Targeting CD38 with Daratumumab in Refractory Systemic Lupus Erythematosus.

Daratumumab, a human monoclonal antibody that targets CD38, depletes plasma cells and is approved for the treatment of multiple myeloma. Long-lived plasma cells are implicated in the pathogenesis of systemic lupus erythematosus because they secrete autoantibodies, but they are unresponsive to standard immunosuppression. We describe the use of daratumumab that induced substantial clinical responses in two patients with life-threatening lupus, with the clinical responses sustained by maintenance therapy with belimumab, an antibody to B-cell activating factor. Significant depletion of long-lived plasma cells, reduction of interferon type I activity, and down-regulation of T-cell transcripts associated with chronic inflammation were documented. (Supported by the Deutsche Forschungsgemeinschaft and others.).

A Rare Case of Acute Myeloid Leukemia with a t(2;3) Chromosomal Translocation Characterized by Thrombophilia and Chemoresistance.

We hereby report a case of acute myeloid leukemia with translocation t(2;3) and involvement of the ectopic virus integration site-1 (EVI1) gene. Like most other 3q26-related disorders reported thus far, we describe a phenotype with elevated platelet counts and dysmegakaryopoesis. The clinical course of our patient was complicated by symptomatic thrombophilia and chemoresistance. In addition, our case exhibited FLT3 (Fms-related tyrosine kinase 3) internal tandem duplication. Although anagrelide was successful in controlling elevated platelet counts, allogeneic stem cell transplantation failed to overcome chemoresistance due to simultaneous graft-versus-host-disease and relapse of acute myeloid leukemia. Given the dismal outcome of our case and previously reported cases, we propagate the implementation of targeted therapies to newly diagnosed patients with acute myeloid leukemia t(2;3). Preclinical models indicate drugs that plausibly target the EVI1-related molecular vulnerability as candidates for basket trials. Anagrelide exhibited a hopeful signal of activity in 3q26-related thrombocytosis and should be evaluated for implementation as supportive care.

Small-cell lung cancer (SCLC) cell adhesion on E- and P-selectin under physiological flow conditions.

Hematogenous metastasis is still a poorly understood phenomenon. The rate-limiting step within the metastatic cascade is not yet clear although it may be estimated that the extravasation of circulating tumor cells is a step of crucial importance, as most tumor cells that are shed into circulation undergo apoptosis. The process of extravasation includes a cascade of consecutive steps, starting with adhesion of tumor cells circulating in the bloodstream to endothelial cells, mimicking leukocyte adhesion and transmigration. Endothelial cell selectin-leukocyte glycan interaction occurs when leukocytes adhere to endothelial cells under conditions of shear stress. As there are parallels between cancer cell endothelial interactions with leukocyte endothelial cell systems an experimental setup has been developed in which adhesion of small cell lung carcinoma adhesive properties can be analyzed under physiological shear stress conditions during their attachment to E- and P-selection.

The interaction between CD44 on tumour cells and hyaluronan under physiologic flow conditions: implications for metastasis formation.

The adhesion of tumour cells to the endothelial cells of blood vessels of the microcirculation represents a crucial step in haematogenous metastasis formation. Similar to leukocyte extravasation, selectins mediate initial tumour cell rolling on endothelium. An additional mechanism of leukocyte adhesion to endothelial cells is mediated by hyaluronan (HA). However, data on the interaction of tumour cells with hyaluronan under shear stress are lacking. The expression of the hyaluronan binding protein CD44 on tumour cell surfaces was evaluated using flow cytometry. The adhesion of tumour cells to HA with regard to adhesive events and rolling velocity was determined in flow assays in the human small cell lung cancer (SCLC) cell lines SW2, H69, H82, OH1 and OH3, the colon carcinoma cell line HT29 and the melanoma cell line MeWo. Hyaluronan deposition in human and mouse lung blood vessels was histochemically determined. MeWo adhered best to HA followed by HT29. SCLC cell lines showed the lowest CD44 expression on the cell surface and lowest number of adhesive events. While hyaluronan was deposited in patches in the microvasculature of the alveolar septum in the human lung, it was only present in the periarterial space in the mouse lung. Certain tumour entities bind to HA under physiological shear stresses so that HA can be considered a further ligand for cell extravasation in haematogenous metastasis. As hyaluronan is deposited within the pulmonary microvasculature, it may well serve as a ligand for its binding partner CD44, which is expressed by many tumour cells.

Adhesion of small cell lung cancer cells to E- and P-selectin under physiological flow conditions: implications for metastasis formation.

Haematogenous metastasis of small cell lung cancer (SCLC) is still a poorly understood process and represents the life threatening event in this malignancy. In particular, the rate-limiting step within the metastatic cascade is not yet clearly defined although, many findings indicate, that extravasation of circulating tumour cells is crucially important as most tumour cells within the circulation undergo apoptosis. If extravasation of SCLC tumour cells mimics leukocyte-endothelial interactions, SCLC cells should adhere to E- and P-selectins expressed on the luminal surface of activated endothelium. The adhesion to E- and P-selectin under physiological shear stress with regard to adhesive events, rolling behaviour and rolling velocity was determined in the human SCLC cell lines SW2, H69, H82, OH1 and OH3. OH1 SCLC cells adhered best to recombinant human (rh) E-selectin FC-chimeras and human lung endothelial cells (HPMEC), H82 SCLC cells adhered best to activated human umbilical vein endothelial cells (HUVEC) under physiological shear stress. As OH1 cells had also produced by far the highest number of spontaneous lung metastases when xenografted into pfp/rag2 mice in previous experiments our findings implicate that adhesion of SCLC cells to E-selectin is of paramount importance in SCLC metastasis formation.

In vivo imaging of mineral deposition in carotid plaque using 18F-sodium fluoride PET/CT: correlation with atherogenic risk factors.

UNLABELLED: The purpose of this study was to correlate (18)F-sodium fluoride accumulation in the common carotid arteries of neurologically asymptomatic patients with cardiovascular risk factors and carotid calcified plaque burden. METHODS: Two hundred sixty-nine oncologic patients were examined by (18)F-sodium fluoride PET/CT. Tracer accumulation in the common carotid arteries was analyzed both qualitatively and semiquantitatively by measuring the blood-pool-corrected standardized uptake value (target-to-background ratio) and comparing it with cardiovascular risk factors and calcified plaque burden. RESULTS: (18)F-sodium fluoride uptake was observed at 141 sites in 94 (34.9%) patients. Radiotracer accumulation was colocalized with calcification in all atherosclerotic lesions. (18)F-sodium fluoride uptake was significantly associated with age (P < 0.0001), male sex (P < 0.0001), hypertension (P < 0.002), and hypercholesterolemia (P < 0.05). The presence of calcified plaque correlated significantly with these risk factors but also with diabetes (P < 0.0001), history of smoking (P = 0.03), and prior cardiovascular events (P < 0.01). There was a highly significant correlation between the presence of (18)F-sodium fluoride uptake and number of present cardiovascular risk factors (r = 0.30, P < 0.0001). CONCLUSION: Carotid (18)F-sodium fluoride uptake is a surrogate measure of calcifying carotid plaque, correlates with cardiovascular risk factors, and is more frequent in patients with a high-risk profile for atherothrombotic events but demonstrates a weaker correlation with risk factors than does calcified plaque burden. This study provides a rationale to conduct further prospective studies to determine whether (18)F-sodium fluoride uptake can predict vascular events, or if it may be used to monitor pharmacologic therapy.

Switching from a preserved to a preservative-free prostaglandin preparation in topical glaucoma medication.

PURPOSE: The purpose of this study was to investigate the tolerability and intraocular pressure (IOP) reducing effect of the first preservative-free prostaglandin tafluprost (Taflotan) in patients exhibiting ocular surface side-effects during latanoprost (Xalatan) treatment. METHODS: A total of 158 patients were enrolled in this open-label multicentre study. Eligible patients had to have at least two ocular symptoms, or one sign and one symptom, during treatment with latanoprost. At baseline, the patients were directly switched from latanoprost to preservative-free tafluprost for 12 weeks. The patients were queried for ocular symptoms, and ocular signs were assessed by using tear break-up time, Schirmer's test, fluorescein staining and evaluation of conjunctival hyperaemia and blepharitis. In addition, HLA-DR and MUC5AC in conjunctival impression cytology specimens were analyzed, and a drop discomfort/quality of life (QoL) questionnaire was employed. IOP was measured at all visits. RESULTS: Preservative-free tafluprost maintained IOP at the same level after 12- weeks treatment (16.4 +/- 2.7 mmHg) as latanoprost at baseline (16.8 +/- 2.5 mmHg). During treatment with preservative-free tafluprost, the number of patients having irritation/burning/stinging (56.3%), itching (46.8%), foreign body sensation (49.4%), tearing (55.1%) and dry eye sensation (64.6%) decreased to 28.4%, 26.5%, 27.1%, 27.1% and 39.4% correspondingly. The number of the patients with abnormal fluorescein staining of cornea (81.6%) and conjunctiva (84.2%), blepharitis (60.1%), conjunctival hyperaemia (84.2%) and abnormal Schirmer's test (71.5%) was also reduced significantly to 40.6%, 43.2%, 40.6%, 60.0% and 59.4% correspondingly. The tear break-up time improved significantly from 4.5 +/- 2.5 seconds to 7.8 +/- 4.9 seconds. A reduction in the number of patients with abnormal conjunctival cells based on HLA-DR and MUC5AC was also detected. CONCLUSIONS: Preservative-free tafluprost maintained IOP at the same level as latanoprost, but was better tolerated in patients having signs or symptoms while on preserved latanoprost. Preservative-free tafluprost treatment resulted in improved QoL, increased patient satisfaction and drop comfort.

Feasibility of 18F-sodium fluoride PET/CT for imaging of atherosclerotic plaque.

UNLABELLED: The aim of this study was to examine the prevalence, distribution, and topographic relationship of vascular (18)F-sodium fluoride uptake and arterial calcification in major arteries. METHODS: Image data obtained from 75 patients undergoing whole-body (18)F-sodium fluoride PET/CT were evaluated retrospectively. Arterial radiotracer uptake and calcification were analyzed qualitatively and semiquantitatively. RESULTS: (18)F-sodium fluoride uptake was observed at 254 sites in 57 (76%) of the 75 study patients, and calcification was observed at 1,930 sites in 63 (84%) of the patients. Colocalization of radiotracer accumulation and calcification could be observed in 223 areas of uptake (88%). However, only 12% of all arterial calcification sites showed increased radiotracer uptake. CONCLUSION: Our data indicate the feasibility of (18)F-sodium fluoride PET/CT for the imaging of mineral deposition in arterial wall alterations. (18)F-sodium fluoride PET/CT may provide relevant information about the morphologic and functional properties of calcified plaque.

The transcription factor Fra-2 promotes mammary tumour progression by changing the adhesive properties of breast cancer cells.

The transcription factor Fra-2 (Fos-related antigen-2) has been implicated in invasion of breast cancer cells, but there is only sparse information about its role in clinical tumours. In the present study, we analysed Fra-2 mRNA expression in a cohort of 167 patients, and found significant correlations between high Fra-2 expression and nodal involvement or reduced disease-free survival. To get more information about the underlying mechanisms, we generated stably transfected MDA-MB231 breast cancer cells with increased Fra-2 expression. Compared with the controls, these clones did not differ in proliferation and motility, but had higher invasive potential. By global gene expression analysis and subsequent validation of selected genes, we identified a number of proteins involved in cell-cell or cell-matrix interactions that were up- or down-regulated in Fra-2 overexpressing cells, e.g. connexin 43, ICAM-1, L1-CAM, integrin beta 2, integrin beta 4, and integrin alpha 6. The association of Fra-2 overexpression and high ICAM-1 or L1-CAM levels could also be demonstrated in our clinical cohort of mammary tumours. In both MDA-MB231 and MCF7 cells, we found an increased attachment of Fra-2 transfectants to components of the extracellular matrix. In addition, we could show a striking increase in the number of rolling cells in flow-through assays using E-selectin coated capillaries, which might indicate a higher capacity of extravasation. In conclusion, our data obtained on breast cancer cell lines and clinical tissue samples suggest that overexpression of Fra-2 promotes breast cancer progression and metastasis by deregulation of genes involved in cell-cell and cell-ECM contacts.

Efficacy and safety levels of preserved and preservative-free tafluprost are equivalent in patients with glaucoma or ocular hypertension: results from a pharmacodynamics analysis.

PURPOSE: Tafluprost is a new prostaglandin F(2alpha) (PGF(2alpha)) derivative in development for the treatment of glaucoma. Tafluprost is the first PGF(2alpha) analogue with a preservative-free formulation. METHODS: This randomized, investigator-masked, multicentre, crossover phase III study evaluated the pharmacodynamics and safety of preserved and preservative-free tafluprost 0.0015% eyedrops administered for 4 weeks in 43 patients with open-angle glaucoma or ocular hypertension. The primary variable was change from baseline in overall diurnal intraocular pressure (IOP) at 4 weeks. Adverse events and other safety parameters were also analysed. RESULTS: Decreased IOP was clearly observed with both formulations at week 1 and was sustained until week 4. The overall treatment difference (preservative-free versus preserved formulations) at week 4 was 0.01 mmHg (95% confidence interval - 0.46 to 0.49; p = 0.96). There were no unexpected safety-related findings. Both formulations were well tolerated and most adverse events were ocular and mild in severity. CONCLUSIONS: THE reduction in IOP achieved by preservative-free tafluprost is equivalent to that obtained with the preserved formulation. The preservative-free formulation was generally well tolerated.