Practices and ethical concerns regarding preimplantation diagnosis. Who regulates preimplantation genetic diagnosis in Brazil?

Preimplantation genetic diagnosis (PGD) was originally developed to diagnose embryo-related genetic abnormalities for couples who present a high risk of a specific inherited disorder. Because this technology involves embryo selection, the medical, bioethical, and legal implications of the technique have been debated, particularly when it is used to select features that are not related to serious diseases. Although several initiatives have attempted to achieve regulatory harmonization, the diversity of healthcare services available and the presence of cultural differences have hampered attempts to achieve this goal. Thus, in different countries, the provision of PGD and regulatory frameworks reflect the perceptions of scientific groups, legislators, and society regarding this technology. In Brazil, several texts have been analyzed by the National Congress to regulate the use of assisted reproduction technologies. Legislative debates, however, are not conclusive, and limited information has been published on how PGD is specifically regulated. The country requires the development of new regulatory standards to ensure adequate access to this technology and to guarantee its safe practice. This study examined official documents published on PGD regulation in Brazil and demonstrated how little direct oversight of PGD currently exists. It provides relevant information to encourage reflection on a particular regulation model in a Brazilian context, and should serve as part of the basis to enable further reform of the clinical practice of PGD in the country.     

A multi-institutional experience in vascular Ehlers-Danlos syndrome diagnosis

ObjectiveVascular Ehlers-Danlos syndrome (vEDS) is a rare disorder and 1 of 13 types of EDS. The syndrome results in aortic and arterial aneurysms and dissections at a young age. Diagnosis is confirmed with molecular testing via skin biopsy or genetic testing for COL3A1 pathogenic variants. We describe a multi-institutional experience in the diagnosis of vEDS from 2000 to 2015.MethodsThis is a multi-institutional cross-sectional retrospective study of individuals with vEDS. The institutions were recruited through the Vascular Low Frequency Disease Consortium. Individuals were identified using the International Classification of Diseases-9 and 10-CM codes for EDS (756.83 and Q79.6). A review of records was then performed to select individuals with vEDS. Data abstraction included demographics, family history, clinical features, major and minor diagnostic criteria, and molecular testing results. Individuals were classified into two cohorts and then compared: those with pathogenic COL3A1 variants and those diagnosed by clinical criteria alone without molecular confirmation.ResultsEleven institutions identified 173 individuals (35.3% male, 56.6% Caucasian) with vEDS. Of those, 11 (9.8%) had nonpathogenic alterations in COL3A1 and were excluded from the analysis. Among the remaining individuals, 86 (47.7% male, 68% Caucasian, 48.8% positive family history) had pathogenic COL3A1 variants and 76 (19.7% male, 19.7% Caucasian, 43.4% positive family history) were diagnosed by clinical criteria alone without molecular confirmation. Compared with the cohort with pathogenic COL3A1 variants, the clinical diagnosis only cohort had a higher number of females (80.3% vs 52.3%; P < .001), mitral valve prolapse (10.5% vs 1.2%; P = .009), and joint hypermobility (68.4% vs 40.7%; P < .001). Additionally, they had a lower frequency of easy bruising (23.7% vs 64%; P < .001), thin translucent skin (17.1% vs 48.8%; P < .001), intestinal perforation (3.9% vs 16.3%; P = .01), spontaneous pneumothorax/hemothorax (3.9% vs 14%, P.03), and arterial rupture (9.2% vs 17.4%; P = .13). There were no differences in mortality or age of mortality between the two cohorts.ConclusionsThis study highlights the importance of confirming vEDS diagnosis by testing for pathogenic COL3A1 variants rather than relying on clinical diagnostic criteria alone given the high degree of overlap with other forms genetically triggered arteriopathies. Because not all COL3A1 variants are pathogenic, the interpretation of the genetic testing results by an individual trained in variant assessment is essential to confirm the diagnosis. An accurate diagnosis is critical and has serious implications for lifelong screening and treatment strategies for the affected individual and family members.     

Animal Models of Barrett's Esophagus and Esophageal Adenocarcinoma–Past,Present, and Future

Esophageal adenocarcinoma is the fastest rising cancer in the United States. It develops from long‐standing gastroesophageal reflux disease which affects >20% of the general population. It carries a very poor prognosis with 5‐year survival <20%. The disease is known to sequentially progress from reflux esophagitis to a metaplastic precursor, Barrett''s esophagus and then onto dysplasia and esophageal adenocarcinoma. However, only few patients with reflux develop Barrett''s esophagus and only a minority of these turn malignant. The reason for this heterogeneity in clinical progression is unknown. To improve patient management, molecular changes which facilitate disease progression must be identified. Animal models can provide a comprehensive functional and anatomic platform for such a study. Rats and mice have been the most widely studied but disease homology with humans has been questioned. No animal model naturally simulates the inflammation to adenocarcinoma progression as in humans, with all models requiring surgical bypass or destruction of existing antireflux mechanisms. Valuable properties of individual models could be utilized to holistically evaluate disease progression. In this review paper, we critically examined the current animal models of Barrett''s esophagus, their differences and homologies with human disease and how they have shaped our current understanding of Barrett''s carcinogenesis.     

Coats plus syndrome (cerebroretinal microangiopathy with calcifications and cysts‐1): A case report

We present a 6‐year‐old girl with skin hyperpigmentation, leukoplakia, and onychodystrophy, the classic mucocutaneous triad usually associated with dyskeratosis congenita. The patient also had premature graying of the hair, bone marrow failure, hepatitis, exudative retinopathy, osteopenia with multiple long bone fractures, and intracranial calcifications and brain cysts. Coats plus syndrome is a rare disease with a clinical and genetic overlap with dyskeratosis congenita. This disease is reviewed, with a focus on the pathogenesis of the genetic anomalies and its background as a telomere biology disorder.     

可切除肺癌预后预测模型的构建及生存分析

目的 探讨构建的可切除肺癌预后预测模型在患者生存及预后预测中的价值。方法 选择山西省肿瘤医院2007年1月至2018年9月原发性肺癌患者2 267例,患者均行一次肺癌手术治疗,无第二原发肿瘤。选取性别、年龄、职业、肿瘤部位、病理类型、手术路径、手术方式、肿瘤分期、治疗方案为预后影响因素。采用Cox比例风险模型构建预后指数(PI)方程,计算每例患者的PI值。根据PI值的不同范围,划分低、中、高危预后组,对各组生存情况进行评估。结果 性别(RR=0.684,P=0.001)、年龄(RR=0.591,P<0.01)、职业(RR=1.439,P=0.001)、病理类型(RR=3.694,P<0.01)、手术路径(RR=0.734,P=0.001)、肿瘤分期(RR=0.352,P=0.007)为可切除肺癌患者预后独立影响因素。其中,女性、≤65岁、胸腔镜手术、肿瘤分期Ⅰ期为预后保护因素,其预后不良风险分别降低31.6%、40.9%、26.6%、64.8%;农民、腺鳞癌为预后危险因素,其预后不良风险分别增加43.9%、269.4%。PI方程为:∑βixi=-0.380 X1-0.526 X2+0.364 X31+1.307 X55-0.309 X6-1.045 X81(X1代表性别,X2代表年龄,X31代表职业为农民,X55代表病理类型为腺鳞癌,X6代表手术路径,X81代表肿瘤分期Ⅰ期)。PI<-1为低危组,PI≥-1且≤-0.5为中危组,PI>-0.5为高危组。1、3、5年生存率低危组分别为96.8%、87.0%、77.9%,中危组分别为91.8%、82.2%、61.7%,高危组分别为86.5%、61.7%、50.3%,各组间生存率差异具有统计学意义(P<0.05)。结论 可切除肺癌预后预测模型能够预测可切除肺癌患者的预后风险及相应生存率,帮助临床医师评估预后及制订后续治疗方案。     

Racial differences in characteristics and prognoses between Asian and white patients with nonsmall cell lung cancer receiving atezolizumab: An ancillary analysis of the POPLAR and OAK studies

This study aimed to compare the differences in characteristics and prognoses between Asian and white patients receiving immunotherapy for nonsmall cell lung cancer (NSCLC). We studied 390 patients who received atezolizumab as part of the POPLAR or OAK trial, and analyzed the differences in baseline characteristics, outcomes and genetic mutations in blood samples between Asian and white patients. Overall survival (OS) was longer in Asian compared to white patients (median OS: 18.7 vs. 11.1 months; p = 0.005). Race was identified as an independent prognostic factor for OS (Asian vs. white: hazard ratio 0.647, 95% confidence interval 0.447–0.936, p = 0.021), together with performance status, histology, baseline sum of the longest tumor diameters (BLSLD) and number of metastatic sites. The two groups also differed in terms of characteristics including smoking history, BLSLD, epidermal growth factor receptor (EGFR) mutation frequency, programmed death-ligand 1 expression and blood-based tumor-mutation burden. Blood mutations of STK11, EGFR, KEAP1, POLE, GRM3, ATM and STAG2 were associated with treatment response, and TP53, KEAP1, APC, RB1, CREBBP, EPHA5 and STAG2 mutations were associated with OS. The blood-based mutation profiles differentiated between Asian and white patients, especially in relation to EGFR (23.8 vs. 8.5%), TP53 (30.2 vs. 46.9%) and STK11 (1.6 vs. 12.3%) mutations (all p < 0.05). The different clinicopathological features and mutation profiles in Asian and white patients may explain the superior outcome following atezolizumab treatment in Asian patients with NSCLC. The results of this study have important implications for further studies on racial disparities in relation to immunotherapy.     

The influence of environmental and health indicators on premature mortality: An empirical analysis of the City of Toronto's 140 neighborhoods

The objective of this paper was to assess the link between premature mortality and a combination of neighbourhood contextual (environmental and health) and compositional (socioeconomic and demographic) characteristics. We statistically and spatially examined six environmental variables (ultrafine particles, carcinogenic and non-carcinogenic pollutants, pollution released to air, tree cover, and walkability index), six health service indicators (number health providers, breast, colorectal and cervical cancer screening uptake rates, student nutrition program uptake rates, and healthy food index), and eight socioeconomic indicators (total income, Gini coefficient, two age categories – below and above 40 years, proportion of females to males, visible minorities, Indigenous peoples, education, less than grade 9) among 140 neighbourhoods of the City of Toronto in Ontario (Canada). We applied principal component analysis to identify patterns and to reduce the number of explanatory variables into combined component axes that represent unique variation in these confounded and overlapping factors. We then applied regression analysis to model the relationship between the indices of enviro-health and socioeconomics and their potential relationship with premature mortality. Residual spatial analysis was used to investigate any remaining spatial structure (such as neighbourhoods with higher residual premature mortality rates). Neighbourhood Equity Index was correlated with our enviro-health and socioeconomic indices. Premature mortality within neighbourhoods was predicted by poor cancer screenings, pollution, lack of tree canopy, increased uptake of student nutrition programs and high walkability index. A negative association between premature mortality and pollution was associated low walkability index and presence of visible minorities within neighbourhoods. There was some unexplained residual spatial variation in our model of premature mortality - especially along the shores of Lake Ontario and in neighbourhoods with major highways or road corridors: premature mortality in Toronto neighbourhoods was higher than expected along highway-corridor neighbourhoods and shorelines. Our analysis revealed a significant relationship between neighbourhood contextual features – both environmental and health – and premature mortality, suggesting that these contextual components of neighbourhoods can predict rates of urban premature mortality in Toronto.