Impact of Neoadjuvant Versus Adjuvant Chemotherapy on the Extent of Axillary Surgery for Clinically Node-Negative Breast Cancers of Triple-Negative and HER2-Overexpressing Phenotypes

BackgroundBreast cancer patients with triple-negative or human epidermal growth factor receptor 2 (HER2)-overexpressing phenotypes are recommended to receive chemotherapy for primary tumors greater than 1 cm regardless of nodal status. Neoadjuvant chemotherapy may eradicate subclinical nodal metastases and reduce the extent of axillary surgery performed.Patients and MethodsA query of the National Cancer Database Participant User File was performed for new cases of female breast cancer from 2012 to 2015. Inclusion criteria were clinical N0 status, receipt of chemotherapy, and receipt of axillary surgery. Exclusions included hormone-positive/HER2-negative tumors and/or distant metastatic disease. Subjects were divided into groups by receipt of neoadjuvant or adjuvant chemotherapy. The primary end point was the extent of axillary surgery, defined as sentinel lymph node biopsy alone or axillary lymph node dissection (ALND). Subgroup analyses were performed on the basis of tumor phenotype and surgery of the primary site.ResultsA total of 66,771 female patients were included, 15,967 of whom underwent neoadjuvant chemotherapy. ALND rates were higher in patients who received adjuvant chemotherapy (30.6% vs. 28.8%, P < .001). Among tumor phenotypes, the extent of axillary surgery was reduced most significantly for hormone-negative, HER2-positive disease (30.0% vs. 25.8%, P < .001). ALND rates were more substantially reduced for patients who underwent mastectomy (41.3% vs. 36.1%, P < .001) compared to partial mastectomy (21.8% vs. 20.1%, P = .002). Adjuvant chemotherapy was an independent predictor of ALND (odds ratio, 1.26; 95% confidence interval, 1.19-1.33).ConclusionNeoadjuvant chemotherapy reduces the extent of axillary surgery in clinically node-negative, nonluminal breast cancers.     

Phenotypical heterogeneity in RAG-deficient patients from a highly consanguineous population

Mutations affecting recombination activation genes RAG1 and RAG2 are associated with variable phenotypes, depending on the residual recombinase activity. The aim of this study is to describe a variety of clinical phenotypes in RAG-deficient patients from the highly consanguineous Egyptian population. Thirty-one patients with RAG mutations (from 28 families) were included from 2013 to 2017. On the basis of clinical, immunological and genetic data, patients were subdivided into three groups; classical T^–B^– severe combined immunodeficiency (SCID), Omenn syndrome (OS) and atypical SCID. Nineteen patients presented with typical T^–B^–SCID; among these, five patients carried a homozygous RAG2 mutation G35V and five others carried two homozygous RAG2 mutations (T215I and R229Q) that were detected together. Four novel mutations were reported in the T^–B^–SCID group; three in RAG1 (A565P, N591Pfs*14 and K621E) and one in RAG2 (F29S). Seven patients presented with OS and a novel RAG2 mutation (C419W) was documented in one patient. The atypical SCID group comprised five patients. Two had normal B cell counts; one had a previously undescribed RAG2 mutation (V327D). The other three patients presented with autoimmune cytopaenias and features of combined immunodeficiency and were diagnosed at a relatively late age and with a substantial diagnostic delay; one patient had a novel RAG1 mutation (C335R). PID disorders are frequent among Egyptian children because of the high consanguinity. RAG mutations stand behind several variable phenotypes, including classical SCID, OS, atypical SCID with autoimmunity and T^–B⁺ CID.     

Prise en charge pédopsychiatrique des patients présentant un syndrome microdélétionnel 22q11.2 : du soin à la prévention

22q11.2DS is one of the more frequent genetic syndromes associated to psychiatric symptoms. It has been associated to an increased risk to develop schizophrenia in adolescence or early adulthood. However, psychiatric symptoms appear early on, and should be recognized as soon as possible by child psychiatrists in order to improve the present well-being of children and their family, and to prevent further risks of developing severe and chronic psychiatric diseases later on. In this paper, we present a review of the recent literature concerning the 22q11.2DS syndrome focused on the risk factors that may be associated to an increased risk of psychotic transition. We advocate for the development of systematic specialized child psychiatry consultations for these patients, included in networks with geneticists, adult psychiatrists, and family associations, in order to improve their psychiatric prognosis and to support the development of translational research.     

Ethnic differences between Asians and non-Asians in clustering-based phenotype classification of adult-onset diabetes mellitus: A systematic narrative review

Several international studies have stratified people with diabetes into phenotypical clusters. However, there has not been a systematic examination of the variation in these clusters across ethnic groups. For example, some clusters appear more frequent among Asians and may have lower weight, age at diagnosis and poorer beta cell function.     

甘肃地区乳腺癌患者的CYP2D6基因多态性及代谢表型特征分析

目的:分析乳腺癌患者的CYP2D6基因多态性和代谢表型，为乳腺癌患者进行他莫西芬（TAM）个体化临床治疗提供参考依据。方法:选取2018年1月至2019年1月于我院乳腺科确诊的170例乳腺癌患者外周血，通过Sanger测序技术对CYP2D6基因的9个外显子进行全面具体分析。结果:本研究主要发现有5个CYP2D6等位基因变异位点:CYP2D6*10、CYP2D6*4、CYP2D6*7、CYP2D6*41和CYP2D6*5，其对应的发生频率分别为66.5%、5.9%、2.4%、0.6%和0.6%；其中，CYP2D6*10/*10基因型在乳腺癌患者中占据主导地位，发生频率为60.6%。结论:中国甘肃地区乳腺癌患者，多以CYP2D6*10等位基因、CYP2D6*10/*10基因型、TAM中间代谢型为主，这可为乳腺癌患者选择相应的个体化药物治疗方案以及本地区乳腺癌患者今后大规模的药物遗传基因组学研究提供参考数据。     

Powerful rare variant association testing in a copula-based joint analysis of multiple phenotypes

In genetic association studies of rare variants, the low power of association tests is one of the main challenges. In this study, we propose a new single-marker association test called C-JAMP (Copula-based Joint Analysis of Multiple Phenotypes), which is based on a joint model of multiple phenotypes given genetic markers and other covariates. We evaluated its performance and compared its empirical type I error and power with existing univariate and multivariate single-marker and multi-marker rare-variant tests in extensive simulation studies. C-JAMP yielded unbiased genetic effect estimates and valid type I errors with an adjusted test statistic. When strongly dependent traits were jointly analyzed, C-JAMP had the highest power in all scenarios except when a high percentage of variants were causal with moderate/small effect sizes. When traits with weak or moderate dependence were analyzed, whether C-JAMP or competing approaches had higher power depended on the effect size. When C-JAMP was applied with a misspecified copula function, it still achieved high power in some of the scenarios considered. In a real-data application, we analyzed sequencing data using C-JAMP and performed the first genome-wide association studies of high-molecular-weight and medium-molecular-weight adiponectin plasma concentrations. C-JAMP identified 20 rare variants with p-values smaller than 10⁻⁵, while all other tests resulted in the identification of fewer variants with higher p-values. In summary, the results indicate that C-JAMP is a powerful, flexible, and robust method for association studies, and we identified novel candidate markers for adiponectin. C-JAMP is implemented as an R package and freely available from https://cran.r-project.org/package=CJAMP .