Accuracy and reproducibility of fetal-fraction measurement using relative quantitation at polymorphic loci with microarray.

OBJECTIVES: Various methods of fetal-fraction measurement have been employed in conjunction with different approaches to cell-free DNA testing for fetal aneuploidy. In this study, we determined the accuracy and reproducibility of fetal-fraction measurement using polymorphic assays that are incorporated into the test design as part of the Harmony® prenatal test and evaluated whether the single nucleotide polymorphisms selected for and used in these assays can be applied broadly to all patient populations. METHODS: Clinical maternal plasma samples were assayed using a custom microarray with Digital ANalysis of Selected Regions (DANSR) assays designed to cover non-polymorphic targets on chromosomes of interest for aneuploidy assessment (13, 18, 21, X and Y) and polymorphic targets for fetal-fraction assessment. In a consecutive series of 47 512 maternal plasma samples, fetal-fraction measurements based on polymorphic assays were compared with those from Y-sequence quantitation. Reproducibility was examined between first- and second-tube measurements for the same patient sample in 734 cases. The fraction of informative loci was calculated for 13 988 samples. RESULTS: There was a strong correlation between fetal fractions determined using the polymorphic assays and using Y-chromosome sequence quantitation (r = 0.97). Fetal-fraction measurement between the first and second tubes was highly reproducible (r = 0.98). The fraction of informative loci observed in a clinical series was consistent with predictions based on assay design. CONCLUSIONS: The method based on relative quantitation at polymorphic loci on a microarray is accurate and reproducible for fetal-fraction estimation and is equally informative across global populations. This study provides a useful benchmark for ensuring the reliability and accuracy of fetal-fraction measurement. © 2018 Roche Sequencing Solutions. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Non-invasive risk assessment of fetal sex chromosome aneuploidy through directed analysis and incorporation of fetal fraction.

OBJECTIVE: To assess the performance of a directed chromosomal analysis approach in the prenatal evaluation of fetal sex chromosome aneuploidy. METHODS: We analyzed 432 frozen maternal plasma samples obtained from patients prior to undergoing fetal diagnostic testing. The cohort included women greater than 18 years of age with a singleton pregnancy of greater than 10 weeks gestation. Samples were analyzed using a chromosome-selective approach (DANSR(TM) ) and a risk algorithm that incorporates fetal fraction (FORTE(TM) ). RESULTS: The cohort included 34 cases of sex chromosome aneuploidy. The assay correctly identified 26 of 27 (92.6%) cases of Monosomy X, one case of XXX, and all six cases of XXY. There were four false positive cases of sex chromosome aneuploidy among 380 euploid cases for an overall false positive rate of less than 1%. DISCUSSION: Analysis of the risk for sex chromosome aneuploidies can be accomplished with a targeted assay with high sensitivity.

Spectrum of EEG abnormalities during clozapine treatment.

Clozapine is a novel antipsychotic agent effective in treating refractory schizophrenia. Clozapine produces fewer extrapyramidal effects than other neuroleptics, although agranulocytosis and seizures are significant adverse effects. To characterize the spectrum of clozapine-related electroencephalographic abnormalities, we identified 10 patients who had electroencephalograms (EEGs) performed before and during clozapine treatment. These 10 patients represented a subset of individuals participating in an investigational trial. During clozapine treatment, five developed myoclonus and one experienced a generalized tonic-clonic seizure. Records were retrospectively reviewed by an electroencephalographer blinded to the patient's history and medications. All patients had normal EEGs before clozapine treatment. While receiving clozapine (250-900 mg daily), all patients developed background slowing in the theta and often delta ranges. Additionally, 7 patients exhibited bilateral spike, polyspike and slow wave discharges, one with a photoparoxysmal response. Follow-up EEGs performed in 4 of these 7 patients after a decrease in clozapine dosage and/or addition in valproic acid showed diminished epileptiform activity.

A rare endobronchial neurilemmoma (Schwannoma).

Primary neurogenic tumors of the lung are rare. Often, their histologic behavior presents a treatment dilemma. We present a case of benign endobronchial neurilemmoma managed by means of YAG laser resection together with a brief discussion of the management options available for these tumors.

Encephalitis associated with Rocky Mountain spotted fever.

We present a fatal case of Rocky Mountain spotted fever. Despite the presence of clinical and laboratory evidence suggesting widespread vasculitis, pathologic lesions were found only in the central nervous system.

Familial embryonal carcinoma in a cancer-prone kindred.

Familial testicular cancer is rare. This report describes a family with an unusual cancer spectrum that included the infantile form of embryonal carcinoma of the testis in the son of a cancer-free but putative obligate gene carrier mother, and the adult form of embryonal carcinoma in this women's maternal half-brother (their mutual mother had malignant melanoma and urinary bladder carcinoma). Hereditary syndrome designation remains elusive. Priority attention to biomarker research in families of this type for elucidation of cause and control is discussed.

Cancer genes, multiple primary cancer, and von Hippel-Lindau disease.

Von Hippel-Lindau disease is inherited by an autosomal dominant gene that may show marked expressive variability of cancer phenotype in certain patients/families. We describe a patient with a strongly positive family history of this disease who, at age 28, underwent craniotomy with removal of a cystic cerebellar hemangioblastoma; at age 48, he developed syringomyelia of the spinal cord, became quadriplegic, and had a progressive downhill course. At autopsy, hemangioblastomas of the cerebellum and spinal cord were found, as well as a left renal cell carcinoma, an oat cell carcinoma of the lung, a hepatocellular carcinoma, and an atypical thyroid adenoma. This tumor spectrum appears to be unique, although chance cannot be excluded. It is possible, however, that these findings might represent an expression of the deleterious genotype that became evident because of this patient's prolonged survival from his initial cerebellar hemangioblastoma.

A benign cystic teratoma with gastrointestinal tract development.

The clinical and histologic features of a benign cystic teratoma with histologic evidence of almost full gastrointestinal tract development are discussed. The literature has previously described only bowel epithelium, segments of bowel, appendix, and esophagus separately. This is the first report of almost complete development of the gastrointestinal tract in a benign cystic teratoma. In this teratoma, the entire gastrointestinal tract from esophagus to colon is represented histologically.

The sarcoma, breast cancer, lung cancer, and adrenocortical carcinoma syndrome revisited. Childhood cancer.

We studied two children who had rhabdomyosarcoma and glioblastoma and who were from a family with a hereditary cancer syndrome that was characterized by sarcoma, breast cancer, brain tumors, lung cancer, laryngeal carcinoma, leukemia, and adrenocortical carcinoma. The deleterious genotype has now been expressed through the fourth generation of this large kindred. The pedigree emphasizes the need for an extended history of several generations to arrive at a hereditary-syndrome diagnosis. A limited pedigree may result in nonappreciation of the genetic component. The pedigree illustrates that, in certain circumstances, the highly specific varieties of cancer may occur in children before it is expressed in the parent who carries the putative gene. Pediatricians, in evaluating the causes of childhood cancer, must be cognizant of cancer among adult relatives, since this recognition may aid in the diagnosis of those hereditary cancer syndromes that are characterized by cancer occurrence in children as well as adults.

Takayasu's arteritis of the upper extremities. A case report and review of literature.

Takayasu's Arteritis is an inflammatory process of the large arteries. It most commonly involves the aorta and its major branches. It is characterized by acute and chronic inflammation and fibrosis of the vessel wall with resultant constriction or occlusion of the vessel lumen. There are various histopathologic stages this disease evolves through which may complicate the diagnosis. In this study we present a case of Takayasu's Arteritis involving the right axillary artery, with a literature review.