ABSTRACT
Multiple myeloma is the second most frequent hematological cancer after lymphoma and remains an incurable disease. The pervasive support provided by the bone marrow microenvironment to myeloma cells is crucial for their survival. Here, an unbiased assessment of receptor tyrosine kinases overexpressed in myeloma identified ROR2, a receptor for the WNT noncanonical pathway, as highly expressed in myeloma cells. Its ligand, WNT5A is the most abundant growth factor in the bone marrow of myeloma patients. ROR2 mediates myeloma cells interactions with the surrounding bone marrow and its depletion resulted in detachment of myeloma cells from their niche in an in vivo model, triggering apoptosis and thus markedly delaying disease progression. Using in vitro and ex vivo 3D-culture systems, ROR2 was shown to exert a pivotal role in the adhesion of cancer cells to the microenvironment. Genomic studies revealed that the pathways mostly deregulated by ROR2 overexpression were PI3K/AKT and mTOR. Treatment of cells with specific PI3K inhibitors already used in the clinic reduced myeloma cell adhesion to the bone marrow. Together, our findings support the view that ROR2 and its downstream targets represent a novel therapeutic strategy for the large subgroup of MM patients whose cancer cells show ROR2 overexpression.
Subject(s)
Bone Marrow/metabolism , Multiple Myeloma/pathology , Receptor Tyrosine Kinase-like Orphan Receptors/metabolism , Tumor Microenvironment/physiology , Animals , Bone Marrow/pathology , Cell Adhesion/physiology , Heterografts , Humans , Mice , Multiple Myeloma/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction/physiologyABSTRACT
Highly aggressive cancer types such as pancreatic cancer possess a mortality rate of up to 80% within the first 6months after diagnosis. To reduce this high mortality rate, more sensitive diagnostic tools allowing an early stage medical imaging of even very small tumours are needed. For this purpose, magnetic, biodegradable nanoparticles prepared using recombinant human serum albumin (rHSA) and incorporated iron oxide (maghemite, γ-Fe2O3) nanoparticles were developed. Galectin-1 has been chosen as target receptor as this protein is upregulated in pancreatic cancer and its precursor lesions but not in healthy pancreatic tissue nor in pancreatitis. Tissue plasminogen activator derived peptides (t-PA-ligands), that have a high affinity to galectin-1 have been chosen as target moieties and were covalently attached onto the nanoparticle surface. Improved targeting and imaging properties were shown in mice using single photon emission computed tomography-computer tomography (SPECT-CT), a handheld gamma camera, and magnetic resonance imaging (MRI).
Subject(s)
Magnetics , Magnetite Nanoparticles , Pancreatic Neoplasms/diagnosis , Animals , Cell Line, Tumor , Ferric Compounds/chemistry , Galectin 1/chemistry , Galectin 1/metabolism , Humans , Magnetic Resonance Imaging , Mice , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Radionuclide Imaging , Radiopharmaceuticals , Recombinant Proteins/chemistry , Serum Albumin/chemistry , Tissue Plasminogen Activator/metabolism , Tomography, Emission-Computed, Single-Photon , Xenograft Model Antitumor AssaysABSTRACT
AIMS: Women undergoing breast-conserving surgery for cancer can present residual disease. We have developed a technique called Radioguided Intraoperative Margins Evaluation (RIME) that uses a radiopharmaceutical to distinguish normal and cancer tissues. The aim of this study was to assess whether RIME is a feasible technique, and if it could help in breast cancer resection with free margins, minimizing residual disease. METHODS: Twenty-three breast cancer patients programmed for mastectomy were selected. Before surgery, the patients were submitted to scintimammography with 99mTc-sestamibi to estimate the optimal time to begin radioguided surgery. Twenty patients were submitted to magnetic resonance imaging (MRI), to evaluate skin, deep fascia and to detect other tumor foci. At the beginning of the surgery, the same dose of 99mTc-sestamibi was intravenously injected into patients. Tumor resection was performed under guidance of a gamma-probe, characterizing the RIME technique. Finally, modified radical mastectomy was performed. Tumor and residual breast were histopathologically examined. RESULTS: The RIME technique was successfully performed in all patients. The principal tumor was removed by this technique and provided 82.6% of histologically free margins (mean margins, 4.8 mm). Additionally, 47.8% of patients were without residual disease. The mean size of residual carcinoma was 3.67 mm and generally located near the tumor bed (<1.5 cm). There was no significant association between presence of residual disease and tumor size or margin status. CONCLUSION: RIME is a feasible technique that could help tumor resection with free margins; however, it seems to be limited for small carcinoma foci.
Subject(s)
Breast Neoplasms/diagnostic imaging , Carcinoma, Ductal, Breast/diagnostic imaging , Neoplasm, Residual/diagnostic imaging , Radiopharmaceuticals , Technetium Tc 99m Sestamibi , Adult , Aged , Breast Neoplasms/diagnosis , Breast Neoplasms/surgery , Carcinoma, Ductal, Breast/diagnosis , Carcinoma, Ductal, Breast/surgery , Feasibility Studies , Female , Humans , Magnetic Resonance Imaging , Mammography , Mastectomy, Modified Radical , Middle Aged , Radionuclide ImagingABSTRACT
Recently, we have shown that the non-psychoactive cannabinoid compound cannabidiol (CBD) induces apoptosis of glioma cells in vitro and tumor regression in vivo. The present study investigated a possible involvement of caspase activation and reactive oxygen species (ROS) induction in the apoptotic effect of CBD. CBD produced a gradual, time-dependent activation of caspase-3, which preceded the appearance of apoptotic death. In addiction, release of cytochrome c and caspase-9 and caspase-8 activation were detected. The exposure to CBD caused in glioma cells an early production of ROS, depletion of intracellular glutathione and increase activity of glutathione reductase and glutathione peroxidase enzymes. Under the same experimental condition, CBD did not impair primary glia. Thus, we found a different sensitivity to the anti-proliferative effect of CBD in human glioma cells and non-transformed cells that appears closely related to a selective ability of CBD in inducing ROS production and caspase activation in tumor cells.
Subject(s)
Cannabidiol/pharmacology , Caspases/metabolism , Glioma/metabolism , Oxidative Stress , Reactive Oxygen Species/metabolism , Cell Line, Tumor , Cells, Cultured , Enzyme Activation , Glutathione/metabolism , HumansABSTRACT
Continuous Ambulatory Peritoneal Dialysis (CAPD) patients may have non infectious abdominal complications that affect the survival of their dialysis treatment. It is important to document the origin of leakages and hernias, causes of catheter malfunction or haemoperitoneum. Therapeutic options will depend on investigations and include catheter removal or replacement, surgical intervention or eventual transfer to automated peritoneal dialysis (APD). In this paper we report our experience of the technical implementation of Peritoneography and Peritoneum Computed Tomography.
Subject(s)
Hemoperitoneum/diagnostic imaging , Hemoperitoneum/etiology , Hernia, Ventral/diagnostic imaging , Hernia, Ventral/etiology , Kidney Failure, Chronic/therapy , Peritoneal Dialysis, Continuous Ambulatory/adverse effects , Drainage , Equipment Failure , Female , Hemoperitoneum/therapy , Hernia, Ventral/therapy , Humans , Male , Risk Factors , Tomography, X-Ray ComputedABSTRACT
This paper shows the most important germs that are responsible for exit-site and tunnel infections in CAPD patients, and the possible action to care for them. Prevention of PD catheter infection begins with good surgical practice in catheter implantation and includes appropriate preoperative patient preparation. Some of the operative protocols for dialytic methods used in our unit are shown.
