Early Cancer Detection in Li-Fraumeni Syndrome with Cell-Free DNA.

People with Li-Fraumeni syndrome (LFS) harbor a germline pathogenic variant in the TP53 tumor suppressor gene, face a near 100% lifetime risk of cancer, and routinely undergo intensive surveillance protocols. Liquid biopsy has become an attractive tool for a range of clinical applications, including early cancer detection. Here, we provide a proof-of-principle for a multimodal liquid biopsy assay that integrates a targeted gene panel, shallow whole-genome, and cell-free methylated DNA immunoprecipitation sequencing for the early detection of cancer in a longitudinal cohort of 89 LFS patients. Multimodal analysis increased our detection rate in patients with an active cancer diagnosis over uni-modal analysis and was able to detect cancer-associated signal(s) in carriers prior to diagnosis with conventional screening (positive predictive value = 67.6%, negative predictive value = 96.5%). Although adoption of liquid biopsy into current surveillance will require further clinical validation, this study provides a framework for individuals with LFS. SIGNIFICANCE: By utilizing an integrated cell-free DNA approach, liquid biopsy shows earlier detection of cancer in patients with LFS compared with current clinical surveillance methods such as imaging. Liquid biopsy provides improved accessibility and sensitivity, complementing current clinical surveillance methods to provide better care for these patients. See related commentary by Latham et al., p. 23. This article is featured in Selected Articles from This Issue, p. 5.

Incidental Meckel's Diverticulum With Neuroendocrine Tumor.

Meckel's diverticulum (MD), the most common congenital disease of the small bowel, commonly presents with symptoms of painless rectal bleeding and intestinal obstruction. The treatment of symptomatic MD involves resection of the lesion regardless of patient age; however, the excision of asymptomatic and incidentally identified MDs in adults remain controversial. On one hand, the complications arising from MDs decrease with age, leading to a lower benefit than risk ratio with prophylactic resection. On the other hand, malignancies, such as neuroendocrine tumors, may arise over time from untreated MDs. This can lead to poor prognostic complications, such as liver or lymph node metastases. In this case report, we describe an incidental Meckel's diverticulum discovered during an exploratory laparotomy for acute sigmoid diverticulitis in an adult male. Later biopsy findings discovered the lesion to contain a grade 1 neuroendocrine tumor. Based on our literature review findings, resection of the incidental Meckel's diverticulum was a reasonable approach given the low complication risks of the procedure and the possibility of malignant transformation and progression.

Large scale genotype- and phenotype-driven machine learning in Von Hippel-Lindau disease.

Von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome where individuals are predisposed to tumor development in the brain, adrenal gland, kidney, and other organs. It is caused by pathogenic variants in the VHL tumor suppressor gene. Standardized disease information has been difficult to collect due to the rarity and diversity of VHL patients. Over 4100 unique articles published until October 2019 were screened for germline genotype-phenotype data. Patient data were translated into standardized descriptions using Human Genome Variation Society gene variant nomenclature and Human Phenotype Ontology terms and has been manually curated into an open-access knowledgebase called Clinical Interpretation of Variants in Cancer. In total, 634 unique VHL variants, 2882 patients, and 1991 families from 427 papers were captured. We identified relationship trends between phenotype and genotype data using classic statistical methods and spectral clustering unsupervised learning. Our analyses reveal earlier onset of pheochromocytoma/paraganglioma and retinal angiomas, phenotype co-occurrences and genotype-phenotype correlations including hotspots. It confirms existing VHL associations and can be used to identify new patterns and associations in VHL disease. Our database serves as an aggregate knowledge translation tool to facilitate sharing information about the pathogenicity of VHL variants.

Spectral-Domain Optical Coherence Tomographic Angiography in Children With Amblyopia.

Importance: Amblyopia is the most common cause of visual impairment in childhood, with a prevalence of 1% to 4% in children in the United States. To date, no studies using noninvasive optical coherence tomographic angiography (OCTA) have measured blood flow in the retinal capillary layers in children with amblyopia. Objective: To evaluate the retinal and microvascular features using OCTA in children (<18 years) with amblyopia. Design, Setting, and Participants: This observational case-control study enrolled patients from September 1, 2016, through May 31, 2017, and was conducted from September 1, 2016, through June 30, 2017, at the Stein Eye Institute at UCLA (University of California, Los Angeles). Participants included 59 children (<18 years) with amblyopia and without amblyopia examined at a pediatric ophthalmology clinic or referred to the clinic by coinvestigators. All patients underwent comprehensive ophthalmological examination, including visual acuity, refraction, and ocular motility tests; anterior and posterior segment examination; and OCTA. Main Outcomes and Measures: Reduced superficial and deep retinal capillary vessel density on OCTA. Results: Of the 63 eyes evaluated, 13 (21%) were amblyopic and 50 (79%) were control eyes. Of the 59 patients, the mean (SD) age of patients with amblyopia was 8.0 (4.0) years and 10.3 (3.3) years for the controls; 33 patients (56%) were female; and 5 of 13 (39%) and 27 of 46 (54%) patients in the amblyopic and control groups, respectively, were identified as white. The macular vessel density of the superficial capillary plexus was lower in the amblyopic group than in the control group in both 3 × 3-mm and 6 × 6-mm scans. After adjusting for age and refractive error, the mean (SD) difference in the superficial capillary plexus in the 6 × 6-mm scan was statistically significant (49.3% [4.1] vs 51.2% [2.9]; P = .02). Macular vessel density of the deep capillary plexus in the 6 × 6-mm scans was also considerably different between groups: mean (SD) vessel density of the deep retinal capillary plexus was 54.4% (4.7%) in the amblyopia group and 60.1% (3.3%) in the control group, with a difference of 5.7% (95% CI, 3.4%-8.1%; P = .002). Conclusions and Relevance: The study found that OCTA reveals subnormal superficial and deep retinal capillary density in the macula of patients with amblyopia. Further studies are needed to determine the clinical relevance of this finding.