Thomas Kühr

p53-Binding Protein 1 Is Fused to the Platelet-Derived Growth Factor Receptor β in a Patient with a t(5;15)(q33;q22) and an Imatinib-Responsive Eosinophilic Myeloproliferative Disorder

We describe the fusion of TP53BP1 to PDGFRB in a patient with a chronic myeloid leukemia-like disorder associated with eosinophilia and a t(5;15)(q33;q22). TP53BP1 encodes 53BP1, a p53-binding protein that plays a role in cellular responses to DNA damage. The 53BP1-PDGFRβ fusion protein is predicted to retain the kinetochore-binding domain of 53BP1 fused to the transmembrane and intracellular tyrosine kinase domain of PDGFRβ. The presence of the fusion was confirmed by two-color fluorescence in situ hybridization, reverse transcription-PCR, and by characterizing the genomic breakpoints. The reciprocal fusion, which would contain the p53-binding 53BP1 BRCA1 COOH-terminal domains, was not detectable by fluorescence in situ hybridization or nested PCR. Imatinib, a known inhibitor of PDGFRβ, blocked the growth of patient colony-forming unit, granulocyte-macrophage in vitro and produced a clinically significant response before relapse and subsequent death with imatinib-resistant disease. We conclude that TP53BP1-PDGFRB is a novel imatinib target in atypical chronic myeloid leukemia.

CpG island methylation of the hTERT promoter is associated with lower telomerase activity in B-cell lymphocytic leukemia

OBJECTIVE Expression of the catalytic subunit of the telomerase enzyme hTERT is essential for prolonging the replicative lifespan and is the rate-limiting step in cellular immortalization and carcinogenesis. Because hTERT expression is positively correlated with telomerase activity, its regulation is suggested as the major determinant of enzymatic activity. The hTERT promoter region contains two CpG islands, which are known to be target sites for de novo DNA methylation. To elucidate the impact of this epigenetic mechanism on telomerase activity, we analyzed the degree of hTERT promoter methylation in 30 patients with B-cell chronic lymphocytic leukemia. MATERIALS AND METHODS hTERT promoter methylation was assessed using a methylation-specific competitive polymerase chain reaction assay. The assay is based on digestion of genomic DNA with a methylation-sensitive restriction enzyme before amplification with an internal standard. RESULTS Patients exhibiting high telomerase activity showed significantly less methylation of the hTERT promoter core domain than patients with low enzyme activity. In addition, telomerase activity was significantly associated with telomere length and overall survival. CONCLUSIONS Our data show that the degree of CpG island methylation of the hTERT promoter exhibits an impact on telomerase activity in a subgroup of patients with B-cell chronic lymphocytic leukemia and therefore is assumed to play a role in regulating hTERT gene expression in these patients.

Thrombotic Microangiopathy with Renal Failure in Two Patients Undergoing Gemcitabine Chemotherapy

Described here are 2 patients who developed thrombotic microangiopathy of the kidneys after receiving high cumulative doses of the new anticancer drug gemcitabine. The first patient, who received gemcitabine for treatment of a carcinoma of the pancreas, required hemodialysis for 6 months. In the second case, a woman suffering from a cholangiocellular carcinoma, end-stage renal disease was irreversible. Clinical awareness, timely detection and discontinuation of gemcitabine are mandatory to prevent this rare but disastrous complication of gemcitabine therapy.

A randomized study comparing interferon (IFNα) plus low-dose cytarabine and interferon plus hydroxyurea (HU) in early chronic-phase chronic myeloid leukemia (CML)

This multicenter randomized phase III study was designed to compare the efficacy and toxicity of IFN alpha-2c (3.5 MU/d) in combination with either araC (10 mg/m(2) d1-10) or hydroxyurea (HU: 25 mg/kg per day) in newly diagnosed CML patients. A total of 114 patients were randomized. Following a median observation period of 36 (range 1-73) months the major cytogenetic response rates were 25 and 27% and the 4-year survival probabilities 62.5 and 63% for the araC and HU group, respectively. While the overall toxicity profile was comparable between both groups, patients in the HU arm exhibited a slightly higher degree of WHO grades 3 and 4 non-hematological toxicities.

Treatment of patients with advanced chronic myelogenous leukemia with interferon-alpha-2b and continuous oral cytarabine ocfosfate (YNK01): a pilot study

The efficacy of continuous oral cytarabine ocfosfate (YNK01) (300 mg/day) in combination with interferon alpha (IFNalpha, 5x10(6) IU/day) was evaluated in patients with advanced chronic myelogenous leukemia, who previously failed to respond to IFNalpha-based therapies. Dose escalations up to 900 mg YNK01 were allowed in patients who failed to respond. In view of our results, four patients developed a complete hematological response after YNK01 was started. Among those who initially responded to YNK01, one complete cytogenetic response was achieved 18 months later. Although the data are preliminary, this is the first study showing that continuous administration of YNK01 along with IFNalpha is effective in patients with advanced chronic myelogenous leukemia.

Expression of LFA-1 identifies different prognostic subgroups in patients with advanced follicle center lymphoma (FCL)

In a retrospective immunohistochemical study based on 27 patients with stage IV follicle center lymphoma (FCL) the expression of CD44standard (CD44s), LFA-1 (CD11a, CD18), VLA-4 (CD49d, CD29) and ICAM-1 (CD54) was analysed on lymphoma cells in bone marrow infiltrates. The results were correlated to clinical data and overall survival. Our data demonstrate that the expression of LFA-1 on lymphoma cells is predictive for the prognosis of patients with advanced FCL. In detail, patients exhibiting weak to moderate expression (+/++) of CD11 and CD18 showed a significantly shorter median survival (51 months and 33 months, respectively) than did those presenting with strong expression ( ) of the LFA-1 adhesion molecule (P = 0.04 and P = 0.0051, respectively). Furthermore, multivariate analysis identified CD18 as a new independent prognostic factor in patients with advanced FCL. Our findings emphasize the relevance of adhesion molecules for the pathology of FCL and give further support for their impact on clinical course and overall survival.

Gastrointestinal stromal tumors: Diagnosis, therapy and follow-up care in Austria

SummaryOptimal treatment for patients suffering from gastrointestinal stromal tumors (GIST) is based on an interdisciplinary treatment approach. Austrian representatives of Medical and Surgical Oncology, Pathology, Radiology, Nuclear Medicine, Gastroenterology, and Laboratory Medicine issued this manuscript on a consensual base within the context of currently available and published literature. This paper contains guidelines and recommendations for diagnosis, therapy, and follow-up of GIST patients in Austria.ZusammenfassungDie interdisziplinäre Behandlung von Gastrointestinalen Stromatumoren ist Grundvoraussetzung für eine adäquate Behandlung dieser seltenen Tumorentität. Österreichische Vertreter aus den Fachdisziplinen der Onkologie, Chirurgie, Pathologie, Radiologie, Nuklearmedizin, Gastroenterologie und Labormedizin verfassten dieses Manuskript konsensuell. Anhand der, bei der Manuskripterstellung verfügbaren und publizierten Fachliteratur, wurden Leitlinien und Empfehlungen für Diagnose, Therapie und Kontrolle von GIST-PatientInnen in Österreich erstellt.

Gastrointestinal stromal tumors: Recommendations on diagnosis, therapy and follow-up care in Austria

ZusammenfassungInterdisziplinäre Behandlung von gastrointestinalen Stromatumoren (GIST) ist Grundvoraussetzung für eine adäquate Behandlung dieser seltenen Tumorentität. Österreichische Vertreter der Fachdisziplinen Onkologie, Chirurgie, Pathologie, Radiologie und Gastroenterologie verfassten dieses Manuskript konsensuell. Anhand der bei der Manuskripterstellung verfügbaren und publizierten Fachliteratur wurden Leitlinien und Empfehlungen für Diagnose, Therapie und Kontrolle von GIST Patienten in Österreich erstellt.SummaryAdequate treatment of gastrointestinal stromal tumors (GISTs) is linked to an interdisciplinary treatment approach. Austrian representatives of medical oncology, surgery, pathology, radiology and gastroenterology have issued this consensus manuscript within the context of currently available and published literature. The paper contains guidelines and recommendations for diagnosis, therapy and follow-up of GIST patients in Austria.

Experience with lenalidomide in an Austrian non-study population with advanced myelofibrosis

SummaryCurrent literature provides conflicting evidence regarding the efficacy of lenalidomide in patients with myelofibrosis (MF). The aim of this work was to evaluate the efficacy of lenalidomide in patients with MF treated within a named patient program in Austria. A total of 22 patients with MF were treated with lenalidomide in 7 different centres throughout Austria. Median age of patients was 68 years. Primary MF was present in 13 patients. Eight patients had post-polycythemia vera (post-PV) and 1 post-essential thrombocythemia (post-ET) MF. According to the Dynamic International Prognostic Scoring System (DIPSS), all patients were scored within the intermediate-2 or high-risk group. Approximately one-third of patients were treated with 2 or more prior therapies. The overall response rate according to International Working Group (IWG) criteria was 12.5 %. Efficacy of lenalidomide was moderate in this non-study patient population. Limiting factors seemed to be stage of disease and risk profile of patients included in this analysis.ZusammenfassungDie Wirksamkeit von Lenalidomid bei Patienten mit Myelofibrose stellt sich in der Literatur nicht ganz einheitlich dar. Das Ziel dieser Arbeit war die Wirksamkeit von Lenalidomid in einer „real world“ Population von Patienten mit Myelofibrose zu evaluieren, die das Medikament im Rahmen eines „named patient“ Programms in Österreich zur Verfügung gestellt bekamen. Das mediane Alter der 22 eingeschlossenen Patienten betrug 68 Jahre. Dreizehn Patienten hatten eine primäre Myelofibrose, 8 eine post-Polycythämia vera- und ein Patient eine post-Essentielle Thrombocythämie–Myelofibrose. Die teilweise schwere Vorbehandlung spiegelte sich im Risikoprofil (Dynamic International Prognostic Scoring System) wider, in dem alle Patienten in der intermediate-2 oder Hochrisikogruppe vertreten waren. Die Gesamtansprechrate lag bei 12,5 %, sodass von einem moderaten Ansprechen auf Lenalidomid in dieser Patientenkohorte auszugehen ist. Limitierende Faktoren scheinen das fortgeschrittene Stadium der Erkrankung sowie das Risikoprofil der Patienten darzustellen.

Dose escalation of ara-C may improve response rates in a subgroup of chronic myeloid leukemia patients with poor response to interferon-α and low-dose ara-C

The present analysis was performed to evaluate the impact of cytosine arabinoside (ara-C) dose escalation on hematological and cytogenetic responses in patients with chronic myelogenous leukemia (CML) who failed to respond to low-dose ara-C (LD ara-C) at a dose of 10 mg/m″/d over 10 days per month and interferon-α (IFNα, 3.5 MU/d). Following the same administration schedule, dose escalation of ara-C to 15 and 20 mg/m2/d 1–10 was performed in 36 of 119 patients (30%) due to inadequate hematological response and/or disease progression. As a result, improvement of hematological and cytogenetic responses was achieved in 22 (61%) and nine (25%) patients, respectively. Escalated ara-C dose levels were usually well tolerated, although some patients experienced deterioration of preexisting side effects. Our results support the critical role of ara-C dose towards a better disease control in CML.