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BackgroundPrimary analysis of the double-blind, phase III Efficacy of XL184 (Cabozantinib) in Advanced Medullary Thyroid Cancer (EXAM) trial demonstrated significant improvement in progression-free survival with cabozantinib versus placebo in patients with progressive medullary thyroid cancer (MTC). Final analysis of overall survival (OS), a key secondary endpoint, was carried out after long-term follow-up.Patients and methodsEXAM compared cabozantinib with placebo in 330 patients with documented radiographic progression of metastatic MTC. Patients were randomized (2:1) to cabozantinib (140 mg/day) or placebo. Final OS and updated safety data are reported.ResultsMinimum follow-up was 42 months. Kaplan-Meier analysis showed a 5.5-month increase in median OS with cabozantinib versus placebo (26.6 versus 21.1 months) although the difference did not reach statistical significance [stratified hazard ratio (HR), 0.85; 95% confidence interval (CI), 0.64-1.12; P = 0.24]. In an exploratory assessment of OS, progression-free survival, and objective response rate, cabozantinib appeared to have a larger treatment effect in patients with RET M918T mutation-positive tumors compared with patients not harboring this mutation. For patients with RET M918T-positive disease, median OS was 44.3 months for cabozantinib versus 18.9 months for placebo [HR, 0.60; 95% CI, 0.38-0.94; P = 0.03 (not adjusted for multiple subgroup analyses)], with corresponding values of 20.2 versus 21.5 months (HR, 1.12; 95% CI, 0.70-1.82; P = 0.63) in the RET M918T-negative subgroup. Median treatment duration was 10.8 months with cabozantinib and 3.4 months with placebo. The safety profile for cabozantinib remained consistent with that of the primary analysis.ConclusionThe secondary end point was not met in this final OS analysis from the trial of cabozantinib in patients with metastatic, radiographically progressive MTC. A statistically nonsignificant increase in OS was observed for cabozantinib compared with placebo. Exploratory analyses suggest that patients with RET M918T-positive tumors may experience a greater treatment benefit with cabozantinib.Trial registration numberNCT00704730.

Objective: Mitochondrial complex‐I deficiency, nuclear type 16, is a rare autosomal recessive disorder caused by biallelic pathogenic variants in NDUFAF5 (C20orf7) (OMIM 618238). The aim of this study was to describe a severe early prenatal manifestation of this disorder, which was previously considered to occur only postnatally. Methods: This was a multicenter retrospective case series including five fetuses from three non‐related families, which shared common sonographic abnormalities, including brain cysts, corpus callosal malformations, non‐immune hydrops fetalis and growth restriction. Genetic evaluation included chromosomal microarray analysis and exome sequencing. Two fetuses from the same family were also available for pathology examination, including electron microscopy. Results: Chromosomal microarray analysis revealed no chromosomal abnormality in any of the tested cases. Trio exome sequencing demonstrated that three affected fetuses from three unrelated families were compound heterozygous or homozygous for likely pathogenic variants in NDUFAF5. No other causative variants were detected. The association between NDUFAF5 variants and fetal malformations was further confirmed by segregation analysis. Histological evaluation of fetal tissues and electron microscopy of the skeletal muscle, liver, proximal tubules and heart demonstrated changes that resembled postmortem findings in patients with mitochondrial depletion disorders as well as previously undescribed findings. Conclusions: Mitochondrial complex‐I deficiency and specifically biallelic mutations in NDUFAF5 have a role in abnormal fetal development, presenting with severe congenital malformations. Mitochondrial complex‐I disorders should be considered in the differential diagnosis of corpus callosal malformations and brain cysts, especially when associated with extracranial abnormalities, such as fetal growth restriction and non‐immune hydrops fetalis. © 2023 International Society of Ultrasound in Obstetrics and Gynecology. Linked article: There is a comment on this article by Finsterer. Click here to view the Correspondence. [ABSTRACT FROM AUTHOR]

Objectives: To determine the incremental diagnostic yield of exome sequencing (ES) after negative chromosomal microarray analysis (CMA) in cases of prenatally diagnosed agenesis of the corpus callosum (ACC) and to identify the associated genes and variants. Methods: A systematic search was performed to identify relevant studies published up until June 2022 using four databases: PubMed, SCOPUS, Web of Science and The Cochrane Library. Studies in English reporting on the diagnostic yield of ES following negative CMA in prenatally diagnosed partial or complete ACC were included. Authors of cohort studies were contacted for individual participant data and extended cohorts were provided for two of them. The increase in diagnostic yield with ES for pathogenic/likely pathogenic (P/LP) variants was assessed in all cases of ACC, isolated ACC, ACC with other cranial anomalies and ACC with extracranial anomalies. To identify all reported genetic variants, the systematic review included all ACC cases; however, for the meta‐analysis, only studies with ≥ three ACC cases were included. Meta‐analysis of proportions was employed using a random‐effects model. Quality assessment of the included studies was performed using modified Standards for Reporting of Diagnostic Accuracy criteria. Results: A total of 28 studies, encompassing 288 prenatally diagnosed ACC cases that underwent ES following negative CMA, met the inclusion criteria of the systematic review. We classified 116 genetic variants in 83 genes associated with prenatal ACC with a full phenotypic description. There were 15 studies, encompassing 268 cases, that reported on ≥ three ACC cases and were included in the meta‐analysis. Of all the included cases, 43% had a P/LP variant on ES. The highest yield was for ACC with extracranial anomalies (55% (95% CI, 35–73%)), followed by ACC with other cranial anomalies (43% (95% CI, 30–57%)) and isolated ACC (32% (95% CI, 18–51%)). Conclusions: ES demonstrated an incremental diagnostic yield in cases of prenatally diagnosed ACC following negative CMA. While the greatest diagnostic yield was observed in ACC with extracranial anomalies and ACC with other central nervous system anomalies, ES should also be considered in cases of isolated ACC. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

This paper provides a detailed description of the general design space for metadata storage capabilities. The design space considers issues of metadata identification, typing and representation, dynamic behavior, predefined and user-defined metadata, schema discovery/update, operations, API packaging/marshalling, searching, and versioning. The design space is used to structure a retrospective analysis of the three major alternative metadata designs considered during the design of the WebDAV distributed authoring protocol. Deployment experience with WebDAV properties is also discussed, with the most successful use occurring in custom client/server pairs and in protocol extensions.

Research has been conducted on the flowering acceleration caused by a long period of low temperature, vernalization. The study of the VERNALIZATION 2 gene which mediates vernalization and encodes a nuclear-localized zinc finger protein has been carried out and the results are discussed.

In addition to ventriculomegaly, abnormal corpus callosum and adducted thumbs, fetal MRI has also detected diencephalic and midbrain-hindbrain malformations in most fetuses affected by the L1 syndrome. L1 syndrome includes a spectrum of X-linked disorders caused by pathogenic variants of L1CAM gene, which encodes a cell adhesion molecule involved in the central nervous system (CNS) development. In addition to the evaluation of lateral ventricles, corpus callosum and cortical development, thalami and midbrain-hindbrain were investigated. [Extracted from the article]

OC12.05: Early second trimester diagnosis of fetal midbrain-hindbrain malformations: a transvaginal neurosonographic study To describe the clinical and neurosonographic features of fetal midbrain-hindbrain (MBHB malformation diagnosed at 14-18 weeks. The MBHB abnormalities include; kinking of the brainstem (KBS) (n = 3), Joubert syndrome (JS) (n = 2), aqueductal stenosis (AS) (n = 11), rhombencephalosynapsis (RES) (n = 3), "open" fourth ventricle (OFV) (n = 6), and Mobius syndrome (MS) (n = 1). [Extracted from the article]