ABSTRACT
BACKGROUND: Severe pulmonary hypoplasia related to congenital diaphragmatic hernia (CDH) continues to be a potentially fatal condition despite advanced postnatal management strategies. OBJECTIVE: To evaluate the effect of the antenatal sildenafil and 2(S)-amino-6-boronohexanoic acid (ABH-Arginase inhibitor) on lung volume, pulmonary vascular development, and nitric oxide (NO) synthesis in a Nitrofen-induced CDH rat model. METHODS: Nitrofen-induced CDH rat model was used. Nitrofen was administrated on embryonic day(E) 9,5. At E14, five intervention groups were treated separately: Nitrofen, Nitrofen+Sildenafil, Nitrofen+ABH, Nitrofen+Sildenafil+ABH and Control. At term, offspring's lungs were weighed, some paraffin-embedded for histology, others snap-frozen to analyze eNOS, Arginase I-II expression, and activity. RESULTS: In CDH-bearing offsprings, ABH or Sildenafil+ABH preserved the total lung/body-weight index (p < 0.001), preventing pulmonary vascular smooth muscle cell hyperproliferation and improving lung morphometry. Sildenafil+ABH increased 1.7-fold the lung nitrite levels (p < 0.01) without changes in eNOS expression. Sildenafil and ABH improved the number of pulmonary vessels. CONCLUSION: These results suggest that in this CDH rat model, the basal activity of Arginase participates in the lung volume and, together with phosphodiesterase-5, regulates NOS activity in the term fetal lung. The combined treatment (Sildenafil+ABH) could revert some of the pulmonary features in CDH by improving the local NO synthesis and preventing smooth muscle cell hyperproliferation. IMPACT: This study presents Arginase inhibition as a new therapeutic target and the importance of the combined antenatal treatment to improve pulmonary vascular development in a congenital diaphragmatic hernia (CDH) rat model. This study shows that the action of an Arginase inhibitor (ABH) enhances the effects already described for sildenafil in this model. These results reinforce the importance of prenatal treatments' synergy in recovering the hypoplastic lung in the Nitrofen-induced CDH rat model.
ABSTRACT
Introduction: Recently, contrast-enhanced mammography (CEM) has emerged as a reliable alternative to breast magnetic resonance imaging (MRI) for the assessment of pathological response in breast cancer patients. Our study sought to determine the diagnostic accuracy of CEM to predict pathological complete response (pCR) in patients who received neoadjuvant chemotherapy (NACT). Methods: We retrieved the medical records of patients who underwent NACT at our institution. Using post-surgery pCR, morphological evidence and CEM enhancement tumours were classified as follows: 1) radiologic complete response (rCR); 2) functional radiological complete response (frCR); and 3) non-complete response. Initially, we used multivariate analyses adjusted by clinical variables and frCR or rCR to determine which variables affected pathological response. Then, CEM diagnostic accuracy to discriminate pCR was assessed using receiver operating characteristic curves in univariate and multivariate models including either frCR or rCR. Results: A total of 48 patients were included in our study. Most patients (68.7%) were hormone receptor (HR)+ and 41.6% (20) of the patients achieved pCR. Using univariate logistic regression analyses we found that HR status, HER2 status, rCR and frCR had a significant impact on CEM diagnostic accuracy. Exploratory analyses found that CEM sensitivity was higher for HR- tumours. Multivariate logistic regression analyses found 60% sensitivity, 92.9% specificity and 79.2% accuracy in a model that included clinical variables and rCR. Conclusion: CEM is a reliable alternative to high-cost, time-consuming breast MRI that predicts pCR in patients undergoing NACT; CEM diagnostic accuracy was higher among patients who harboured HR- tumours.
ABSTRACT
El Tumor de Wilms (TW) es el tumor renal más frecuente entre los 1 y 5 años de edad. La evidencia existente respecto de aspectos clínicos, terapéuticos y de supervivencia (SV) del TW es escasa. El objetivo de este estudio fue determinar diferencias en la SV actuarial global (SVAG) y SV libre de enfermedad (SVLE) a 5 años en pacientes con TW tratados con quimioterapia neoadyuvante (QTNA) y cirugía inicial (CI). Serie de casos. Se incluyeron pacientes con TW de 11 meses y 13 años de edad, tratados en el Instituto del Cáncer SOLCA, Cuenca (1994-2019). Las variables resultado fueron SVAG y SVLE a 5 años. Otras variables de interés fueron: localización, estadio, histología, seguimiento y remisión completa (RC). Una vez concluidos sus tratamientos, los pacientes fueron sometidos a un seguimiento clínico. Se utilizó estadística descriptiva (medidas de tendencia central y dispersión) y analítica (Chi2, exacto de Fisher y corrección por continuidad). Se realizaron análisis de SV con curvas de Kaplan Meier y log-rank. Se reclutaron 36 pacientes (52,8 % hombres), con una mediana de edad de 44 meses; 55,5 % de ellos tuvieron histología favorable. La localización y estadio más frecuente fue riñón izquierdo (55,5 %) y I (33,3 %) respectivamente. El 58,3 % fueron sometidos a CI y el 41,7 % QTNA. Luego de aplicados los tratamientos 21 pacientes (58,3 %), alcanzaron RC. La SVAG y SVLE general a 5 años fue 72,0 % y 69,0 % respectivamente. Al comparar los subgrupos con QTNA y CI; se verificaron SVAG y SVLE a 5 años de 60,0 % y 81,0 % (p=0,118); y de 66,7 % y 71,4 % (p=0,536) respectivamente. La SVAG y SVLE verificadas son similares a las reportadas en otros estudios. No se evidenciaron diferencias de éstas con los tratamientos QTNA y CI.
Wilms tumor (WT) is the most common pediatric kidney tumor between 1 and 5 years of age. The existing evidence regarding clinical, therapeutic and survival (SV) aspects of TW is scarce. The aim of this study was to determine differences in 5-year overall survival (OS) and 5-year disease-free survival (DFS), in patients treated by WT with neoadjuvant chemotherapy (NACT) and initial surgery (IS). Case series. Patients with TW between 11 months and 13 years of age, treated at SOLCA Cancer Institute, Cuenca, Ecuador (1994-2019) were included. The outcome variables were OS and DFS. Once their treatments were completed, patients were followed clinically. Descriptive (measures of central tendency and dispersion) and analytical (Chi2, Fisher's exact and continuity correction) statistics were applied. SV analysis with Kaplan Meier curves and log-rank were performed. 36 patients (52.8 % men), with a median age of 44 months; 55.5 % of which had favorable histology were recruited. The most frequent location and stage was left kidney (55.5 %) and I (33.3 %) respectively. 58.3 % underwent IC and 41.7 % QTNA. After treatments, 21 patients (58.3 %) achieved complete remission. General OS and DFS were 72.0 % and 69.0 % respectively. When comparing subgroups with QTNA and CI. When comparing the subgroups with QTNA and CI, OS and DFS of 60.0 % and 81.0 % were verified (p=0.118); and of 66.7 % and 71.4 % (p=0.536) respectively. General OS and DFS observed are similar to those reported in other studies. No differences were evidenced with QTNA and CI treatments.
