RAD51 foci as a functional biomarker of homologous recombination repair and PARP inhibitor resistance in germline BRCA-mutated breast cancer.

Background: BRCA1 and BRCA2 (BRCA1/2)-deficient tumors display impaired homologous recombination repair (HRR) and enhanced sensitivity to DNA damaging agents or to poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi). Their efficacy in germline BRCA1/2 (gBRCA1/2)-mutated metastatic breast cancers has been recently confirmed in clinical trials. Numerous mechanisms of PARPi resistance have been described, whose clinical relevance in gBRCA-mutated breast cancer is unknown. This highlights the need to identify functional biomarkers to better predict PARPi sensitivity. Patients and methods: We investigated the in vivo mechanisms of PARPi resistance in gBRCA1 patient-derived tumor xenografts (PDXs) exhibiting differential response to PARPi. Analysis included exome sequencing and immunostaining of DNA damage response proteins to functionally evaluate HRR. Findings were validated in a retrospective sample set from gBRCA1/2-cancer patients treated with PARPi. Results: RAD51 nuclear foci, a surrogate marker of HRR functionality, were the only common feature in PDX and patient samples with primary or acquired PARPi resistance. Consistently, low RAD51 was associated with objective response to PARPi. Evaluation of the RAD51 biomarker in untreated tumors was feasible due to endogenous DNA damage. In PARPi-resistant gBRCA1 PDXs, genetic analysis found no in-frame secondary mutations, but BRCA1 hypomorphic proteins in 60% of the models, TP53BP1-loss in 20% and RAD51-amplification in one sample, none mutually exclusive. Conversely, one of three PARPi-resistant gBRCA2 tumors displayed BRCA2 restoration by exome sequencing. In PDXs, PARPi resistance could be reverted upon combination of a PARPi with an ataxia-telangiectasia mutated (ATM) inhibitor. Conclusion: Detection of RAD51 foci in gBRCA tumors correlates with PARPi resistance regardless of the underlying mechanism restoring HRR function. This is a promising biomarker to be used in the clinic to better select patients for PARPi therapy. Our study also supports the clinical development of PARPi combinations such as those with ATM inhibitors.

Resolution of hydrops fetalis caused by atrioventricular block: good postnatal evolution with terbutaline treatment.

INTRODUCTION: Complete atrioventricular block (CAVB) is rarely seen, as it occurs in only 1:11 000 to 1:20 000 newborns. There is a serious risk of mortality in CAVB, mainly in those cases associated with hydrops, fetal cardiac frequency ≤ 55 beats/minute, and premature delivery. CASE REPORT: Case of complete atrioventricular block with a poor prognosis (hydrops fetalis and foetal cardiac frequency < 5 beats/minute) caused by anti-La and anti-Ro antibodies. Intrauterine symptoms improved after treatment with terbutaline, permit- ting foetal viability and successful postnatal treatment with a cardiac pacemaker. DISCUSSION: In case of complete atrioventricular block of cause autoimmune with poor prognosis should be treated with positive inotropic drugs, anticholinergics or b-mimetic in the attempt to maintain adequate ventricular frequency, and thus prevent hydrops fetalis from occurring.

[Atrial septostomy with a balloon catheter under echocardiographic control. Our experience]. / Atrioseptostomía con catéter-balón bajo control ecocardiográfico. Nuestra experiencia.

INTRODUCTION: We report our experience in balloon atrial septostomy using two-dimensional echocardiography as control for the catheter placement and performance of the procedure instead of traditional fluoroscopic control. PATIENTS AND METHODS: We carried out atrial septostomy in 12 consecutive neonates with age between 1 and 18 days (mean = 3.6 +/- 5 days) diagnosed as d-transposition of the great arteries (10 cases) and pulmonary atresia with intact ventricular septum (2 cases). The procedures were performed in the catheterization laboratory in 7 cases. In the five remaining cases it was done in the neonatal intensive care unit. We emphasise the good visualization of the full balloon within the left atrium and its relationship with the mitral valve and the pulmonary veins, as well as, the problems found in case number 2 for initial placement of the catheter in the left atrium. RESULTS: An adequate atrial septal defect was achieved in all patients with diameter between 6 and 12 mm (mean = 8.6 +/- 2 mm). There were no complications using this technique, except a supraventricular tachycardia which stopped spontaneously. The evolution of the patients have been satisfactory, and 11 of them underwent surgery. Patient number 2 died suddenly on the third day after atrial septostomy. CONCLUSIONS: We conclude that atrial septostomy with balloon catheter can be carried out safely, under echocardiographic control in the intensive care unit. Above all, critical patients should not be removed from the unit because they are high risk patients.

[Double-outlet right ventricle with mitral atresia. Study of 9 cases]. / Ventrículo derecho de doble salida con atresia mitral. Estudio de 9 casos.

Double-outlet right ventricle with mitral atresia is an uncommon anomaly with a few cases reported in the literature. We present 9 cases of this malformation that have been diagnosed by two-dimensional echocardiography (7 cases), cardiac catheterization (9 cases) and anatomical study (2 cases). We classify them into two groups according to whether or not they have associated pulmonary stenosis. The dominant symptoms were cyanosis and hypoxemia in the first group and cardiac insufficiency signs in the other. The left ventricle was hypoplastic in eight and normal in the one with tricuspid overriding. Six of the cases had ventricular septal defect. The great arteries were in normal relationship in 4 cases, with D-malposition in 3 cases and side-by-side in 2 cases. Rashkind atrial septotomy was performed in 5 patients, but was effective only in two. Palliative surgical treatment was performed on six of them. The actual survival rate is 44%.

Diagnóstico prenatal de estenosis aórtica crítica y fibroelastosis endocárdica / Prenatal diagnosis of critical aortic stenosis and endocardial fibroelastosis

La fibroelastosis endocárdica (FE) se caracteriza por un engrosamiento difuso de la pared ventricular. Su etiología y patogenia no son bien conocidas y presenta un pronóstico variable, en general grave. Los casos de FE descritos prenatalmente suelen diagnosticarse en el segundo y tercer trimestres. A continuación, describimos un caso de diagnóstico prenatal de estenosis aórtica crítica y fibroelastosis endocárdica efectuado a las 26 semanas de gestación

Endocardial fibroelastosis is characterized by a diffuse thickenning of the ventricular endocardium. The cause and natural history of endocardial fibroelastosis is uncertain and controversial. Prognosis of endocardial fibroelastosis is variable and use to be severe. Prenatal diagnosis has been reported in a few cases, predominantley detected in the second and third trimester. Here we report the prenatal diagnosis of critical aortic estenosis and endocardial fibroelastosis at 26th weeks of gestational age

Diagnóstico prenatal de aneurisma subvalvular de ventrículo izquierdo / Prenatal diagnosis of subvalvular left ventricular aneurysm

El aneurisma congénito del ventrículo izquierdo es una malformación cardíaca infrecuente caracterizada por la dilatación de la pared ventricular, cuya historia natural no es bien conocida y, al contrario de lo que ocurre en el divertículo ventricular congénito, no se asocia con otras malformaciones. El pronóstico de esta afección depende de su tamaño y localización, así como de su crecimiento durante el embarazo. En el aneurisma congénito del ventrículo izquierdo subvalvular el pronóstico empeora por la alteración de la función de la válvula mitral. En nuestro caso, así como en el único caso publicado hasta la fecha, se produjo un considerable crecimiento del aneurisma, lo que finalmente condujo a un desenlace perinatal desfavorable. (AU)

Diagnóstico prenatal de estenosis aórtica crítica y fibroelastosis endocárdica / Prenatal diagnosis of critical aortic estenosis and endocardial fibroelastosis

La fibroelastosis endocárdica se caracteriza por un engrosamiento difuso de la pared ventricular. Su etiología y patogenia no es bien conocida y presenta un pronóstico variable, en general grave. Los casos de fibroelastosis endocárdica descritos prenatalmente suelen diagnosticarse en el segundo y tercer trimestre. Describimos a continuación el diagnóstico prenatal de estenosis aórtica crítica y fibroelastosis endocárdica efectuado a las 26 semanas de gestación (AU)