Search

To improve the understanding of chemo-refractory high-grade serous ovarian cancers (HGSOCs), we characterized the proteogenomic landscape of 242 (refractory and sensitive) HGSOCs, representing one discovery and two validation cohorts across two biospecimen types (formalin-fixed paraffin-embedded and frozen). We identified a 64-protein signature that predicts with high specificity a subset of HGSOCs refractory to initial platinum-based therapy and is validated in two independent patient cohorts. We detected significant association between lack of Ch17 loss of heterozygosity (LOH) and chemo-refractoriness. Based on pathway protein expression, we identified 5 clusters of HGSOC, which validated across two independent patient cohorts and patient-derived xenograft (PDX) models. These clusters may represent different mechanisms of refractoriness and implicate putative therapeutic vulnerabilities.

* Context.--Next-generation sequencing is a powerful clinical tool for cancer management but can produce incidental/secondary findings that require special consideration. Objective.--To discuss clinical and laboratory issues related to incidental or secondary germline findings in the clinical setting of tumor testing and inform future guidelines in this area. Design.--A College of American Pathologists workgroup including representation from the American Society of Clinical Oncology, the Association for Molecular Pathology, and the American College of Medical Genetics and Genomics created a review of items that should be considered when developing guidelines for incidental or secondary findings when performing clinical tumor testing. Results.--Testing recommendations should be cognizant of the differences among anticipated incidental, unanticipated incidental, and secondary findings, and whether normal tissue is also tested. In addition to defining which variants will be reported, robust recommendations must also take into account test design and validation, reimbursement, cost, infrastructure, impact on reflex testing, and maintenance of proficiency. Care providers need to consider the potential of a test to uncover incidental or secondary findings, the recommendation of upfront counseling, the need for consent, the timing of testing and counseling, and that the exact significance of a finding may not be clear. Conclusions.--As clinical oncology testing panels have become a mainstay of clinical cancer care, guidelines addressing the unique aspects of incidental and secondary findings in oncology testing are needed. This paper highlights clinical and laboratory considerations with regard to incidental/secondary findings and is a clarion call to create recommendations., Next-generation sequencing (NGS) has greatly improved upon traditional diagnostic molecular tests because of concurrent testing of many genes, resulting in improved efficiency and reduced costs. However, this expanded testing also [...]

BackgroundMolecular analysis represents an increasingly important component of the pathologic examination of tumor specimens. Notably, the characterization of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression in breast cancer specimens provides critical prognostic and predictive information. The objective of the current study was to compare the concordance of these markers as determined on fine-needle aspiration (FNA) cell blocks compared with tissue blocks prepared from surgical specimens.MethodsA total of 134 cases of breast carcinoma were identified from 2002 through 2014 with both FNA cell blocks (fixed in 10% formalin) and corresponding available tissue blocks and ER, PR, and HER2 were characterized in both specimens. Negative and positive concordances were determined for ER and PR in cell blocks compared with tissue blocks, and for HER2 immunohistochemistry on cell blocks and tissue blocks versus the corresponding reference method, fluorescence in situ hybridization (FISH).ResultsConcordance for ER expression evaluated on a cell block compared with the corresponding tissue block was 96.2%. Concordance for PR expression was 77.5%. Overall agreement of HER2 FISH testing between cell blocks and tissue blocks was 96.7%. For both cell blocks and tissue blocks, HER2 expression by immunohistochemistry demonstrated ≥98% positive and negative concordance with the FISH reference method.ConclusionsER, PR, and HER2 determination on FNA-acquired cell block (fixed exclusively in 10% formalin) showed excellent agreement for ER and HER2 and moderate agreement for PR with the corresponding tissue block. These findings support the equivalency of ER and HER2 evaluation performed on FNA cell blocks compared with surgical tissue blocks. Cancer Cytopathol 2016;124:828-35. © 2016 American Cancer Society.

ObjectivesNodular fasciitis (NF) is a self-limited, mass-forming, fibrous proliferation that can occur in the head and neck and may mimic malignancy. Fine-needle aspiration biopsy (FNAB) is a minimally invasive, rapid, accurate method of obtaining diagnostic material from head and neck masses. In this study, we verify the usefulness of FNAB in obtaining a definitive diagnosis of NF.MethodsCases were identified from our laboratory information system. Cytology slides were reviewed to note morphologic features and confirm diagnoses. Clinical history was obtained to document the case presentations and outcomes.ResultsAll 9 cases were found to have clinical presentations and common distinguishing morphologic features consistent with NF. Two cases were excised surgically, and the remainder regressed spontaneously. There were no recurrences.ConclusionsFNAB can produce a definitive diagnosis of NF, providing an opportunity to avoid surgical excision in patients with a typical clinical presentation.

* Context.--Cancer immunotherapy provides unprecedented rates of durable clinical benefit to late-stage cancer patients across many tumor types, but there remains a critical need for biomarkers to accurately predict clinical response. Although some cancer immunotherapy tests are associated with approved therapies and considered validated, other biomarkers are still emerging and at various states of clinical and translational exploration. Objective.--To provide pathologists with a current and practical update on the evolving field of cancer immunotherapy testing. The scientific background, clinical data, and testing methodology for the following cancer immunotherapy biomarkers are reviewed: programmed death ligand-1 (PD-L1), mismatch repair, microsatellite instability, tumor mutational burden, polymerase 5 and e mutations, cancer neoantigens, tumor-infiltrating lymphocytes, transcriptional signatures of immune responsiveness, cancer immunotherapy resistance biomarkers, and the microbiome. Data Sources.--Selected scientific publications and clinical trial data representing the current field of cancer immunotherapy. Conclusions.--The cancer immunotherapy field, including the use of biomarker testing to predict patient response, is still in evolution. PD-L1, mismatch repair, and microsatellite instability testing are helping to guide the use of US Food and Drug Administration-approved therapies, but there remains a need for better predictors of response and resistance. Several categories of tumor and patient characteristics underlying immune responsiveness are emerging and may represent the next generation of cancer immunotherapy predictive biomarkers. Pathologists have important roles and responsibilities as the field of cancer immunotherapy continues to develop, including leadership of translational studies, exploration of novel biomarkers, and the accurate and timely implementation of newly approved and validated companion diagnostics. (Arch Pathol Lab Med. 2020;144:706-724; doi: 10.5858/arpa.2018-0584-CP), Cancer immunotherapy has revolutionized the field of oncology by delivering unprecedented levels of durable survival benefit for cancer patients, including some patients with previously incurable late-stage disease. It is now [...]

* 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 [...]

BackgroundImmunoCyt/uCyt (Scimedx, Denville, NJ, USA) is a well-established urinary marker assay with high sensitivity for the diagnosis of urothelial carcinoma (UC) and can function as a second-level test to arbitrate atypical reads of urine cytology.ObjectiveTo determine the utility of uCyt as a reflex test for atypical cytology in patients undergoing a hematuria evaluation or surveillance with a history of UC.Design, setting, and participantsThe uCyt assay was performed as a second-level reflex test on all voided urine cytology tests read as atypical between January 2007 and June 2010 in an academic medical center. Records were retrospectively reviewed. Three hundred twenty-four patients underwent a total of 506 uCyt assays.InterventionReflex uCyt assay on atypical urine cytology.Outcome measurements and statistical analysisThe uCyt test characteristics include sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV).Results and limitationsReflex uCyt was performed on 506 atypical voided urine samples that were followed by cystoscopy within 90 d. Reflex uCyt with a history of UC showed a sensitivity of 73%, a specificity of 49%, and an NPV of 80%. In those with a history of low-grade UC, reflex uCyt had a sensitivity of 75%, a specificity of 50%, and an NPV of 82%, while in those with a history of high-grade UC, it had a sensitivity of 74%, a specificity of 44%, and an NPV of 79%. Without prior history of UC, reflex uCyt had a sensitivity of 85%, a specificity of 59%, and an NPV of 94%. This study's limitations include its retrospective design and interobserver variability inherent to cystoscopy, which was used as the reference test.ConclusionsWhen used as a reflex test on atypical urine cytology, negative uCyt may predict a negative cystoscopy in select patients and modulate the urgency and further work-up in those with no prior history or low-grade disease.

This study investigated the role of concurrent musical parts in pitching ability in sight-singing, concentrating on the effects of melodic and harmonic coherence. Twenty-two experienced singers sang their part twice in each of four novel chorales. The chorales contained either original or altered melody and original (tonal) or altered (atonal) harmony. Participants also performed an interval-singing task. Alterations from the original in both melody and harmony increased pitching errors in sight-singing. These results indicate respectively that pattern recognition and harmonic prediction are integral to sight-singing ability. Singers made fewer errors on the second reading, showing the role of familiarity. Error rate correlated with interval-singing performance. Less skilled sight-singers were significantly more affected by a disruption in harmony than were better sight-singers. The results suggest an increasing role for internal auditory representations with increasing expertise. (Contains 1 table and 4 figures.)