- Sarkomkonferenz

EINGEREICHTE ABSTRACTS
Session 1
TRANSLATIONALE FORSCHUNG (TL)
Session 2
KLINISCH ORIENTIERTE STUDIEN (KLOS)
TL/S1-01
Targeting hedgehog and PI3K signaling pathways with small molecule inhibitors provides a new
approach to enhance cell death in Rhabdomyosarcoma.
Ulrike Graab1, Heidi Hahn2, Simone Fulda1
1
Institute for Experimental Cancer Research in Pediatrics, Goethe University, Frankfurt am Main, Germany
2
Institute of Human Genetics, University Medical Center, Göttingen, Germany
Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children. Deregulation of the
Hedgehog (Hh) signaling pathway, which is essential for proper embryonal development, has been
observed in multiple human cancers, including RMS as we previously reported (Zibat et al. 2010
Oncogene).
In the present study we evaluated the Hh signaling pathway as a therapeutic target in RMS using small
molecule inhibitors. We found a brought pattern of upregulated gene expression of different Hh
signaling genes, including Ptch, Shh, Gli1, 2 and Gli3, in several RMS cell lines compared to normal
skeletal muscle tissue. Importantly, treatment of RMS cells with different Hedgehog inhibitors that block
distinct components of the Hh pathway like the Smoothened (Smo) inhibitor GDC-0449 as well as
GANT-61 and Arsenic Trioxide, which antagonizes Gli1 and Gli2, inhibits cell proliferation and induces
cell death, with different efficiency.
Interestingly, we found that canonical Hh signaling, which is characterized by Smo-dependent activation
of the Gli transcription factors, is not the primary cause of aberrant Hh signaling activation in RMS cells,
since the Smo inhibitor GDC-0449 has no marked effect on cell viability and cell death. In contrast,
inhibition of Gli1 and Gli2 via GANT61 is much more efficient in inducing cell death than GDC-0449,
pointing to non-canonical Hh pathway activation independent of Ptch/Smo in RMS cells.
In addition to elevated Hh signaling, we also found aberrant activation of PI3K signaling in RMS cells.
Intriguingly, simultaneous inhibiting of both Hh and PI3K pathways by GANT61 and PI-103,
respectively, results in synthetic lethality and synergistically inhibits cell growth and triggers cell death in
RMS cells.
Our findings highlight the importance of targeting Gli genes downstream of Smo for blocking Hhdependent survival of RMS cells. Taken together, the Hh signaling pathway represents a novel and
clinically relevant therapeutic target in RMS cells that warrants further investigation.
Seite 1
TL/S1-02
Destabilization of microtubules cooperates synergistically with inhibition of polo-like kinase 1 to
induce cell death in Rhabdomyosarcoma
Manuela Hugle and Simone Fulda
Institute for Experimental Cancer Research in Pediatrics, Goethe-University Frankfurt
Overexpression of polo-like kinase 1 (Plk1) has recently been identified in rhabdomyosarcoma, the most
common pediatric sarcoma. Therefore, we investigated the potential of inhibiting Plk1 to sensitize
rhabdomyosarcoma cell lines to chemotherapy. Indeed, we show that BI 2536, an ATP-competitive
small molecule inhibitor of Plk1, results in cell cycle arrest at G2/M-phase and subsequently in cell
death of rhabdomyosarcoma cells. Furthermore, we found that BI 2536 already at subtoxic, low
nanomolar concentrations cooperates with vincristine, a chemotherapeutic agent that destabilizes
microtubules, to induce cell death. Calculation of combination index revealed that the interaction of BI
2536 and vincristine is synergistic. Similarly, BI 2536 acts synergistically together with vinblastine and
vinorelbine, two additional microtubule-destabilizing drugs. In contrast, no cooperative interaction was
detected for BI 2536 together with taxol, a microtubule-stabilizing drug, nor doxorubicin, a DNAdamaging agent. Mechanistic studies reveal that combination treatment with BI 2536 and vincristine
leads to massive cell cycle arrest in mitosis, followed by phosphorylation and degradation of Bcl-2 family
proteins, yet only minor activation of caspase-9 and caspase-3. As addition of the pan-caspase inhibitor
zVAD.fmk significantly reduces, but does not at all prevent cell death upon treatment with BI 2536 and
vincristine, we suggest mainly caspase-independent mechanisms to be involved in our cellular system.
Additionally, we observe strong phosphorylation of c-Jun N-terminal kinases (JNK) following
combination treatment with BI 2536 and vincristine, pointing to involvement of activated stress-signaling
pathways. Of note, inhibition of JNK by pharmacological inhibitor SP-600125 can reduce cell death
induction significantly in our system. So far, combination treatment with BI 2536 and vincristine did not
show any influence on cell viability of non-malignant fibroblast or high-proliferative murine myoblast cell
lines, indicating a tumor selective anticancer activity of Plk1 inhibition. Thus, the synergistic effect of BI
2536 combined with conventional chemotherapeutics like vincristine provides a promising new
approach to enhance efficacy of common treatment strategies for rhabdomyosarcoma. Consequently, it
is very important to investigate the exact mechanisms of the synergistic drug combination.
TL/S1-03
Src activity is increased in Gastrointestinal Stromal Tumors (GIST) - analysis of associations
with clinical and other molecular tumor characteristics
Julia Valerie Rotert1,2*, Jörg Leupold1, Peter Hohenberger3*, Kai Nowak2,3, Heike Allgayer1
1
Department of Experimental Surgery and Molecular Oncology of Solid Tumors, Mannheim Medical Faculty, Heidelberg
University, and DKFZ (German Cancer Research Center), Heidelberg, Germany;
2
3
Department of Surgery, Mannheim Medical Faculty, Heidelberg University, Germany; Division of Surgical Oncology and
Thoracic Surgery, Mannheim Medical Faculty, Heidelberg University, Germany
Increased activity of the non-receptor tyrosine kinase Src has been found in several human cancers in
vitro and in vivo, and often is associated with poor clinical outcome. The purpose of the present study
was to determine whether Src activity is increased in gastrointestinal stromal tumors (GISTs), and
whether it correlates with established tumor or patient characteristics and prognosis. Tumor and normal
tissues of 29 patients were analyzed for Src activity and Src protein with kinase assays, and for VEGF
and VEGFR with immunohistochemical staining. Src activity was higher in tumor than in normal tissues
Seite 2
at a statistical trend (p=0.093). However, when imatinib responders were excluded from the analyses, it
was significantly higher in the tumor tissue (p=0.017). Additionally, it was significantly higher in primary
compared to recurrent tumors or metastasis (p=0.04). Univariate survival analysis showed a significantly
longer overall survival for patients with high Src activity (p=0.038). In multivariate analysis, response to
imatinib treatment was seen as the only survival influencing factor at a statistical trend (p=0.072).
VEGFR-expression was significantly lower in tumor tissue with high Src activity (p=0.001) and VEGFexpression was significantly higher in tumors of patients who never were disease-free (p=0.025). Src
activity is increased in GISTs compared to normal tissue. In contrast to most other tumor entities, it does
not go along with poor clinical outcome. It seems to decrease in the development from primary tumor to
recurrence and metastasis, especially under therapy with imatinib. In addition, our results show that
higher Src activity is associated with longer overall survival.
TL/S1-04
Chondro-osseous differentiation, metastasis and osteolysis in Ewing Sarcoma.
Günther H.S. Richter, Kristina Hauer, Stefan Burdach
Labor für Funktionelle Genomik & Transplantationsbiologie, Forschungszentrum für krebskranke Kinder, Kinderklinik des
Klinikums rechts der Isar der Technischen Universität München, 80804 München
Ewing sarcoma (ES), an osteolytic malignancy that mainly affects children and young adults, is
characterized by early metastasis to lung and bone. Microarray analysis revealed BRICHOS domain
containing proteins important for chondrogenic differentiation and canonical Wnt agonist Dickkopf,
Xenopus, Homolog of, (DKK) 2 critical for terminal bone development, to be over-expressed in ES. RNA
interference of DKK2 expression in ES decreased the ability for colony formation as well as invasive
growth of ES cells in vitro, while BRICHOS proteins, Chondromodulin-I (CHM1) and Integral Membrane
Protein 2A (ITM2A) seemed essential for the maintenance of a precursor state of chondrogenic
differentiation. DKK2 was critical for malignant outgrowth in an orthotopic xenograft mouse model in
vivo. Analysis of invasion potential revealed a strong correlation of DKK2 expression to ES invasiveness
that may be mediated by the DKK effector matrix metalloproteinase 1 (MMP1)1. BRICHOS proteins in
contrast, suppressed ES invasiveness. Gene expression analyses proved DKK2 to induce genes such
as CXCR4, PTHrP, RUNX2 and TGFβ1, associated with homing, invasion and growth of cancer cells in
bone tissue as well as genes important for osteolysis, like HIF1α, IL6, JAG1, RANKL and VEGF, while
BRICHOS domain containing proteins suppressed the expression of osteolytic genes. Clinically, high
DKK2 expression seems associated with increased bone infiltration and decreased survival of ES
patients. Thus, DKK2 and BRICHOS proteins orchestrate and promote bone invasiveness and
metastatic spread of this tumor, and provide significant conceptual progress in understanding both the
pathogenesis of invasive bone growth of ES and osteotropism in general.
1. Hauer K, Calzada-Wack J, Steiger K, Grunewald TG, Baumhoer D, Plehm S, Buch T, da Costa OP,
Esposito I, Burdach S, Richter GH. DKK2 Mediates Osteolysis, Invasiveness, and Metastatic Spread in
Ewing Sarcoma. Cancer Res. 2013 Jan 15;73(2):967-977.
Seite 3
TL/S1-05
Establishment and characterization of patient-derived xenografts of Soft Tissue Sarcomas
Jana Rolff1,2, F. Traub3, D. Andreou3, M. Niethard3, C. Tiedke3, A. Richter3, M. Werner4, P-U. Tunn3,
I. Fichtner2
1. Experimantal pharmacology and oncology Berlin-Buch GmbH, Berlin, Germany
2. Experimental Pharmacology , Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
3. Department Tumororthopädie, Sarkomzentrum Berlin-Brandenburg, HELIOS Klinikum Berlin Buch
4. Institut für Pathologie, Sarkomzentrum Berlin-Brandenburg , HELIOS Klinikum Emil von Behring, Berlin
Sarcomas are a rare form of cancer and very heterogeneous as evidenced by the fact that these
cancers arise from a plethora of different tissues and cell types. Thus, the identification of novel
molecular mechanisms leading to sarcoma formation and the establishment of new therapies has been
limited. Studies in cell lines have greatly improved the understanding of sarcomas, but they have severe
limitations. Therefore, well-characterized animal models are needed to improve the therapeutic outcome
of soft tissue sarcomas. The objective of the present study was to establish xenograft models of primary
human soft tissue sarcomas in mice and to compare the model with the natural history of the disease.
Tissue from 14 primary human soft tissue sarcomas was directly transferred from the surgical theatre to
the laboratory. The tumour samples were taken from representative peripheral areas of the original
tumour. A fragment from each tumor tissue was transplanted subcutaneously into immunodeficient
mice. After successful and stable growing of the tumor within the next passage a pharmacological study
was initiated. The mice were treated with several chemotherapeutics to evaluate the response of
tumors.
Until now, six out 14 derived sarcoma xenografts could be successfully established, leading to solid
tumors in nude mice. Histological and immunohistochemical staining showed a similar morphology of
the xenografts compared with the original tumor. In all specimens, tumor necrosis and inflammation was
observed. Heterogeneity of tumor cells in size and shape and nuclear irregularities were seen. The
tumor response rates were: 6/6 Docetaxel, 6/6 Gemcitabine, 1/6 Ifosfamide, 2/6 Doxorubicin and none
of the sarcoma xenografts responded to Dacarbazine.
The development of new cancer therapeutics requires animal models that closely resemble the human
patient. Patient-derived sarcoma xenografts allow detailed investigation of therapy-related markers and
their dynamic regulation in a well-standardised and clinically related way.
TL/S1-06
Phase I Study of panobinostat and imatinib in patients with refractory GIST - from bench-to-bed
and backwards
Johanna Falkenhorst, Sebastian Bauer, Essen
Westdeutsches Tumorzentrum, Innere Klinik (Tumorforschung), Sarkomzentrum Hufelandstr. 55, 45122 Essen
Seite 4
KLOS/S2-01
A pancreatic head tumor arising as a duodenal GIST - a case report
Bormann F.1 , Aksoy H. 1, Schmeck S.2, Schwarzbach M.1
1
Klinikum Frankfurt Höchst, Klinik für Allgemein-, Visceral-, Thorax- und Gefäßchirurgie, Frankfurt/M., Lehrkrankenhaus der
Johan Wolfgang Goethe Universität Frankfurt
2
Klinikum Frankfurt Höchst, Institut für Pathologie, Frankfurt/M.
Kontakt: [email protected]
A sixty-four year old woman in good physical condition was transferred in our clinic with abdominal pain
and cardialgia since 4 weeks. In the anamnesis she described a slowly increasing pain within the last
few days, mostly located in the right upper abdomen. She could not tell any relief or aggravation, nor
any kind of radiation. She was not suffering from fever, night sweat, vomitting, jaundice or weight loss.
The history of bowel movement was empty. The physical examination showed a soft abdomen, without
any resistance. The pain slightly increased by pressure in the epigastric area. The gallbladder could not
be palpated, the liver margin seemed to be inconspicuous. The routine laboratory tests showed no
pathological findings. The ultrasound showed a suspicious heterogeneous formation of 3 x 5 cm in the
pancreas and a 3 x 1cm cystic formation in liver segment 6. The CT-scan proved the ultrasound
findings, a connection to the duodenum could not be found. Gastroscopy, blood examinations and
tektrotyd-scintigraphy showed no pathological findings. On exploratory laparotomy the tumor could
easily be seen as a hypervascular mass arising from the pancraetic head, mobile to the retroperitoneum
and resectable. No infiltration to the pylorus and macroscopically no attachemend to the duodenum, no
metastasis in the peritoneum. PD modified after Traverso-Longmire was performed, the liver area was
resected in liver wedge technique of the segment 6.
Histopathology showed a 4 cm measuring mesenchymal, sharply margined tumor with spindel cells,
isolated apoptosis and no necrosis. The amount of mitosis was less then 5 per 50 HPF. On one side of
the tumor a small area seemed to be connected to the duodenal serosa. Immunhistologically the tumor
was positiv for smooth muscle actin (ASMA), bcl-2, CD 99, CD 117, DOG-1 and some cells also for CD
34. Negativ staining for desmin and S-100. Based on these findings the tumor was finally diagnosed as
a low risk GIST according to Miettinen et al., arising from the duodenal wall incorporating into the
pancreatic head. Therefore no further adjuvant chemotherapy e.g. with Glivec® is suggested. After 2
weeks the patient was discharged in good condition and the advice to take pankreatin beside the meals.
The patient was included into a follow up regime according to the ESMO guidelines.
KLOS/S2-02
Risk factors leading to grading changes within 300 low grade Soft Tissue Sarcomas
Stefan Langer2, Tanja Khosrawipour1, Hans Ulrich Steinau1, Andrea Tannapfel 4, Ingo Stricker 4
1
Department of Plastic and Hand Surgery, Burn Center, University Hospital Bergmannsheil, Ruhr University Bochum, Bochum,
Germany
2
Department of Plastic Surgery, University Hospital Leipzig, Leipzig, Germany
4
Department of Pathology, BG University Hospital Bergmannsheil, Ruhr University Bochum, Bochum, Germany
Introduction: Soft tissue sarcomas (STS) are rare, mesenchymal derived tumors. Based on
histopathological criteria, three grades are distinguished from low grade (G1) to intermediate grade (G2)
and high grade (G3). Studies have shown that some G1 tumors which underwent complete surgical
resection reoccurred as lesions with a grading shift toward higher malignancy, associated with a poorer
Seite 5
prognosis. Patients with grading changes were examined in our study. Our aim was to find possible risk
factors for such grading shifts such as age, localization of tumor and tumor type.
Methods: This retrospective case control study evaluated 333 Patients, who received surgical
treatment of their low grade STS at Bergmannsheil Bochum between 1996 and 2011. These patients
received complete initial surgical resection (R0). Among our 333 patients, 9.9% (n=33) developed
grading shifts. The processed data includes age, gender, tumor type, tumor localization, local
recurrence and grading change.
Results: Patients with up gradings were found to have a higher mean age of 5.5 years than reference
collective. The tumor type has a strong, statistically significant effect on grading change as patients with
fibrosarcomas have a threefold risk of developing grading shifts when compared to patients with other
G1 STS.
Conclusion: Our results indicate that age and tumor type play the key role in the development of up
gradings in low malignant STS. Patients aged 60 and above diagnosed with fibrosarcoma are at a three
times higher risk of developing a grading shift as opposed to patients younger than 60 with other low
grade STS. We discussed the significance of these risk factors and whether, in addition to complete
tumor resection, a short term postoperative radiotherapy should be applied for these patients to improve
therapeutic outcome.
KLOS/S2-03
ILP und Resektion vs. Standardtherapie bei lokal fortgeschrittenen, primären
Weichgewebesarkomen.
Jens Jakob1, Michelle Wilkinson2, Per-Ulf Tunn3, Lothar Pilz1, Dirk Strauss2, Joseph M. Thomas2, Peter
Hohenberger1, Andrew J. Hayes2
1
Department of Surgery, Division of Surgical Oncology and Thoracic Surgery, University Medical Center Mannheim, University of
Heidelberg, Mannheim, Germany.
2
Sarcoma and Melanoma Unit, Royal Marsden Hospital, London, United Kingdom.
3
Department of Orthopedic Oncology, Helios Klinikum Berlin-Buch, Sarcoma Center Berlin-Brandenburg, Berliln, Germany.
Hintergrund: Die Extremitätenperfusion (ILP) mit Melphalan und rekombinantem Tumornekrosefaktor
(TNF) gilt als effektive präoperative Therapie bei lokal fortgeschrittenen Weichgewebssarkomen. Bisher
wurde die Methode jedoch nicht mit der Standardtherapie (Resektion in Kombination mit Bestrahlung)
verglichen. Wir präsentieren hier eine Kohortenstudie, die zwei Kohorten vergleicht. Die Patienten
wurden entweder mit einer Extremitätenperfusion und Resektion (ILP, 2 deutsche Zentren) oder mit der
Standardtherapie (Resektion und Bestrahlung, 1 Zentrum in London) behandelt.
Methode: Es erfolgte die retrospektive Auswertung der prospektive geführten Datenbanken. Patienten
mit Weichgewebssarkomen der unteren Extremität mit einer Größe von 10cm oder größer, Grad 2 oder
3 nach FNLCC wurden eingeschlossen (Grafik 1). Primärer Endpunkt war das lokalrezidivfreie
Überleben.
Ergebnisse: Die zwei Kohorten umfassten 44 (ILP) und 80 (Standard) Patienten. Tumorgröße,
histologisches Grading und Subtyp unterschieden sich nicht wesentlich (Tabelle 1). In der ILP Kohorte
erhielten 12/44 Patienten eine zusätzliche postoperative Strahlentherapie. Bei drei Patienten erfolgte
die Amputation aufgrund von Komplikationen nach ILP oder Tumorresektion. In der Standardkohorte
Seite 6
erhielten 66/80 Patienten eine postoperative Bestrahlung. Keine Komplikationsbedingten Amputationen
wurden durchgeführt. Insgesamt traten in der ILP Kohorte weniger Lokalrezidive auf (4/40 vs. 13/67, OR
0.52 (95% CI 0.16-1.69, p=0.15, Grafik 2). Wurden den Lokalrezidiven die therapiebedingten
Amputationen hinzugerechnet i.S. einer Rate des lokalen Therapieversagens bestand kein Unterschied
mehr zwischen den Kohorten (7/37 vs. 13/67, OR 0.98, 95% CI 0.36-2.66, p=0.73). Ebenso bestand
kein Unterschied in der Häufigkeit von Metastasen (24/20 vs. 43/37, OR 1.03, 95% CI 0.49-2.16,
p=0.71).
Schlussfolgerung: Nach ILP und Tumorresektion traten weniger Lokalrezidive auf als nach
Standardtherapie. Das Auftreten von komplikationsbedingten Amputationen scheint diesen Vorteil
jedoch aufzuwiegen.
KLOS/S2-04
Nicht invasive Messung von Blutfluss, Sauerstoffsättigung und Hämoglobingehalt im
Tumorgewebe während der Isolierten Extremitätenperfusion (ILP)
Lars Erik Podleska1, Kristina Funk2, Benjamin Schwindenhammer3, Florian Grabellus3, Georg Taeger1,
Herbert De Groot2
1
Klinik für Unfallchirurgie und muskuloskelettale Tumorchirurgie, Universitätsklinikum Essen
2
Institut für physiologische Chemie, Universitätsklinikum Essen
3
Institut für Pathologie und Neuropathologie, Universitätsklinikum Essen
1
Einleitung
Die isolierte Extremitätenperfusion mit TNF-alpha und Melphalan (TM-ILP) gilt als eine der wirksamsten
lokalen Therapiemethoden bei fortgeschrittenen Weichteilsarkomen und malignen Melanomen mit
Ansprechraten von 70-80% bei Weichteilsarkomen und 90% bei Melanomen.
Trotz zahlreicher in vitro Untersuchungen zur Wirkungsweise der ILP ist die Zahl der in vivo
Untersuchungen unter realen Bedingungen einer ILP beim Menschen sehr begrenzt. Dank neuer
kontaktloser Messmethoden mittels Weißlicht- und Laserlicht-Reflexion die in den vergangenen Jahren
Einzug in die medizinische Forschung erhalten hat stand uns dieses Messverfahren (O2C bzw.
Oxygen2See) zur Untersuchung während der TM-ILP zur Verfügung. Dieses erlaubt die kontinuierliche
und nicht-invasive (transkutane) Messung von Blutfluss, Hämoglobingehalt und Sauerstoffsättigung im
Gewebe. Ziel der vorliegenden Untersuchung war es die Eignung dieses Systems für eine regelmäßige
Anwendung bei der ILP zu überprüfen und eine erste Auswertung der gewonnenen Daten aus dem
Tumorgewebe im Vergleich mit gesundem Muskelgewebe vorzunehmen.
2
Material und Methoden
In der Zeit zwischen März und September 2011 wurden alle Patienten mit einer isolierten
Extremitätenperfusion (TM-ILP), die sich mit der Untersuchung einverstanden erklärt hatten und bei
denen ein Anteil des Tumors weniger als 2cm von der Hautoberfläche entfernt lag in die Untersuchung
eingeschlossen. Die zwei Mess-Sonden (Oxygen2See, Fa. LEA-Messtechnik, Giessen) wurden zu
Beginn der Operation mit sterilem Klebeband (Kimberly-Clark, Roswell, USA) an der Extremität
angebracht. Die Messungen wurden kontinuierlich während der ILP an zwei vordefinierten Punkten
(Tumor und Muskel) durchgeführt (über dem oberflächlichsten Tumoranteil und über der Tibialis
anterior-Loge bzw. über dem proximalen Unterarm/M. brachioradialis). Während der Operation wurden
kontinuierlich die Parameter Blutfluss (BF), Hämoglobingehalt (rHb) und Sauerstoffsättigung (SO2)
gemessen. Der Blutfluss und der Hämoglobingehalt wurden gerätebedingt in relativen Einheiten (AU)
gemessen; die Sauerstoffsättigung in Prozent.
Seite 7
Die Messungen wurden in Zeitabschnitte, entsprechend den Phasen der Operation, unterteilt:

HLM: Von Beginn der HLM bis zur TNF-Gabe

Melph: Von der Melphalan-Gabe bis zum Beginn des Auswaschens

reperf: Nach der endgültigen Reperfusion.
3
Ergebnisse
Es konnten bei 12 Patienten Messungen während der ILP durchgeführt werden. Der Blutfluss im
Tumorgewebe war im Verlauf der OP gegenüber dem Muskelgewebe um 150% gesteigert (Tabelle:
Zeilen 2-4) mit rückläufiger Tendenz nach Abschluss der ILP (114%). Auch der Hämoglobingehalt im
Tumorgewebe war auf knapp 150% gesteigert (Tabelle: Zeilen 7-8). Die Sauerstoffsättigung im
Tumorgewebe hingegen zeigte eine Verminderung gegenüber dem Muskelgewebe (Tabelle: Zeilen 5-6)
um 10% was als Hinweis auf einen höheren Sauerstoffbedarf des Tumorgewebes verstanden werden
kann.
HLM
Melph
reperf
Flow
[AU]
SO2 [%]
rHb [AU]
MW
Stabw.
MW
Stabw.
MW
Stabw.
Muskel
97
43,4
112
48,6
153
44,9
Tumor
Muskel
Tumor
Muskel
Tumor
146
65
57
32
52
54,0
16,3
28,0
10,9
18,2
168
68
62
41
55
53,3
9,1
28,1
17,2
19,4
174
68
58
41
56
52,9
17,7
18,4
9,5
14,0
Eine Einzelanalyse der Patienten konnte zeigen, dass diese Tendenz bei Patienten mit
oberflächlichsten Tumoren (weniger als 10mm Messtiefe, n=2) um ein Vielfaches stärker ausgeprägt
war als im Gesamtkollektiv: SO2 Tumor zu Muskel im Mittel von 17%.
4
Zusammenfassung und Schlussfolgerung
Die Auswertung der O2C-Messung zeigt einen gesteigerten Blutfluss und eine erhöhte
Hämoglobinkonzentration im Tumorgewebe während die kapillare-Sauerstoffsättigung, als Zeichen
eines erhöhten Sauerstoffverbrauchs im Tumorgewebe, erniedrigt ist. Obwohl alle Messungen an
möglichst oberflächlichen Anteilen des Tumorgewebes (weniger als 2 cm) durchgeführt wurden,
konnten deutliche Effekte erst in sehr oberflächlichen Geweben (< 10 mm) beobachtet werden.
Es konnte gezeigt werden, dass die nicht-invasive Messung von Sauerstoffsättigung, Hämoglobingehalt
und Blutfluss während einer ILP ohne Probleme durchführbar ist. Es scheint jedoch, dass nur sehr
oberflächliche Tumoren (in diesem Fall mit weniger als 5mm Abstand zur Haut) sehr zuverlässige
Messungen erlauben. Weitere Untersuchungen sind hier notwendig um die Vergleichbarkeit der Daten
zu belegen.
Seite 8
KLOS/S2-05
Percutaneous Core Needle Biopsy (PCNB) is a sensitive, quick and reliable tool for preoperative
diagnosis of Soft Tissue Sarcoma
A. Agaimy1, F. Stirkat 2, M. Lell3, J. Göhl2, W. Hohenberger2, R.S. Croner2
1
2
3
Department of Surgery, Institute of Pathology & Department of Radiology, University Hospital Erlangen
Background: Superficial and deep-seated soft tissue sarcomas (STTs) vary greatly in their histogenetic
derivation/line of differentiation and their biological potentials. Precise early histological diagnosis and
appropriate treatment of soft tissue sarcomas (STS) are essential to improve patient’s outcome. Radical
surgery with clear resection margins (R0 resection) is a key prognostic factor for survival of patients with
STS. Since histopathological verification of diagnosis is essential for treatment planning, percutaneous
core needle biopsy (PCNB) has emerged as an alternative to open surgical biopsy and can be
performed by blind or image-guided techniques.
Material and Methods: Forty-eight PCNBs of STTs from 2007 to 2011 were examined retrospectively.
Thirty biopsies (63%) were blind and 18 biopsies (37%) were obtained ultrasound- (15 patients; 80%) or
CT-guided (3 patients; 20%). The majority of lesions were located on the extremities (40 lesions; 83%);
only 8 lesions (17%) affected the trunk. In most cases, obtained PCNBs have been processed using a
fast embedding programme to obtain initial results within 6 hours. Multiple tissue sections were stained
routinely (H&E) and a mean of 5 unstained slides have been prepared for potential
immunohistochemistry or FISH analysis.
Results: Failure rate (false-negative cases) was 11% (2 cases) and 17% (5 cases) for imaging-guided
and blind PCNB, respectively (p=0.165). Of the 48 cases, 32 (67%) were subsequently surgically
removed. The final histopathology (entity diagnosis and grading into low or high grade) was concordant
in 30 tumors (94%). The two discordant cases included one huge hibernoma mistaken for probable
atypical lipomatous tumor and one sclerosed intramuscular myxoma interpreted as possible desmoid
tumor. No complications were reported.
Conclusions: Blind PCNB is a safe, rapid and cost-effective technique for preoperative diagnosis of
peripherally located soft tissue masses. Image-guided techniques are more expensive but offer a realtime imaging of the tumor and adjacent structures. Tissue material gained by PCNB is generally
sufficient for a quick diagnosis and grading of STS for optimal preoperative planning of treatment,
particularly with regard to the possibility of neoadjuvant therapy for downstaging larger and/or initially
inoperable tumors. Discordant diagnoses are uncommon when biopsy interpretation is done by
pathologists with sufficient experience in soft tissue pathology.
Seite 9
KLOS/S2-06
Die prognostische Aussagekraft des histologischen Ansprechens nach neoadjuvanter
Behandlung von primären, lokalisierten, hochmalignen Weichgewebssarkomen
D. Andreou1,2, M. Werner3, F. Traub1, D. Pink4, B. Jobke5, P. Reichardt6, P.U. Tunn1
1
Department Tumororthopädie, Zentrum für Orthopädie und Unfallchirurgie, Sarkomzentrum Berlin-Brandenburg,
HELIOS Klinikum Berlin-Buch, Berlin
2
Klinik für Allgemeine Orthopädie und Tumororthopädie, Universitätsklinikum Münster, Münster
3
Institut für Gewebediagnostik, Sarkomzentrum Berlin-Brandenburg, HELIOS Klinikum Emil von Behring, Berlin
4
Klinik für Hämatologie, Onkologie und Palliativmedizin, Sarkomzentrum Berlin-Brandenburg, HELIOS Klinikum Bad Saarow
5
Institut für Röntgendiagnostik, HELIOS Klinikum Berlin-Buch, Berlin
6
Klinik für Interdisziplinäre Onkologie, Sarkomzentrum Berlin-Buch, HELIOS Klinikum Berlin-Buch, Berlin
Fragestellung: Die Beurteilung des Tumoransprechens auf eine neoadjuvante Behandlung ist ein
wichtiges Instrument in multidisziplinären Therapieplänen. Sie trägt dazu bei, Patienten rechtzeitig zu
identifizieren, die von einer Behandlungsintensivierung oder von experimentellen Therapieoptionen
profitieren könnten – vorausgesetzt, dass sie mit der Prognose der Patienten korreliert. Ziel dieser
Studie war es, die prognostische Aussagekraft des histologischen Ansprechens nach neoadjuvanter
Behandlung von primären, lokalisierten, hochmalignen Weichgewebssarkomen zu evaluieren.
Methodik: Die Akten von 107 konsekutiven Patienten, bei denen eine neoadjuvante regionale (isolierte
hypertherme Extremitätenperfusion – ILP, n=57) oder systemische Chemotherapie (SC, n=50) gefolgt
von der chirurgischen Tumorresektion zwischen 2001 und 2011 in unserer Klinik durchgeführt wurde,
wurden retrospektiv ausgewertet. Die Tumornekroserate im Resektat (kategorisiert als hoch, wenn sie
>90% und als niedrig, wenn sie ≤ 90% betrug) sowie die Mitoserate in der Probebiopsie und im
Resektat (kategorisiert als hoch, wenn sie > 20 Mitosen/10 Hauptgesichtsfelder (HPF) und als niedrig,
wenn sie ≤ 20 Mitosen/10 HPF betrug) wurden bezüglich ihrer prognostischen Aussagekraft untersucht.
Analysen der Überlebenswahrscheinlichkeiten wurden nach der Kaplan-Meier-Methode durchgeführt
und mit dem log-rank-Test verglichen. Die mediane Nachbeobachtungszeit betrug 43 (5 – 138) Monate
für alle Patienten. Bei den Patienten, die zum Zeitpunkt der statistischen Auswertung noch lebten, lag
sie bei 56 (12 – 138) Monaten.
Ergebnisse: Die Gesamtüberlebenswahrscheinlichkeit nach 5 Jahren betrug 64,6% nach systemischer
Chemotherapie und 61,7% nach ILP (p=0,987). Die ereignisfreie Überlebenswahrscheinlichkeit nach 5
Jahren lag bei 61,3% nach SC und 47,3% nach ILP (p=0,166). Nach einer ILP korrelierten weder die
Mitoserate in der Probebiopsie noch die Tumornekroserate im Resektat mit der Gesamt- und der
ereignisfreien Überlebenswahrscheinlichkeit. Eine niedrige Mitoserate im Resektat ging mit einer
signifikanten Verbesserung der ereignisfreien Überlebenswahrscheinlichkeit (54,8% vs. 28.6% nach 5
Jahren, p=0,040) aber nicht mit einer signifikanten Verbesserung der GesamtÜüberlebenswahrscheinlichkeit (64,3% vs. 49,2% nach 5 Jahren, p=0,117) einher.
Auch bei den Patienten nach SC wies die Mitoserate in der Probebiopsie keine Korrelation zur Gesamt(p=0,175) und zur ereignisfreien Überlebenswahrscheinlichkeit (p=0,691) auf. Auf der anderen Seite
hatten Patienten mit einer niedrigen Tumornekroserate im Resektat eine signifikante Verbesserung der
ereignisfreien Überlebenswahrscheinlichkeit (81,7% vs. 51,0% nach 5 Jahren, p=0,017) und einen
Trend für eine Verbesserung der Gesamtüberlebenswahrscheinlichkeit (93,3% vs. 55,3% nach 5
Jahren, p=0,053). Des Weiteren ging eine niedrige Mitoserate im Resektat nach SC mit einer statistisch
hochsignifikanten Verbesserung sowohl der Gesamtüberlebenswahrscheinlichkeit (80,2% vs. 27,7%
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nach 5 Jahren, p<0,001) als auch der ereignisfreien Überlebenswahrscheinlichkeit (72,0% vs. 30,8%
nach 5 Jahren, p<0,001) einher.
Schlussfolgerungen: Die Mitoserate nach neoadjuvanter systemischer Chemotherapie für primäre,
lokalisierte, hochmaligne Weichgewebssarkome scheint eine signifikante Korrelation zur Prognose zu
haben. Sollten sich diese Ergebnisse in größeren Studien bestätigen lassen, so wird die Entwicklung
neoadjuvanter Therapieoptimierungsstudien für Weichgewebssarkome, analog der EURAMOS 1 und
EURO-B.O.S.S. Studien für Knochensarkome, ermöglicht werden.
KLOS/S2-07
Interim analysis of a Phase II study to evaluate imatinib mesylate to induce progression arrest in
Aggressive Fibromatosis / Desmoid Tumors not amenable to surgical resection with R0 intent or
accompanied by unacceptable function loss
A study of the German Interdisciplnary Sarcoma Group (GISG)
Bernd Kasper1, Peter Reichardt2, Viktor Gruenwald3, Sebastian Bauer4, Michaela Sommer1, Peter
Hohenberger1
1
University of Heidelberg, Mannheim University Medical Center, ITM - Interdisciplinary Tumor Center Mannheim, Sarcoma Unit,
Mannheim, Germany;
2
HELIOS Klinikum Bad Saarow, Sarcoma Center Berlin-Brandenburg, Bad Saarow, Germany;
3
Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover,
Germany;
4
Sarcoma Center, West German Cancer Center, Essen, Germany.
Background: Desmoid tumors describe a rare monoclonal, fibroblastic proliferation characterized by a
variable and often unpredictable clinical course. Surgery is the therapeutic mainstay, except if mutilating
and associated with considerable function loss. For advanced disease different treatment approaches
have been investigated. Promising results have been demonstrated using imatinib.
Methods: Therefore, we initiated within the GISG a phase II trial evaluating imatinib to induce
progression arrest in desmoid tumor patients not amenable to surgical resection with R0 intent or
accompanied by unacceptable function loss (NCT01137916). Patients are treated with a dose of 800
mg imatinib daily over two years. Major eligibility criteria are patients with a histological confirmed
desmoid tumor showing progressive disease according to RECIST 1.0 within six months. The primary
endpoint is the non-progression rate after six months of treatment. Interim analysis was performed at 17
patients; a total of 37 patients are necessary. Following the inclusion of the first 17 patients, if ≥ four
patients are progression-free at six months, the accrual will continue. Accrual started in July 2010 in five
GISG centers.
Results: As of November 2012, 25 patients have been included in the study. The planned interim
statistical analysis in June 2012 showed that eleven out of 17 evaluable patients had stable disease
indicating that imatinib had reached the primary endpoint to justify continuing accrual after the first step
of the study. Out of the six patients counted as non-successors, three patients had documented disease
progression. One patient terminated the trial due to toxicity. There was one study withdrawal and one
treatment change to radiotherapy.
Conclusion: With a 65 % progression-free rate at the interim analysis, imatinib clearly exceeded its
primary endpoint of the study and warrants further accrual and final analysis in this GISG study.
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