Academic literature on the topic 'S-Flt-1'

TPS4146 Background: Pancreatic cancer (PC) has one of the lowest 5-year survival rates. Gemcitabine (G)-based chemotherapy is standard-of-care first-line systemic therapy. Fluorine-18 radiolabelled 3-deoxy-3-fluorothymidine (FLT), a thymidine analogue, is a substrate for thymidine kinase 1 (TK1), which is highly expressed in proliferating cells in late G1/S phase. FLT uptake (imaged and quantified by positron emission tomography (PET)) correlates with pathology-based proliferation markers and with decreases with therapy in a number of cancers. G, a nucleoside analogue, decreases proliferation by inhibiting DNA synthesis, primarily acting on S and G1/S phase thus decreasing tumour FLT uptake. Human equilibrative nucleoside transporter (hENT1) transports G and FLT into cells, making hENT1 activity a key determinant of both FLT uptake and G efficacy. Methods: Two parallel proof-of-concept studies are designed to explore the feasibility of assessing proliferation, nucleoside transport, magnitude of treatment-related FLT uptake changes and understanding the pathophysiological basis of FLT-PET imaging in patients (pts) with (1) localized or (2) advanced PC. Up to 24 PC pts with ECOG PS 0-2, able to undergo imaging and with at least one potentially evaluable lesion larger than 2cm on CT/MRI are eligible. Pts with localized disease (study 1) will have dynamic FLT-PET pre-operatively preceded by a radiolabelled H2O PET scan to assess tumour perfusion. These pts will also undergo 2-deoxy-2-fluoro-D-glucose (FDG)-PET and diffusion-weighted MR scans. For pts with metastatic disease (study 2), dynamic FLT-PET will be performed before and after G-based chemotherapy. FLT uptake expressed as a standardized uptake value (SUV), will be determined. Tumour pathological markers from the surgical samples and imaging parameters will be correlated; hENT1 status will be assessed (by immunohistochemistry) after surgery (study 1) and before treatment (study 2). Reproducibility FLT-PET studies will be performed in a cohort of subjects to assess the variability in uptake quantification.

Under conditions associated with local and systemic inflammation, mesangial cells and invading immune cells are likely to be responsible for the release of large amounts of nitric oxide (NO) in the glomerulus. To further define the mechanisms of NO action in the glomerulus, we attempted to identify genes which are regulated by NO in rat glomerular mesangial cells. We identified vascular endothelial growth factor (VEGF) and its receptor fms-like tyrosine kinase (FLT-1) to be under the regulatory control of exogenously applied NO in these cells. Using S-nitroso-glutathione (GSNO) as an NO-donating agent, VEGF expression was strongly induced, whereas expression of its FLT-1 receptor simultaneously decreased. Expressional regulation of VEGF and FLT-1 mRNA was transient and occurred rapidly within 1–3 h after GSNO treatment. Expression of a second VEGF-specific receptor, fetal liver kinase-1 (FLK-1/KDR), could not be detected. The inflammatory cytokine interleukin-1β mediated a moderate increase in VEGF expression after 24 h and had no influence on FLT-1 expression. In contrast, platelet-derived growth factor–BB and basic fibroblast growth factor had no effect on VEGF expression, but strongly induced FLT-1 mRNA levels. Obviously, there is a differential regulation of VEGF and its receptor FLT-1 by NO, cytokines and growth factors in rat mesangial cells.

Abstract Abstract 3529 Poster Board III-466 Pet imaging using F-18 glucose (FDG) is increasingly being used for evaluation and staging of malignancy. However, staging in hematopoietic tissue using this agent has been hampered by poor specificity. F-18 flourothymidine (FLT) is currently being evaluated clinically as an imaging technique for tumor detection and staging. Secondary to its inclusion in DNA during the S phase, FLT is much more specific to proliferative tissue and less hampered by inflammatory background. As FLT uptake occurs in proliferating cell populations, we attempted to determine if imaging could provide useful information for evaluating global hematopoietic injury and recovery following radiation and transplantation. Three major groups of Wistar-Furth rats were studied. Group 1 consisted of rats receiving 950cGy of Whole Body Irradiation (TBI). Group 2 consisted of rats transplanted with syngeneic bone marrow 24-48 hrs following irradiation. Group 3 consisted of 6 rats exposed to a potentially sub-lethal dose of 500cGy and not transplanted. FLT imaging was performed before irradiation (n=4), 24-48 hrs. following irradiation, and on day 4-5 post transplantation. Subsequent imaging was carried out in 4 transplanted rats on days 8 and 14. Comparative FDG studies were also performed in selected animals. Table 1 summarizes the imaging studies performed in various subsets of rats. Table 1 Imaging Subsets of Experimental Animals and Histologic Correlations Experimental rat subsets FLT # studies performed FDG # studies performed Histologic correlation Normal or baseline rat studies n=10 n=6 Normal cellular marrow 24-48hrs post 950 cGy TBI n=6 n=4 Marrow damage hypocellularity Day 7 post 950 cGy TBI n=4 not done Aplastic marrow Day 6-7 post 950cGy TBI (4-5 days post transplantation) n=4 n=4 Focal areas of cellular regeneration Day 10 post 950 cGy TBI (and transplantation) n=4 n=2 Cellular marrow Day 6-7 post 500cGy TBI (No transplantation) n=6 not done Moderate hypocellularity FLT imaging results were correlated with marrow histology and clinical survival in treated and control groups. Six of 6 irradiated control rats died with marrow aplasia during the second week following 950 cGy. Sub-lethally irradiated and transplanted rats animals showed clear evidence of definitive recovery as early as 6 days post irradiation or 4 days post transplantation respectively. FLT activity of all major marrow sites was easily identified and was superior to FDG images. Findings correlated with histologic evidence of early marrow repopulation and survival. Figure 1 illustrates FLT and FDG imaging performed in normal, post radiation and post transplanted rats. We conclude that FLT imaging represents a practical noninvasive technique to evaluate marrow injury and early recovery following radiation and hematopoietic transplantation. Disclosures: No relevant conflicts of interest to declare.

Background/Aims: Peptide receptor radionuclide therapy (PRRT) is becoming clinical routine for management of neuroendocrine tumours. The number of PRRT cycles is correlated with treatment effect but theoretically limited by off-target radiation damage to kidneys and bone marrow. New imaging biomarkers for assessment of PRRT tissue damage would enable evaluation of novel renal and bone marrow protective agents, as well as personalised PRRT treatment regiments. Methods: Mice treated with [177Lu]Lu-DOTA-TATE PRRT or vehicle were examined at baseline and following treatment with [18F]fluorothymidine (FLT) positron emission tomography (PET) and technetium-99m-mercapto-acetyl-tri-glycine ([99mTc]Tc-Mag3) single-photon emission tomography (SPECT) to assess dynamic changes in bone marrow proliferation and renal function, respectively. Results: Bone marrow proliferation as assessed by [18F]FLT was decreased 2 days after PRRT treatment, but not vehicle, compared to baseline (target-to-background ratio [TBRmax] baseline:1.69 ± 0.29 vs. TBRmax PRRT: 0.91 ± 0.02, p < 0.01). Renal function as assessed by [99mTc]Tc-Mag3 SPECT was similarly decreased 2 days following PRRT compared to vehicle (fractional uptake rate [FUR] vehicle: 0.030 ± 0.014 s–1 vs. FUR PRRT: 0.0051 ± 0.0028 s–1, p < 0.01). Conclusion: [18F]FLT PET and [99mTc]Tc-Mag3 SPECT are promising techniques for assessing bone marrow and renal injury from [177Lu]Lu-DOTA-TATE PRRT and may potentially improve patient management by allowing evaluation of protective interventions as well as enabling personalised PRRT treatments.

11116 Background: Uptake of radiolabeled thymidine (tdR) or its analogs is frequently used to assess tumor cell proliferation as well as tumor DNA repair synthesis after inhibition of tumor cell proliferation with certain drugs. We determined whether the relationship between thymidine (td) uptake and tumor cell proliferation may be different between indolent and aggressive NHLs. Methods: Twenty-four patients with histologically confirmed aggressive (n=16; all DLC) or indolent NHLs (n=8; 7 FL gr I-II, 1 MZL) underwent pretherapy imaging with the td analog 18F-fluorothymidine (FLT) and biopsy to determine the proliferative cell fraction by the Ki-67 index. Tumoral FLT uptake was determined by the maximum standardized uptake values (SUVmax) and correlated with the Ki-67 index. The FLT-SUV to Ki-67 ratio was also compared between indolent and aggressive NHLs. Results: Disproportional increase in FLT-SUVmax relative to tumor cell proliferation was found in indolent NHLs: median %Ki-67 was 5% in indolent vs. 80% in aggressive NHL whereas median FLT-SUVmax was 3.6 vs. 9.4, respectively. The disproportional increase in FLT-SUV in indolent NHLs could not be explained by nonspecific FLT uptake in tumor extracellular space estimated to account for <0.2 SUV unit. Difference in the ratio of FLT-SUVmax to Ki-67 index between indolent and aggressive NHLs was highly significant (1.21 ± 0.77 vs. 0.18± 0.20; P=0.006). These data are in line with a previous study using tdR where the ratios of median tdR (in cpm) to median %-Ki-67 or %-S phase cells in indolent were ∼1.5x those in aggressive NHLs which was associated with relatively increased expression of DNA repair proteins (PCNA) in indolent NHLs (Holte et. al. Acta Oncologica, 1999) Conclusions: Disproportional increase in td uptake relative to %proliferating tumor cells in indolent NHLs likely reflects enhanced DNA repair in quiescent cells or, less likely, constitutively increased Tk1 expression. Studies are underway to determine expression of proteins that, unlike Ki-67, are associated with both DNA repair and replication (e.g., RFA, PCNA). If enhanced DNA repair is confirmed in indolent NHLs this could have major implications with respect to understanding their natural course and treatment options. No significant financial relationships to disclose.

e19054 Background: EGFR mutations predict response to erlotinib treatment in advanced NSCLC. However, also a subgroup of patients with wildtype EGFR benefits from erlotinib treatment. This subgroup could not yet be defined by molecular means. In this trial we set out to prospectively evaluate the accuracy of [18F]FDG-/[18F]FLT-PET analyses for early prediction of non-progression in chemo-naive patients with advanced NSCLC treated with erlotinib. Methods: Patients with NSCLC stage IIIB/IV without prior systemic treatment for NSCLC were eligible and treated for 6 weeks with erlotinib in this single centre diagnostic pilot trial. Primary endpoint was the accuracy of [18F]FDG/18F[FLT] PET after 1 week of treatment to predict non-progression as defined by RECIST criteria in CT scans after 6 weeks of treatment. Here we present the evaluation of 20 patients of this ongoing trial in accordance with the data monitoring board (EudraCT number 2005–005393–73; NCT00568841 ). Results: Twenty patients were recruited from 9/07 to 9/08. Seventeen patients were eligible for final analysis. The AUC for [18F]FDG PET at week 1 to predict non-progression was 0.857 ±0.105 (p=0.013) and 0.643±0.137 (p=0.32) for [18F]FLT PET. Using [18F]FDG PET specificity was 1 and sensitivity 0.71 for prediction of non- progression after six weeks (p=0.006 Fishers exact). In addition, [18F]FDG PET after 1 week of treatment clearly predicted tumor non- progression after 18 weeks of treatment with a predefined cut-off of -20% change in sSUVmax. (p=0.0004, Fisher´s exact). Finally, using this cut-off value [18F]FDG-PET after one week of treatment, predicted progression free survival (p=0.001, log rank test), with differences in median PFS of 45 days vs 320 days. Using univariable Cox regression, both [18F]FDG and [18F]FLT PET predicted PFS [hazard ratio 2.1 (p=0.006, Wald test) and 2.3 (p=0.011), respectively, per standard deviation]. Conclusions: Our observations indicate that early [18F]FDG but not [18F]FLT PET analysis predicts non-progression after 6 weeks of first-line erlotinib treatment in patients with advanced NSCLC. In addition, early [18F]FDG PET predicts non-progression after 18 weeks of treatment and progression free survival. [Table: see text]

Abstract Introduction: FLT-3/ITDs are present in nearly 25% of AML patients, and when treated with conventional chemotherapy have been associated with poor prognosis because of lower induction remission rates; lower 5 year Event Free Survival (EFS of ~30%); and a high risk of relapse even after allogeneic- Stem Cell Transplantation (SCT). These patients do not benefit with intensive chemotherapy alone and should prospectively receive alternate therapeutic approaches. Monotherapy with the multikinase inhibitor sorafenib shows excellent initial responses in FLT-3/ITD+ AML, however, the responses are short-lived, and therefore sorafenib has been combined with chemotherapeutic regimens without significant adverse events. Assessment of Minimal Residual Disease (MRD) negativity by flow after induction and consolidation therapy has shown to provide ondependent prognostic information in patients with FLT-3/ITD+ AML (3 year RFS of 9% v/s 44%). Methods: We retrospectively analyzed initial outcomes of 10 FLT-3/ITD+ AML patients who received various chemotherapeutic regimens +/- sorafenib during the period from May 2013 to May 2015. Patients were treated with either standard chemotherapy with daunorubicin 60mg/m2/ cytarabine 100 mg/m2 (3+7); high dose ara-C 12 G/m2 (HDAC) or oral metronomic therapy (etoposide 50 mg/m2 + 6-thioguanine 40 mg/m2 +/- prednisolone 40 mg/m2) or cladribine (2CDA) (9 mg/m2) + ara-C (500 mg/m2) d1 to d5. Sorafenib was given orally in the dose of 150 to 200 mg/m2 twice a day, every day. Results: There were 10 children with newly diagnosed FLT-3/ITD+ AML; 6 males, 4 females. The median age at presentation was 11 years (range 6 to 15) with median WBC count of 118 x 106/L (range 40-308). Of these 10 patients, 8 had allelic ratio of > 0.4. All except 1 patient [t(8;21)+] had normal cytogenetics. MRD negativity (by flow) was achieved in 5/5 patients post 2CDA/ ara-C + sorafenib; 3/5 patients post oral metronomic chemotherapy (MCT) +/- sorafenib; 1/1 patient post 3+7 + sorafenib. Interestingly only1/6 patients receiving HDAC+ sorafenib achieved MRD negativity. 9/10 (90%) patients achieved deep remission post treatment with chemo + sorafenib and the remaining 1 patient is yet to receive 2CDA/ara-C + sorafenib chemotherapy. None of the patients could be transplanted for socio-economic reasons. So far there have been no relapses. There were 2 remission deaths, 1 due to sepsis post 2CDA+ ara-C and 1 at home (village) due to unknown cause. At a median follow-up of 8 months (range 4 to 19 months), 8/10 patients are alive, 7 in MRD negative remission. Sorafenib was overall well tolerated with 2 patients having Grade III skin rash and 1 having Grade II rash; all receiving 200 mg/m2 twice a day dose. Conclusions: Modifying therapy in FLT-3/ITD+ AML may improve the depth of remission and reduce risk of relapse thereby improving survival. Sorafenib in combination with chemotherapeutic agents has shown good activity in FLT-3/ITD+ AML without significant adverse effects. Our preliminary data suggests that patients with FLT-3/ITD+ may best be treated with 2CDA/ara-C + sorafenib as induction regimen followed by oral MCT + sorafenib maintenance after completion of consolidation regimen. Disclosures Off Label Use: Sorafenib is being used in the treatment of FLT3/ITD positive AML, though it is not FDA approved for the same at present. .

Abstract Abstract 2849 Purpose: The thymidine analogue [18F]fluorothymidine (FLT) has been shown to reflect proliferation of high-grade lymphoma cells both in preclinical and clinical studies. In this preclinical in vitro and in vivo study we assessed early FLT-uptake as an adequate and robust surrogate marker for response to inhibitors of Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK)-dependent pathways in an anaplastic large cell lymphoma (ALCL) xenotransplant model. Methods: In vitro investigations included viability assessment (MTT assay), cell cycle analysis using propidium iodide staining and western blotting to characterize response of the ALCL cell lines SUDHL-1 and Karpas299 to treatment with heat shock protein 90 (Hsp90) inhibitor NVP-AUY922, the Phosphoinositide 3-kinase (PI3K) inhibitor BGT226 or the mammalian target of rapamycin (mTOR) inhibitor RAD001. Thymidine metabolism in severe combined immunodeficient (SCID) mice bearing SUDHL-1 or Karpas 299 lymphoma xenotransplants was assessed non-invasively prior to and early in the course of therapy (48h to 7 days) by FLT and FDG positron emission tomography (FLT-PET and FDG-PET) using a dedicated small animal PET system. Tumor-to-background ratios (TBR) of FLT-PET were compared to that of PET using the standard radiotracer [18F]fluorodeoxyglucose (FDG). Reference for tumor response was local control of the tumor measured by shifting calliper and histopathological analysis of explanted lymphomas. Results: In vitro, SUDHL-1 cells were sensitive to all three inhibitors (IC50 AUY922= 50 nM; IC50 BGT266= 10 nM; IC50 RAD001= 1 nM). These cells showed a dose-dependent induction of cell-cycle arrest in G1-phase and reduction of S-Phase after 24 to 48 hours and - to a lesser extent - increase of apoptosis. Incubation of SUDHL-1 cells with NVP-AUY922 (50 nM) for 24 hours led to a 70% reduction of ALK level and a abrogation of Akt phosphorylation as determined by western blot analysis. Likewise, no phosphorylation of Akt was detectable after incubation with BGT266 (10 nM) already after 4 hours. RAD001 (0.1-1nM, 24h) completely inhibited phosphorylation of p70 S6K. In contrast, Karpas299 cells were only sensitive to RAD001-induced cell cycle arrest, but insensitive to NVP-AUY922 and BGT266. In vivo, we performed FLT- and FDG-PET scans to monitor inhibition of tumor growth in the course of therapy with NVP-AUY922. Tumor volume in treated animals bearing SUDHL-1 lymphomas showed modest increase within the first week (median increase= + 25%, range -30% to + 80%, n=8) as opposed to a 3.8-fold increase in untreated control animals. After 14 days a clear reduction of tumor mass could be observed (median= - 25%, range -40% to + 30%, n=4). Median TBR of FLT-PET decreased significantly to 40% compared to baseline as earlier as 5 days after initiation of therapy (range 32–67%, n=8, p=0,008). In contrast, the pattern of TBR in FDG-PET did not show any clear tendency (median TBR 79%, range 36%-161%, n=8, p=0,73). We then investigated the ability of FLT-PET to differentiate between sensitive and resistant lymphoma cells. Therefore, mice bearing Karpas299 lymphomas were treated with NVP-AUY922 (resistant in vitro) or RAD001 (sensitive in vitro). According to our in vitro results, no effect was seen during treatment with NVP-AUY299 as indicated by about 3-fold tumor growth on day 7 and increase of median TBR in FLT-PET to 162% (range 106–177%, p=0,008, n=8) on day 2. In contrast, mice receiving RAD001 showed a deceleration of tumor development with doubling of tumor volume within the first week (range -20% to + 320%, n=10) that remained fairly constant over the following weeks. FLT-PET imaging indicated a slight increase of TBR correctly reflecting tumor growth kinetics (median=126%, range 60–129%, no p-value). A larger cohort is currently investigated as well as histopathological analysis of explanted lymphomas. The updated data will be presented at the meeting. Conclusion: In contrast to FDG-PET, FLT-PET is able to predict response to specific inhibitors early in the course of the therapy using a anaplastic large cell lymphoma xenograft model and is able to distinguish between sensitive and resistant lymphoma cells. Disclosures: No relevant conflicts of interest to declare.

Abstract Introduction: Patients with acute myeloid leukemia (AML) characterized by FMS-like tyrosine kinase-3 (FLT-3) internal tandem duplication (ITD) mutations have poor outcomes, especially in the relapsed setting. Although small molecule inhibitors of FLT-3 have been explored for these patients, many inhibitors have demonstrated limited single-agent efficacy with short response durations. Sorafenib, a multi-kinase inhibitor with activity against FLT-3, has previously been evaluated alone and in combination with induction chemotherapy or azacytidine in AML patients. Here we describe our experience with the combination of the DNA hypomethylating agent, decitabine (D), and sorafenib (S) for the treatment of FLT-3 ITD mutant AML. Methods: We retrospectively reviewed records of patients with FLT-3 ITD mutant AML who were treated off protocol with decitabine and sorafenib from 2011-present. Descriptive statistics, treatment response, and overall survival were recorded. Results: A total of six patients were identified. Mean age was 56 (range 34-70) years. Two-thirds (4/6) were female. All patients were confirmed to have recurrence of de novo AML characterized by FLT-3 ITD mutations prior to therapy. Patients received at least 1-2 cycles of concurrent decitabine 20 mg/m2 for 10 days and sorafenib 200-400 mg twice a day for 28 days. Five patients had relapsed/refractory AML (RR-AML) following 1-3 prior therapies. One patient had de novo AML in complete remission with incomplete count recovery (CRi) and received DS as consolidation. The overall response rate was 83%. Eighty percent (4/5) of patients with RR-AML attained CRi. One patient receiving DS consolidation attained complete remission (CR). Two patients received subsequent allogeneic stem cell transplantation with one individual still alive after 348 days. FLT3 ITD allelic ratio (available on 3 patients) decreased after DS therapy and correlated with CRi. Median overall survival was 111 days (range 59-348) from the initiation of DS to death from any cause or last known follow-up. Two patients developed treatment-related neutropenic fever/sepsis and elevated liver enzymes, respectively, which did not require dose adjustment. One patient developed heart failure of uncertain etiology. Conclusions: In this single institute case series, we demonstrated that the combination of decitabine (10 days) and sorafenib was well tolerated, resulted in high CR/CRi rates (80%), and prolonged overall survival in patients with heavily pretreated relapsed/refractory FLT-3 ITD mutant AML. Further investigation of this regimen in clinical trials is warranted. Table 1: Case series Patient Age(years) Sex No. of Prior therapies PriorAlloSCT * Blasts Prior to DS (%) No. of DSCycles Responseto therapy Overall survival (Days) 1 54 Female 3 N BM 70% 1 CRi 141 2 70 Female 1 N PB 53% 2 CRi 82 3 64 Male 1 N BM 68% 2 CRi 62 4 60 Male 1 N BM 2% 1 CR 198 5 34 Female 3 Y PB 48% 1 NR 348 6 58 Female 3 Y NA 2 CRi 59 Figure 1 Figure 1. *Allogeneic stem cell transplantation Disclosures Off Label Use: We are going to discuss the use of decitabine and sorafenib combination in relapsed/refractory FLT3 mutant AML. Decitabine is a DNA hypomethylating agent and sorafenib is a multikinase inhibitor, both of which have been evaluated individually in AML patients..

626 Background: Cell cycle dysregulation is a hallmark of most cancers. At the G1/S transition, cyclin dependent kinase (CDK) 4 and CDK 6 proteins associate with cyclin D proteins to allow cell cycle progression. Tumor cells that are driven by abnormalities of the cell cycle through activation of the cdk4/6-cyclin D axis showed increased phosphorylation of retinoblastoma protein (Rb), the major substrate for CDKs at the G1/S transition. Palbociclib is a potent specific inhibitor of cdk 4/6, with preclinical data showing G1 arrest in Rb-positive cells. Since activation of the MAP kinase pathway impacts directly on cdk-cyclin activation, we performed a phase II trial of palbociclib in patients with metastatic, KRAS-mutant colorectal cancer (mCRC). Methods: We screened 36 patients with KRAS mutant mCRC for Rb expression and 35 (97%) were Rb positive. We enrolled 15 patients, 9 (60%) of which were male and 6 (40%) female, median age was 62, 10 (67%) colon, 4 (27%) rectal (27%) rectal, and 1 (7%) appendiceal malignancy. Patients received 125mg daily of palbociclib for 21 days of a 28-day cycle, the recommended phase II dose. Results: Six patients (33%) experienced grade 3 neutropenia, 1 patient had grade 3 neutropenic fever (6%), and 2 patients (11%) had grade 3 AST/ALT elevation. There were no responses, but 5 patients (33%) had stable disease by RECIST criteria after 2 cycles of treatment, and 1 patient had stable disease for 8 cycles. The median number of cycles was two. As a pharmacodynamic marker of activity, 9 patients underwent FLT-PET at baseline and after 1 cycle of therapy. FLT-PET uses the tracer 3’-deoxy-3’[18F]-fluorothymidine, uptake of which is proportional to cellular proliferation. Six of the 9 patients (67%) had a decrease in uptake in target lesions, with an average 20% decrease in uptake in target lesions. FLT uptake in the bone marrow decreased by an average 4.85% and this correlated with a decrease in absolute neutrophil count of 62.3% (r2 0.59). Conclusions: While palbociclib has limited activity in KRAS mutant mCRC as a single agent, there is a clear pharmacodynamic effect as determined by FLT-PET imaging. Given the limited toxicity profile, combinations with non-myelosuppressive agents hold great promise. Clinical trial information: NCT01037790.

Einleitung: Die Dysbalance proangiogener (Placental Growth Factor = PlGF) und antiangiogener Faktoren (soluble fms-like tyrosine kinase 1 = sFlt-1) gilt heute als pathophysiologische Grundlage bei der Entstehung einer Präeklampsie (PE), eines HELLP-Syndroms (Haemolysis, Elevated Liver enzymes, Low Platelets) oder einer intrauterinen Wachstumsretardierung (IUGR). Der sFlt1/PlGF-Quotient, ein sensitiver und robuster diagnostischer Marker, ist bereits Wochen vor der Krankheitsmanifestation erhöht. Ziel dieser Studie war es, die Wertigkeit des sFlt1/PlGFQuotienten als prädiktiven Faktor bei Risikopatientinnen zu untersuchen. Patienten und Methode: In diese prospektive Studie wurden 68 Patientinnen mit einer Einlingsschwangerschaft und mindestens einem Risikofaktor für das Auftreten einer PE, eines HELLP-Syndrom oder einer IUGR im Schwangerschaftsverlauf eingeschlossen. Die Patientinnen wurden je nach Verlauf der Schwangerschaft in eine Gruppe mit Symptomen (Fallgruppe) und eine Gruppe ohne Symptome (Kontrollgruppe) für eine der oben genannten Erkrankungen unterteilt. Der sFlt1/PlGF-Quotient wurde bei der Aufnahme in die Studie und im weiteren Schwangerschaftsverlauf bestimmt. Ergebnisse: Eine PE, ein HELLP-Syndrom oder eine IUGR trat bei 41 % der Risikopatientinnen auf… Der absolute Wert des sFlt-1/PlGF-Quotienten war nur bei der Gruppe mit Symptomen auf ≥ 85 erhöht und zeigte sich in der 25 + 0-31 + 0 SSW (p = 0,005) und ab der 35 + 0 SSW (p = 0,044) als prädiktiver Faktor für eine PE, ein HELLP-Syndrom oder eine IUGR. Ab 7–10 Wochen vor der Entbindung war, in der Fallgruppe stärker als in der Kontrollgruppe, ein Anstieg des sFlt1/PlGFQuotienten zu beobachten. Dieser war 0–2 Wochen vor der Entbindung bei beiden Gruppen (Kontrollgruppe (MW ± SA 66,9 ± 134) vs. Fallgruppe (MW ± SA 393,3 ± 147,4, p = 0,021) am ,stärksten und zeigte sich ebenfalls als prädiktiver Faktor für eine der genannten Schwangerschaftserkrankungen (p = 0,025). Schlussfolgerung: Bei Risikoschwangeren kann der sFlt1/ PlGF-Quotient für die Einschätzung des individuellen Risikos für eine PE, ein HELLP-Syndrom oder eine IUGR im Schwangerschaftsverlauf genutzt werden. Wiederholte Messungen des Quotienten versprechen eine risikoangepasste Betreuung dieser Patientinnen
Background: A dysbalance of proangiogenic [placental growth factor (PlGF)] and antiangiogenic [soluble fms-like tyrosine kinase 1 (sFlt-1)] proteins is known to cause the symptoms of preeclampsia (PE), HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) or intrauterine growth restriction (IUGR). An increased sFlt-1/ PlGF ratio ≥ 85 is considered a reliable diagnostic marker. Altered sFlt1 and PlGF concentrations can be detected several weeks prior to the onset of clinical symptoms. In this study we analysed the role of the sFlt1/PlGF ratio as a predictive marker for preeclampsia in a high-risk patient group. Patients and materials: We prospectively included 68 singleton pregnancies with at least one risk factor for PE, HELLP syndrome or IUGR. During the study the patients were divided into one group with symptoms (patient group) and one group without symptoms (control group) for the above-mentioned diseases. The sFlt1/PlGF ratios were measured on admission and during the course of pregnancy. Results: During pregnancy 41 % of patients developed PE, HELLP syndrome or IUGR. An increase of the absolute value of the sFlt1/PlGF ratio ≥ 85 was only observed in the patient group and was found to be a predictive factor for PE, HELLP syndrome or IUGR at 25 + 0 to 31 + 0 weeks of gestation (p = 0.005) and after 35 + 0 weeks of gestation (p = 0.044). Alterations of the sFlt1/PlGF ratio were observed in all patients but were higher in the patient group from 7–10 weeks prior to delivery and with the highest peak 0–2 weeks prior to delivery. Compared to the control group (mean ± SD 66.9 ± 134) absolute values of sFlt1/PlGF ratio were signifi cantly (p = 0.021) increased 0–2 weeks prior to delivery in the patient group (mean ± SD 393.3 ± 147.4). An increase of the sFlt1/PlGF ratio ≥ 85 0–2 weeks before delivery has shown to be predictive for one of the mentioned diseases (p = 0.025).Conclusions: In high-risk patients the sFlt1/PlGF ratio can be used for an individual risk assessment with regard to PE, HELLP syndrome or IUGR. Serial measurements permit a risk-adapted prenatal care of these patients

Einleitung: Die Dysbalance proangiogener (Placental Growth Factor = PlGF) und antiangiogener Faktoren (soluble fms-like tyrosine kinase 1 = sFlt-1) gilt heute als pathophysiologische Grundlage bei der Entstehung einer Präeklampsie (PE), eines HELLP-Syndroms (Haemolysis, Elevated Liver enzymes, Low Platelets) oder einer intrauterinen Wachstumsretardierung (IUGR). Der sFlt1/PlGF-Quotient, ein sensitiver und robuster diagnostischer Marker, ist bereits Wochen vor der Krankheitsmanifestation erhöht. Ziel dieser Studie war es, die Wertigkeit des sFlt1/PlGFQuotienten als prädiktiven Faktor bei Risikopatientinnen zu untersuchen. Patienten und Methode: In diese prospektive Studie wurden 68 Patientinnen mit einer Einlingsschwangerschaft und mindestens einem Risikofaktor für das Auftreten einer PE, eines HELLP-Syndrom oder einer IUGR im Schwangerschaftsverlauf eingeschlossen. Die Patientinnen wurden je nach Verlauf der Schwangerschaft in eine Gruppe mit Symptomen (Fallgruppe) und eine Gruppe ohne Symptome (Kontrollgruppe) für eine der oben genannten Erkrankungen unterteilt. Der sFlt1/PlGF-Quotient wurde bei der Aufnahme in die Studie und im weiteren Schwangerschaftsverlauf bestimmt. Ergebnisse: Eine PE, ein HELLP-Syndrom oder eine IUGR trat bei 41 % der Risikopatientinnen auf… Der absolute Wert des sFlt-1/PlGF-Quotienten war nur bei der Gruppe mit Symptomen auf ≥ 85 erhöht und zeigte sich in der 25 + 0-31 + 0 SSW (p = 0,005) und ab der 35 + 0 SSW (p = 0,044) als prädiktiver Faktor für eine PE, ein HELLP-Syndrom oder eine IUGR. Ab 7–10 Wochen vor der Entbindung war, in der Fallgruppe stärker als in der Kontrollgruppe, ein Anstieg des sFlt1/PlGFQuotienten zu beobachten. Dieser war 0–2 Wochen vor der Entbindung bei beiden Gruppen (Kontrollgruppe (MW ± SA 66,9 ± 134) vs. Fallgruppe (MW ± SA 393,3 ± 147,4, p = 0,021) am ,stärksten und zeigte sich ebenfalls als prädiktiver Faktor für eine der genannten Schwangerschaftserkrankungen (p = 0,025). Schlussfolgerung: Bei Risikoschwangeren kann der sFlt1/ PlGF-Quotient für die Einschätzung des individuellen Risikos für eine PE, ein HELLP-Syndrom oder eine IUGR im Schwangerschaftsverlauf genutzt werden. Wiederholte Messungen des Quotienten versprechen eine risikoangepasste Betreuung dieser Patientinnen.:1. BIBLIOGRAFISCHE BESCHREIBUNG 2 2. EINFÜHRUNG 3 2.1. Allgemeines 3 2.2. Klassifikationen 3 2.3. Risikofaktoren 5 2.4. Neue molekulare Erkenntnisse: angiogene Faktoren 6 2.5. Klinische Studien 7 2.6. Differentialdiagnostik anhand angiogener Faktoren 11 2.7. Die Methode für die automatisierte Messung 12 2.8. Die Bedeutung der Dopplersonografie 12 2.9. Weitere Marker und First-Trimester-Screening 13 2.10. Prävention 14 3. PUBLIKATIONSMANUSKRIPT Die Wertigkeit des sFlt-1/PlGF-Quotienten als Prädiktionsparameter bei Schwangeren mit erhöhtem Präeklamsierisiko......................................................15 4. ZUSAMMENFASSUNG DER ARBEIT 22 5. ANLAGEN 27 5.1. Literaturverzeichnis 27 5.2. Erklärung über die eigenständige Abfassung der Arbeit 332 5.3. Lebenslauf 33 5.4. Danksagung 35
Background: A dysbalance of proangiogenic [placental growth factor (PlGF)] and antiangiogenic [soluble fms-like tyrosine kinase 1 (sFlt-1)] proteins is known to cause the symptoms of preeclampsia (PE), HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) or intrauterine growth restriction (IUGR). An increased sFlt-1/ PlGF ratio ≥ 85 is considered a reliable diagnostic marker. Altered sFlt1 and PlGF concentrations can be detected several weeks prior to the onset of clinical symptoms. In this study we analysed the role of the sFlt1/PlGF ratio as a predictive marker for preeclampsia in a high-risk patient group. Patients and materials: We prospectively included 68 singleton pregnancies with at least one risk factor for PE, HELLP syndrome or IUGR. During the study the patients were divided into one group with symptoms (patient group) and one group without symptoms (control group) for the above-mentioned diseases. The sFlt1/PlGF ratios were measured on admission and during the course of pregnancy. Results: During pregnancy 41 % of patients developed PE, HELLP syndrome or IUGR. An increase of the absolute value of the sFlt1/PlGF ratio ≥ 85 was only observed in the patient group and was found to be a predictive factor for PE, HELLP syndrome or IUGR at 25 + 0 to 31 + 0 weeks of gestation (p = 0.005) and after 35 + 0 weeks of gestation (p = 0.044). Alterations of the sFlt1/PlGF ratio were observed in all patients but were higher in the patient group from 7–10 weeks prior to delivery and with the highest peak 0–2 weeks prior to delivery. Compared to the control group (mean ± SD 66.9 ± 134) absolute values of sFlt1/PlGF ratio were signifi cantly (p = 0.021) increased 0–2 weeks prior to delivery in the patient group (mean ± SD 393.3 ± 147.4). An increase of the sFlt1/PlGF ratio ≥ 85 0–2 weeks before delivery has shown to be predictive for one of the mentioned diseases (p = 0.025).Conclusions: In high-risk patients the sFlt1/PlGF ratio can be used for an individual risk assessment with regard to PE, HELLP syndrome or IUGR. Serial measurements permit a risk-adapted prenatal care of these patients.:1. BIBLIOGRAFISCHE BESCHREIBUNG 2 2. EINFÜHRUNG 3 2.1. Allgemeines 3 2.2. Klassifikationen 3 2.3. Risikofaktoren 5 2.4. Neue molekulare Erkenntnisse: angiogene Faktoren 6 2.5. Klinische Studien 7 2.6. Differentialdiagnostik anhand angiogener Faktoren 11 2.7. Die Methode für die automatisierte Messung 12 2.8. Die Bedeutung der Dopplersonografie 12 2.9. Weitere Marker und First-Trimester-Screening 13 2.10. Prävention 14 3. PUBLIKATIONSMANUSKRIPT Die Wertigkeit des sFlt-1/PlGF-Quotienten als Prädiktionsparameter bei Schwangeren mit erhöhtem Präeklamsierisiko......................................................15 4. ZUSAMMENFASSUNG DER ARBEIT 22 5. ANLAGEN 27 5.1. Literaturverzeichnis 27 5.2. Erklärung über die eigenständige Abfassung der Arbeit 332 5.3. Lebenslauf 33 5.4. Danksagung 35