the TP53 gene. Murine double minute 2 (MDM2) negatively regulates p53 expression and promotes oncogenesis in TP53 wild-type ( TP53 WT) tumors. Navtemadlin (nvtm) is a potent, selective, orally available MD...
Clonal hematopoiesis (CH) is characterized by the acquisition of defined somatic mutations in hematopoietic stem cells (HSC). It is well known that CH contributes to the development of hematological malignancies but also increases the risk of developing non-malignant conditions such as cardiovascular, pulmonary, and inflammatory liver disease.
Howe...
Background and Objectives
Hereditary alpha-Tryptasemia (HaT) and Systemic Mastocytosis (SM) both display elevated basal serum tryptase (BST) levels and share mast cell-mediated digestive, neuropsychiatric, cardiovascular, cutaneous and musculoskeletal symptoms. Lack of awareness and numerous differential diagnoses complicate and often delay diagnos...
Growth Factor Independence 1 (GFI1) is a DNA-binding transcription factor and a key regulator of haematopoiesis. GFI1-36N is a germline variant causing a change of serine (S) to asparagine (N) at position 36. We previously reported that the GFI1-36N allele has a prevalence of 10-15% among patients with acute myeloid leukemia (AML) and 5-7% among he...
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) constitutes a rare and aggressive malignancy originating from plasmacytoid/common dendritic cells (pDCs/cDCs) with a primarily cutaneous tropism followed by dissemination to the bone marrow and other organs. We conducted a genome-wide analysis of the tumor methylome in an extended cohort of 45 BP...
Background:
There is growing evidence supporting multidisciplinary molecular tumor boards (MTB) in solid tumors whereas hematologic malignancies remain underrepresented in this regard.
Objective:
The present study aimed to assess the clinical relevance of MTBs in primary refractory diffuse large B-cell lymphomas/high-grade B-cell lymphomas with...
Growth factor independence 1 (GFI1) is a transcriptional repressor protein that plays an essential role in the differentiation of myeloid and lymphoid progenitors. We and other groups have shown that GFI1 has a dose‐dependent role in the initiation, progression, and prognosis of acute myeloid leukaemia (AML) patients by inducing epigenetic changes....
Introduction:
Myelofibrosis (MF) is a clonal hematopoietic disorder characterized by aberrant JAK2 signaling, megakaryocyte hyperplasia, abnormal cytokine production, and dysregulated trafficking of MF cells to extramedullary sites. While the JAK1/2 inhibitor ruxolitinib (rux) can control symptoms and improve splenomegaly, treatment is often limite...
e16557
Background: Extracellular vesicles are involved in the homeostatic functions and extracellular matrix remodeling in the body. We previously found that the antithrombotic drug Tinzaparin, at clinical concentrations, induces the sufficient release of the tissue factor pathway inhibitor TFPI to functionally inhibit the prothrombotic effector ti...
In ischemic tissue, platelets can modulate angiogenesis. The specific factors influencing this function, however, are poorly understood. Here, we characterized the complement anaphylatoxin C5a-mediated activation of C5a receptor 1 (C5aR1) expressed on platelets as a potent regulator of ischemia-driven revascularization. We assessed the relevance of...
GFI1 is a transcriptional repressor and plays a pivotal role in regulating the differentiation of hematopoietic stem cells (HSCs) towards myeloid and lymphoid cells. Serial transplantation of Gfi1 deficient HSCs repopulated whole hematopoietic system but in a competitive setting involving wild-type HSCs, they lose this ability. The underlying mecha...
Ruxolitinib (Jakavi) is a potent JAK1/JAK2 specific inhibitor, approved for the treatment of myeloproliferative neoplasia (MPN) such as primary myelofibrosis (PMF) and polycythemia Vera (PV). The primary clinical benefit of ruxolitinib in MPN patients is reduction in spleen size and alleviation of constitutional symptoms and significant improvement...
Background
Artificial intelligence (AI) is influencing our society on many levels and has broad implications for the future practice of hematology and oncology. However, for many medical professionals and researchers, it often remains unclear what AI can and cannot do, and what are promising areas for a sensible application of AI in hematology and...
Background:
Mutations in cKIT or PDGFRA are found in up to 90% of patients with gastrointestinal stromal tumors (GISTs). Previously, we described the design, validation, and clinical performance of a digital droplet (dd)PCR assay panel for the detection of imatinib-sensitive cKIT and PDFGRA mutations in circulating tumor (ct)DNA. In this study, we...
Aims:
How and why lymphoma cells home to the central nervous system and vitreoretinal compartment in primary diffuse large B-cell lymphoma of the central nervous system remain unknown. Our aim was to create an in vivo model to study lymphoma cell tropism to the central nervous system.
Methods:
We established a patient-derived central nervous sys...
Introduction
Hematologic malignancies are currently underrepresented in multidisciplinary molecular-tumor-boards (MTB). This study assesses the potential of precision-oncology in primary-refractory plasmablastic-lymphoma (prPBL), a highly lethal blood cancer.
Methods
We evaluated clinicopathological and molecular-genetic data of 14 clinically anno...
Systemic steroids are the standard first-line treatment for acute graft-vs-host disease (aGVHD), but approximately 50% of patients become steroid refractory or dependent (SR/D). Ruxolitinib is the only FDA and EMA approved therapy for patients with SR/D aGVHD. In the phase 3 REACH2 trial (NCT02913261), ruxolitinib demonstrated superior efficacy to...
Peripheral T-cell lymphomas (PTCL) - especially angioimmunoblastic (AITL) and follicular TCL - have a dismal prognosis due to lack of efficient therapies, and patients` symptoms are often dominated by an inflammatory phenotype including fever, night sweats, weight loss and skin rash. In this study, we investigated the role of inflammatory granulocy...
Patients (pts) with polycythemia vera (PV) suffer from pruritus, night sweats, and other symptoms, as well as from thromboembolic complications and progression to post-PV myelofibrosis. Ruxolitinib (RUX) is approved for second-line therapy in high-risk PV pts with hydroxyurea intolerance or resistance. The RuxoBEAT trial (NCT02577926, registered on...
Background:
Across a variety of solid tumors, prognostic implications of nutritional and inflammation-based risk scores have been identified as a complementary resource of risk stratification.
Methods:
In this retrospective study, we performed a comparative analysis of several established risk scores and ratios, such as the Glasgow Prognostic Sc...
Background
Organomegaly, including splenomegaly, hepatomegaly, and/or lymphadenopathy are important diagnostic and prognostic features in patients with cutaneous (CM) or systemic mastocytosis (SM).
Objectives
To investigate the prevalence and prognostic impact of one or more organomegalies on clinical course and survival in patients with CM/SM.
M...
Background:
Primary vitreoretinal lymphoma (PVRL), a rare malignancy of the eye, is strongly related to primary central nervous system lymphoma (PCNSL). We hypothesized that lymphoma cells disseminate to the CNS and eye tissue via distinct homing receptors. The objective of this study was to test expression of CXCR4, CXCR5, CXCR7 and CD44 homing r...
Systemic pan-tumor analyses may reveal the significance of common features implicated in cancer immunogenicity and patient survival. Here, we provide a comprehensive multi-omics data set for 32 patients across 25 tumor types by combining proteogenomics with phenotypic and functional analyses. By using an optimized computational approach, we discove...
Background
The multi-receptor tyrosine kinase inhibitor pazopanib is approved for the treatment of advanced soft-tissue sarcoma and has also shown activity in other sarcoma subtypes. However, its clinical efficacy is highly variable, and no reliable predictors exist to select patients who are likely to benefit from this drug.
Patients and methods...
Testing for genetic alterations in tumor tissue allows clinicians to identify patients who most likely will benefit from molecular targeted treatment. EXLIQUID – exploiting liquid biopsies to advance cancer precision medicine – investigates the potential of additional non-invasive tools for guiding therapy decisions and monitoring of advanced cance...
TPS7063
Background: Patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) secondary to myeloproliferative neoplasms (MPN) have limited treatment options, resulting in poor prognosis with median overall survival < 6 months (Dunbar 2020). Although conventional AML therapy can induce responses in a subset of patients, it does not prolon...
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive malignancy assumed to originate from plasmacytoid dendritic cells (pDCs), which mostly affects the skin, bone marrow, lymph nodes and sequentially other organ systems. RNA-, targeted- and exome sequencing studies have identified molecular characteristics, associated with BPDCN-pa...
FLT3-ITD is the most predominant mutation in AML being expressed in about one-third of AML patients and is associated with a poor prognosis. Efforts to better understand FLT3-ITD downstream signaling to possibly improve therapy response are needed. We have previously described FLT3-ITD-dependent phosphorylation of CSF2RB, the common receptor beta c...
High-grade B-cell lymphoma accompanied with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/TH) poses a cytogenetically-defined provisional entity among aggressive B-cell lymphomas that is traditionally associated with unfavorable prognosis. To better understand the mutational and molecular landscape of HGBL-DH/TH we here performed whole-exome-seq...
There is an increasing demand for optimization-free multiplex assays to rapidly establish comprehensive target panels for cancer monitoring by liquid biopsy. We present the mediator probe (MP) PCR for the quantification of the seven most frequent point mutations and corresponding wild types (KRAS and BRAF) in colorectal carcinoma. Standardized para...
Introduction: Mutations (muts) in JAK2, MPL, and CALR are genetic hallmarks in myeloproliferative neoplasms such as myelofibrosis (MF). Prognostication in MF is predominantly based on clinical parameters according to the Dynamic International Prognostic Scoring System (DIPSS). However, gene mutations become increasingly important allowing for a mor...
Background
Effective treatments are needed to improve outcomes for high-grade glioma and low-grade glioma. The activity and safety of dabrafenib plus trametinib were evaluated in adult patients with recurrent or progressive BRAFV600E mutation-positive high-grade glioma and low-grade glioma.
Methods
This study is part of an ongoing open-label, sing...
Circulating tumor DNA (ctDNA) has demonstrated great potential as a non‐invasive biomarker to assess minimal residual disease (MRD) and to profile tumor genotypes in patients with non‐small cell lung cancer (NSCLC). However, little is known about its dynamics during and after tumor resection, or its potential for predicting clinical outcomes. Here,...
Plasmablastic-lymphoma (PBL) represents a clinically heterogeneous subtype of aggressive-B-cell-non-Hodgkin-lymphoma. Although targeted-sequencing-studies and a single-center whole-exome-sequencing (WES) study in HIV+ patients recently revealed several genes, associated with PBL-pathogenesis, the global mutational-landscape and transcriptional-prof...
Liver metastases are the most common site of metastatic spread in colorectal cancer. Current treatment approaches involve effective systemic therapies in combination with surgical and/or interventional strategies. Multimodal strategies greatly improved clinical outcomes of patients with metastatic colorectal cancer over the last decades. Identifica...
Purpose
Plasmablastic lymphoma (PBL) is a rare and aggressive B-cell malignancy with a heterogenous clinical and prognostic spectrum, determined by multiple factors, including age, HIV- and MYC-status. While there exist several validated scoring systems for diffuse large B-cell lymphoma, which incorporate basic clinical features (age, lactate dehyd...
The recent characterization of a group of non-MYC rearranged aggressive B-cell-lymphomas, resembling Burkitt lymphoma (BL), characteristically harboring a telomeric 11q-loss or combined 11q-proximal gains/loss-pattern has led to the introduction of the provisional entity of Burkitt-like lymphoma with 11q aberration (BLL-11q). Prompted by the discov...
The recent characterization of a group of non-MYC rearranged aggressive B-cell-lymphomas, resembling Burkitt lymphoma (BL), characteristically harboring a telomeric 11q-loss or combined 11q-proximal gains/loss-pattern has led to the introduction of the provisional entity of Burkitt-like lymphoma with 11q aberration (BLL-11q). Prompted by the discov...
Background
Momelotinib (MMB) is a JAK1, JAK2, and ACVR1/ALK2 inhibitor with clinical activity against the hallmark features of myelofibrosis (MF), namely anemia, constitutional symptoms, and splenomegaly, across the continuum of JAK inhibitor (JAKi)-naïve or previously JAKi-treated patients. Inhibition of ACVR1/ALK2 reduces hepcidin; elevated level...
Background
Guidance regarding adjuvant treatment decisions in stage II colorectal cancer (CRC) remains uncertain due to lack of predictive clinical or molecular markers. Recently, postoperative circulating tumour (ct)DNA has been demonstrated to be a strong prognostic marker in early colon cancer.
Patients and Methods
CIRCULATE enrols patients wit...