Citations

Objectives Unbiased information regarding the surgical management of patients with mitral regurgitation (MR) at the nationwide level are scarce and mainly US-based. The Programme de Médicalisation des Systèmes d’Information, a mandatory national database, offers the unique opportunity to assess the presentation and outcomes of all consecutive mitral valve (MV) surgeries performed in France in the contemporary era. Methods We collected all MV surgeries performed for MR in France in 2014–2016. MR aetiology was classified as degenerative (DMR), secondary (SMR) or Other (rheumatic or congenital disease and infective endocarditis). Results During the 3-year period, 18 167 MV surgeries were performed in France (55% repair and 45% replacement; 52% isolated). Age was 66±12 years and 59% were male. Aetiology was DMR in 42%, SMR in 16% and other in 42% including 19% with uncertain aetiologies. Overall, in-hospital mortality was 6.5% and increased with age, female gender, Charlson Comorbidity Index, type of surgery (replacement vs repair), associated surgery (combined vs isolated) and MR aetiology (all p<0.01). In-hospital mortality and rate of death/readmission for heart failure (HF) at 1 year were 3.4% and 13%, respectively for DMR (2.4% and 11% for isolated DMR) and 7.8% and 27%, respectively for SMR (5.5% and 23% for isolated SMR). Repair rate was 55% overall, 68% in DMR and 72% for isolated DMR surgery (70% of all DMR). Repair rates decreased with age, Charlson Comorbidity Index and female sex (all p<0.0001). Conclusion In this cross-sectional contemporary prospective nationwide database, in-hospital mortality and 1 year rate of death and HF readmission were considerable overall and in all subsets. Repair rates were suboptimal overall especially in the elderly and women subsets. These results underline the need to develop strategies to improve management and outcomes of patients with both DMR and SMR.

Background Although US recent data suggest that mitral regurgitation (MR) is severely undertreated and carries a poor outcome, population‐based views on outcome and management are limited. We aimed to define the current treatment standards, clinical outcomes, and costs related to MR at the nationwide level. Methods and Results In total, 107 412 patients with MR were admitted in France in 2014 to 2015. Within 1 year, 8% were operated and 92% were conservatively managed and constituted our study population (68% primary MR and 32% secondary MR). The mean age was 77±15 years; most patients presented with comorbidities. In‐hospital and 1‐year mortality rates were 4.1% and 14.3%, respectively. Readmissions were common (63% at least once and 37% readmitted ≥2 times). Rates of 1‐year mortality or all‐cause readmission and 1‐year mortality or heart failure readmission were 67% and 34%, respectively, and increased with age, Charlson index, heart failure at admission, and secondary MR etiology; however, the event rate remained notably high in the primary MR subset (64% and 28%, respectively). The mean costs of hospital admissions and of readmissions were 5345±6432 and 10 080±10 847 euros, respectively. Conclusions At the nationwide level, MR was a common reason for admission and affected an elderly population with frequent comorbidities. Less than 10% of patients underwent a valve intervention. All subsets of patients who were conservatively managed incurred high mortality and readmissions rates, and MR represented a major societal burden with an extrapolated annual cost of 350 to 550 million euros (390–615 million US dollars). New strategies to improve the management and outcomes of patients with both primary and secondary MR are critical and warranted.

AbstractThe WHO Classification of Tumours provides the international standards for the classification and diagnosis of tumours. It enables direct comparisons to be made between different countries. In the new fifth edition, the series has gone digital with the launch of a website as well as a series of books, known widely as the WHO Blue Books. The first volume to be produced is on the classification of Digestive System tumours, replacing the successful 2010 version. It has been rewritten and updated accordingly. This article summarises the major diagnostic innovations that have occurred over the last decade and that have now been incorporated in the classification. As an example, it incorporates the recently proposed classification of neuroendocrine tumours, based on the recognition that neuroendocrine tumours and carcinomas differ substantially in the genetic abnormalities that drive their growth, findings relevant to treatment selection and outcome prediction. Several themes have emerged during the production process. One is the importance of the progression from hyperplasia to dysplasia to carcinoma in the evolution of the malignant process. Advances in imaging techniques and endoscopy have resulted in enhanced access to precancerous lesions in the gastrointestinal and biliary tract, necessitating both changes in classification schema and clinical practice. Diagnosis of tumours is no longer the sole purview of pathologists, and some patients now receive treatment before tissue is obtained, based on clinical, radiological and liquid biopsy results. This makes the classification relevant to many disciplines involved in the care of patients with tumours of the digestive system.

Abstract Background: A polygenic hazard score (PHS), the weighted sum of 54 SNP genotypes, was previously validated for association with clinically significant prostate cancer and for improved prostate cancer screening accuracy. Here, we assess the potential impact of PHS-informed screening. Methods: United Kingdom population incidence data (Cancer Research United Kingdom) and data from the Cluster Randomized Trial of PSA Testing for Prostate Cancer were combined to estimate age-specific clinically significant prostate cancer incidence (Gleason score ≥7, stage T3–T4, PSA ≥10, or nodal/distant metastases). Using HRs estimated from the ProtecT prostate cancer trial, age-specific incidence rates were calculated for various PHS risk percentiles. Risk-equivalent age, when someone with a given PHS percentile has prostate cancer risk equivalent to an average 50-year-old man (50-year-standard risk), was derived from PHS and incidence data. Positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was calculated using PHS-adjusted age groups. Results: The expected age at diagnosis of clinically significant prostate cancer differs by 19 years between the 1st and 99th PHS percentiles: men with PHS in the 1st and 99th percentiles reach the 50-year-standard risk level at ages 60 and 41, respectively. PPV of PSA was higher for men with higher PHS-adjusted age. Conclusions: PHS provides individualized estimates of risk-equivalent age for clinically significant prostate cancer. Screening initiation could be adjusted by a man's PHS. Impact: Personalized genetic risk assessments could inform prostate cancer screening decisions.

Voltage-gated Ca2+(CaV) channels are expressed in endocrine cells where they contribute to hormone secretion. Diverse chemical messengers, including epidermal growth factor (EGF), are known to affect the expression of CaVchannels. Previous studies have shown that EGF increases Ca2+currents in GH3 pituitary cells by increasing the number of high voltage-activated (HVA) CaVchannels at the cell membrane, which results in enhanced prolactin (PRL) secretion. However, little is known regarding the mechanisms underlying this regulation. Here, we show that EGF actually increases the expression of the CaVα2δ-1 subunit, a key molecular component of HVA channels. The analysis of the gene promoter encoding CaVα2δ-1 ( CACNA2D1) revealed binding sites for transcription factors activated by the Ras/Raf/MEK/ERK signaling cascade. Chromatin immunoprecipitation and site-directed mutagenesis showed that ELK-1 is crucial for the transcriptional regulation of CACNA2D1 in response to EGF. Furthermore, we found that EGF increases the membrane expression of CaVα2δ-1 and that ELK-1 overexpression increases HVA current density, whereas ELK-1 knockdown decreases the functional expression of the channels. Hormone release assays revealed that CaVα2δ-1 overexpression increases PRL secretion. These results suggest a mechanism for how EGF, by activating the Ras/Raf/MEK/ERK/ELK-1 pathway, may influence the expression of HVA channels and the secretory behavior of pituitary cells.

AbstractIn the US, mortality in sickle cell disease (SCD) increases after age 18‐20 years. Biomarkers of mortality risk can identify patients who need intensive follow‐up and early or novel interventions. We prospectively enrolled 510 SCD patients aged 3‐20 years into an observational study in 2006‐2010 and followed 497 patients for a median of 88 months (range 1‐105). We hypothesized that elevated pulmonary artery systolic pressure as reflected in tricuspid regurgitation velocity (TRV) would be associated with mortality. Estimated survival to 18 years was 99% and to 25 years, 94%. Causes of death were known in seven of 10 patients: stroke in four (hemorrhagic two, infarctive one, unspecified one), multiorgan failure one, parvovirus B19 infection one, sudden death one. Baseline TRV ≥2.7 m/second (>2 SD above the mean in age‐matched and gender‐matched non‐SCD controls) was observed in 20.0% of patients who died vs 4.6% of those who survived (P = .012 by the log rank test for equality of survival). The baseline variable most strongly associated with an elevated TRV was a high hemolytic rate. Additional biomarkers associated with mortality were ferritin ≥2000 μg/L (observed in 60% of patients who died vs 7.8% of survivors, P < .001), forced expiratory volume in 1 minute to forced vital capacity ratio (FEV1/FVC) <0.80 (71.4% of patients who died vs 18.8% of survivors, P < .001), and neutrophil count ≥10x109/L (30.0% of patients who died vs 7.9% of survivors, P = .018). In SCD children, adolescents and young adults, steady‐state elevations of TRV, ferritin and neutrophils and a low FEV1/FVC ratio may be biomarkers associated with increased risk of death.