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Bone marrow transplantation 09/2012; · 3.00 Impact Factor
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F Klemm,
A Bleckmann,
L Siam,
H N Chuang,
E Rietkötter,
D Behme,
M Schulz,
M Schaffrinski,
S Schindler, L Trümper,
F Kramer,
T Beissbarth,
C Stadelmann,
C Binder,
T Pukrop
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ABSTRACT: A role of WNT signaling for primary breast cancers of the basal-like subtype and as a predictor of brain metastasis has been described. However, a responsible WNT ligand has not been identified. To further clarify this question, we comparatively investigated 22 human breast cancer brain metastases as well as the highly invasive human breast cancer cell line MDA-MB-231 and the weakly motile MCF-7 as models for the basal-like and the luminal A subtype. WNT5A and B were found overexpressed in MDA-MB-231 cells as compared with MCF-7. This corresponded to reduction of MDA-MB-231 invasiveness by WNT inhibitors, whereas MCF-7 invasion was enhanced by recombinant WNT5B and abolished by WNT and Jun-N-terminal kinase antagonists. Expression and subcellular distribution of β-catenin remained uninfluenced. Consistently, β-catenin was not localized in the nuclei of brain metastases while there was strong nuclear c-Jun staining. Similar to MDA-MB-231, metastases showed expression of WNT5A/B and the alternative WNT receptors ROR1 and 2. These findings were validated using external gene expression datasets (Gene Expression Omnibus) of different breast cancer subtypes and brain metastases. Hierarchical cluster analysis yielded a close relation between basal-like cancers and brain metastases. Gene set enrichment analyses confirmed WNT pathway enrichment not only in basal-like primaries but also in cerebral metastases of all subtypes. In conclusion, WNT signaling seems highly relevant for basal-like and other subtypes of breast cancers metastasizing into the brain. β-catenin-independent WNT signaling, presumably via ROR1-2, plays a major role in this context.
Carcinogenesis 03/2011; 32(3):434-42. · 5.70 Impact Factor
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ABSTRACT: We aimed to determine safety and efficacy of rituximab (R) in combination with repetitive high-dose therapy (HDT) as primary treatment for diffuse large B-cell lymphoma (DLBCL).
Patients aged 18-60 years and elevated lactate dehydrogenase were treated with four cycles of MegaCHOEP and transplantation of autologous stem cells after cycles 2, 3 and 4. Rituximab (375 mg/m²) was given before each cycle and 12 and 33 days after start of the last cycle of chemotherapy. Sixty-four patients given R-MegaCHOEP were compared with 29 patients who had received identical treatment without rituximab.
Overall survival (OS) and event-free survival (EFS) after 3 years were significantly improved in patients treated with R-MegaCHOEP (OS: 78.7% versus 55.0%, P = 0.045; EFS: 72.7% versus 47.2%, P = 0.013). In a Cox regression model adjusted for performance status and stage, relative risk of treatment failure was lower (relative risk 0.5, P = 0.041) and OS was better (relative risk 0.4, P = 0.054) for patients given R-MegaCHOEP. Grade 3/4 infections were more frequent in the R-MegaCHOEP group (18.5% versus 6.0%, P = 0.003).
The addition of rituximab to MegaCHOEP significantly improved outcome in young patients with high-risk DLBCL. The higher incidence of grade 3/4 infections needs consideration when rituximab and HDT regimens are combined.
Annals of Oncology 05/2010; 21(11):2255-61. · 6.43 Impact Factor
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ABSTRACT: This guideline is a prerequisite for the quality management in the treatment of non-Hodgkon-lymphomas in patients with relapsed or refractory follicular lymphoma after rituximab therapy and as consolidation therapy after first remission following CHOP like treatment using radioimmunotherapy. It is based on an interdisciplinary consensus and contains background information and definitions as well as specified indications and detailed contraindications of treatment. Essential topics are the requirements for institutions performing the therapy. For instance, presence of an expert for medical physics, intense cooperation with all colleagues committed to treatment of lymphomas, and a certificate of instruction in radiochemical labelling and quality control are required. Furthermore, it is specified which patient data have to be available prior to performance of therapy and how treatment has to be carried out technically. Here, quality control and documentation of labelling are of great importance. After treatment, clinical quality control is mandatory (work-up of therapy data and follow-up of patients). Essential elements of follow-up are specified in detail. The complete treatment inclusive after-care has to be realised in close cooperation with those colleagues (hemato-oncologists) who propose, in general, radioimmunotherapy under consideration of the development of the disease.
Nuklearmedizin 11/2009; 48(6):215-20. · 1.28 Impact Factor
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ABSTRACT: Recently published data indicate that host germline variations in immune genes can influence the outcome of lymphoma patients. Interleukin (IL)-4 and IL13 are crucial immune factors and may influence the course of the disease. Both cytokines signal through the interleukin-4 receptor (IL4R). Therefore, we investigated whether polymorphisms of IL4, IL13 and IL4R genes could predict the outcome of diffuse large B-cell lymphoma (DLBCL) patients.
In 228 DLBCL samples of the German High-Grade Non-Hodgkin's Lymphoma Study Group, the polymorphisms of IL4 (-524CT, rs2243250), IL13 (-1069CT, rs1800925) and IL4R (I75V, rs1805010; S503P, rs1805015; Q576R, rs1801275) were analyzed and the soluble interleukin-4 receptor (sIL4R) serum level was measured before the start of chemotherapy.
Patients harboring IL4R V75 (IL4R(I75V-AG) and IL4R(I75V-GG)) had shorter overall survival (OS) (P = 0.044) and event-free survival (EFS) (P = 0.056) periods compared with I75 carriers (IL4R(I75V-AA)). Multivariate analysis adjusted to the International Prognostic Index revealed a relative risk of 1.9 for carriers of the IL4R V75 (P = 0.011) in relation to OS. DLBCL patients homozygous for the IL4R I75 and low sIL4R serum levels have the most favorable OS and EFS.
These data support the role for host germline gene variations of immunologically important factors like the IL4R I75V gene variation to predict the survival in DLBCL patients.
Annals of Oncology 07/2009; 20(9):1548-54. · 6.43 Impact Factor
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Cell Communication and Signaling. 01/2009;
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ABSTRACT: Recent retrospective studies of heterogeneously treated patients have suggested that chromosomal aberrations of the MYC gene locus indicate an unfavorable prognosis in diffuse large B-cell lymphoma (DLBCL). Here, we investigated the prognostic impact of MYC aberrations analyzed by interphase fluorescence in situ hybridization in 177 patients with de novo DLBCL treated within the two prospective, randomized trials non-Hodgkin's lymphoma NHL-B1 and NHL-B2. MYC aberrations were detected in 14 DLBCL (7.9%). In a univariate analysis compared with MYC-negative DLBCL, MYC-positive cases showed a significantly shorter overall survival (OS) (P=0.047) and relevantly, though not significantly, shorter event-free survival (EFS) (P=0.062). In a Cox model adjusted for the international prognostic index, the presence of a MYC gene rearrangement was the strongest statistically independent predictor of OS (relative risk 3.4, P=0.004) and EFS (relative risk 2.5, P=0.015), and this also held true when the cell-of-origin signature detected by immunohistochemistry was included in the model.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 09/2008; 22(12):2226-9. · 8.30 Impact Factor
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ABSTRACT: Constitutive activation of the phosphoinositide 3-kinase (PI3K)-AKT pathway is observed in up to 70% of acute myelogenous leukemia. To investigate the relevance of an intrinsic PI3K-AKT pathway activation in hematopoietic malignancies, we analysed the effect of point mutations in the catalytic (p110alpha) and regulatory (p85alpha) subunit of class IA PI3K. We demonstrated that mutations in the helical (E542K, E545A) and kinase domain (H1047R) of p110alpha constitutively activate the PI3K-AKT pathway and lead to factor-independent growth of early hematopoietic cells. Proliferation and survival of the cells were inhibited in a time- and dose-dependent manner using either PI3K or AKT inhibitors. The mammalian target of rapamycin (mTOR) was demonstrated to be important for mitogenic, but not antiapoptotic signaling of mutant p110alpha. In a syngenic mouse model, hematopoietic cells expressing mutated p110alpha induced a leukemia-like disease characterized by anemia, neoplastic infiltration of hematopoietic organs and 90% mortality within 5 weeks, whereas activated mutants of the receptor tyrosine kinase c-KIT led to 100% mortality within 10 days. Our data show that point mutations in the p110alpha subunit of class IA PI3K confer factor independence to hematopoietic cells in vitro and leukemogenic potential in vivo, but have lower transforming activity than a deregulated class III receptor tyrosine kinase.
Oncogene 08/2008; 27(29):4096-106. · 6.37 Impact Factor
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ABSTRACT: Molecular genetic analysis adds important information for lymphoma biology and classification, but the latter is challenged by recent improvement of combined chemo-immunotherapy. In aggressive lymphoma, molecular profiling identifies risk groups with certain genetic background but still the International Prognostic Index (IPI) remains the most important clinically applicable predictor of outcome. In follicular lymphoma (FL), the importance of the meshwork of bystander cells becomes increasingly evident. As combined immuno-chemotherapy improved the prognosis of the patients, several clinical trials indicated that the FLIPI still efficiently discriminates patients at risk for transformation and relapse, although several mechanisms of transformation seem to exist. In mantle cell lymphoma it has been proven that pathogenesis and prognosis mainly depend on deregulation of the cell cycle. A reliable clinical risk score could be established.
British Journal of Haematology 06/2008; 142(2):166-78. · 4.94 Impact Factor
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ABSTRACT: Besides acute inflammatory swelling of a lymph node, acute lymphadenitis, enlarged lymph nodes occur in conjunction with various benign and malignant diseases. Lymphadenopathy can appear in a localized or generalized form and requires further diagnostic measures. Possible causes are primarily infectious, immunological, neoplastic, and metabolic disorders. The medical history and physical examination provide the first clues to the diagnosis. Localized swollen glands often have an infectious etiology so that the first step is to identify the possible focus of infection. Generalized lymphadenopathy is frequently a sign of a hematological systemic disease, particularly in adults. Therefore, in every case of lymphadenopathy persisting for more than 1 month, invasive diagnostic procedures are indicated to rule out a malignant cause. The aim should be to perform a histological analysis; excision of entire lymph nodes is exigent, especially for the work-up of lymphoma. In cases of malignant lymphoma, staging examinations should subsequently be conducted to assess the prognosis and formulate a treatment plan.
Der Internist 04/2008; 49(3):305-318; quiz 319-20. · 0.30 Impact Factor
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ABSTRACT: Natural killer (NK) cells identify cells with altered human leucocyte antigen (HLA) expression as targets through lacking engagement of self-HLA-specific inhibitory receptors (e.g. killer cell immunoglobulin-like receptor, KIR). Thus, they eliminate cells with 'missing self' because of viral or malignant transformation. We performed analysis of HLA, KIR genotypes and KIR receptor expression patterns at single cell level in NK cells in 17 donors. The function of NK cell subsets is determined by degranulation assays using target cells expressing self, cognate, control or no HLA class I. Donors could be grouped into three groups: their NK cells possess potential for alloreactivity, autoreactivity based on the presence of NK cells expressing particular KIR only (mono-KIR) in the absence of its ligand or lack alloreactivity. All donors possess NK cells lacking all detectable inhibitory receptors. Both potential autoreactive subpopulations did not respond to HLA class I-positive target cells. They retain partial reactivity against HLA class I-negative tumour target cells. Mono-KIR NK cells without the corresponding ligands in the individuals and NK cells lacking all inhibitory receptors behave self-tolerant. Our results suggest alternative mechanisms than HLA-specific inhibitory receptors to control NK cell activity. But HLA seems to be involved in shaping effector function of the NK cell repertoire.
Scandinavian Journal of Immunology 04/2008; 67(3):218-29. · 2.23 Impact Factor
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ABSTRACT: Little is known on the heterogeneity of hematotoxicity in patients receiving multicycle chemotherapy.
We analyzed data of 1399 patients with aggressive lymphoma from trials using CHOP (combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone)-like therapies. Multivariate modeling was carried out for leukocytopenia, thrombocytopenia and anemia and the models were validated by two large independent datasets from trials with/without usage of the CD20-antibody rituximab.
On the basis of these models, we are able to predict the remarkable heterogeneity of hematotoxicity and propose to use risk groups. Regarding leukocytopenia, the low toxicity risk group experienced World Health Organization grade 4 in <10% of the cycles while the high toxicity risk group in almost all cycles. For thrombocytopenia, groups were detectable with almost no grade 3 or 4 toxicity and others where two out of three cycles were affected. In a separate set of models, the first cycle toxicity was the strongest predictor for later hematotoxicity. The risk for leukocytopenia was associated with infections, antibiotic use, hospitalization and treatment-related mortality, indicating the clinical usefulness of the models. For the first time, a Web-based tool is made available to easily predict the hematotoxicity in clinical practice (www.toxcalculator.com).
This analysis has implications for patient management and prophylaxis.
Annals of Oncology 04/2008; 19(4):752-62. · 6.43 Impact Factor
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L Trümper,
C Zwick,
M Ziepert,
K Hohloch,
R Schmits,
M Mohren,
R Liersch,
M Bentz,
U Graeven,
U Wruck,
M Hoffmann,
B Metzner,
D Hasenclever,
M Loeffler,
M Pfreundschuh
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ABSTRACT: To determine the maximum tolerated dose of a bi- and tri-weekly combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone plus etoposide (CHOEP) regimen without stem-cell support.
Randomized phase I/II multicenter four-level (cyclophosphamide: 1000-1200-1400-1600 mg/m2; doxorubicin: 55-60-65-70 mg/m2; etoposide: 375-450-525-600 mg/m2) dose escalation study with CHOEP-14 and CHOEP-21 in young patients (18-60 years) with newly diagnosed aggressive non-Hodgkin's lymphoma. Dose-limiting toxicity was defined as thrombocytopenia <80,000/mm3 and leukocytopenia <2500/mm3 on days 16 (CHOEP-14) and 23 (CHOEP-21) or prolonged (>4 days) leukocytopenia (<1000/mm3) or thrombocytopenia (<20,000/mm3).
One hundred and thirty-nine patients (high-CHOEP-14: 47, high-CHOEP-21: 92) were randomly allocated to the study. Maximal tolerated dose was level 2 for CHOEP-14 and level 4 for CHOEP-21. With a less favorable profile of patients in CHOEP-14, 4-year event-free survival was 47.9% after high-CHOEP-14 and 66.2% after high-CHOEP-21, 4-year overall survival 62.1% after high-CHOEP-14 and 73.4% after high-CHOEP-21, respectively.
Significant dose escalations of CHOEP are possible with granulocyte colony-stimulating factor support, with different chemotherapy models favoring the maximally escalated bi- or tri-weekly regimen, respectively. Because a higher total dose can be achieved with six cycles of the tri-weekly compared with the biweekly regimen, CHOEP-21 at dose escalation level 3 was chosen for a nationwide randomized comparison with baseline CHOEP-21 in a subsequent phase III trial.
Annals of Oncology 03/2008; 19(3):538-44. · 6.43 Impact Factor
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M Pfreundschuh,
C Zwick,
S Zeynalova,
U Dührsen,
K-H Pflüger,
T Vrieling,
R Mesters,
H-G Mergenthaler,
H Einsele,
M Bentz,
E Lengfelder, L Trümper,
C Rübe,
N Schmitz,
M Loeffler
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ABSTRACT: The addition of etoposide to combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone [etoposide to combination chemotherapy with cyclophosphamide, vincristine and prednisone (CHOEP)] improved outcome of young patients with good-prognosis aggressive lymphoma. To improve results further, the maximal dose-escalated version of CHOEP-21 tolerable without stem-cell support (high CHOEP: cyclophosphamide 1400 mg/m2, doxorubicin 65 mg/m2, vincristine 2 mg, etoposide 175 mg/m2 x3, prednisone 100 mg x5) was compared with CHOEP-21.
Intention-to-treat analysis of 389 young (18-60 years) patients with good-prognosis (age-adjusted International Prognostic Index = 0, 1) aggressive lymphoma randomized to CHOEP-21 (n = 194) or high CHOEP (n = 195).
There was no difference in 3-year event-free (64% versus 67%; P = 0.734) or overall survival (83% versus 87%; P = 0.849). Neither low-risk nor low-intermediate risk patients benefited from high CHOEP. High CHOEP was more toxic than CHOEP-21 (grades 3 and 4 leukocytopenia 100% versus 87.2%, P < 0.001; thrombocytopenia 80.8% versus 9.6%, P < 0.001; infections 35% versus 11%, P < 0.001; therapy-associated deaths 3.1% versus 0%, P = 0.03).
Dose-escalated CHOEP-21 does not provide clinical benefit for young patients with good-prognosis aggressive lymphomas. Since differences between chemotherapy regimens are compressed by the addition of rituximab, the results of this trial have bearing on strategies aiming to improve outcome of good-prognosis aggressive lymphomas in the rituximab era.
Annals of Oncology 03/2008; 19(3):545-52. · 6.43 Impact Factor
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ABSTRACT: Neben der akuten entzündlichen Schwellung eines Lymphknotens, der akuten Lymphadenitis, kommen Lymphknotenvergrößerungen bei
verschiedensten gut- und bösartigen Erkrankungen vor. Eine solche „Lymphadenopathie“ kann in lokalisierter oder generalisierter
Form auftreten und bedarf einer weiterführenden Diagnostik. Als Ursache kommen v.a. infektiöse, immunologische, neoplastische
und metabolische Erkrankungen in Frage. Anamnese und klinischer Untersuchungsbefund liefern erste diagnostische Hinweise.
Lokalisierte Lymphknotenschwellungen sind oft infektiöser Genese, sodass zunächst der mögliche Infektionsherd zu identifizieren
ist. Eine generalisierte Lymphadenopathie ist insbesondere im Erwachsenenalter oft Zeichen einer hämatologischen Systemerkrankung.
Daher ist bei jeder über einen Monat persistierenden Lymphknotenschwellung eine invasive Diagnostik zum Ausschluss einer malignen
Ursache indiziert. Hierbei ist eine histologische Untersuchung anzustreben, besonders in der Lymphomdiagnostik ist die Exzision
ganzer Lymphknoten zwingend notwendig. Bei malignen Lymphomen schließen sich Staging-Untersuchungen zur Prognoseeinschätzung
und Therapieplanung an.
Besides acute inflammatory swelling of a lymph node, acute lymphadenitis, enlarged lymph nodes occur in conjunction with various
benign and malignant diseases. Lymphadenopathy can appear in a localized or generalized form and requires further diagnostic
measures. Possible causes are primarily infectious, immunological, neoplastic, and metabolic disorders. The medical history
and physical examination provide the first clues to the diagnosis. Localized swollen glands often have an infectious etiology
so that the first step is to identify the possible focus of infection. Generalized lymphadenopathy is frequently a sign of
a hematological systemic disease, particularly in adults. Therefore, in every case of lymphadenopathy persisting for more
than 1 month, invasive diagnostic procedures are indicated to rule out a malignant cause. The aim should be to perform a histological
analysis; excision of entire lymph nodes is exigent, especially for the work-up of lymphoma. In cases of malignant lymphoma,
staging examinations should subsequently be conducted to assess the prognosis and formulate a treatment plan.
Der Internist 01/2008; 49(3):305-320. · 0.30 Impact Factor
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ABSTRACT: Non-Hodgkin's lymphomas represent a clinically and biologically heterogeneous group of diseases. Over the last few years, new treatment approaches such as humoral immunotherapy and high dose therapy with stem cell rescue have improved the chances for a cure in most patients with malignant lymphoma. However, only with the correct diagnosis and staging, including the evaluation of novel prognostic factors, are treating physicians able to choose the optimal treatment for their patients. This review focuses on conventional staging procedures and their role in the management of lymphoma patients, as well as on some new aspects of the molecular classification of lymphomas.
Der Internist 05/2007; 48(4):362-71. · 0.30 Impact Factor
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ABSTRACT: A 32 year old female smoker (20 pack years) presented with an asymptomatic lymphocytosis of 13,000/nl and splenomegaly. The patient's blood smear showed an absolute lymphocytosis with 65% atypical lymphocytes. A total of 1% of the lymphocytes were bilobulated. Bone marrow histology and immunphenotyping of blood and bone marrow excluded leukemia and non-Hodgkin's lymphoma. IgH-CDR-3 PCR analysis revealed a polyclonal pattern. In summary, a persistent polyclonal B-cell-lymphocytosis (PPBL) was diagnosed. The exact etiology of PPBL is still unclear, however, it is associated with a polyclonal raise in the lymphocyte count of CD27+IgD+-memory-B-lymphocytes due to a defect in apoptosis signaling and leukocyte homing to secondary lymphoid tissues. An association with cigarette smoking is obvious since all patients are smokers. From all published cases, only two developed a malignancy with an uncertain association with PPBL. We have been monitoring our patient for 6.5 years without any evidence of the development of a lymphoma.
Der Internist 04/2007; 48(3):314-8. · 0.30 Impact Factor
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ABSTRACT: The Interleukin 10 (IL-10) gene is highly polymorphic, and the IL-10(-1087AG) (rs1800896) gene variation is the only so far studied intensively in association with certain diseases. Conflicting data have been published about an association of IL-10(-1087AG) gene variation with lower rates of complete remission and lower overall survival (OS) in patients with diffuse large B-cell lymphoma. To further investigate this in malignant lymphoma, we established the IL-10 genotypes in patients from the NHL-B1/ B2 studies from the German High-Grade Non-Hodgkin's Lymphoma Study Group. In our study, allele frequencies of lymphoma patients are comparable as in healthy controls. No increase of IL-10(-1087G) alleles was found. In addition we did not find any difference in OS or event-free survival between patients with IL-10(-1087AA) and the other genotypes. Comparable results were obtained for the IL-10 loci at -3538 (A/T), -1354 (A/G), -824 (C/T) and -597 (A/C) (rs1800890, rs1800893, rs1800871 and rs1800872).
Genes and Immunity 04/2007; 8(2):164-7. · 3.87 Impact Factor
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ABSTRACT: Non-Hodgkin-Lymphome stellen eine klinisch und biologisch heterogene Gruppe von Erkrankungen dar. Neue Therapieanstze wie die humorale Immuntherapie und die Hochdosistherapie haben eine wesentliche Verbesserung der Heilungschancen fr Lymphompatienten ermglicht. Nur bei korrekter Diagnosestellung und exakter Ermittlung des initial vorliegenden Ausbreitungsstadiums der Erkrankung ist jedoch eine optimale Auswahl der bestehenden Therapieoptionen und somit die bestmgliche Behandlung des Lymphompatienten gewhrleistet. Die klassischen klinischen, laborchemischen und bildgebenden Verfahren wie die neuen molekulargenetischen Diagnoseverfahren werden in dieser bersicht dargestellt.Non-Hodgkins lymphomas represent a clinically and biologically heterogeneous group of diseases. Over the last few years, new treatment approaches such as humoral immunotherapy and high dose therapy with stem cell rescue have improved the chances for a cure in most patients with malignant lymphoma. However, only with the correct diagnosis and staging, including the evaluation of novel prognostic factors, are treating physicians able to choose the optimal treatment for their patients. This review focuses on conventional staging procedures and their role in the management of lymphoma patients, as well as on some new aspects of the molecular classification of lymphomas.
Der Internist 03/2007; 48(4):362-371. · 0.30 Impact Factor
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ABSTRACT: Radioimmunotherapy (RIT) was approved for the treatment of relapsed or refractory CD20-positive follicular lymphoma (FL), subsequent to rituximab containing primary therapy. However, an increasing number of clinical studies have suggested that RIT may be more efficacious in an earlier phase of the disease. Therefore, a consensus meeting was held in May 2005 to define the optimal setting of RIT in the therapeutic algorithm of patients with advanced stage of FL. RIT is an established therapeutic option in relapsed FL. According to the reviewed data, RIT should be preferably used as consolidation after initial tumor debulking. First-line RIT may be applied in patients not appropriate for chemotherapy induction. Current study concepts evaluate the role of RIT consolidation in combination with antibody maintenance to achieve a potentially curative approach even in patients with advanced stage disease.
Annals of Hematology 03/2007; 86(2):81-7. · 2.62 Impact Factor
