Valoración de los factores pronósticos radiopatológicos del cáncer de mama triple negativo y análisis del carcinoma in situ como factor pronóstico / Imaging and histologic prognostic factors in triple-negative breast cancer and carcinoma in situ as a prognostic factor

Objetivos. Analizar qué factores valorados en resonancia magnética (RM) y anatomopatológicos de los tumores triple negativo (TN) se relacionan con la recidiva tumoral y con una menor supervivencia libre de enfermedad. Valorar la supervivencia y las recidivas en función de la presencia de componente in situ (CIS). Material y métodos. Estudio retrospectivo de las RM realizadas desde 2007 a 2014, con inclusión de 122 mujeres con cáncer de mama TN y RM de estadificación. En RM se valoraron las características morfológicas (tamaño, márgenes, morfología y señal interna en secuencia T2) y dinámicas (perfusión y difusión). Se estudiaron también los factores anatomopatológicos (Ki67, p53, CK5/6, grado nuclear y Scarff-Bloom) y se analizó la presencia de CIS y el grado tumoral (alto o no alto grado). Se compararon las distintas variables con la presencia de recidiva y se realizó estudio de supervivencia. Resultados. El realce no nodular presentó mayor porcentaje en el grupo de recidivas, y la diferencia fue estadísticamente significativa (p=0,038) y se relacionó con una menor supervivencia libre de enfermedad (p=0,023). La restricción a la difusión (p=0,079) y el ki67 (p=0,052) no asociaron un peor pronóstico. Se detectó CIS en el 44% de los TN, con mayor proporción en el grupo de recidiva, sin relación con una menor supervivencia (p = 0,185). Conclusión. El realce no nodular demostró ser un factor de peor pronóstico. La restricción a la difusión, el ki67 y la presencia de CIS no se asociaron a una menor supervivencia libre de enfermedad (AU)

Objectives. To analyze what factors in magnetic resonance imaging (MRI) and histological study of triple-negative breast cancers are related to tumor recurrence and to shorter disease-free survival. To analyze survival and recurrence in function of the presence of an in situ component. Material and methods. This was a retrospective study of MRI staging examinations in 122 women with triple-negative breast cancer done from 2007 through 2014. In the MRI, we evaluated morphological variables (size, margins, morphology, internal signal in T2-weighted sequences) and dynamic variables (perfusion and diffusion). In the histological study, we evaluated Ki67, p53, CK5/6, nuclear grade, and Scarff-Bloom grade, as well as the presence of an in situ component and tumor grade (high grade or not high grade). We compared the variables between patients with tumor recurrence and those without, and we conducted a survival analysis. Results. Non-nodular enhancement was more common in patients with tumor recurrence (p=0.038) and was associated with shorter disease-free survival (p=0.023). Neither diffusion restriction (p=0.079) nor ki67 (p=0.052) was associated with a worse prognosis. An in situ component was detected in 44% of triple-negative tumors, and a greater proportion of patients in the group with tumor recurrence had an in situ component; however, the presence of an in situ component was not associated with shorter survival (p = 0.185). Conclusion. Non-nodular enhancement was associated with a worse prognosis. Diffusion restriction, ki67, and the presence of an in situ component were not associated with shorter disease-free survival (AU)

Light-Controlled Delivery of Monoclonal Antibodies for Targeted Photoinactivation of Ki-67.

The selective inhibition of intracellular and nuclear molecules such as Ki-67 holds great promise for the treatment of cancer and other diseases. However, the choice of the target protein and the intracellular delivery of the functional agent remain crucial challenges. Main hurdles are (a) an effective delivery into cells, (b) endosomal escape of the delivered agents, and (c) an effective, externally triggered destruction of cells. Here we show a light-controlled two-step approach for selective cellular delivery and cell elimination of proliferating cells. Three different cell-penetrating nano constructs, including liposomes, conjugates with the nuclear localization sequence (NLS), and conjugates with the cell penetrating peptide Pep-1, delivered the light activatable antibody conjugate TuBB-9-FITC, which targets the proliferation associated protein Ki-67. HeLa cells were treated with the photosensitizer benzoporphyrin monoacid derivative (BPD) and the antibody constructs. In the first optically controlled step, activation of BPD at 690 nm triggered a controlled endosomal escape of the TuBB-9-FITC constructs. In more than 75% of Ki-67 positive, irradiated cells TuBB-9-FITC antibodies relocated within 24 h from cytoplasmic organelles to the cell nucleus and bound to Ki-67. After a second light irradiation at 490 nm, which activated FITC, cell viability decreased to approximately 13%. Our study shows an effective targeting strategy, which uses light-controlled endosomal escape and the light inactivation of Ki-67 for cell elimination. The fact that liposomal or peptide-assisted delivery give similar results leads to the additional conclusion that an effective mechanism for endosomal escape leaves greater variability for the choice of the delivery agent.

Proliferation and cell death of human glioblastoma cells after carbon-ion beam exposure: morphologic and morphometric analyses.

Histological analyses of glioblastoma cells after carbon-ion exposure are still limited and ultrastructural characteristics have not been investigated in detail. Here we report the results of morphological and morphometric analyses of a human glioblastoma cell line, CGNH-89, after ionizing radiation to characterize the effect of a carbon-beam on glioblastoma cells. Using CGNH-89 cells exposed to 0-10 Gy of X-ray (140 kVp) or carbon-ions (18.3 MeV/nucleon, LET=108 keV/microm), we performed conventional histology and immunocytochemistry with MIB-1 antibody, transmission electron microscopy, and computer-assisted, nuclear size measurements. CGNH-89 cells with a G to A transition in codon 280 in exon 8 of the TP53 gene had nuclei with pleomorphism, marked nuclear atypia and brisk mitotic activity. After carbon-ion and X-ray exposure, living cells showed decreased cell number, nuclear condensation, increased atypical mitotic figures, and a tendency of cytoplasmic enlargement at the level of light microscopy. The deviation of the nuclear area size increased during 48 h after irradiation, while the small cell fraction increased in 336 h. In glioblastoma cells of the control, 5 Gy carbon-beam, and 10 Gy carbon-beam, and MIB-1 labeling index decreased in 24 h (12%, 11%, 7%, respectively) but increased in 48 h (10%, 20%, 21%, respectively). Ultrastructurally, cellular enlargement seemed to depend on vacuolation, swelling of mitochondria, and increase of cellular organelles, such as the cytoskeleton and secondary lysosome. We could not observe apoptotic bodies in the CGNH-89 cells under any conditions. We conclude that carbon-ion irradiation induced cell death and senescence in a glioblastoma cell line with mutant TP53. Our results indicated that the increase of large cells with enlarged and bizarre nuclei, swollen mitochondria, and secondary lysosome occurred in glioblastoma cells after carbon-beam exposure.

The inhibitory effect of UVB irradiation on the expression of p53 and Ki-67 proteins in arsenic-induced Bowen's disease.

The aim of this study is to evaluate the effect of ultraviolet B (UVB) on arsenic-induced Bowen's disease. Four patients were irradiated with 750 mJ/cm2 of UVB and biopsies were performed before treatment and 2 weeks later. Immunohistochemical stains of p53 and Ki-67 were compared by the labelled-streptavidin method before and after the UVB treatment. We found that the number of p53 and Ki-67 positive cells after the UVB treatment were significantly fewer than those of non-UVB-treated specimens. These results suggest that the UVB inhibitory effect in Bowen's disease needs further studies to clarify its value in potentially retarding the progression of the hyperproliferative status in overt skin cancer on a molecular basis.