Salvage lymphadenectomy in recurrent ovarian cancer patients: Analysis of clinical outcome and BRCA1/2 gene mutational status.

OBJECTIVE: This study is aimed to analyze the clinical outcome of recurrent ovarian cancer patients bearing isolated lymph-node recurrence (ILNR) who underwent salvage lymphadenectomy (SL). The prognostic role of clinicopathological variables and the mutational status of BRCA1/2 have also been investigated. METHODS: This retrospective, single-institutional study included women with platinum-sensitive lymph node recurrence underwent to SL between June 2008 and June 2018. Univariate and multivariate analysis was performed to evaluate the impact of clinical parameters, and BRCA1/2 mutational status on post salvage lymphadenectomy progression-free survival (PSL-PFS). RESULTS: As of June 2019, the median follow-up after SL was 30 months, and the relapse has been documented in 48 (56.5%) patients. In the whole series, the median PSL-PFS was 21 months, and the 3-year PSL-PFS was 36.7%. The median PSL-PFS, according to patients with ILNR (N = 71) versus patients with lymph-nodes and other sites of disease (N = 14), was 27 months versus 12 months, respectively. Univariate analysis of variables conditioning PSL-PFS showed that platinum-free interval (PFI) ≥12 months, normal Ca125 serum levels, and number of metastatic lymph-nodes ≤3 played a statistically significant favorable role. In multivariate analysis, PFI duration ≥12 months and the number of metastatic lymph nodes ≤3 were shown to keep their favorable, independent prognostic value on PSL-PFS. CONCLUSIONS: In the context of SL, the patients with long PFI and low metastatic lymph node numbers at ILNR diagnosis have the best outcome. The BRCA mutational status seems not associated with clinical variables and PSL-PFS, differently from other sites of disease in ROC patients.

Infections occurring in adult patients receiving mechanical circulatory support: The two-year experience of an Italian National Referral Tertiary Care Center

Objective Infection during mechanical circulatory support is a frequent adverse complication. We analyzed infections occurring in this population in a national tertiary care center, and assessed the differences existing between the setting of extracorporeal membrane oxygenation (ECMO) and ventricular assist devices (VADs). Design, setting, and participants An observational study was made of patients treated with ECMO or VAD in the San Raffaele Scientific Institute (Italy) between 2009 and 2011. InterventionsNone. ResultsThirty-nine percent of the 46 patients with ECMO and 69% of the 15 patients with VAD developed infection. We observed a mortality rate of 36.1% during mechanical circulatory support and of 55.7% during the global hospitalization period. Although Gram-negative infections were predominant overall, patients with ECMO were more prone to develop Candida infection (29%), and patients with VAD tended to suffer Staphylococcus infection (18%). Patients with infection had longer ECMO support (p=0.03), VAD support (p=0.01), stay in the intensive care unit (p=0.002), and hospital admission (p=0.03) than patients without infection. Infection (regression coefficient=3.99, 95% CI 0.93–7.05, p=0.02), body mass index (regression coefficient=0.46, 95% CI 0.09–0.83, p=0.02), fungal infection (regression coefficient=4.96, 95% CI 1.42–8.44, p=0.009) and obesity (regression coefficient=10.47, 95% CI 1.77–19.17, p=0.02) were predictors of the duration of ECMO support. Stepwise logistic regression analysis showed the SOFA score at the time of implant (OR=12.33, 95% CI 1.15–132.36, p=0.04) and VAD (OR=1.27, 95% CI 1.04–1.56, p=0.02) to be associated with infection. Conclusions Infection is a major challenge during ECMO and VAD support. Each mechanical circulatory support configuration is associated with specific pathogens; fungal infections play a major role (AU)

Objetivos La infección es una complicación asociada habitualmente al soporte circulatorio mecánico. Analizamos las infecciones manifestadas en esta población en un centro de atención terciaria italiano y evaluamos las diferencias existentes entre la oxigenación con membrana extracorpórea (ECMO) y los dispositivos de asistencia ventricular (VAD).Diseño, ámbito y participantes Se llevó a cabo un estudio observacional de pacientes tratados con ECMO o VAD en el Instituto Científico de San Raffaele (Italia) entre 2009 y 2011. Intervenciones: Ninguna. Resultados: El 39 % de los 46 pacientes tratados con ECMO y el 69 % de los 15 pacientes tratados con VAD manifestaron una infección. Observamos una tasa de mortalidad del 36,1 % durante el soporte circulatorio mecánico y del 55,7 % durante el periodo de hospitalización global. Si bien en general las infecciones gramnegativas eran las predominantes, los pacientes con ECMO fueron más propensos a desarrollar infección por Candida (29 %), mientras que los pacientes tratados con VAD tendieron a sufrir infección por Staphylococcus (18 %). Los pacientes con infección recibieron más soporte con ECMO (p=0,03), más soporte con VAD (p=0,01), permanecieron durante más tiempo en la unidad de cuidados intensivos (p=0,002), y presentaron una tasa de ingreso hospitalario más elevada (p=0,03) que los pacientes que no sufrieron una infección. Las infecciones (coeficiente de regresión=3.99, IC del 95 % 0,93-7,05, p=0,02), el índice de masa corporal

Infections occurring in adult patients receiving mechanical circulatory support: the two-year experience of an Italian National Referral Tertiary Care Center.

OBJECTIVE: Infection during mechanical circulatory support is a frequent adverse complication. We analyzed infections occurring in this population in a national tertiary care center, and assessed the differences existing between the setting of extracorporeal membrane oxygenation (ECMO) and ventricular assist devices (VADs). DESIGN, SETTING, AND PARTICIPANTS: An observational study was made of patients treated with ECMO or VAD in the San Raffaele Scientific Institute (Italy) between 2009 and 2011. INTERVENTIONS: None. RESULTS: Thirty-nine percent of the 46 patients with ECMO and 69% of the 15 patients with VAD developed infection. We observed a mortality rate of 36.1% during mechanical circulatory support and of 55.7% during the global hospitalization period. Although Gram-negative infections were predominant overall, patients with ECMO were more prone to develop Candida infection (29%), and patients with VAD tended to suffer Staphylococcus infection (18%). Patients with infection had longer ECMO support (p=0.03), VAD support (p=0.01), stay in the intensive care unit (p=0.002), and hospital admission (p=0.03) than patients without infection. Infection (regression coefficient=3.99, 95% CI 0.93-7.05, p=0.02), body mass index (regression coefficient=0.46, 95% CI 0.09-0.83, p=0.02), fungal infection (regression coefficient=4.96, 95% CI 1.42-8.44, p=0.009) and obesity (regression coefficient=10.47, 95% CI 1.77-19.17, p=0.02) were predictors of the duration of ECMO support. Stepwise logistic regression analysis showed the SOFA score at the time of implant (OR=12.33, 95% CI 1.15-132.36, p=0.04) and VAD (OR=1.27, 95% CI 1.04-1.56, p=0.02) to be associated with infection. CONCLUSIONS: Infection is a major challenge during ECMO and VAD support. Each mechanical circulatory support configuration is associated with specific pathogens; fungal infections play a major role.

Clinical use of placental hormones in pregnancy management.

Across human pregnancy, placenta represents a transit of oxygen and nutrients from the mother to the fetus and actively produces a large number of hormones that serve to regulate and balance maternal and fetal physiology. An abnormal secretion of placental hormones may be part of the pathogenesis of the main obstetric syndrome, from early to late pregnancy, in particular chromosomopathies, miscarriage, gestational trophoblastic diseases, preeclampsia, gestational diabetes, and pre-term delivery. The possibility to measure placental hormones represents an important tool not only for the diagnosis and management of gestational disorders, but it is also fundamental in the early identification of women at risk for these pregnancy complications. In the last decades, the use of ultrasound examination has provided additional biophysical markers, improving the early diagnosis of gestational diseases. In conclusion, while few placental hormones have sufficient sensitivity for clinical application, there are promising new biochemical and biophysical markers that, if used in combination, may provide a valid screening tool.

BDNF Val66Met polymorphism and brain volumes in multiple sclerosis.

Brain derived neurotrophic factor (BDNF) regulates several CNS physiological and pathological processes. To investigate in multiple sclerosis (MS) patients, the relationship between the Val66Met polymorphism of BDNF and clinical markers of disease activity and MRI markers of focal and diffuse brain pathologies. 45 MS patients and 34 healthy controls (HCs) were genotyped and subjected to clinical-MRI examination. Global white matter fraction (gWM-f), gray matter-f (GM-f), cerebrospinal fluid-f (CSF-f), and abnormal WM-f were measured. We studied 26 Val/Val and 19 Val/Met patients and 23 Val/Val and 11 Val/Met HCs. We found that Val/Val patients had lower GM-f and higher CSF-f than Val/Val HCs; such differences were not statistically significant comparing Val/Met patients to HCs. The regression analysis showed that both Val/Met genotype and relapse number were associated with lower CSF-f. Our data suggest that Met allele might be a protective factor against MS as it is associated to a lower brain atrophy.

The edge-to-edge technique for mitral valve repair.

The edge-to-edge technique was introduced in the surgical armamentarium of mitral valve repair in 1991 and has progressively been used to restore mitral competence in the setting of degenerative, post-endocarditis and functional mitral regurgitation. Appropriate indications and awareness of the important technical aspects of the procedure are prerequisites for a good outcome. The free edges of the mitral leaflets have to be approximated in correspondence of the site of the regurgitant jet in such a way that mitral regurgitation is corrected without producing stenosis. A prosthetic ring is usually implanted to stabilize the repair. Middle and long-term results are now available for degenerative mitral regurgitation (bileaflet prolapse, anterior leaflet prolapse and commissural prolapse). Of particular interest is the finding that the edge-to-edge technique for correction of anterior leaflet prolapse is providing a freedom from reoperation similar to that obtained in patients with posterior leaflet prolapse treated with quadrangular resection. Degenerative or post-endocarditis commissural prolapse/flail of the mitral valve can be effectively corrected by this technique. In patients with functional mitral regurgitation, the use of the edge-to-edge repair, added to the undersized annuloplasty, has been associated with a significantly lower recurrence of mitral regurgitation in the follow-up compared to isolated undersized annuloplasty. Almost 20 years after its introduction, the edge-to-edge technique remains an effective and versatile method to treat mitral regurgitation. Its simplicity and reproducibility have led to its clinical application by percutaneous methods opening a new age in the fascinating field of reconstructive mitral valve surgery.

Determinants of the degree of functional aortic regurgitation in patients with anatomically normal aortic valve and ascending thoracic aorta aneurysm. Transoesophageal Doppler echocardiography study.

OBJECTIVES: To identify functional aortic regurgitation (FAR) determinants in patients with ascending thoracic aortic aneurysm (ATAA) and surgically confirmed normal aortic valve anatomy. DESIGN: Case-control study. SETTING: Non-invasive Cardiology and Cardiac Surgery Department. PATIENTS: Eighty-nine patients with ATAA and varying degrees of FAR undergoing surgery, 40 age-matched patients with ATAA without aortic regurgitation and 20 normal control subjects. INTERVENTIONS: Doppler and two-dimensional transoesophageal echocardiography. MAIN OUTCOME MEASURES: Vena contracta (VC) of aortic regurgitant jet, diastolic tented area and coaptation height (CH) of aortic valve leaflets, aortic dimension indexes-Valsalva sinus, sinotubular junction (STJ), tubular tract, annulus (A), STJ/A ratio. RESULTS: When VC was used, a wide range of FAR was seen (mean (SD) 5.59 (2.59) mm, ranging from 2 to 13 mm). Of the variables tested, the most strongly associated with FAR severity in multivariate analysis was diastolic leaflet tenting, measured as CH (R(2) = 0.69) (sensitivity 98%, specificity 95% using a cut-off value of CH > or =1.1 cm). In turn, the diastolic leaflet tenting was strongly identified by the STJ/A ratio (sensitivity 87%, specificity 71% using a cut-off value of STJ/A >1.66). CONCLUSION: The diastolic tenting of aortic leaflets is strongly related to FAR severity in patients with ATAA. The mismatch of STJ/A is significantly associated with diastolic leaflet tenting and its correlated valve regurgitation, independently of the actual ATAA dimension. These findings provide new insight into the mechanism of FAR arising from ATAA.

Lessons from two human chromatin diseases, ICF syndrome and Rett syndrome.

Spatial organisation of DNA into chromatin profoundly affects gene expression and function. The recent association of genes controlling chromatin structure to human pathologies resulted in a better comprehension of the interplay between regulation and function. Among many chromatin disorders we will discuss Rett and immunodeficiency, centromeric instability and facial anomalies (ICF) syndromes. Both diseases are caused by defects related to DNA methylation machinery, with Rett syndrome affecting the transduction of the repressive signal from the methyl CpG binding protein prototype, MeCP2, and ICF syndrome affecting the genetic control of DNA methylation, by the DNA methyltransferase DNMT3B. Rather than listing survey data, our aim is to highlight how a deeper comprehension of gene regulatory web may arise from studies of such pathologies. We also maintain that fundamental studies may offer chances for a therapeutic approach focused on these syndromes, which, in turn, may become paradigmatic for this increasing class of diseases.

Influence of concomitant mitral valve dysfunction on survival after aortic valve replacement.

Aortic valve pathology is the most common acquired valvular heart disease in the adults of western countries, and mitral regurgitation (MR) is often clinically present in patients with degenerative aortic stenosis or insufficiency. Many studies report an incidence of MR between 65-75% in patients evaluated for aortic valve replacement. Severe aortic valve disease may be associated with functional mitral regurgitation (FMR) defined as the failure of mitral valve to prevent systolic backward flow in the absence of any significant structural or intrinsic valvular disease. Increased afterload and left ventricular remodeling have been implicated to explain FMR in patients with aortic valve disease. Moreover, organic mitral valve disease can be associated with aortic stenosis and can be rheumatic or degenerative. We have examined the data of the literature to understand the evolution of MR, the impact of mitral regurgitation on the outcome of patients undergoing aortic valve replacement, and to determine clinical predictors of prognosis in patients with concomitant MR at the time of aortic valve replacement.

Multiple binding of methyl-CpG and polycomb proteins in long-term gene silencing events.

Epigenetic regulation is involved in the maintenance of long-term silencing phenomena, such as X-inactivation and genomic imprinting in mammals. Gene repression is mediated by several mechanisms, such as histone modifications, DNA methylation, and recruitment of Polycomb proteins. To understand the mechanistic relationships between these mechanisms for stable gene silencing, we analyzed the mechanisms of X- and Y-inactivation of the PAR2 gene SYBL1, previously showed to be regulated by concerted epigenetic mechanisms. Maintenance of stable repression occurs via the recruitment of both MBDPs and PRC2 complexes to SYBL1 promoter. Their binding is equally sensitive to defective DNA methylation seen in cells derived from ICF syndrome patients. Multiple occupancy is a feature shared within long-term repressed genes, such as the X-inactivated PGK1 and the imprinted IGF2. MBD2, MBD3, and MeCP2 occupy SYBL1 promoter simultaneously, as revealed by sequential ChIP. We did not find this co-occurring binding when looked for members of PRC2 complex together with any of the methyl-binding proteins. Furthermore, in co-transfection assays, MECP2 can silence methylated SYBL1 promoter, whereas the mutated protein fails. However, RNA interference of endogenous MECP2 does not induce the expression of the inactive SYBL1 alleles, suggesting that its silencing activity can be replaced by the other methyl-binding proteins. Our data suggest that maintenance of long-term silencing involves multiple layers of epigenetic control functionally redundant. PRC2 and MBD proteins could collaborate to different phases of this process, the former possibly recruiting DNMTs to the silenced promoters, the latter dictating the lock of the transcription.

Maintenance of X- and Y-inactivation of the pseudoautosomal (PAR2) gene SPRY3 is independent from DNA methylation and associated to multiple layers of epigenetic modifications.

Maintenance of X-inactivation is achieved through a combination of different repressive mechanisms, thus perpetuating the silencing message through many cell generations. The second human X-Y pseudoautosomal region 2 (PAR2) is a useful model to explore the features and internal relationships of the epigenetic circuits involved in this phenomenon. Recently, we demonstrated that DNA methylation plays an essential role for the maintenance of X- and Y-inactivation of the PAR2 gene SYBL1; here we report that the silencing of the second repressed PAR2 gene, SPRY3, appears to be independent of DNA methylation. In contrast to SYBL1, the inactive X and Y alleles of SPRY3 are not reactivated in cells treated with a DNA methylation inhibitor and in cells from ICF (immunodeficiency, centromeric instability, facial anomalies) syndrome patients, which have mutations in the DNA methyltransferase gene DNMT3B. SPRY3 X- and Y-inactivation is associated with a differential enrichment of repressive histone modifications and the recruitment of Polycomb 2 group proteins compared to the active X allele. Another major factor in SPRY3 repression is late replication; the inactive X and Y alleles of SPRY3 have delayed replication relative to the active X allele, even in ICF syndrome cells where the closely linked SYBL1 gene is reactivated and advanced in replication. The relatively stable maintenance of SPRY3 silencing compared with SYBL1 suggests that genes without CpG islands may be less prone to reactivation than previously thought and that genes with CpG islands require promoter methylation as an additional layer of repression.

Changes in effective connectivity during incidental and intentional perception of fearful faces.

The present fMRI study examined effective connectivity within an emotional network composed of three brain areas: Amygdala (AMY), Anterior Cingulate Cortex (AAC) and Orbito-Frontal (OFC) in processing fearful faces. Two tasks: an incidental perception (gender identification) and an intentional detection (effortful discrimination) task were performed by 14 and 10 young healthy volunteers, respectively. Participants were scanned while viewing fearful, neutral and ambiguous facial expressions. Effective connectivity was assessed using Structural Equation Modeling (SEM). Results show that the hypothetical network fits the experimental data for both tasks and in both hemispheres. The comparison between Tasks 1 and 2 reveals significant differences in strength and direction of the connectivity patterns for the left and to a less stringent threshold for the right hemisphere. The path coefficients analysis suggests that the fearful information generated in AMY, reaches the OFC through the ACC in incidental perception, while in intentional perception, the route followed is in a reverse direction from OFC to ACC. Our findings confirm a differential brain connectivity between incidental and intentional processing of fearful faces.

Pulsed tissue Doppler imaging detects early myocardial dysfunction in asymptomatic patients with severe mitral regurgitation.

OBJECTIVE: To assess whether tissue Doppler myocardial imaging (TDI) indices can predict postoperative left ventricular function in patients with mitral regurgitation (MR) after surgical correction. METHODS: 84 patients (mean (SD) age 54.3 (10.8) years) with asymptomatic severe MR, an end systolic diameter < 45 mm, and an ejection fraction (EF) > 60% were subdivided in two groups: 43 patients with a postoperative EF reduction < 10% (group 1) and 41 patients with a postoperative EF reduction > or = 10% (group 2).TDI systolic indices of the lateral annulus were analysed preoperatively to assess myocardial systolic wave (Sm) velocity, myocardial precontraction time (PCTm), myocardial contraction time (CTm), and the PCTm:CTm ratio. RESULTS: Postoperative EF decreased significantly (from 67 (5)% to 60 (5.5)%, p = 0.0001). Group 2 had a higher PCTm, CTm, and PCTm:CTm ratio and a lower Sm velocity than group 1 (PCTm 100.4 (19) ms v 82 (21.8) ms, p = 0.004; CTm 222 (3.1) ms v 215 (2.3) ms, p = 0.01; PCTm:CTm 0.45 (0.08) v 0.38 (0.09), p = 0.001; Sm velocity 10.4 (1.1) cm/s v 13 (1.3) cm/s, p = 0.0001). Multivariate regression analysis showed that the combination of PCTm:CTm ratio > or = 40 ms and Sm velocity < or = 10.5 cm/s was the main independent predictor of postoperative EF reduction > or = 10% (sensitivity 78%, specificity 95%). CONCLUSIONS: TDI systolic indices can predict postoperative left ventricular function in patients with asymptomatic MR undergoing surgical correction.

The "clover technique" as a novel approach for correction of post-traumatic tricuspid regurgitation.

OBJECTIVE: To describe a novel technique, named "clover," to correct complex post-traumatic tricuspid valve lesions. METHODS: Five patients with severe post-traumatic tricuspid insufficiency underwent valve reconstruction with the clover technique, a new surgical approach that consists of stitching together the middle point of the free edges of the tricuspid leaflets, producing a clover-shaped valve. The mechanism of tricuspid regurgitation was complex in all patients, and right ventricular function was always moderately to severely depressed. An echocardiographic study was performed after cardiopulmonary bypass, at discharge, and at follow-up. RESULTS: Cardiopulmonary bypass time was 32 +/- 6.3 minutes and crossclamp time was 23 +/- 7.4. There was no hospital mortality or morbidity. Intraoperative transesophageal and predischarge transthoracic echocardiography showed perfect results in all patients. No late deaths occurred. At the latest follow-up, extending to 14.2 months (mean 11.3; median 12.4), all patients were asymptomatic (New York Heart Association class I) with trivial (2 patients) or no residual regurgitation (3 patients) on 2-dimensional echocardiogram. No transvalvular gradient was revealed in any patient. A significant reduction of the right ventricular end-diastolic dimensions was noted as well (from 54 +/- 7.1 mm to 40 +/- 7.5 mm, P <.001). CONCLUSIONS: In this preliminary experience, the clover technique increased the feasibility of tricuspid valve repair in case of severe traumatic tricuspid valve insufficiency, leading to very satisfactory mid-term results even in the presence of complex lesions or dilatation and deterioration of the right ventricle.

Simultaneous surgical treatment of chronic post-traumatic aneurysm of the thoracic aorta, diaphragmatic hernia and giant emphysema bulla.

Thoraco-abdominal blunt trauma can lead to multiple injuries of several organs. We report a case of a patient in whom, 10 years after a trauma, a chest X-ray showed visceral herniation into the left thorax. Angio computed tomographic scan (CTS) and magnetic resonance imaging (MRI) confirmed these lesions and also showed a saccular thoracic aortic aneurysm. During the surgical procedure a giant post-traumatic emphysema bulla of the left lower pulmonary lobe was discovered and repaired. In the presence of diaphragmatic injuries, CTS and MRI are mandatory for excluding other organ involvement, and during the surgical procedure, careful inspection of left thorax and abdomen should always be done to repair other possible injuries not seen before.

MECP2 gene mutation analysis in the British and Italian Rett Syndrome patients: hot spot map of the most recurrent mutations and bioinformatic analysis of a new MECP2 conserved region.

Rett syndrome (RTT) is an X-linked dominant neurological disorder, which appears to be the most common genetic cause of profound combined intellectual and physical disability in Caucasian females. This syndrome has been associated with mutations of the MECP2 gene, a transcriptional repressor of unknown target genes. We report a detailed mutational analysis of a large cohort of RTT patients from the UK and Italy. This study has permitted us to produce a hot spot map of the mutations identified. Bioinformatic analysis of the mutations, taking advantage of structural and evolutionary data, leads us to postulate the existence of a new functional domain in the MeCP2 protein, conserved among brain-specific regulatory factors.

The double-orifice technique in mitral valve repair: a simple solution for complex problems.

OBJECTIVE: The aim of this study is to report our results with the central double-orifice technique used for the treatment of complex mitral valve lesions. METHODS: The central double-orifice repair has been used in 260 patients (mean age, 56 +/- 14.3 years) over a period of 7 years. The mechanism responsible for mitral regurgitation was prolapse of both leaflets in 148 patients, prolapse of the anterior leaflet in 68, prolapse of the posterior leaflet with annular calcification or other unfavorable features in 31, and lack of leaflet coaptation for restricted motion or erosion of the free edge in 13. Degenerative disease was the cause of mitral regurgitation in 80.8% of the patients, rheumatic disease was the cause in 9.6%, endocarditis was the cause in 6.1%, and ischemic disease was the cause in 2.3%. RESULTS: Hospital mortality was 0.7%, and the overall survival at 5 years was 94.4% +/- 2.59%. Thirteen patients required a reoperation (2 early postoperatively and 11 late during the follow-up), for an overall freedom from reoperation of 90.0% +/- 3.37% at 5 years. Freedom from reoperation was lower in patients with rheumatic valve disease and in patients who did not undergo an annuloplasty procedure. CONCLUSIONS: The effectiveness and durability of the central double-orifice technique were assessed in this study. This type of repair can be a useful addition to the surgical armamentarium in mitral valve reconstruction.