PubMed · 13536472
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F STARER, D SUTTON. 1958-05-31. Aortic thrombosis.. https://doi.org/10.1136/bmj.1.5082.1255
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PURPOSE: To evaluate the feasibility of dose-escalated para-aortic lymph node (PALN) intensity modulated radiation therapy (IMRT) in reducing the dose to bone marrow, bowel, spinal cord, and kidneys, compared with conventional radiation techniques of PALNs in patients with locally advanced cervical cancer and PALN metastases. METHODS AND MATERIALS: Computed tomography scans and MRI studies of 5 cervical cancer patients with PALN involvement were transferred to an IMRT treatment planning workstation (Eclipse/Helios) for image fusion and definition of target volumes and critical structures. The positive PALNs identified on fused computed tomography-magnetic resonance images were defined as the gross target volume (GTV), and the PALN region was defined as the planning target volume. There were 2 distinct treatment regions: the PALN region superior to the isocenter and the whole-pelvis region inferior to the isocenter. Three treatment planning techniques were compared: AP/PA (both regions), 4-field box (both regions), and PALN-IMRT with 4-field box to the whole-pelvis field. With IMRT, the radiation dose to the GTV was escalated from the conventional 45 Gy to 60 Gy (2.4 Gy/fraction), whereas the planning target volume and whole-pelvis region received 45 Gy. The treatment planning isocenter was placed at the L4-L5 vertebral body interspace, and this allowed the two treatment regions to be abutted using independent jaws. RESULTS: This study has demonstrated the feasibility of escalating the dose delivered to grossly positive PALNs to 60 Gy (2.4 Gy/fraction) with a 95.6% median GTV coverage, concomitantly with conventional treatment of the whole-pelvis region. PALN-IMRT significantly reduced V(40) bone marrow compared to the AP/PA and 4-field box techniques with a median of 21.3%, 98%, and 49.7%, respectively. The PALN-IMRT and 4-field box techniques showed a reduction in V(45) bowel over the AP/PA technique, but a level of statistical significance was not reached. The spinal cord received a significantly higher maximum dose when PALNs were treated with AP/PA fields. Alternatively, the use of the 4-field box technique yielded a significant increase in V(22) kidney on both sides. The placement of the treatment planning isocenter at the L4-L5 interspace allowed the PALN-IMRT and whole-pelvis regions to be treated with a relatively uniform dose at the abutment region. CONCLUSION: In this dosimetric analysis, we demonstrated that dose-escalated PALN-IMRT with conventional whole-pelvis radiotherapy is feasible with significant sparing of critical normal structures compared to PALN conventional radiation techniques.
OBJECTIVE: We tested the hypothesis that carvedilol, a beta-adrenoceptor and alpha-adrenoceptor antagonist with potent antioxidant property, could inhibit tumor necrosis factor-alpha (TNF-alpha)-induced endothelial adhesiveness to human mononuclear cells (MNCs), an early sign of atherogenesis. METHODS AND RESULTS: Circulating MNCs were isolated from the peripheral blood of healthy subjects. Compared with control condition, pretreatment of carvedilol (10 micromol/L for 18 hours) or probucol (5 micromol/L for 18 hours), but not propanolol, prazosin, or both propanolol and prazosin significantly decreased TNF-alpha-stimulated adhesiveness of cultured human aortic endothelial cells (HAECs) to MNCs. Carvedilol inhibited TNF-alpha-stimulated endothelial vascular cell adhesion molecule-1 (VCAM-1) and E-selectin (66.0+/-2.0% and 55.60+/-1.0% of control, P<0.05, respectively) expression, whereas probucol inhibited only VCAM-1 expression (79.0+/-5.0% of control, P<0.05). Propanolol, prazosin, or both did not alter the expression of adhesion molecules. Further, pretreatment with carvedilol significantly inhibited TNF-alpha-stimulated intracellular reactive oxygen species (ROS) production and the activation of redox sensitive nuclear factor kappa B and activator protein-1 transcription pathways. CONCLUSIONS: Carvedilol reduced TNF-alpha-stimulated endothelial adhesiveness to human MNCs by inhibiting intracellular ROS production, transcription factor activation, and VCAM-1 as well as E-selectin expression, suggesting its potential role in clinical atherosclerosis disease.
Endothelial cell-cell junctional proteins and cortical actin are of central importance for regulating vascular permeability. Rap1, a member of the Ras family of GTPases, is enriched at endothelial cell-cell contacts and activated by cyclic AMP (cAMP) through a PKA-independent pathway. Activation of a cAMP-inducible guanine-exchange factor for Rap, Epac, results in markedly enhanced basal endothelial barrier function by increasing cortical actin and subsequent redistribution of adherens and tight junctional molecules to cell-cell contacts. Activation of Epac also counteracts thrombin-induced hyperpermeability through down-regulation of Rho GTPase activation, suggesting cross-talk between Rap and Rho GT-Pases. Thus, Epac/Rap activation represents a new pathway for regulating endothelial cell barrier function.