Publications by authors named "Christine Beham-Schmid"

85 Publications

Vinorelbine as substitute for vincristine in patients with diffuse large B cell lymphoma and vincristine-induced neuropathy.

Support Care Cancer 2021 Feb 24. Epub 2021 Feb 24.

Division of Hematology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.

Background: A combination of rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the standard first-line therapy for diffuse large B cell lymphoma (DLBCL), the most common aggressive lymphoma in adults. One of the major adverse effects of this regimen is vincristine-induced polyneuropathy which leads to discontinuation of vincristine in up to 30% of DLBCL-patients. Dose reduction of vincristine might worsen treatment outcomes of DLBCL but identification of treatment alternatives for patients exhibiting peripheral neuropathy during R-CHOP is an unmet need in hematology.

Methods: In this retrospective cohort study, comprising 987 patients with de novo DLBCL, we delineated the role of vinorelbine as a substitute for vincristine in R-CHOP by measuring improvements in neuropathy and outcome variables.

Results: Five-year overall survival (OS) and progression-free survival (PFS) were 72.6% and 63.1% in patients who received regular doses of vincristine, as compared to 60.6% and 51.7% in patients who received reduced doses of vincristine (p = 0.022 and p = 0.003, respectively). Of 199 patients who switched to vinorelbine, the majority experienced an improvement of neuropathy Furthermore, vinorelbine-switched patients showed favorable oncologic outcomes.

Conclusion: Replacement of vincristine by vinorelbine due to neuropathy is effective and safe, and results in a significant improvement in neuropathy as compared to treatment with R-CHOP.
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http://dx.doi.org/10.1007/s00520-021-06059-2DOI Listing
February 2021

Austrian recommendations for the management of essential thrombocythemia.

Wien Klin Wochenschr 2021 Jan 19;133(1-2):52-61. Epub 2020 Nov 19.

Department of Internal Medicine I, Division of Hematology and Blood Coagulation, Medical University of Vienna, Vienna, Austria.

According to the World Health Organization (WHO) classification, essential (primary) thrombocythemia (ET) is one of several Bcr-Abl negative chronic myeloproliferative neoplasms (MPN). The classical term MPN covers the subcategories of MPN: ET, polycythemia vera (PV), primary myelofibrosis (PMF), and prefibrotic PMF (pPMF). ET is marked by clonal proliferation of hematopoietic stem cells, leading to a chronic overproduction of platelets. At the molecular level a JAK2 (Janus Kinase 2), calreticulin, or MPL mutation is found in the majority of patients. Typical ongoing complications of the disease include thrombosis and hemorrhage. Primary and secondary prevention of these complications can be achieved with platelet function inhibitors and various cytoreductive drugs including anagrelide, hydroxyurea and interferon. After a long follow up, in a minority of ET patients the disease transforms into post-ET myelofibrosis or secondary leukemia. Overall, life expectancy with ET is only slightly decreased.
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http://dx.doi.org/10.1007/s00508-020-01761-3DOI Listing
January 2021

Progression, transformation, and unusual manifestations of myelodysplastic syndromes and myelodysplastic-myeloproliferative neoplasms: lessons learned from the XIV European Bone Marrow Working Group Course 2019.

Ann Hematol 2021 Jan 31;100(1):117-133. Epub 2020 Oct 31.

Institute of Medical Genetics and Pathology, University Hospital of Basel, Schoenbeinstrasse 40, CH-4031, Basel, Switzerland.

Disease progression in myelodysplastic syndromes (MDS) and myelodysplastic-myeloproliferative neoplasms (MDS/MPN) is a major source of mortality. The European Bone Marrow Working Group organized a dedicated workshop to address MDS and MDS/MPN progression, and myeloid neoplasms with histiocytic and lymphoblastic outgrowths in 2019 in Frankfurt, Germany. In this report, we summarize clinical, histopathological, and molecular features of 28 cases. Most cases illustrate that prognostic mutational profiles change during follow-up due to accumulation of high-risk mutations in the trunk clone, and that results from repeated molecular testing can often explain the clinical progression, suggesting that regular genetic testing may predict transformation by early detection of aggressive clones. Importantly, identical mutations can be linked to different clinical behaviors or risks of fibrotic progression and/or transformation in a context-dependent manner, i.e., MDS or MDS/MPN. Moreover, the order of mutational acquisition and the involved cell lineages matter. Several cases exemplify that histiocytic outgrowths in myeloid neoplasms are usually accompanied by a more aggressive clinical course and may be considered harbinger of disease progression. Exceptionally, lymphoblastic transformations can be seen. As best estimable, the histiocytic and lymphoblastic compounds in all occasions were clonally related to the myeloid compound and-where studied-displayed genomic alterations of, e.g., transcription factor genes or genes involved in MAPK signaling that might be mechanistically linked to the respective type of non-myeloid outgrowth.
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http://dx.doi.org/10.1007/s00277-020-04307-9DOI Listing
January 2021

Bone marrow aspirations in Ewing sarcomas: Are they still necessary? A single-center retrospective analysis and review of the literature.

J Cancer Res Ther 2020 Jul-Sep;16(4):713-717

Department of Orthopaedic Surgery, Medical University of Graz, Graz, Austria.

Background And Objectives: Currently, one of the most useful prognostic indicators in Ewing sarcomas (ES) is the presence of metastatic disease at diagnosis. According to various clinical guidelines, the assessment of bone marrow (BM) metastases, using light microscopy examination of bone marrow aspirates and biopsies (BMAB) is mandatory. However, the prognostic value of BM positivity is discussed controversially. Therefore, the primary aim of this study was to retrospectively review BM samples from patients with ES.

Materials And Methods: This retrospective single centre study included 31 patients that were newly diagnosed with ES between 2000 and 2014. Twenty-seven patients had skeletal ES and in 4 patients the tumour was localized in the soft tissue only. Metastases at diagnosis were present in 5 out of 31 patients. BM samples were morphologically and immunohistochemically searched and screened for the presence or absence of BM metastases. Furthermore, in 15 of the 31 patients BM samples were still available and were reanalysed, using nested-polymerase chain reaction.

Results: All BM samples of our 31 ES patients, including the 5 metastatic patients, were, morphologically and immunohistochemically tested negative for tumour cell appearance. The nested-PCR results were also negative in all of our 15 retested patients, including two patients with metastatic disease.

Conclusions: Based on our results and on the contradictory results reported in the literature we recommend a re-evaluation of the necessity and the prognostic value of BMAB in the initial staging process of newly diagnosed ES patients.
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http://dx.doi.org/10.4103/jcrt.JCRT_941_16DOI Listing
November 2020

The Role of Immunohistochemical Overexpression of p53 as Adverse Prognostic Factor in Primary Testicular Diffuse Large B Cell Lymphoma.

Pathol Oncol Res 2020 Oct 29;26(4):2831-2833. Epub 2020 Jun 29.

Division of Hematology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 38D, A-8036, Graz, Austria.

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http://dx.doi.org/10.1007/s12253-020-00864-6DOI Listing
October 2020

Immunohistochemistry for c-myc and bcl-2 overexpression improves risk stratification in primary central nervous system lymphoma.

Hematol Oncol 2020 Aug 7;38(3):277-283. Epub 2020 Mar 7.

Division of Hematology, Department of Internal Medicine, Medical University of Graz (MUG), Austria.

Overexpression of bcl-2 and c-myc are defining features of double-expressor-lymphoma (DEL) but may also occur separately in patients with primary central nervous system lymphoma (PCNSL). Despite all progress in optimizing treatment regimen, there is lack of sufficient risk stratification models. Here, we first describe the relationship between DEL biology, the National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI), treatment response, disease progression, and mortality in PCNSL. In this study, we determined c-myc and bcl-2 status immunohistochemically in samples of 48 patients with newly diagnosed PCNSL and followed these patients for a median interval of 6.2 years. Twelve, 18, and 17 patients harbored none, one, or both DEL features. Corresponding overall response rates after first-line therapy were strongly associated with DEL biology (100%, 42%, and 44% in patients with 0, 1, or 2 DEL features). Patients with one or both DEL features had a 5-fold and 13-fold higher 5-year risk of progression and/or death than patients without DEL features. These associations prevailed after adjusting for the NCCN-IPI. DEL improved the discriminatory capability of the NCCN-IPI (P = .0001). Furthermore, we could show that addition of DEL biology to the NCCN-IPI significantly improved the score's discriminatory potential both toward progression-free survival (increase in Harell's c = 0.15, P = .005) and overall survival (increase in Harell's c = 0.11, P = .029). In conclusion, DEL biology is a strong and simple-to-use predictor of adverse outcome in PCNSL. Addition of DEL to the NCCN-IPI improves its prognostic potential. Disease progression from PCNSL harboring both DEL features is invariably fatal. This defines a novel PCNSL patient subset with a great unmet need for improved therapy.
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http://dx.doi.org/10.1002/hon.2727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496545PMC
August 2020

Management of children and adolescents with gray zone lymphoma: A case series.

Pediatr Blood Cancer 2020 05 9;67(5):e28206. Epub 2020 Feb 9.

Department of Pediatric Hematology and Oncology, St. Anna Children's Hospital, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.

Background: Data on management of gray zone lymphoma (GZL) in children and adolescents are scarce.

Procedure: This retrospective study assessed clinical characteristics and outcome in six Austrian patients with GZL less than 18 years of age (male-to-female ratio: 1:1; median age: 15.8 years).

Results: Two patients each had a classical Hodgkin lymphoma (cHL)-like and composite GZL subtype, and one patient each had a large B-cell non-Hodgkin lymphoma (LBCL)-like and sequential GZL subtype. All had advanced disease with mediastinal and extranodal involvement. Five patients received an LBCL- and one patient a cHL-directed polychemotherapy ± radiotherapy. Out of the former patients, three survived, including two who relapsed and underwent high-dose chemotherapy with autologous stem cell rescue. The latter patient survived.

Conclusions: GZL remains a diagnostic and therapeutic challenge, necessitating the development of novel treatment concepts performed in a prospective setting.
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http://dx.doi.org/10.1002/pbc.28206DOI Listing
May 2020

Choroidal Infiltration as First Clinical Manifestation of T-cell Large Granular Lymphocyte (T-LGL) Leukemia.

Ocul Immunol Inflamm 2020 Oct 2;28(7):1133-1135. Epub 2019 Oct 2.

Department of Ophthalmology, General Hospital Klagenfurt , Klagenfurt, Austria.

: To report of a 55-year-old woman suffering from choroidal infiltrates as a first clinical manifestation of T-LGL leukemia. : Retrospective case report. : A healthy woman presented with photophobia in both eyes since 1 month. She showed a panuveitis with anterior chamber as well as vitreous cells, creamy-white choroidal lesions in both eyes and a cystoid macular edema in the left eye. Lab testing showed only a moderate lymphocytosis, all other tests, including a pars plana vitrectomy and an anterior chamber tap, were negative. Due to the persistent lymphocytosis, she was referred to the oncologist. A biopsy of the bone marrow revealed T-LGL leukemia. A subsequent biopsy of the choroid showed an infiltration of T-LGL and therefore systemic therapy with cyclophosphamide was started. : This is a very rare case describing an involvement of the choroid in T-LGL leukemia.
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http://dx.doi.org/10.1080/09273948.2019.1645186DOI Listing
October 2020

The -Axis Is of Prognostic Relevance in DLBCL and Its Antagonists Exert Pro-Apoptotic Effects In Vitro.

Int J Mol Sci 2019 Sep 24;20(19). Epub 2019 Sep 24.

Division of Hematology, Medical University Graz; Auenbruggerplatz 38, 8036 Graz, Austria.

In tumor cells of more than 20 different cancer types, the -axis is involved in multiple key processes including proliferation, survival, migration, invasion, and metastasis. Since data on this axis in diffuse large B cell lymphoma (DLBCL) are inconsistent and limited, we comprehensively studied the -axis in our DLBCL cohort as well as the effects of CXCR4 antagonists on lymphoma cell lines in vitro. In DLBCL, we observed a 140-fold higher expression compared to non-neoplastic controls, which was associated with poor clinical outcome. In corresponding bone marrow biopsies, we observed a correlation of expression and lymphoma infiltration rate as well as a reduction of expression in remission of bone marrow involvement after treatment. Additionally, we investigated the effects of three CXCR4 antagonists in vitro. Therefore, we used AMD3100 (Plerixafor), AMD070 (Mavorixafor), and WKI, the niacin derivative of AMD070, which we synthesized. WK1 demonstrated stronger pro-apoptotic effects than AMD070 in vitro and induced expression of pro-apoptotic genes of the BCL2-family in CXCR4-positive lymphoma cell lines. Finally, WK1 treatment resulted in the reduced expression of JNK-, ERK1/2- and NF-κB/BCR-target genes. These data indicate that the -axis impacts the pathogenesis of DLBCL and represents a potential therapeutic target in aggressive lymphomas.
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http://dx.doi.org/10.3390/ijms20194740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801866PMC
September 2019

Loss of RAF kinase inhibitor protein is involved in myelomonocytic differentiation and aggravates RAS-driven myeloid leukemogenesis.

Haematologica 2020 31;105(2):375-386. Epub 2020 Jan 31.

Division of Hematology, Medical University of Graz, Graz, Austria

-signaling mutations induce the myelomonocytic differentiation and proliferation of hematopoietic stem and progenitor cells. Moreover, they are important players in the development of myeloid neoplasias. RAF kinase inhibitor protein (RKIP) is a negative regulator of -signaling. As RKIP loss has recently been described in -mutated myelomonocytic acute myeloid leukemia, we now aimed to analyze its role in myelomonocytic differentiation and -driven leukemogenesis. Therefore, we initially analyzed RKIP expression during human and murine hematopoietic differentiation and observed that it is high in hematopoietic stem and progenitor cells and lymphoid cells but decreases in cells belonging to the myeloid lineage. By employing short hairpin RNA knockdown experiments in CD34 umbilical cord blood cells and the undifferentiated acute myeloid leukemia cell line HL-60, we show that RKIP loss is indeed functionally involved in myelomonocytic lineage commitment and drives the myelomonocytic differentiation of hematopoietic stem and progenitor cells. These results could be confirmed , where Rkip deletion induced a myelomonocytic differentiation bias in mice by amplifying the effects of granulocyte macrophage-colony-stimulating factor. We further show that RKIP is of relevance for -driven myelomonocytic leukemogenesis by demonstrating that deletion aggravates the development of a myeloproliferative disease in -mutated mice. Mechanistically, we demonstrate that RKIP loss increases the activity of the -MAPK/ERK signaling module. Finally, we prove the clinical relevance of these findings by showing that RKIP loss is a frequent event in chronic myelomonocytic leukemia, and that it co-occurs with -signaling mutations. Taken together, these data establish RKIP as novel player in -driven myeloid leukemogenesis.
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http://dx.doi.org/10.3324/haematol.2018.209650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012480PMC
January 2020

Comments on pre-fibrotic myelofibrosis and how should it be managed.

Br J Haematol 2019 07 7;186(2):358-360. Epub 2019 Mar 7.

Mayo Clinic, Rochester, MN, USA.

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http://dx.doi.org/10.1111/bjh.15840DOI Listing
July 2019

Operative R0 resection of diffuse large B-cell lymphoma of the pelvis: a case report.

J Med Case Rep 2018 Oct 13;12(1):293. Epub 2018 Oct 13.

Department of General Surgery, Medical University of Graz, Auenbruggerplatz 29, 8036, Graz, Austria.

Background: Diffuse large B-cell lymphoma is the most common subtype of non-Hodgkin lymphoma with or without involvement of extranodal sites. Rituximab in combination with cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) therapy represents the current standard therapy, achieving a rather dissatisfying outcome in approximately 30-40% of all cases.

Case Presentation: We present the case of a 43-year-old Austrian woman with an incidentally detected large pelvic mass which was diagnosed as diffuse large B-cell lymphoma. Initially, the lymphoma intraoperatively appeared to be an inoperable conglomerate tumor. Soon, intestinal perforation induced by tumor infiltration occurred, which initiated a closure of the small intestine and application of a jejunal probe and a percutaneous endoscopic gastrotomy tube. Treatment utilizing the gold standard rituximab in combination with cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) was performed, partly resulting in remission according to radiological follow-up. In view of diagnosis and primary treatment development, the predictive outcome appeared unsound. However, within the procedure of the latest surgical intervention, which was intended to at least reconstruct the intestinal passage in order to improve quality of life, a surgical R0 resection of the residual tumor mass was achieved.

Conclusions: The case presented here reports an unanticipated process of diffuse large B-cell lymphoma, underlining the importance of interdisciplinary cooperation and surgical intervention within the realms of state-of-the-art treatment.
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http://dx.doi.org/10.1186/s13256-018-1838-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6186087PMC
October 2018

Cytoplasmic location of NR4A1 in aggressive lymphomas is associated with a favourable cancer specific survival.

Sci Rep 2018 09 28;8(1):14528. Epub 2018 Sep 28.

Division of Hematology, Department of Internal Medicine, Medical University Graz, Graz, Austria.

The nuclear orphan receptor NR4A1 functions as tumour suppressor in aggressive lymphomas by pro-apoptotic genomic and non-genomic effects. Here, we immunohistochemically studied the clinico-pathological relevance of NR4A1 protein expression patterns in a cohort of 60 diffuse large B cell lymphoma (DLBCL) patients and non-neoplastic lymph nodes. We observed a significant association between high cytoplasmic NR4A1 and favourable cancer-specific survival and the germinal centre B cell-like subtype, respectively. Moreover, the percentage of lymphoma cells exhibiting cytoplasmic NR4A1 significantly correlated to those showing cleaved caspase 3. Complementary, functional profiling using gene set enrichment of Reactome pathways based on publicly available microarray data was applied to determine pathways potentially implicated in cytoplasmic localization of NR4A1 and validated by means of semi quantitative real-time PCR. The pathway analysis revealed changes in the ERK1/2 pathway, and this was corroborated by the finding that high cytoplasmic NR4A1 was associated with higher expression of ERK1/2 targets in our cohort. These data indicate that high cytoplasmic NR4A1 is associated with a favourable lymphoma-specific survival and highlights the importance of NR4A1 expression patterns as potential prognostic marker for risk assessment in aggressive lymphomas.
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http://dx.doi.org/10.1038/s41598-018-32972-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6162226PMC
September 2018

Austrian recommendations for the management of polycythemia vera.

Wien Klin Wochenschr 2018 Sep 19;130(17-18):535-542. Epub 2018 Jul 19.

Department of Internal Medicine I, Division of Hematology and Blood Coagulation, Medical University of Vienna, Vienna, Austria.

Polycythemia vera (PV) is a clonal disease arising from hematopoietic stem cells. Erythrocytosis is the hallmark of the disease but leukocytosis, thrombocytosis and splenomegaly may also be present. Thromboembolic complications occur in about 20% of patients. Circulatory disturbances as well as pruritus represent frequent symptoms of the disease. Mutations in the JAK2 gene are present in 95% of patients in exon 14 (V617F) and in 3% in exon 12. The main goal of the treatment for patients with PV is the prevention of thromboembolic events, transformation to myelofibrosis and acute myeloid leukemia. Interferon alpha and hydroxyurea are used as first-line treatment for high risk patients. For patients unresponsive to first-line therapy ruxolitinib is available.
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http://dx.doi.org/10.1007/s00508-018-1359-3DOI Listing
September 2018

The WHO diagnostic criteria for polycythemia vera-role of red cell mass versus hemoglobin/hematocrit level and morphology.

Ann Hematol 2018 Sep 1;97(9):1581-1590. Epub 2018 May 1.

Institute of Pathology, University of Cologne, Kerpener Str. 62, 50924, Cologne, Germany.

Regarding diagnosis of polycythemia vera (PV), discussion persists about hemoglobin (Hb) and/or hematocrit (Hct) threshold values as surrogate markers for red cell mass (RCM) and the diagnostic impact of bone marrow (BM) morphology. We performed a retrospective study on 290 patients with PV (151 males, 139 females; median age 65 years) presenting with characteristic BM features (initial biopsies, centralized evaluation) and endogenous erythroid colony (EEC) formations. This cohort included (1) a group of 229 patients when following the 2008 versus 256 patients diagnosed according to the 2016 World Health Organization (WHO) guidelines, all presented with increased RCM; (2) masked PV patients with low Hb (n = 143)/Hct (n = 45) recruited from the 2008 WHO cohort; (3) a cohort of 17 PV patients with elevated diagnostic Hb/Hct levels but low RCM; and (4) nine PV patients with increased RCM, opposing low Hb/Hct values. All patients were treated according to current PV guidelines (phlebotomies 87%, hydroxyurea 79%, and acetylsalicylic acid 87%). Applying the 2016 WHO criteria significantly increased concordance between RCM and Hb values compared with the 2008 WHO criteria (90 vs. 43% in males and 83 vs. 64% in females). Further analysis of the WHO 2016 PV cohort revealed that increased RCM is associated with increased Hb/Hct (93.8/94.6%). Our study supports and extends the diagnostic impact of the 2016 revised WHO classification for PV by highlighting the importance of characteristic BM findings and implies that Hb/Hct threshold values may be used as surrogate markers for RCM measurements.
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http://dx.doi.org/10.1007/s00277-018-3344-3DOI Listing
September 2018

Visceral leishmaniasis in a patient with diabetes mellitus type 2 and discrete bicytopenia.

Clin Case Rep 2018 01 28;6(1):78-81. Epub 2017 Nov 28.

Department of Internal Medicine Section of Infectious Diseases and Tropical Medicine Medical University of Graz Auenbruggerplatz 158036 Graz Austria.

An Austrian patient with diabetes mellitus type 2 developed visceral leishmaniasis after trips to Spain and Crete, presenting with slight bicytopenia, later developing severe pancytopenia. Travel history taking is important due to an extended incubation period. Coexistence of diabetes mellitus can impair T lymphocyte function and cause higher relapse rates.
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http://dx.doi.org/10.1002/ccr3.1259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5771930PMC
January 2018

Spuriously low lymphocyte count associated with pseudoerythroblastemia in a patient with chronic lymphocytic leukemia treated with ibrutinib.

Clin Chem Lab Med 2018 04;56(5):e112-e114

Department of Internal Medicine, Hospital of the Brothers of St. John of God, Graz, Austria.

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http://dx.doi.org/10.1515/cclm-2017-0836DOI Listing
April 2018

Aggressive lymphoma 2016: revision of the WHO classification.

Memo 2017 30;10(4):248-254. Epub 2017 Nov 30.

Institute of Pathology, Medical University Graz, Neue Stiftingtalstr. 6, 8010 Graz, Austria.

Aggressive lymphomas are a heterogeneous group of malignancies reflecting clinical, biological and pathological diversity. Diffuse large B‑cell lymphoma is the most common histological subtype and therefore will constitute the key aspect in this article. This lymphoma affects patients of all age groups with wide range presentations concerning localization, morphology and molecular mechanisms. The median age at presentation is about 60 years with a slight male preponderance. Up to 50% of patients present with advanced disease. About 70% of these lymphomas occur nodal, about 30% extranodal, the most common sites of the latter being the gastrointestinal tract, Waldeyer's ring, skin, cerebrum, mediastinum, testis, salivary gland, thyroid and bone. However, diffuse large B‑cell lymphoma can involve virtually any organ.Since the last WHO classification 2008 the adoption of new genomic technologies has provided new insights into the biology of these lymphomas and led to the identification of distinct separate molecular entities and novel pathogenic pathways. These findings induced an expanding number of entities in the new WHO classification of 2016, the knowledge of which is essential concerning treatment options and survival of the patients. Therefore, the clinicians request an accurate diagnosis from the investigating pathologist, which can be quite challenging. The diagnosis of lymphomas requires multiple immunohistochemical studies, and often additional tests, such as fluorescent in situ hybridization and/or polymerase chain reaction techniques and occasionally, in particular cases, next generation sequencing for identification of recurrent somatic mutations. This review summarizes relevant aspects of the new WHO classification in aggressive B‑cell lymphomas, especially from a haematopathologist's point of view.
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http://dx.doi.org/10.1007/s12254-017-0367-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5725508PMC
November 2017

Essential thrombocythemia vs. pre-fibrotic/early primary myelofibrosis: discrimination by laboratory and clinical data.

Blood Cancer J 2017 12 13;7(12):643. Epub 2017 Dec 13.

Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.

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http://dx.doi.org/10.1038/s41408-017-0006-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5802530PMC
December 2017

Immunohistochemical double hit score enhances NCCN-IPI and is associated with detrimental outcomes in refractory or relapsing patients with diffuse large B cell lymphoma.

Br J Haematol 2018 10 6;183(1):142-146. Epub 2017 Sep 6.

Division of Haematology, Department of Internal Medicine, Medical University of Graz (MUG), Graz, Austria.

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http://dx.doi.org/10.1111/bjh.14912DOI Listing
October 2018

Detection of prognostically relevant mutations and translocations in myeloid sarcoma by next generation sequencing.

Leuk Lymphoma 2018 02 20;59(2):501-504. Epub 2017 Jun 20.

b Division of Hematology , Medical University of Graz , Graz , Austria.

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http://dx.doi.org/10.1080/10428194.2017.1339879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5743000PMC
February 2018

Pre-fibrotic/early primary myelofibrosis vs. WHO-defined essential thrombocythemia: The impact of minor clinical diagnostic criteria on the outcome of the disease.

Am J Hematol 2017 Sep 9;92(9):885-891. Epub 2017 Jun 9.

Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.

The 2016 revised WHO criteria for the diagnosis of pre-fibrotic/early primary myelofibrosis (pre-PMF) require at least one of the following four borderline expressed minor clinical criteria: anemia, leukocytosis, elevated lactate dehydrogenase and splenomegaly. In this study, we evaluated the relative frequency of these four criteria in a group of 170 pre-PMF patients and compared them to 225 ET cases. More than 91% of pre-PMF cases showed one or more of these features required for diagnosis, by contrast with only 48% of ET patients. According to clinical data the cumulative risk of progression to advanced/overt PMF in pre-PMF was 36.9% after 15 years. After fitting cox regression models to analyze the impact of the minor criteria on overall survival, only leukocytosis remained as a significant predictor of survival in both pre-PMF and ET. Molecular characterization showed differences in survival in pre-PMF but not ET, with CALR being a more favorable mutation than JAK2. The different outcome of pre-PMF versus ET and associated molecular genetic data supports the concept of two different entities, rather than a continuum of the same disease. Although slightly less than 50% of ET patients also show one or more minor clinical criteria, accurate distinction between ET and pre-PMF is possible by following an integrated approach including histomorphological diagnosis and presence of minor clinical criteria.
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http://dx.doi.org/10.1002/ajh.24788DOI Listing
September 2017

NR4A3 Suppresses Lymphomagenesis through Induction of Proapoptotic Genes.

Cancer Res 2017 05 1;77(9):2375-2386. Epub 2017 Mar 1.

Division of Hematology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.

Nuclear orphan receptor NR4A1 exerts an essential tumor suppressor function in aggressive lymphomas. In this study, we investigated the hypothesized contribution of the related NR4A family member NR4A3 to lymphomagenesis. In aggressive lymphoma patients, low expression of NR4A3 was associated with poor survival. Ectopic expression or pharmacological activation of NR4A3 in lymphoma cell lines led to a significantly higher proportion of apoptotic cells. In a mouse NSG xenograft model of lymphoma (stably transduced SuDHL4 cells), NR4A3 expression abrogated tumor growth, compared with vector control and uninduced cells that formed massive tumors. Transcript analysis of four different aggressive lymphoma cell lines overexpressing either NR4A3 or NR4A1 revealed that apoptosis was driven similarly by induction of BAK, Puma, BIK, BIM, BID, and Trail. Overall, our results showed that NR4A3 possesses robust tumor suppressor functions of similar impact to NR4A1 in aggressive lymphomas. .
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http://dx.doi.org/10.1158/0008-5472.CAN-16-2320DOI Listing
May 2017

Austrian recommendations for the management of primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis: an expert statement.

Wien Klin Wochenschr 2017 May 13;129(9-10):293-302. Epub 2016 Dec 13.

Department of Internal Medicine I, Division of Hematology and Blood Coagulation, Medical University of Vienna, Vienna, Austria.

The entity "myelofibrosis" represents a subgroup of the Philadelphia chromosome-negative myeloproliferative neoplasms. It comprises primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis. This heterogeneous disease is characterized by clonal myeloproliferation, dysregulated kinase signalling and the abnormal expression of several proinflammatory cytokines. Clinically, patients present with symptoms related to thrombocytosis/leukocytosis, anemia and/or progressive splenomegaly. Mutations in Janus kinase 2, an enzyme that is essential for the normal development of erythrocytes, granulocytes, and platelets, notably the V617F mutation, have been identified in approximately 60% of patients with primary myelofibrosis. Recent molecular advances have not only elucidated critical pathways in the pathogenesis of the disease, but also contributed to a more precise assessment of a patient's individual risk. While allogeneic stem cell transplantation remains the only curative treatment, the natural course of the disease and the patient's survival and quality of life may be improved by new treatments, notably ruxolitinib, the first Janus kinase 1/2 inhibitor approved for the management of myelofibrosis. Additional treatment options are being explored.
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http://dx.doi.org/10.1007/s00508-016-1120-8DOI Listing
May 2017

NCCN-IPI score-independent prognostic potential of pretreatment uric acid levels for clinical outcome of diffuse large B-cell lymphoma patients.

Br J Cancer 2016 Nov 20;115(10):1264-1272. Epub 2016 Oct 20.

Division of Oncology, Department of Internal Medicine, Medical University of Graz (MUG), Graz 8036, Austria.

Background: Blood-based parameters are gaining increasing interest as potential prognostic biomarkers in patients with diffuse large B-cell lymphoma (DLBCL). The aim of this study was to comprehensively evaluate the prognostic significance of pretreatment plasma uric acid levels in patients with newly diagnosed DLBCL.

Methods: The clinical course of 539 DLBCL patients, diagnosed and treated between 2004 and 2013 at two Austrian high-volume centres with rituximab-based immunochemotherapy was evaluated retrospectively. The prognostic influence of uric acid on overall survival (OS) and progression-free survival (PFS) were studied including multi-state modelling, and analysis of conditional survival.

Results: Five-year OS and PFS were 50.4% (95% CI: 39.2-60.6) and 44.0% (33.4-54.0) in patients with uric acid levels above the 75th percentile of the uric acid distribution (Q3, cut-off: 6.8 mg dl), and 66.2% (60.4-71.5) and 59.6% (53.7-65.0%) in patients with lower levels (log-rank P=0.002 and P=0.0045, respectively). In univariable time-to-event analysis, elevated uric acid levels were associated with a worse PFS (hazard ratio (HR) per 1 log increase in uric acid 1.47, 95% CI: 1.10-1.97, P=0.009) and a worse OS (HR=1.60, 95% CI: 1.16-2.19, P=0.004). These associations prevailed upon multivariable adjustment for the NCCN-IPI score. Uric acid levels significantly improved the predictive performance of the R-IPI and NCCN-IPI scores, and in multi-state analysis, it emerged as a highly significant predictor of an increased risk of death without developing recurrence (transition-HR=4.47, 95% CI: 2.17-9.23, P<0.0001).

Conclusions: We demonstrate that elevated uric acid levels predict poor long-term outcomes in DLBCL patients beyond the NCCN-IPI risk index.
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http://dx.doi.org/10.1038/bjc.2016.325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5104895PMC
November 2016

Case Report: Epstein-Barr-Virus negative diffuse large B-cell lymphoma detected in a peri-prosthetic membrane.

Diagn Pathol 2016 Aug 18;11(1):80. Epub 2016 Aug 18.

Institute of Pathology, Medical University of Graz, Graz, Austria.

Background: Primary bone lymphomas (PBL) are extremely rare malignant neoplasms. The most commonly described subtype of PBL is diffuse large B-cell lymphoma (DLBCL). DLBCL within peri-prosthetic membrane of a joint is exceedingly rare. To the best of our knowledge this case is the second reported Epstein-Bar-Virus (EBV) negative DLBCL in a peri-prosthetic membrane in the literature.

Case Presentation: We report an 80 year old female patient who developed a DLBCL with chronic inflammation in association to a metallic implant in the left knee. This lymphoma in contrast to the usually described DLBCL in the peri-prosthetic membrane was EBV negative by EBER in situ hybridization as well as by polymerase chain reaction (PCR).

Conclusion: This report challenges the concept of DLBCL associated with chronic inflammation and raises the question of other pathogenetic factors involved in the pathogenesis of this rare disease.
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http://dx.doi.org/10.1186/s13000-016-0533-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4990836PMC
August 2016

The clinical significance of fibrinogen plasma levels in patients with diffuse large B cell lymphoma.

J Clin Pathol 2016 Apr 7;69(4):326-30. Epub 2015 Dec 7.

Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Background: Fibrinogen plays a crucial role in the pathophysiology of tumour cell growth, invasion and metastasis. The aim of this study was to evaluate the prognostic significance of pretreatment plasma fibrinogen levels in patients with diffuse large B cell lymphoma (DLBCL) METHODS: Data from 372 patients with DLBCL, diagnosed and treated between 2004 and 2013 at two Austrian centres, were evaluated retrospectively. The prognostic influences of plasma fibrinogen levels and other factors, including age, tumour stage and the National Comprehensive Cancer Network-International Prognostic Index, on 5-year overall survival (OS) and 5-year disease-free survival (DFS) were studied using Kaplan-Meier curves as well as univariate and multivariate Cox regression models.

Results: Kaplan-Meier analysis revealed that a high fibrinogen plasma level is associated with decreased 5-year OS and 5-year DFS in patients with DLBCL (p<0.001, log-rank test). Furthermore, in multivariate analysis, elevated serum fibrinogen was found to be an independent marker of poor clinical outcome: 5-year OS (HR=1.69, 95% CI 1.06 to 2.72, p=0.029) and 5-year DFS (HR=1.68, 95% CI 1.08 to 2.61, p=0.021).

Conclusions: In the current study, we demonstrate that high plasma fibrinogen levels at diagnosis predict poor outcome in patients with DLBCL.

Trial Registration Number: 25-434 ex 12713 and 415-EP/73/127-2012.
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http://dx.doi.org/10.1136/jclinpath-2015-203356DOI Listing
April 2016