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3626 Background: CRC still is one of the leading causes of cancer related death though prognosis has improved through guideline based management. The COVID-19 pandemic lead to re-allocation of resources subordinating all sections of care for CRC patients. We present data on changes of CRC care during the pandemic from 22 German AIO CC and our high volume Institute of Pathology (pathology). Methods: Data was collected retrospectively comparing the months (mo) of the first wave (fw) (4-6/2020) and second wave (sw) (11-12/2020) of the pandemic with corresponding periods (cp) in 2019 focusing on the number of precancerous (ICD-O/0+2) and malignant (ICD-O/3+6) colorectal lesions (CRL) diagnosed by our pathology, the number/stage of primary diagnoses (PD) and the number of surgeries (surg) at AIO CC. There, quality criteria of CRC care were also assessed (number of PD discussed within a multidisciplinary tumor board (tb), received social service (soc)/ psychological (psy) counseling or recruited into a clinical trial). Statistical analysis was performed using students t-test for paired data. Results: Numbers of CRL detected upon histology (row 1-3), number of cases, surg and quality criteria from AIO CC (row 4-9) are displayed in the table. We saw a dip in diagnosed CRL and number of surg (p=0.007) only during fw, whereas PD dipped significantly in both waves. A significant reduction in diagnosis of stage III CRC was detected for 2019 vs. 2020 (p=0.001), not for other stages. Quality criteria showed a significant reduction in clinical trial inclusion, a small dip in soc/psy counseling and persistently high tb presentation. Conclusions: We detected a significant decrease of premalignant lesions and primary cancers during the first year of the pandemic which may impact cancer mortality in the future. Certified German CC provided CRC care with significant reduction in clinical trial inclusion only, suggesting high stability of established certified cancer care infrastructure.[Table: see text]

Osteopontin (OPN) is a glycoprotein that is secreted by osteoblasts and hematopoietic cells. OPN suppresses the proliferation of hematopoietic stem cells in vitro and may regulate the hematopoietic stem cell pool. Increased serum OPN concentrations occur in chronic myeloid leukemia, multiple myeloma, and acute myeloid leukemia (AML). In the present study, we analyzed the prognostic impact of OPN in AML by investigating the expression and relevance of OPN in newly diagnosed AML patients from 2 large study groups (the German AML Cooperative Group and the Dutch-Belgian Hematology Oncology Cooperative group). IHC (n = 84), ELISAs of blood/BM sera (n = 41), and microarray data for mRNA levels (n = 261) were performed. Expression of OPN protein was increased in AML patients both in BM blasts (IHC) and in BM serum (ELISA) compared with healthy controls. Patients expressing high levels of OPN within the BM (IHC) experienced shortened overall survival (OS; P = .025). Multivariate analysis identified karyotype, blast clearance (day 16), and the level of OPN expression as independent prognostic factors for OS. This prompted us to analyze microarray data from 261 patients from a third cohort. The analysis confirmed OPN as a prognostic marker. In summary, high OPN mRNA expression indicated decreased event-free survival (P = .0002) and OS (P = .001). The prognostic role of OPN was most prominent in intermediate-risk AML. These data provide evidence that OPN expression is an independent prognostic factor in AML.

Ausschlaggebend fur die individuelle Therapieentscheidung und die Abschatzung der Prognose bei Patienten mit vermutetem Lungenkarzinom ist die korrekte Klassifizierung der Erkrankung. Hierfur liegt die momentan gultige 7. Version der TNM-Klassifikation vor, die auf einer Analyse einer grosen Zahl von Patientendatensatzen beruht und somit eine valide prognostische Gruppierung der Patienten mit Lungenkarzinom erlaubt. Sowohl fur die initiale Diagnostik als auch fur das Staging gibt es eine Vielzahl an invasiven und nicht invasiven Untersuchungsmethoden. Eine evidenzbasierte Grundlage fur das diagnostische Vorgehen und die anschliesende Therapie bietet die aktuell gultige nationale S3-Leitlinie fur die Pravention, Diagnostik, Therapie und Nachsorge des Lungenkarzinoms. Basierend auf dieser Leitlinie sollen in dieser Ubersicht die etablierten diagnostischen Verfahren bewertet werden.

Up to 30% of patients with acute myeloid leukemia (AML) harbor internal tandem duplications (ITD) within the FLT3 gene, encoding a receptor tyrosine kinase. These mutations induce constitutive tyrosine kinase activity in the absence of the natural Flt3 ligand and confer growth factor independence, increased proliferation, and survival to myeloid precursor cells. The signaling pathways and downstream nuclear targets mediating leukemic transformation are only partly identified. Here, we show that the presence of Flt3-ITD constitutively activates Akt (PKB), a key serine-threonine kinase within the phosphatidylinositol 3-kinase pathway. Constitutive activation of Akt phosphorylated and inhibited the transcription factor Foxo3a. Restored Foxo3a activity reversed Flt3-ITD–mediated growth properties and dominant-negative Akt prevented Flt3-ITD–mediated cytokine independence. Conditional Akt activation targeted to the cell membrane induced cytokine-independent survival, cell cycle progression, and proliferation. Importantly, Akt activation was sufficient to cause in vitro transformation of 32D myeloid progenitor cells and in vivo promoted the development of a leukemia-like myeloid disease. Akt phosphorylation was found in myeloid blasts of 86% of AML patients, suggesting an important role in leukemogenesis. In summary, Akt is necessary for increased survival, proliferation, and leukemic transformation by Flt3-ITD, possibly by inactivation of Foxo transcription factors. These findings indicate that Akt and Foxo transcription factors are attractive targets for therapeutic intervention in AML.

Recurrent respiratory papillomatosis (RRP) is a primary benign disease, which is characterized by papillomatous growth in the respiratory tract. Malignant transformation occurs in only 3-5% of cases, however, local growth of the benign papillomas is interpreted as clinically malignant in a markedly higher proportion of patients. Local surgical or endoscopic interventional debulking or excision is currently the commonly selected treatment method and antiviral therapy is a potential adjuvant approach. However, the long-term management of RRP patients, who commonly require multiple procedures over numerous years, is challenging and the overall therapeutic armamentarium remains unsatisfactory. The administration of systemic bevacizumab treatment in a series of five patients with long histories of RRP, who required repeated local interventions to control papilloma growth is evaluated. Treatment with the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab was administered at a dose of 5 mg/kg (n=1), 10 mg/kg (n=3) or 15 mg/kg (n=1) intravenously to the five RRP patients, who were clinically classified as exhibiting progressive disease. Endoscopic evaluations were performed prior to the first infusion of bevacizumab and intermittently at variable time points during the course of therapy. Histopathological analyses were performed using pre- and post-treatment papilloma biopsies, including immunohistochemical analyses of VEGF and phosphorylated VEGF receptor (VEGFR)-2 expression. The patients received between three and 16 courses of bevacizumab (median, six courses). The first course was initiated when progression following the previous intervention was observed. An immediate response to bevacizumab treatment was demonstrated in all five RRP patients. While the cumulative number of interventions in the five patients was 18 throughout the 12 months prior to the initiation of bevacizumab treatment, only one patient required interventional treatment due to a malignant transformation during the 12 months following treatment with bevacizumab (18 vs. 1 interventions, P=0.042). Histopathological analyses revealed regressive perivascular edema and normalization of the vascular structure, however, immunohistochemical analyses of the VEGF and phosphorylated VEGFR-2 expression did not demonstrate any changes following therapy. Due to the limited number of alternative treatments, VEGF-targeted therapies may represent a promising novel strategy in the treatment of RRP, which may have the potential to modify the current treatment standards, particularly in patients with poorly accessible papilloma lesions, however, this requires further investigation in clinical trials.

Although the lymphatic system has been initially described in the sixteenth century, basic research has been limited. Despite its importance for the maintenance of tissue fluid homeostasis and for the afferent immune response, research of the molecular mechanisms of lymphatic vessel formation and function has for a long time been hampered. One reason could be because of the difficulties of visibility due to the lack of lymphatic markers. But since the discovery of several molecules specifically expressed in lymphatic endothelial cells, a rediscovery of the lymphatic vasculature has taken place. New scientific insights has facilitated detailed analysis of the nature and organization of the lymphatic system in physiological and pathophysiological conditions, such as in chronic inflammation and metastatic cancer spread. Knowledge about the molecules that control lymphangiogenesis and tumor-associated lymphangiogenesis is now expanding, allowing better opportunities for the development of drugs interfering with the relevant signaling pathways. Advances in our understanding of the mechanisms have translated into a number of novel therapeutic studies.

Although the lymphatic system has been initially described in the sixteenth century, basic research has been limited. Despite its importance for the maintenance of tissue fluid homeostasis and for the afferent immune response, research of the molecular mechanisms of lymphatic vessel formation and function has for a long time been hampered. One reason could be because of the difficulties of visibility due to the lack of lymphatic markers. But since the discovery of several molecules specifically expressed in lymphatic endothelial cells, a rediscovery of the lymphatic vasculature has taken place. New scientific insights has facilitated detailed analysis of the nature and organization of the lymphatic system in physiological and pathophysiological conditions, such as in chronic inflammation and metastatic cancer spread. Knowledge about the molecules that control lymphangiogenesis and tumor-associated lymphangiogenesis is now expanding, allowing better opportunities for the development of drugs interfering with the relevant signaling pathways. Advances in our understanding of the mechanisms have translated into a number of novel therapeutic studies.

Abstract 4694 BACKGROUND AND OBJECTIVES Osteopontin (OPN) is a secreted glycoprotein that is widely expressed in various kinds of cells and is involved in normal tissue remodelling processes as well as in certain diseases such as tumorigenesis and tumor metastasis. In the bone marrow (BM) OPN is predominantly secreted by osteoblasts and hematopoietic cells, which have been shown recently to express the OPN-binding integrins alpha4beta1 and alpha9beta1. In addition, OPN has been defined as an important factor for hematopoietic stem cells (HSCs). OPN suppressed the proliferation of HSCs in vitro and may regulate the hematopoietic stem cell pool. Increased serum OPN concentrations have been reported in chronic myeloid leukemia (CML), multiple myeloma (MM) and acute myeloid leukemia (AML). DESIGN AND METHODS We investigated the expression of OPN in newly diagnosed AML patients by immunohistochemistry (n=84), enzyme-linked immunoassays (ELISA) of blood /bone marrow sera (n=40) and on the RNA level by analyzing microarray data (n=261). RESULTS Expression of OPN was increased in AML patients bone marrow sera (ELISA) as well as in bone marrow blasts (IHC) Patients expressing high levels of OPN within the bone marrow (IHC: > 10 arbitrary units [AU]; ELISA: > 10 ng/ml) had significantly shorter overall survival (OS) than those with lower OPN levels. In contrast, blood OPN levels showed no predictive value. There was no correlation found between OPN expression and FAB-subtypes M0 to M7 or different karyotypes. Multivariate analysis identified the already known risk factors karyotype, blast clearance (day 16) and the level of OPN expression as independent prognostic factors for OS. Furthermore, analyses of microarray data from 261 patients of a different cohort confirmed OPN as a prognostic marker. In detail, high OPN expression demonstrated a negative predictive value for EFS and OS. Subgroup analysis revealed a significant difference in EFS and OS for OPN levels above the median in FLT3-ITD/TKD mutation negative leukemias, only. No difference was found in FLT3-mutated leukemias or in patients with favorable cytogenetics such as t(8/21) or inv (16). INTERPRETATION AND CONCLUSIONS These data provide evidence for OPN as prognostic marker in AML. OPN might be of pathogenetic relevance in AML. Although the mechanism is not yet understood modulation of the OPN axis might be a promising approach to improve the outcome of AML patients in the future. Disclosures: No relevant conflicts of interest to declare.

Up to 30% of patients with acute myeloid leukemia (AML) harbor internal tandem duplications (ITD) within the FLT3 gene, a tyrosine kinase receptor. The signalling pathways and downstream targets are only partly understood. We demonstrated that the presence of Flt3-ITD constitutively activated Akt (PKB), a key serine-threonine kinase within the PI3-kinase pathway. The constitutive activation of Akt induced phosphorylation and transcriptional inhibition of the transcription factor Foxo3a. Also, forced Foxo3a activity reversed Flt3-ITD-mediated growth properties. Using a novel Akt inhibitor, we showed that Flt3-ITD-mediated Foxo3a phosphorylation was dependent on Akt. Conditional Akt activation targeted to the cell membrane conferred cytokine-independent survival, proliferation and transformation of myeloid progenitor cells. Induction of Akt activity in vivo promoted the development of a myeloproliferative disease in a syngeneic mouse model. Importantly, phosphorylation of Akt was frequently found in primary myeloid blasts, supporting that this signalling pathway may be important in the development of AML. Furthermore, activation of Akt constitutively activated the downstream kinase mammalian target of rapamycin (mTOR). mTOR has several important biological functions, notably in nutrient sensing and protein translation. Treatment with rapamycin, a specific inhibitor of mTOR, inhibited mTOR kinase activity at 1nM in all examined cell systems. Rapamycin caused cell cycle arrest, apoptosis and completely inhibited transformation in FLT3-ITD-positive cells. These effects were most pronounced in the low nanomolar range, which are therapeutic concentrations of rapamycin-treated patients. The biological advantage in Akt-expressing cells was fully reversed by treatment with rapamycin. In all examined primary blasts from AML patients, mTOR was inhibited by rapamycin. In short term proliferation assays, twelve out of 18 (67%) examined showed marked sensitivity with an IC50 below 10nM rapamycin, while one third were found to be more resistant. Taken together, increased survival, proliferation and leukemic transformation by Flt3-ITD is mediated by Akt and mTOR, and can be inhibited by rapamycin. We conclude that rapamycin may be an attractive substance for the treatment of patients with AML.