CaRLO — Cancer Research Library Online

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The Use of Positron Emission Tomography in Soft Tissue Sarcoma Patients under Therapy with Trabectedin

Kasper,B. ; Schmitt,T. ; Wuchter,P. ; [et al.]

Marine Drugs 7 (3), 331-340

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Type of Publication: Journal article published

PubMed ID: 19841717

Deep Link: http://www.dkfz.de/cgi-bin/sel?http://www.dkfz.de/PublicationManager/Show/ShowJournal.aspx%3fpublishedId=8668

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A phase II study evaluating neo-/adjuvant EIA chemotherapy, surgical resection and radiotherapy in high-risk soft tissue sarcoma

Schmitt,T. ; Lehner,B. ; Kasper,B. ; [et al.]

BMC Cancer 11 (1), Art. Nr.: 510-

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Keywords: CANCER ; radiotherapy ; RISK ; TISSUE ; RADIATION-THERAPY ; METASTASIS ; CLINICAL-TRIALS ; PROGNOSTIC-FACTORS ; LOCALIZATION ; POSITRON-EMISSION-TOMOGRAPHY ; ADULT PATIENTS ; EUROPEAN-ORGANIZATION ; ADJUVANT CHEMOTHERAPY ; HIGH-GRADE ; NEOADJUVANT CHEMOTHERAPY ; REGIONAL HYPERTHERMIA

Abstract: Background: The role of chemotherapy in high-risk soft tissue sarcoma is controversial. Though many patients undergo initial curative resection, distant metastasis is a frequent event, resulting in 5-year overall survival rates of only 50-60%. Neo-adjuvant and adjuvant chemotherapy (CTX) has been applied to achieve pre-operative cytoreduction, assess chemosensitivity, and to eliminate occult metastasis. Here we report on the results of our non-randomized phase II study on neo-adjuvant treatment for high-risk STS. Method: Patients with potentially curative high-risk STS (size 〉= 5 cm, deep/extracompartimental localization, tumor grades II-III [FNCLCC]) were included. The protocol comprised 4 cycles of neo-adjuvant chemotherapy (EIA, etoposide 125 mg/m(2) iv days 1 and 4, ifosfamide 1500 mg/m(2) iv days 1 - 4, doxorubicin 50 mg/m(2) day 1, pegfilgrastim 6 mg sc day 5), definitive surgery with intra-operative radiotherapy, adjuvant radiotherapy and 4 adjuvant cycles of EIA. Result: Between 06/2005 and 03/2010 a total of 50 subjects (male = 33, female = 17, median age 50.1 years) were enrolled. Median follow-up was 30.5 months. The majority of primary tumors were located in the extremities or trunk (92%), 6% originated in the abdomen/retroperitoneum. Response by RECIST criteria to neo-adjuvant CTX was 6% CR (n = 3), 24% PR (n = 12), 62% SD (n = 31) and 8% PD (n = 4). Local recurrence occurred in 3 subjects (6%). Distant metastasis was observed in 12 patients (24%). Overall survival (OS) and disease-free survival (DFS) at 2 years was 83% and 68%, respectively. Multivariate analysis failed to prove influence of resection status or grade of histological necrosis on OS or DFS. Severe toxicities included neutropenic fever (4/50), cardiac toxicity (2/50), and CNS toxicity (4/50) leading to CTX dose reductions in 4 subjects. No cases of secondary leukemias were observed so far. Conclusion: The current protocol is feasible for achieving local control rates, as well as OS and DFS comparable to previously published data on neo-/adjuvant chemotherapy in this setting. However, the definitive role of chemotherapy remains unclear in the absence of large, randomized trials. Therefore, the current regimen can only be recommended within a clinical study, and a possibly increased risk of secondary leukemias has to be taken into account

DOI: 10.1186/1471-2407-11-510

Type of Publication: Journal article published

PubMed ID: 22152120

Deep Link: http://www.dkfz.de/cgi-bin/sel?http://www.dkfz.de/PublicationManager/Show/ShowJournal.aspx%3fpublishedId=28133

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3

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Mesenchymal stromal cells (MSCs): science and f(r)iction

Bieback K ; Wuchter P ; Besser D ; [et al.]

Journal of Molecular Medicine - JMM 90 (7), 773-782

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Keywords: IN-VITRO ; BONE-MARROW ; HEMATOPOIETIC STEM-CELLS ; ADIPOSE-TISSUE ; VERSUS-HOST-DISEASE ; UMBILICAL-CORD BLOOD ; HEART-MUSCLE CELLS ; fetal bovine serum ; AREA-COMPOSITA ; HUMAN SOMATIC-CELLS

Abstract: Due to their multi-lineage differentiation capacity, support of haematopoiesis, immunomodulation and secretion of proregenerative factors, mesenchymal stem/stromal cells (MSCs) are in the focus of intense research since decades. The literature is replete with reports on their potential in preclinical model systems. However, the heterogeneity of the primary cell population as starting material and the diverse protocols for isolation and cultivation are hampering progress in their clinical application. Consensus on common standards and harmonised isolation and characterisation protocols are important to ensure safety and efficacy. This review focuses on the recent scientific evidence of clinically relevant properties and on the speculative cardiomyogenic and hepatic differentiation potential of MSCs. Special emphasis is put on the importance of standardisation and harmonisation in clinical-scale manufacturing.

DOI: 10.1007/s00109-012-0915-y

Type of Publication: Journal article published

PubMed ID: 22648521

Deep Link: http://www.dkfz.de/cgi-bin/sel?http://www.dkfz.de/PublicationManager/Show/ShowJournal.aspx%3fpublishedId=32547

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4

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Excellent local control with IOERT and postoperative EBRT in high grade extremity sarcoma: results from a subgroup analysis of a prospective trial

Roeder F ; Lehner B ; Schmitt T ; [et al.]

BMC Cancer 14 (1), 350-

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Keywords: PROGNOSTIC-FACTORS ; HIGH-RISK ; PHASE-II ; EXTERNAL-BEAM RADIOTHERAPY ; ADJUVANT CHEMOTHERAPY ; NEOADJUVANT CHEMOTHERAPY ; soft-tissue sarcoma ; intraoperative radiotherapy ; RADIATION RECALL DERMATITIS ; COMBINED-MODALITY TREATMENT

Abstract: BACKGROUND: To report the results of a subgroup analysis of a prospective phase II trial focussing on radiation therapy and outcome in patients with extremity soft tissue sarcomas (STS). METHODS: Between 2005 and 2010, 50 patients (pts) with high risk STS (size 〉/= 5 cm, deep/extracompartimental location, grade II-III (FNCLCC)) were enrolled. The protocol comprised 4 cycles of neoadjuvant chemotherapy with EIA (etoposide, ifosfamide and doxorubicin), definitive surgery with IOERT, postoperative EBRT and 4 adjuvant cycles of EIA. 34 pts, who suffered from extremity tumors and received radiation therapy after limb-sparing surgery, formed the basis of this subgroup analysis. RESULTS: Median follow-up from inclusion was 48 months in survivors. Margin status was R0 in 30 pts (88%) and R1 in 4 pts (12%). IOERT was performed as planned in 31 pts (91%) with a median dose of 15 Gy, a median electron energy of 6 MeV and a median cone size of 9 cm. All patients received postoperative EBRT with a median dose of 46 Gy after IOERT or 60 Gy without IOERT. Median time from surgery to EBRT and median EBRT duration was 36 days, respectively. One patient developed a local recurrence while 11 patients showed nodal or distant failures. The estimated 5-year rates of local control, distant control and overall survival were 97%, 66% and 79%, respectively. Postoperative wound complications were found in 7 pts (20%), resulting in delayed EBRT (〉60 day interval) in 3 pts. Acute radiation toxicity mainly consisted of radiation dermatitis (grade II: 24%, no grade III reactions). 4 pts developed grade I/II radiation recall dermatitis during adjuvant chemotherapy, which resolved during the following cycles. Severe late toxicity was observed in 6 pts (18%). Long-term limb preservation was achieved in 32 pts (94%) with good functional outcome in 81%. CONCLUSION: Multimodal therapy including IOERT and postoperative EBRT resulted in excellent local control and good overall survival in patients with high risk STS of the extremities with acceptable acute and late radiation side effects. Limb preservation with good functional outcome was achieved in the majority of patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT01382030, EudraCT 2004-002501-72, 17.06.2011.

DOI: 10.1186/1471-2407-14-350

Type of Publication: Journal article published

PubMed ID: 24885755

Deep Link: http://www.dkfz.de/cgi-bin/sel?http://www.dkfz.de/PublicationManager/Show/ShowJournal.aspx%3fpublishedId=50506

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5

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Performance assessment and benchmarking of autologous peripheral blood stem cell collection with two different apheresis devices

Wuchter, P. ; Hundemer, M. ; Schmitt, A. ; [et al.]

Transfusion Medicine 27 (1), 36-42

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Type of Publication: Journal article published

PubMed ID: 27726235

Deep Link: http://www.dkfz.de/cgi-bin/sel?http://www.dkfz.de/PublicationManager/Show/ShowJournal.aspx%3fpublishedId=73871

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6

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Peptide vaccination in the presence of adjuvants in patients after hematopoietic stem cell transplantation with CD4+T cell reconstitution elicits consistent CD8+T cell responses

Schmitt,M. ; Schmitt,A. ; Wiesneth,M. ; [et al.]

Theranostics 7 (6), 1705-1718

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Type of Publication: Journal article published

Deep Link: http://www.dkfz.de/cgi-bin/sel?http://www.dkfz.de/PublicationManager/Show/ShowJournal.aspx%3fpublishedId=78760

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7

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Cyclophosphamide-based stem cell mobilization in relapsed multiple myeloma patients: A subgroup analysis from the phase III trial ReLApsE

Baertsch MA ; Schlenzka J ; Lisenko K ; [et al.]

European Journal of Haematology 99 (1), 42-50

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Abstract: OBJECTIVE: Analysis of the efficiency and toxicity of cyclophosphamide-based stem cell mobilization in patients with relapsed multiple myeloma (RMM). METHODS: Peripheral blood stem cells (PBSCs) were mobilized with high dose cyclophosphamide (2 g/m2 daily on days 1 and 2) and G-CSF plus pre-emptive/rescue plerixafor in RMM patients (first to third relapse) treated within the ReLApsE trial of the German-Speaking Myeloma Multicenter Group (GMMG). RESULTS: Mobilization was initiated with high-dose cyclophosphamide (HD-CY) and G-CSF in 30 patients. Fifteen patients received additional pre-emptive/rescue administration of plerixafor. Stem cell collection was successful (〉/=2x106 CD34+ cells per kg bw) in 77% (23/30 patients). Patients with prior high-dose melphalan collected a significantly lower median total number of PBSCs than patients without prior high-dose melphalan (3.3x106 vs 17x106 CD34+ cells/kg bw). Toxicity of HD-CY was frequent with 12 serious adverse events (SAE) in 37% of patients (11/30 patients). Infections accounted for the majority of SAE reports. In two patients, SAEs were lethal (septic shock). CONCLUSIONS: These data proof feasibility of PBSC collection at relapse but emphasize the importance of collection and storage of additional PBSC transplants during first-line treatment when mobilization is more efficient and less toxic.

Type of Publication: Journal article published

PubMed ID: 28370401

Deep Link: http://www.dkfz.de/cgi-bin/sel?http://www.dkfz.de/PublicationManager/Show/ShowJournal.aspx%3fpublishedId=79909

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8

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A combination of granulocyte-colony-stimulating factor (G-CSF) and plerixafor mobilizes more primitive peripheral blood progenitor cells than G-CSF alone: results of a European phase II study

Fruehauf S ; Veldwijk MR ; Seeger T ; [et al.]

Cytotherapy 11 (8), 992-1001

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Type of Publication: Journal article published

PubMed ID: 19929463

Deep Link: http://www.dkfz.de/cgi-bin/sel?http://www.dkfz.de/PublicationManager/Show/ShowJournal.aspx%3fpublishedId=9959

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The rarity of ALDH+ cells is the key to separation of normal versus leukemia stem cells by ALDH activity in AML patients

Hoang VT ; Buss EC ; Wang W ; [et al.]

International Journal of Cancer 137 (3), 525-536

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Keywords: EXPRESSION ; POPULATION ; MARKER ; TARGET ; IDENTIFICATION ; EVOLUTION ; HETEROGENEITY ; ACUTE MYELOID-LEUKEMIA ; INITIATING CELLS ; ALDEHYDE DEHYDROGENASE-ACTIVITY

Abstract: To understand the precise disease driving mechanisms in acute myeloid leukemia (AML), comparison of patient matched hematopoietic stem cells (HSC) and leukemia stem cells (LSC) is essential. In this analysis, we have examined the value of aldehyde dehydrogenase (ALDH) activity in combination with CD34 expression for the separation of HSC from LSC in 104 patients with de novo AML. The majority of AML patients (80 out of 104) had low percentages of cells with high ALDH activity (ALDH(+) cells; 〈1.9%; ALDH-rare AML), whereas 24 patients had relatively numerous ALDH(+) cells (1.9%; ALDH-numerous AML). In patients with ALDH-rare AML, normal HSC could be separated by their CD34(+)ALDH(+) phenotype, whereas LSC were exclusively detected among CD34(+)ALDH(-) cells. For patients with ALDH-numerous AML, the CD34(+)ALDH(+) subset consisted mainly of LSC and separation from HSC was not feasible. Functional analyses further showed that ALDH(+) cells from ALDH-numerous AML were quiescent, refractory to ARA-C treatment and capable of leukemic engraftment in a xenogenic mouse transplantation model. Clinically, resistance to chemotherapy and poor long-term outcome were also characteristic for patients with ALDH-numerous AML providing an additional risk-stratification tool. The difference in spectrum and relevance of ALDH activity in the putative LSC populations demonstrates, in addition to phenotypic and genetic, also functional heterogeneity of leukemic cells and suggests divergent roles for ALDH activity in normal HSC versus LSC. By acknowledging these differences our study provides a new and useful tool for prospective identification of AML cases in which separation of HSC from LSC is possible. What's new? To understand the precise disease-driving mechanisms in acute myeloid leukemia (AML), comparison of patient-matched hematopoietic stem cells (HSC) and leukemia stem cells (LSC) is essential. This study demonstrates the relevance of aldehyde dehydrogenase (ALDH) for the prospective identification of AML cases in which separation of functionally normal HSC from LSC is possible. Increased activity of this biomarker also characterizes a subgroup of patients with adverse outcome, which might be helpful in risk stratification prior to therapy. Overall, this study demonstrates functional heterogeneity of leukemia cells and suggests divergent roles for ALDH activity in normal HSC versus leukemia-initiating cells.

DOI: 10.1002/ijc.29410

Type of Publication: Journal article published

PubMed ID: 25545165

Deep Link: http://www.dkfz.de/cgi-bin/sel?http://www.dkfz.de/PublicationManager/Show/ShowJournal.aspx%3fpublishedId=57743

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Pre-Osteoblasts Stimulate Migration of Breast Cancer Cells via the HGF/MET Pathway

Vallet S ; Bashari MH ; Fan FJ ; [et al.]

PLoS ONE 11 (3), e0150507-

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Abstract: INTRODUCTION: The occurrence of skeletal metastases in cancer, e.g. breast cancer (BC), deteriorates patient life expectancy and quality-of-life. Current treatment options against tumor-associated bone disease are limited to anti-resorptive therapies and aimed towards palliation. There remains a lack of therapeutic approaches, which reverse or even prevent the development of bone metastases. Recent studies demonstrate that not only osteoclasts (OCs), but also osteoblasts (OBs) play a central role in the pathogenesis of skeletal metastases, partly by producing hepatocyte growth factor (HGF), which promotes tumor cell migration and seeding into the bone. OBs consist of a heterogeneous cell pool with respect to their maturation stage and function. Recent studies highlight the critical role of pre-OBs in hematopoiesis. Whether the development of bone metastases can be attributed to a particular OB maturation stage is currently unknown. METHODS AND RESULTS: Pre-OBs were generated from healthy donor (HD)-derived bone marrow stromal cells (BMSC) as well as the BMSC line KM105 and defined as ALPlow OPNlow RUNX2high OSX high CD166high. Conditioned media (CM) of pre-OBs, but not of undifferentiated cells or mature OBs, enhanced migration of metastatic BC cells. Importantly, HGF mRNA was significantly up-regulated in pre-OBs versus mature OBs, and CM of pre-OBs activated the MET signaling pathway. Highlighting a key role for HGF, CM from HGF-negative pre-OBs derived from the BMSC line HS27A did not support migration of BC cells. Genetically (siMET) or pharmacologically (INCB28060) targeting MET inhibited both HGF- and pre-OB CM- mediated BC cell migration. CONCLUSIONS: Our data demonstrate for the first time a role for pre-OBs in mediating HGF/MET- dependent migration of BC cells and strongly support the clinical evaluation of INCB28060 and other MET inhibitors to limit and/or prevent BC-associated bone metastases.

Type of Publication: Journal article published

PubMed ID: 26934743

Deep Link: http://www.dkfz.de/cgi-bin/sel?http://www.dkfz.de/PublicationManager/Show/ShowJournal.aspx%3fpublishedId=69619

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