[Show abstract][Hide abstract] ABSTRACT: Here, we studied 83 unselected multiple myeloma patients from December 2007 through December 2014. Lower 25(OH) D levels (<10 ng/mL) were associated with higher number of plasma cells in the bone marrow. Supplementation of vitamin D was accompanied with a significant increase in hemoglobin (11.8 to 12.3 p = .039), leukocyte (4.9 to 5.8 p = .011), and erythrocyte (3.8 to 4.0 p = .004) levels, while thrombocytes (200.5 to 175.2 p = .036) decreased. In conclusion, the present study found a high incidence of vitamin D deficiency and insufficiency in MM patients. In myeloma patients, vitamin D levels and supplementation should be more widely taken into account.
Preview · Article · Oct 2015 · Cancer Investigation
[Show abstract][Hide abstract] ABSTRACT: Tyrosine kinase inhibitors represent today's treatment of choice in chronic myeloid leukemia (CML). Allogeneic hematopoietic stem cell transplantation (HSCT) is regarded as salvage therapy. This prospective randomized CML-study IIIA recruited 669 patients with newly diagnosed CML between July 1997 and January 2004 from 143 centers. Of these, 427 patients were considered eligible for HSCT and were randomized by availability of a matched family donor between primary HSCT (group A; N=166 patients) and best available drug treatment (group B; N=261). Primary endpoint was long-term survival. Survival probabilities were not different between groups A and B (10-year survival: 0.76 [95% CI: 0.69-0.82] vs 0.69 [95% CI: 0.61-0.76]), but influenced by disease and transplant risk. Patients with a low transplant risk showed superior survival compared to patients with high (P<0.001) and non-high risk disease (P=0.047) in group B; after entering blast crisis, survival was not different with or without HSCT. Significantly more patients in group A were in molecular remission (56 vs 39%; P=0.005) and free of drug treatment (56 vs 6%; P<0.001). Differences in symptoms and Karnofsky score were not significant. In the era of tyrosine kinase inhibitors, HSCT remains a valid option when both disease and transplant risk are considered.Leukemia accepted article preview online, 14 October 2015. doi:10.1038/leu.2015.281.
No preview · Article · Oct 2015 · Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
[Show abstract][Hide abstract] ABSTRACT: Treatment options for patients with relapsed and refractory multiple myeloma have improved since the introduction of immune-modulating agents such as lenalidomide and thalidomide. However, almost all patients relapse and suffer from an increasing amount of adverse events due to multiple lines of therapy that eventually lead to a reduced quality of life.
In this bicentric retrospective analysis, 58 patients who had been treated with either bendamustine monotherapy (62 % of the patients) or combined steroid therapy were included. Further inclusion criteria were at least relapsed disease. Patients had previously been treated with a mean of four lines of therapy (range 1-10). They received a median of three cycles of treatment. Dosage varied from 60 to 300 mg/m(2) (median 120 mg/m(2)) and was administered intravenously on day 1 and 2 of a 28-day cycle.
Observed toxicity was mild and most commonly led to hematological side effects such as thrombopenia and anemia. Response rates were as follows: no complete response, 20 % partial response, 39 % minimal response, 27 % stable disease and 14 % progressive disease. Median overall survival (OS) was 17 months. Median event-free survival was 7 months. Patients who had not received a concomitant steroid had a median OS of 17 months compared to 13 months median OS for patients who had received a concomitant steroid.
Bendamustine monotherapy is an effective treatment option for heavily pre-treated myeloma patients due to its favorable response rate and mild toxicity.
No preview · Article · Jul 2015 · Journal of Cancer Research and Clinical Oncology
[Show abstract][Hide abstract] ABSTRACT: We aimed at demonstrating non-inferiority of bortezomib/cyclophosphamide/dexamethasone (VCD) compared to bortezomib/doxorubicin/dexamethasone (PAd) induction therapy with respect to very good partial response rates or better (≥VGPR) in 504 newly diagnosed, transplant-eligible multiple myeloma (MM) patients. VCD was found to be non-inferior to PAd with respect to ≥VGPR rates (37.0% vs. 34.3%, p=0.001). The rates of progressive disease (PD) were 0.4% (VCD) vs. 4.8% (PAd) (p=0.003). In the PAd arm, 11 of 12 patients with PD had either renal impairment (creatinine ≥2 mg/dl) at diagnosis or the cytogenetic abnormality gain 1q21, whereas no PD was observed in these subgroups in the VCD arm. Leucocytopenia/neutropenia (≥3°) occurred more frequently in the VCD arm (35.2% vs. 11.3%, p<0.001). Neuropathy rates (≥2°) were higher in the PAd group (14.9% vs. 8.4%, p=0.03). Serious Adverse Events (SAEs), both overall and those related to thromboembolic events, were higher in the PAd group (32.7% vs. 24.0%, p=0.04 and 2.8% vs. 0.4%, p=0.04). Stem cell collection was not impeded by VCD. VCD is as effective as PAd in terms of achieving ≥VGPR rates with fewer PD and has a favorable toxicity profile. Therefore, VCD is preferable to PAd as induction therapy.Leukemia accepted article preview online, 19 March 2015. doi:10.1038/leu.2015.80.
No preview · Article · Mar 2015 · Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
[Show abstract][Hide abstract] ABSTRACT: Cytokine-induced killer (CIK) cells represent an exceptional T cell population uniting a T cell and natural killer cell like phenotype in their terminally differentiated CD3(+)CD56(+) subset, which features non-MHC-restricted tumor-killing activity. CIK cells are expandable from peripheral blood mononuclear cells and mature following the addition of certain cytokines. CIK cells have provided encouraging results in initial clinical studies and revealed synergistic antitumor effects when combined with standard therapeutic procedures.
Therefore, we established the international registry on CIK cells in order to collect and evaluate data about clinical trials using CIK cells for the treatment of cancer patients. Moreover, our registry is expected to set new standards on the reporting of results from clinical trials using CIK cells. Clinical responses, overall survival (OS), adverse reactions and immunologic effects were analyzed in 45 studies present in our database. These studies investigated 22 different tumor entities altogether enrolling 2,729 patients.
A mean response rate of 39 % and significantly increased OS, accompanied by an improved quality of life, were reported. Interestingly, side effects of CIK cell treatment were minor. Mild fevers, chills, headache and fatigue were, however, seen regularly after CIK cell infusion. Moreover, CIK cells revealed numerous immunologic effects such as changes in T cell subsets, tumor markers, cytokine secretion and HBV viral load.
Due to their easy availability and potent antitumor activity, CIK cells emerged as a promising immunotherapy approach in oncology and may gain major importance on the prognosis of cancer.
No preview · Article · Nov 2014 · Journal of Cancer Research and Clinical Oncology
[Show abstract][Hide abstract] ABSTRACT: This largest prospective multicenter trial for adult patients with Burkitt lymphoma/leukemia aimed to prove efficacy and feasibility of a short-intensive chemotherapy combined with the anti-CD20 antibody Rituximab. 363 patients 16 to 85 years old (median 42 yrs) were recruited in 98 centers from 8/2002 until 06/2011. Treatment consisted of 6 five-day chemotherapy cycles with high-dose methotrexate, high-dose cytosine arabinoside, cyclophosphamide, etoposide, ifosphamide, corticosteroids, and triple intrathecal therapy. Patients >55 years received a reduced regimen. Rituximab was given d -1 before each cycle and twice as maintenance, for a total of 8 doses. The complete remission rate was 88% (319/363), the overall survival (OS) at 5 years 80%, and the progression-free survival (PFS) 71%, with significant difference between adolescents (≥15-25 yrs), adults (26-55 yrs) and elderly (>55 yrs) patients with an OS of 90%, 84%, and 62%. Full treatment could be applied in 86% of the patients. Most important prognostic factors were IPI (0-2 vs. 3-5, p=0.0005), aaIPI (0-1 vs. 2-3, p=0.0001), and gender (male vs. female, p=0.004). The high cure rate in this prospective trial with a substantial number of participating hospitals demonstrates the efficacy and feasibility of chemoimmunotherapy, also in elderly patients. The study is registered to www.clinicaltrials.gov as NCT00199082.
[Show abstract][Hide abstract] ABSTRACT: Unlabelled:
Multiple myeloma (MM) is with an incidence of 4-6/100 000 inhabitants a fairly frequent malignancy of B cells. The incidence increases markedly with age. In this review changes in the treatment of relapsed / refractory myeloma during the last decade have been analysed. The present standard of care in the progressive or refractory myeloma was elaborated by the working group "Refractory Multiple Myeloma" using an extensive literature search for studies published between 2003 and 2013. Outside of clinical trials, high-dose therapy with stem cell transplantation is recommended in fit patients up to 75 years without significant comorbidities. Ongoing studies address the question about the least toxic and the most effective treatment. Therefore, inclusion of patients in therapeutic trials and use of novel agent combinations is highly recommended, e.g. with 3(rd) generation-IMIDs (pomalidomide), new proteasome inhibitors, such as carfilzomib, ixazomib or oprozomib, antibodies, such as elotuzumab, daratumumab or SAR650984, siltuximab, tabalumab, denosumab, romosozumab, BTK-, HSP-inhibitors and other innovative phase I/II agents.
Based on new insights in the pathogenesis of the disease, treatment options for MM have changed significantly in recent years. There is a significantly larger treatment diversity, i.e. more MM-active agents and combinations are available today. Even with relapsed MM, patients with the disease often live longer and have fewer complications.
No preview · Article · Oct 2014 · DMW - Deutsche Medizinische Wochenschrift
[Show abstract][Hide abstract] ABSTRACT: Background/aim:
Activated Wnt signaling in cancer cells leads to cell proliferation. It has been shown that the Wnt pathway is activated in pancreatic adenocarcinoma cells. Therefore, we tested the effect of Wnt inhibitors in human and murine pancreatic cancer cell lines.
Materials and methods:
The Wnt inhibitors ethacrynic acid (EA), ciclopirox olamine (CIC), piroctone olamine (PO) and griseofulvin (GF) were tested in murine and human pancreatic cancer cell lines with the 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide (MTT) assay.
We showed that the Wnt inhibitors significantly reduced cell viability in murine, as well as human pancreatic cancer cell lines.
These results may lead to a new therapeutic option with Wnt inhibitors for patients with pancreatic adenocarcinoma.
No preview · Article · Oct 2014 · Anticancer research
[Show abstract][Hide abstract] ABSTRACT: Cytokine-induced killer (CIK) cells are a heterogeneous population of immune effector cells that feature a mixed T- and Natural killer (NK) cell-like phenotype in their terminally-differentiated CD3+CD56+ subset. The easy availability, high proliferation rate and widely major histocompatibility complex (MHC)-unrestricted antitumor activity of CIK cells contribute to their particularly advantageous profile, making them an attractive approach for adoptive immunotherapy. CIK cells have shown considerable cytotoxicity against both solid tumors and hematological malignancies in vitro and in animal studies. Recently, initial clinical experiences demonstrated the feasibility and efficacy of CIK cell immunotherapy in cancer patients, even at advanced disease stages. Likewise, the clinical application of CIK cells in combination with standard therapeutic procedures revealed synergistic antitumor effects. In this report, we will focus our consideration on CIK cells in the treatment of hematological malignancies. We will give insight into the latest advances and future perspectives and outline the most prominent results obtained in 17 clinical studies. Overall, CIK cells demonstrated a crucial impact on the treatment of patients with hematological malignancies, as evidenced by complete remissions, prolonged survival durations and improved quality of life. However, up to now, the optimal application schedule eventually favoring their integration into clinical practice has still to be developed.
Full-text · Article · Aug 2014 · International Journal of Molecular Sciences
[Show abstract][Hide abstract] ABSTRACT: Background/aim:
Advanced renal cancer still has a very poor prognosis. In this regard recent investigations demonstrated a constitutive activation of the Wnt signaling pathway in renal cell carcinoma (RCC) thereby promoting an exaggerated cell proliferation. Especially, β-catenin overactivation and the functional loss of endogenous Wnt antagonists are associated with RCC carcinogenesis and progression. Thus, influencing Wnt signaling might represent a promising target in RCC treatment.
Materials and methods:
It was recently confirmed that ethacrynic acid (EA), ciclopirox olamine (CIC) and piroctone olamine (PO) can inhibit Wnt signaling in various cancer cell lines. Herein we investigated their cytotoxic potential towards human RCC cells and their influence on the Wnt pathway concerning apoptosis as determined by 3,3'-dihexyloxacarbocyanine iodide (DiOC6) and propidium iodide (PI) staining in flow cytometry and immunoblotting.
All three agents, EA, CIC and PO triggered a significant apoptotic activity in tested RCC cell lines in a time- and concentration-dependent manner. Moreover, exposure to CIC and PO decreased the expression of β-catenin as the pivotal feature within the canonical Wnt pathway. However, β-catenin expression increased upon the treatment with EA.
These results reveal a significant selective induction of apoptosis by EA, CIC and PO and suggest a suppression of RCC survival in part due to inhibition of Wnt/β-catenin signaling. The development of targeted-therapies affecting the Wnt signaling pathway might therefore lead to novel treatment options for RCC patients.
No preview · Article · Aug 2014 · Anticancer research
[Show abstract][Hide abstract] ABSTRACT: Hintergrund Das multiple Myelom ist eine maligne lymphoproliferative B-Zell-Erkrankung, die durch die Vermehrung von monoklonalen Plasmazellen gekennzeichnet ist. Ein Rezidiv tritt bei ca. 95 % der Patienten auf. Ziel Basierend auf der aktuellen Literatur soll eine Zusammenfassung der Therapieoptionen beim refraktären multiplen Myelom erarbeitet werden. Ergebnisse Beim rezidivierten und/oder refraktären multiplen Myelom (RRMM) haben „novel drugs“ wie Thalidomid, Bortezomib und Lenalidomid die Therapieergebnisse verbessert und zu einer Verlängerung des Gesamtüberlebens geführt. Die Hochdosistherapie, gefolgt von der autologen Blutstammzelltransplantation, ist auch im Rezidiv eine Therapieoption für „fitte“ Patienten (guter Allgemeinzustand) mit langer Remission (12 bis 24 Monate) nach erster Hochdosistherapie. Schlussfolgerung In die Wahl der Rezidivtherapie sind das Ergebnis und die Nebenwirkungen der Initialtherapie sowie patienten- und erkrankungsspezifische Faktoren einzubeziehen. Für refraktäre Patienten bzw. Patienten, die auf die Behandlung mit den etablierten neuen Medikamenten nicht ansprechen, sind mit Pomalidomid und Carfilzomib weitere Therapieoptionen in Deutschland gegeben. Neue Substanzen mit anderen Wirkprinzipien befinden sich beim RRMM in der klinischen Prüfung. Die allogene Transplantation mit hämatopoetischen Stammzellen ist in Studien weiter zu prüfen.
[Show abstract][Hide abstract] ABSTRACT: Hairy cell leukemia (HCL) is part of the low-grade non-Hodgkin lymphoma family and represents approximately 2% of all leukemias. Treatment with splenectomy and interferon-α historically belonged to the first steps of therapeutic options, achieving partial responses/remissions (PR) in most cases with a median survival between 4 and 6 years in the 1980s. The introduction of the purine analogs (PA) pentostatin and cladribine made HCL a well-treatable disease: overall complete response rates (CRR) range from 76 to 98%, with a median disease-free survival (DFS) of 16 years a normal lifespan can be reached and HCL-related deaths are rare. However, insufficient response to PA with poorer prognosis and relapse rates of 30-40% after 5-10 years of follow-up may require alternative strategies. Minimal residual disease can be detected by additional examinations of bone marrow specimens after treatment with PA. The use of immunotherapeutic monoclonal antibodies (mAB) like rituximab as a single agent or in combination with a PA or more recently clinical trials with recombinant immunotoxins (RIT) show promising results to restrict these problems. Recently, the identification of the possible disease-defining BRAF V600E mutation may allow the development of new therapeutic targets.
Preview · Article · Feb 2014 · Blood Cancer Journal