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Context.--Chimeric antigen receptor T-cell (CAR-T) technology has shown great promise in both clinical and preclinical models in mediating potent and specific antitumor activity. With the advent of US Food and Drug Administration-approved CAR-T therapies for B-cell lymphoblastic leukemia and B-cell non-Hodgkin lymphomas, CAR-T therapy is poised to become part of mainstream clinical practice. Objective.--To educate pathologists on CAR-T and chimeric antigen receptor-derived cellular therapy, provide a better understanding of their role in this process, explain important regulatory aspects of CAR-T therapy, and advocate for pathologist involvement in the delivery and monitoring of chimeric antigen receptor-based treatments. Much of the focus of this article addresses US Food and Drug Administration-approved therapies; however, more general issues and future perspectives are considered for therapies in development. Design.--A CAR-T workgroup, facilitated by the College of American Pathologists Personalized Health Care Committee and consisting of pathologists of various backgrounds, was convened to develop a summary guidance paper for the College of American Pathologists Council on Scientific Affairs. Results.--The workgroup identified gaps in pathologists' knowledge of CAR-T therapy, including uncertainty in the role of the clinical laboratory in supporting CAR-T therapy. The workgroup considered these issues and summarized the findings to assist pathologists to become stakeholders in CAR-T therapy administration. Conclusions.--This manuscript serves to both educate pathologists on CAR-T therapy and serve as a point of initial discussions in areas of CAR-T science, clinical therapy, and regulatory issues as CAR-T therapies continue to be introduced into clinical practice. (Arch Pathol Lab Med. 2021;145:704-716; doi: 10.5858/arpa.2019-0632-CP, Precision medicine for cancer therapy has used both targeted molecular approaches that are directed against a specific tumor-associated molecular aberration and immunomodulatory therapies, which enhance antitumor immunity. Immunomodulatory therapies either [...]

* Biospecimens acquired during routine medical practice are the primary sources of molecular information about patients and their diseases that underlies precision medicine and translational research. In cancer care, molecular analysis of biospecimens is especially common because it often determines treatment choices and may be used to monitor therapy in real time. However, patient specimens are collected, handled, and processed according to routine clinical procedures during which they are subjected to factors that may alter their molecular quality and composition. Such artefactual alteration may skew data from molecular analyses, render analysis data uninterpretable, or even preclude analysis altogether if the integrity of a specimen is severely compromised. As a result, patient care and safety may be affected, and medical research dependent on patient samples may be compromised. Despite these issues, there is currently no requirement to control or record preanalytical variables in clinical practice with the single exception of breast cancer tissue handled according to the guideline jointly developed by the American Society of Clinical Oncology and College of American Pathologists (CAP) and enforced through the CAP Laboratory Accreditation Program. Recognizing the importance of molecular data derived from patient specimens, the CAP Personalized Healthcare Committee established the Preanalytics for Precision Medicine Project Team to develop a basic set of evidence-based recommendations for key preanalytics for tissue and blood specimens. If used for biospecimens from patients, these preanalytical recommendations would ensure the fitness of those specimens for molecular analysis and help to assure the quality and reliability of the analysis data. (Arch Pathol Lab Med. 2019;143:1346-1363; doi: 10.5858/arpa.2019-0009-SA), OVERVIEW: THE CRITICAL ROLE OF PREANALYTICS IN THE MOLECULAR ANALYSIS OF PATIENT BIOSPECIMENS Biospecimens acquired during routine medical practice are the primary sources of the molecular information about patients and [...]

Context.--Soft tissue pathology encompasses a remarkably diverse assortment of benign and malignant soft tissue tumors. Rendering a definitive diagnosis is complicated not only by the large volume of existing histologic subtypes (>100) but also frequently by the presence of overlapping clinical, histologic, immunohistochemical, and/or radiographic features. During the past 3 decades, mesenchymal tumor-specific, cytogenetic and molecular genetic abnormalities have demonstrated an increasingly important, ancillary role in mesenchymal tumor diagnostics. Objectives.--To review molecular diagnostic tools available to the pathologist to further classify specific soft tissue tumor types and recurrent aberrations frequently examined. Advantages and limitations of individual approaches will also be highlighted. Data Sources.--Previously published review articles, peer-reviewed research publications, and the extensive cytogenetic and molecular diagnostic experience of the authors to include case files of The University of Nebraska Medical Center. Conclusions.--Cytogenetic and molecular genetic assays are used routinely for diagnostic purposes in soft tissue pathology and represent a powerful adjunct to complement conventional microscopy and clinicoradiographic evaluation in the formulation of an accurate diagnosis. Care should be taken, however, to recognize the limitations of these approaches. Ideally, more than one technical approach should be available to a diagnostic laboratory to compensate for the shortcomings of each approach in the assessment of individual specimens. (Arch Pathol Lab Med. 2011;135:588-601), Soft tissue tumors constitute a rare, heterogeneous group of mesenchymal neoplasms that during the past 3 decades have been shown by cytogenetic analysis to have a remarkably high incidence of [...]

Objective: To compare the performance of assays used to assess KRAS mutations in tumor specimens. Methods: We analyzed DNA extracted from 30 formal in-fixed paraffin-embedded (FFPE) tumor specimens using the QIAGEN Therascreen KRAS RGQ and QIAGEN Pyro reagents, with dideoxy sequencing (colloquially considered to be the gold standard) as the reference method. Results: We detected 22 codon 12 or 13 KRAS mutations using the Pyro assay, whereas the RGQ assay detected 19 mutations. For mutation detection, the clinical sensitivity was 86% for the RGQ assay compared with 100% for the Pyro but 100% for the KRAS mutations that the RGQ was predesigned to detect. The Pyro could detect rare mutations. The RGQ demonstrated a lower limit of detection compared with the Pyro; However, the Pyro required less DNA input than the RGQ. Conclusion: The 2 assays that we tested yielded comparable performance in detecting KRAS mutations, as we had expected based on assay design. Overall, the Pyro assay detects more mutations and requires less DNA input but is less analytically sensitive, compared with the RGQ assay. [ABSTRACT FROM AUTHOR]

Introduction: Epidermal growth factor receptor ( EGFR ) mutations in non-small-cell lung cancers (NSCLC) may be more common in patients with brain metastases. Previous studies, however, did not adjust for effects of confounding variables., Methods: This retrospective study included 1,522 consecutive patients with NSCLC, whose tumors were diagnosed and tested for EGFR mutations at the University of Nebraska Medical Center (Omaha, NE) and Tata Memorial Hospital (Mumbai, India). Multivariate logistic regression was used to identify any association between EGFR status and clinical factors., Results: EGFR mutations were more common in females than males (38.7% v 24.8%), Asians than whites (31.3% v 13.4%), nonsmokers than smokers (40.2% v 14.6%), alcohol nonconsumers than users (32.4% v 15.8%), adenocarcinoma than other histology types (32.7% v 10.3%), and patients with brain metastases than extracranial or no metastases (39.4% v 29.8% v 15.1%; P < .001 for all comparisons). There was a higher likelihood of an EGFR mutation among patients with brain metastases (odds ratio, 1.8; P < .001). The median overall survival (OS) was 19.8 months. Patients with brain metastases had a shorter median OS (15 v 20.6 months; P = .02). However, in the cohort of EGFR mutation-positive patients, there was no difference in median OS between patients with and without brain metastases (20.8 v 25.1 months; P = .11)., Conclusion: There is a nearly two-fold higher incidence of EGFR mutations in NSCLC among patients with brain metastases at diagnosis. EGFR mutations did not predict for outcomes from brain metastases., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc. Vijaya Raj BhattNo relationship to discloseSanyo P. D’SouzaNo relationship to discloseLynette M. SmithNo relationship to discloseAllison M. Cushman-VokounNo relationship to discloseVanita NoronhaNo relationship to discloseVivek VermaNo relationship to discloseAmit JoshiNo relationship to discloseAnuradha ChouguleNo relationship to discloseNirmala JambhekarNo relationship to discloseAnne KessingerNo relationship to discloseAlissa MarrResearch Funding: Merck Sharp and Dohme (Inst)Vijay PatilNo relationship to discloseSripad D. BanavaliNo relationship to discloseApar Kishor GantiConsulting or Advisory Role: Otsuka Pharmaceutical, Boehringer Ingelheim, Biodesix, Pfizer Research Funding: Pfizer (Inst), Amgen (Inst), NewLink Genetics (Inst), ARIAD (Inst), Astex Pharmaceuticals (Inst), Bristol-Myers Squibb (Inst), Merck Serono (Inst), Merck (Inst), Janssen Biotech (Inst)Kumar PrabhashNo relationship to disclose