Intensity-Modulated Radiotherapy in Patients with Cervical Cancer. An intra-individual Comparison of Prone and Supine Positioning

<p>Abstract</p> <p>Background</p> <p>Chemoradiation for cervical cancer patients is associated with considerable gastrointestinal toxicity. Intensity-modulated radiotherapy (IMRT) has demonstrated superiority in terms of target coverage and normal tissue sparing in comparison to conventional 3D planning in gynaecological malignancies. Whether IMRT in prone (PP) or supine position (SP) might be beneficial for cervical cancer patients remains partially unanswered.</p> <p>Methods</p> <p>10 patients on FIGO stage IB-III cervical cancer, 6 patients for definitive and 4 patients for adjuvant external beam pelvic RT, were planned in PP and SP using a 7-field IMRT technique. IMRT plans for PP and SP (mean dose, D_mean50.4 Gy) were optimized in terms of PTV coverage (1^stpriority) and small bowel sparing (2^ndpriority). A comparison of DVH parameters for PTV, small bowel, bladder, and rectum was performed.</p> <p>Results</p> <p>The comparison showed a similar PTV coverage of 95% of the prescribed dose and for target conformity in IMRT plans (PP, SP). PTV, rectum and bladder volumes were comparable for PP and SP. Significantly larger volumes of small bowel were found in PP (436 cc, + 35%, p = 0.01). PP decreased the volume of small bowel at 20-50.4 Gy (p < 0.05) and increased the rectum volumes covered by doses from 10-40 Gy (p < 0.01), the V50.4 was < 5% in both treatment positions. Bladder sparing was significant better at 50.4 Gy (p = 0.03) for PP.</p> <p>Conclusion</p> <p>In this dosimetric study, we demonstrated that pelvic IMRT in prone position for patients with cervical cancer seems to be beneficial in reducing small bowel volume at doses ≥20 Gy while providing similar target coverage and target conformity. The use of frequent image guidance with KV (kilovolt) or MV (megavolt) computertomography can reduce set-up deviations, and treatment in prone position can be done with a higher set-up accuracy. Clinical outcome studies are needed to affirm lower toxicity.</p

CD56 is a pathogen recognition receptor on human natural killer cells

Aspergillus (A.) fumigatus is an opportunistic fungal mold inducing invasive aspergillosis (IA) in immunocompromised patients. Although antifungal activity of human natural killer (NK) cells was shown in previous studies, the underlying cellular mechanisms and pathogen recognition receptors (PRRs) are still unknown. Using flow cytometry we were able to show that the fluorescence positivity of the surface receptor CD56 significantly decreased upon fungal contact. To visualize the interaction site of NK cells and A. fumigatus we used SEM, CLSM and dSTORM techniques, which clearly demonstrated that NK cells directly interact with A. fumigatus via CD56 and that CD56 is re-organized and accumulated at this interaction site time-dependently. The inhibition of the cytoskeleton showed that the receptor re-organization was an active process dependent on actin re-arrangements. Furthermore, we could show that CD56 plays a role in the fungus mediated NK cell activation, since blocking of CD56 surface receptor reduced fungal mediated NK cell activation and reduced cytokine secretion. These results confirmed the direct interaction of NK cells and A. fumigatus, leading to the conclusion that CD56 is a pathogen recognition receptor. These findings give new insights into the functional role of CD56 in the pathogen recognition during the innate immune response

Antamanide, a Derivative of Amanita phalloides, Is a Novel Inhibitor of the Mitochondrial Permeability Transition Pore

Antamanide is a cyclic decapeptide derived from the fungus Amanita phalloides. Here we show that antamanide inhibits the mitochondrial permeability transition pore, a central effector of cell death induction, by targeting the pore regulator cyclophilin D. Indeed, (i) permeability transition pore inhibition by antamanide is not additive with the cyclophilin D-binding drug cyclosporin A, (ii) the inhibitory action of antamanide on the pore requires phosphate, as previously shown for cyclosporin A; (iii) antamanide is ineffective in mitochondria or cells derived from cyclophilin D null animals, and (iv) abolishes CyP-D peptidyl-prolyl cis-trans isomerase activity. Permeability transition pore inhibition by antamanide needs two critical residues in the peptide ring, Phe6 and Phe9, and is additive with ubiquinone 0, which acts on the pore in a cyclophilin D-independent fashion. Antamanide also abrogates mitochondrial depolarization and the ensuing cell death caused by two well-characterized pore inducers, clotrimazole and a hexokinase II N-terminal peptide. Our findings have implications for the comprehension of cyclophilin D activity on the permeability transition pore and for the development of novel pore-targeting drugs exploitable as cell death inhibitors