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Pharmacogenetic testing for CYP3A4 is increasingly provided by clinical and research laboratories; however, only a limited number of quality control and reference materials are currently available for many of the CYP3A4 variants included in clinical tests. To address this need, the Division of Laboratory Systems, CDC-based Genetic Testing Reference Material Coordination Program (GeT-RM), in collaboration with members of the pharmacogenetic testing and research communities and the Coriell Institute for Medical Research, has characterized 30 DNA samples derived from Coriell cell lines for CYP3A4. Samples were distributed to five volunteer laboratories for genotyping using a variety of commercially available and laboratory-developed tests. Sanger and next-generation sequencing were also utilized by some of the laboratories. Whole-genome sequencing data from the 1000 Genomes Projects were utilized to inform genotype. Twenty CYP3A4 alleles were identified in the 30 samples characterized for CYP3A4: CYP3A4∗4, ∗5, ∗6, ∗7, ∗8, ∗9, ∗10, ∗11, ∗12, ∗15, ∗16, ∗18, ∗19, ∗20, ∗21, ∗22, ∗23, ∗24, ∗35, and a novel allele, CYP3A4∗38. Nineteen additional samples with preexisting data for CYP3A4 or CYP3A5 were re-analyzed to generate comprehensive reference material panels for these genes. These publicly available and well-characterized materials can be used to support the quality assurance and quality control programs of clinical laboratories performing clinical pharmacogenetic testing., (Copyright © 2023 Association for Molecular Pathology and American Society for Investigative Pathology. All rights reserved.)

Background: Next-generation sequencing (NGS), including whole genome sequencing (WGS) and whole exome sequencing (WES), is increasingly being used for clinic care. While NGS data have the potential to be repurposed to support clinical pharmacogenomics (PGx), current computational approaches have not been widely validated using clinical data. In this study, we assessed the accuracy of the Aldy computational method to extract PGx genotypes from WGS and WES data for 14 and 13 major pharmacogenes, respectively., Methods: Germline DNA was isolated from whole blood samples collected for 264 patients seen at our institutional molecular solid tumor board. DNA was used for panel-based genotyping within our institutional Clinical Laboratory Improvement Amendments- (CLIA-) certified PGx laboratory. DNA was also sent to other CLIA-certified commercial laboratories for clinical WGS or WES. Aldy v3.3 and v4.4 were used to extract PGx genotypes from these NGS data, and results were compared to the panel-based genotyping reference standard that contained 45 star allele-defining variants within CYP2B6 , CYP2C8 , CYP2C9 , CYP2C19 , CYP2D6 , CYP3A4 , CYP3A5 , CYP4F2 , DPYD , G6PD , NUDT15 , SLCO1B1 , TPMT , and VKORC1 ., Results: Mean WGS read depth was >30x for all variant regions except for G6PD (average read depth was 29 reads), and mean WES read depth was >30x for all variant regions. For 94 patients with WGS, Aldy v3.3 diplotype calls were concordant with those from the genotyping reference standard in 99.5% of cases when excluding diplotypes with additional major star alleles not tested by targeted genotyping, ambiguous phasing, and CYP2D6 hybrid alleles. Aldy v3.3 identified 15 additional clinically actionable star alleles not covered by genotyping within CYP2B6 , CYP2C19 , DPYD , SLCO1B1 , and NUDT15 . Within the WGS cohort, Aldy v4.4 diplotype calls were concordant with those from genotyping in 99.7% of cases. When excluding patients with CYP2D6 copy number variation, all Aldy v4.4 diplotype calls except for one CYP3A4 diplotype call were concordant with genotyping for 161 patients in the WES cohort., Conclusion: Aldy v3.3 and v4.4 called diplotypes for major pharmacogenes from clinical WES and WGS data with >99% accuracy. These findings support the use of Aldy to repurpose clinical NGS data to inform clinical PGx., Competing Interests: Authors JH and AB are laboratory directors of The Indiana University School of Medicine Pharmacogenomics Laboratory, a fee-for-service laboratory that offers clinical pharmacogenetic testing. Authors SS and IN have a patent US 20200168298A1 for the Aldy genotyping platform. Authors RR, BAS, and SB are current or former employees of the company LifeOmic Inc., a commercial entity that supports management and analysis of genetic data. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Shugg, Ly, Osei, Rowe, Granfield, Lynnes, Medeiros, Hodge, Breman, Schneider, Sahinalp, Numanagić, Salisbury, Bray, Ratcliff and Skaar.)

Patients in the pediatric intensive care unit are exposed to multiple medications and are at high risk for adverse drug reactions. Pharmacogenomic (PGx) testing could help decrease their risk of adverse reactions. Although whole blood is preferred for PGx testing, blood volume in this population is often limited. However, for patients on mechanical ventilation, tracheal secretions are abundant, frequently suctioned, and discarded. Thus, the aim of this pilot study was to determine if tracheal aspirates could be used as a source of human genomic DNA for PGx testing. We successfully extracted DNA from tracheal secretions of all 23 patients in the study. The samples were successfully genotyped for 10 clinically actionable single nucleotide variants across 3 cytochrome P450 genes (CYP2D6, CYP2C19, and CYP3A5). Using DNA from whole blood samples in 11 of the patients, we confirmed the accuracy of the genotyping with 100% concordance. Therefore, our results support the use of tracheal aspirates from mechanically ventilated children as an adequate biospecimen for clinical genetic testing., (© 2020 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Multiple myeloma is a disseminated malignant neoplasm usually derived from a single clone of plasma cells. Patients with myeloma have diverse signs such as anemia, hypercalcemia, uremia, pathologic fractures, and recurrent infections. Extraosseous manifestations are found in less than 5% of patients with multiple myeloma. They can arise in any tissue, and their presence has been associated with more aggressive disease. The purpose of this essay is to illustrate the imaging findings of extraosseous myeloma and heighten awareness of this unusual manifestation of multiple myeloma.

The distribution of regional lymph node metastases in carcinomas of the cecum, ascending colon, and transverse colon follows the vascular distribution in the ileocolic mesentery, ascending mesocolon, and transverse mesocolon. The location of these metastatic nodes can be recognized on CT scans when the anatomy of the vessels in the ileocolic mesentery and mesocolon is well understood. This knowledge is important in the preoperative staging of carcinomas of the colon for curative surgery and in the early detection of recurrent nodal disease after curative surgery.

The distribution of regional lymph node metastases in carcinoma of the left side of the colon, rectum, and anus can be well shown by routine CT of the abdomen and pelvis. Recognition of the location of nodes in the mesocolic, left colic, and IMA nodal groups can help in developing a systematic approach to the detection of nodal metastasis. This can be especially important in preoperative planning for cases in which resection may be curative. In addition, an understanding of the distribution of nodal metastasis will make it possible to recognize early recurrent nodal disease, particularly with an increase in associated increase in levels of carcinoembryonic antigen, and to predict certain clinical sequences such as hydronephrosis of the left kidney associated with left colic nodal metastases.

Malignant small round cell tumor of the abdomen is a newly described clinicopathologic entity. The features of this entity include a predilection for young men, predominant abdominopelvic location, and aggressive behavior. Pathologic analysis demonstrates a small-cell tumor unusually coexpressing desmin and keratin. This study describes CT characteristics in five patients with malignant small round cell tumor of the abdomen. All patients were young white men, 20-36 years old (mean, 28 years). In all five cases, CT scans revealed lobulated masses appearing to arise primarily from peritoneal surfaces and predominantly involving the peritoneal cavity of the abdomen (two cases) and pelvis (two cases); diffuse abdominopelvic involvement was noted in one case. The masses were centrally necrotic and enhanced inhomogeneously after administration of iodinated contrast material. Additional CT features included ascites (one case), calcifications in the dominant mass (one case), omental implants (two cases), hydronephrosis (four cases), anterior diaphragmatic lymphadenopathy (two cases), liver metastases (two cases), and retroperitoneal lymphadenopathy (two cases). CT findings of abdominal malignant small round cell tumor are nonspecific and mimic findings noted in other conditions, such as peritoneal carcinomatosis and leiomyosarcomatosis.