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Batrachochytrium salamandrivorans (Bsal), a species related to the destructive pathogen Batrachochytrium dendrobatidis (Bd), was found and identified in Europe in 2013. Now, a decade later, a large amount of information is available. This includes data from studies in the field, reports of infection in captive amphibians, laboratory studies testing host susceptibility, and data from prospective studies that test for Bsal's presence in a location. We conducted a systematic review of the published literature and compiled a dataset of Bsal tests. We identified 67 species that have been reported positive for Bsal, 20 of which have a threatened conservation status. The distribution of species that have been found with infection encompasses 69 countries, highlighting the potential threat that Bsal poses. We point out where surveillance to detect Bsal have taken place and highlight areas that have not been well monitored. The large number of host species belonging to the families Plethodontidae and Salamandridae suggests a taxonomic pattern of susceptibility. Our results provide insight into the risk posed by Bsal and identifies vulnerable species and areas where surveillance is needed to fill existing knowledge gaps. [ABSTRACT FROM AUTHOR]

Background: To improve identification of patients with cutaneous squamous cell carcinoma (SCC) at high risk for metastatic disease, the DecisionDx-SCC assay, a prognostic 40-gene expression profile (40-GEP) test, was developed and validated. The 40-GEP assay utilizes RT-PCR gene expression analysis on primary tumor biopsy tissue to evaluate the expression of 34 signature gene targets and 6 normalization genes. The test provides classifications of low risk (Class 1), moderate risk (Class 2A), and high risk (Class 2B) of metastasis within 3 years of diagnosis. The primary objective of this study was to validate the analytical performance of the 40-gene expression signature. Methods: The repeatability and reproducibility of the 40-GEP test was evaluated by performance of inter-assay, intra-assay, and inter-operator precision experiments along with monitoring the reliability of sample and reagent stability for class call concordance. The technical performance of clinical orders from September 2020 through July 2021 for the 40-GEP test was assessed. Results: Patient hematoxylin and eosin (H&E) stained slides were reviewed by a board-certified pathologist to assess minimum acceptable tumor content. Class specific controls (Class 1 and Class 2B) were evaluated with Levey-Jennings analysis and demonstrated consistent and reproducible results. Inter-assay, inter-operator and intra-assay concordance were all ≥90%, with short-term and long-term RNA stability also meeting minimum concordance requirements. Of the 2586 orders received, 93.5% remained eligible for testing, with 97.1% of all tested samples demonstrating actionable class call results. Conclusion: DecisionDx-SCC demonstrates a high degree of analytical precision, yielding high concordance rates across multiple performance experiments, along with exhibiting robust technical reliability on clinical samples. [ABSTRACT FROM AUTHOR]

Sentinel lymph node (SLN) biopsy should be performed with the technical expertise required to correctly identify the sentinel node, in the context of understanding both the likelihood of positivity in a given patient and the prognostic significance of a positive or negative result. National Comprehensive Cancer Network guidelines recommend SLN biopsy for all cutaneous melanoma patients with primary tumor thickness greater than 1 mm and in select patients with thickness between 0.8 and 1 mm, yet admit a lack of consistent clarity in its utility for prognosis and therapeutic value in tumors < 1 mm and leave the decision for undergoing the procedure up to the patient and treating physician. Recent studies have evaluated specific patient populations, tumor histopathologic characteristics, and gene expression profiling and their use in predicting SLN positivity. These data have given insight into improving the physician's ability to potentially predict SLN positivity, shedding light on if and when omission of SLN biopsy in specific patients based on clinicopathological characteristics might be appropriate. This review provides discussion and insight into these recent advancements. [ABSTRACT FROM AUTHOR]

Infection records of Batrachochytrium dendrobatidis (Bd), a pathogen that has devastated amphibian populations worldwide, have rapidly increased since the pathogen's discovery. Dealing with so many records makes it difficult to (a) know where, when and in which species infections have been detected, (b) understand how widespread and pervasive Bd is and (c) prioritize study and management areas. We conducted a systematic review of papers and compiled a database with Bd infection records. Our dataset covers 71 amphibian families and 119 countries. The data revealed how widespread and adaptable Bd is, being able to infect over 50% of all tested amphibian species, with over 1000 confirmed host species and being present in 86 countries. The distribution of infected species is uneven among and within countries. Areas where the distributions of many infected species overlap are readily visible; these are regions where Bd likely develops well. Conversely, areas where the distributions of species that tested negative overlap, such as the Atlantic Coast in the USA, suggest the presence of Bd refuges. Finally, we report how the number of tested and infected species has changed through time, and provide a list of oldest detection records per country. [ABSTRACT FROM AUTHOR]

Aim: Can gene expression profiling be used to identify patients with T1-T2 melanoma at low risk for sentinel lymph node (SLN) positivity?Patients& Methods: Bioinformatics modeling determined a population in which a 31-gene expression profile test predicted <5% SLN positivity. Multicenter, prospectively-tested (n = 1421) and retrospective (n = 690) cohorts were used for validation and outcomes, respectively.Results: Patients 55-64 years and ≥65 years with a class 1A (low-risk) profile had SLN positivity rates of 4.9% and 1.6%. Class 2B (high-risk) patients had SLN positivity rates of 30.8% and 11.9%. Melanoma-specific survival was 99.3% for patients ≥55 years with class 1A, T1-T2 tumors and 55.0% for class 2B, SLN-positive, T1-T2 tumors.Conclusion: The 31-gene expression profile test identifies patients who could potentially avoid SLN biopsy. [ABSTRACT FROM AUTHOR]

Background: Approximately 10% of pancreatic adenocarcinoma (PC) cases are attributed to hereditary causes. Individuals with PC and a personal history of another cancer associated with hereditary breast and ovarian cancer (HBOC) or Lynch syndrome (LS) may be more likely to carry germline mutations.Methods: Participants with PC and a history of cancer were selected from a pancreatic disease registry. Of 1296 individuals with PC, 149 had a relevant history of cancer. If banked DNA was available, a multigene panel was performed for individuals who had not 1) previously had a mutation identified through clinical testing or 2) undergone clinical multigene panel testing with no mutations detected.Results: Twenty-two of 124 individuals with PC and another HBOC- or LS-related cancer who underwent genetic testing had a mutation identified in a PC susceptibility gene (18%). If prostate cancer is excluded, the mutation prevalence increased to 23% (21/93). Mutation carriers were more likely to have more than 1 previous cancer diagnosis (P = .001), to have had clinical genetic testing (P = .001), and to meet National Comprehensive Cancer Network (NCCN) genetic testing criteria (P < .001). Approximately 23% of mutation carriers did not meet NCCN HBOC or LS testing guidelines based on their personal cancer history and reported cancer history in first-degree relatives.Conclusion: At least 18% of individuals with PC and a personal history of other HBOC- or LS-related cancers carry mutations in a PC susceptibility gene based on our data, suggesting that criteria for genetic testing in individuals with PC should include consideration of previous cancer history. Cancer 2018;124:1691-700. © 2018 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: A 15-gene expression profile test has been clinically validated and is widely utilized in newly diagnosed uveal melanoma (UM) patients to assess metastatic potential of the tumor. As most patients are treated with eye-sparing radiotherapy, there is limited tumor tissue available for testing, and technical reliability and success of prognostic testing are critical. This study assessed the analytical performance of the 15-gene expression test for UM and the correlation of molecular class with pathologic characteristics. Methods: Inter-assay, intra-assay, inter-instrument/operator, and inter-site experiments were conducted, and concordance of the 15-gene expression profile test results and associated discriminant scores for matched tumor samples were evaluated. Technical success was determined from de-identified clinical reports from January 2010 - May 2016. Pathologic characteristics of enucleated tumors were correlated with molecular class results. Results: Inter-assay concordance on 16 samples run on 3 consecutive days was 100%, and matched discriminant scores were strongly correlated (R² = 0.9944). Inter-assay concordance of 46 samples assayed within a one year period was 100%, with an R² value of 0.9747 for the discriminant scores. Intra-assay concordance of 12 samples run concurrently in duplicates was 100%; discriminant score correlation yielded an R² of 0.9934. Concordance between two sites assessing the same tumors was 100% with an R² of 0.9818 between discriminant scores. Inter-operator/instrument concordance was 96% for Class 1/2 calls and 90% for Class 1A/1B calls, and the discriminant scores had a correlation R² of 0.9636. Technical success was 96.3% on 5516 samples tested since 2010. Increased largest basal diameter and thickness were significantly associated with Class 1B and Class 2 vs. Class 1A signatures. Conclusions: These results show that the 15-gene expression profile test for UM has robust, reproducible performance characteristics. The technical success rate during clinical testing remains as high as first reported during validation. As molecular testing becomes more prevalent for supporting precision medicine efforts, high technical success and reliability are key characteristics when testing such limited and precious samples. The performance of the 15-gene expression profile test in this study should provide confidence to physicians who use the test's molecular classification to inform patient management decisions. [ABSTRACT FROM AUTHOR]

Objectives: To develop evidence-based guideline recommendations through a systematic review of the literature to establish standard molecular biomarker testing of colorectal cancer (CRC) tissues to guide epidermal growth factor receptor (EGFR) therapies and conventional chemotherapy regimens. Methods: The American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology convened an expert panel to develop an evidence-based guideline to establish standard molecular biomarker testing and guide therapies for patients with CRC. A comprehensive literature search that included more than 4,000 articles was conducted. Results: Twenty-one guideline statements were established. Conclusions: Evidence supports mutational testing for EGFR signaling pathway genes, since they provide clinically actionable information as negative predictors of benefit to anti-EGFR monoclonal antibody therapies for targeted therapy of CRC. Mutations in several of the biomarkers have clear prognostic value. Laboratory approaches to operationalize CRC molecular testing are presented. [ABSTRACT FROM AUTHOR]

Objective: DecisionDx-Melanoma * is a 31-gene expression profile test that predicts the risk of metastasis in patients with primary cutaneous melanoma (CM). This study was designed to ascertain clinical management changes determined by the test outcome, which classifies CM patients being at low (Class 1) or high (Class 2) risk for recurrence.Research Design and Methods: Medical charts were reviewed from 156 CM patients from six institutions (three dermatology and three surgical oncology practices) who were consecutively tested between May 2013 and December 2015. Clinical management data that were compiled and compared before and after receipt of the 31-gene expression test result included frequency of physical exams, frequency and modality of imaging, and referrals to surgical and medical oncologists.Results: Forty-two percent of patients were Stage I, 47% were Stage II and 8% were Stage III. Overall, 95 patients (61%) were Class 1 and 61 (39%) were Class 2. Documented changes in management were observed in 82 (53%) patients, with the majority of Class 2 patients (77%) undergoing management changes compared to 37% of Class 1 patients (p < 0.0001 by Fisher's exact test). The majority (77/82, 94%) of these changes were concordant with the risk indicated by the test result (p < 0.0001 by Fisher's exact test), with increased management intensity for Class 2 patients and reduced management intensity for Class 1 patients.Conclusions: Molecular risk classification by gene expression profiling has clinical impact and influences physicians to direct clinical management of CM patients. The vast majority of the changes implemented after the receipt of test results were reflective of the low or high recurrence risk associated with the patient's molecular classification. Because follow-up data was not collected for this patient cohort, the study is limited for the assessment of the impact of gene expression profile based management changes on healthcare resource utilization and patient outcome. [ABSTRACT FROM AUTHOR]

We report a novel, modular approach to immuno-detection based on antibody recognition and PCR read-out that employs antibody-conjugated bacteriophage and easily-manipulated non-pathogenic viruses as affinity agents. Our platform employs phage genetically tagged for in vivo biotinylation during phage maturation that can easily be linked, through avidin, to any biotinylated affinity agent, including full-length antibodies, peptides, lectins or aptamers. The presence of analyte is reported with high sensitivity through real-time PCR. This approach avoids the need to clone antibody-encoding DNA fragments, allows the use of full-length, high affinity antibodies and, by having DNA reporters naturally encapsulated inside the bacteriophage, greatly reduces nonspecific binding of DNA. We validate the efficacy of this new approach through the detection of Vascular Endothelial Growth Factor, a known angiogenic cancer biomarker protein, at attomolar concentrations in bronchoalveolar lavage fluid. [ABSTRACT FROM AUTHOR]

Metachronous bilateral renal cell carcinomas ( RCCs) are rare but well known. We present a case of metachronous bilateral RCCs with a ureter orifice metastasis, for which the pathological diagnosis was confirmed with single nucleotide polymorphism microarray ( SNP- M) and gene expression assay ( GEA). A 53-year-old man presented with a right ureteral obstruction. A cystoscopy showed a large pedunculated tumor emanating from the right ureteral orifice, consistent with a drop metastasis, which was biopsied. He had a history of a clear cell RCC ( ccRCC) 1.5 years prior and a right renal pelvic mass found 8 months later. Histologically, the biopsied right ureteral tumor demonstrated sheets of poorly differentiated cancer cells composed of a mixture of spindled and focal clear cell components. The main differential diagnosis was metastatic RCC versus urothelial carcinoma, but the immunohistochemical profile was not contributory. SNP- M revealed a genomic profile consistent with a metastatic ccRCC with loss of chromosome 3p. GEA showed a gene expression pattern consistent with kidney origin. The cytogenomic array also identified chromosome copy number patterns that were shared between both kidney tumors. This finding suggests that both tumors had a common origin, and thus, the metachronous ccRCC in the contralateral kidney represents a metastasis. [ABSTRACT FROM AUTHOR]

BACKGROUND: Body fluid specimens may be the first and only pathologic specimen for clinical evaluation in metastatic cancer cases. The challenge of identifying the tissue of origin in metastatic cancer has led to the emergence of molecular-based assays, such as the microarray-based Pathwork Tissue of Origin gene expression test. The ability to use body fluid specimens in this test would be valuable in providing diagnoses to cancer patients without clearly identifiable primary sites. In the current study, the authors evaluated the Tissue of Origin Test for use with malignant effusion specimens. METHODS: A total of 27 metastasis-positive body fluid specimens from different body sites, including pleural, ascites, pericardial, and pelvic wash fluids, were obtained from patients with known diagnoses. Nine specimens from nonmalignant body fluids were included as controls. RNA was extracted from formalin-fixed, paraffin-embedded (FFPE) tissue and gene expression analysis was performed with the Tissue of Origin Test. RESULTS: Seventeen of 27 metastasis-positive samples were non-necrotic with ≥60% tumor and yielded sufficient RNA. Of these samples, 94.1% (16 of 17) were in agreement with the available diagnosis. Of the 9 negative control samples evaluated, 7 (77.8%) demonstrated microarray expression profiles most similar to lymphoma, which is consistent with the predominance of inflammatory cells in these specimens. CONCLUSIONS: The results of the current study demonstrated that FFPE cell blocks from cytologic body fluid specimens yield adequate diagnostic material for the Pathwork test and can be used in the workup of patients with unknown primary tumors. Cancer (Cancer Cytopathol) 2012. © 2011 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: Carcinomas of unknown primary (CUP) represent approximately 3%-5% of malignant neoplasms. Identifying the tissue of origin (TOO) in these tumors allows for more specific treatment and improves outcomes. However, primary classification remains a challenge in many cases. We evaluated the ability of a microarray-based gene expression test to identify the TOO in tumor specimens from 21 patients with a diagnosis of CUP. Methods: The Pathwork® TOO Test was used to measure gene expression patterns for 1550 genes; these were compared for similarity to patterns from 15 known tissue types. Results: The TOO Test yielded a clear single positive call for the primary site in 16 of 21 (76%) specimens and was indeterminate in 5 (24%). The positive results were consistent with clinicopathologic suggestions in 10 of the 16 cases (62%). In the remaining six cases the positive results were considered plausible based on clinical information. Positive calls included colorectal (5), breast (4), ovarian (3), lung (2), and pancreas (2). The TOO Test ruled out an average of 11 primary tissues in each CUP specimen. Conclusion: The Pathwork TOO Test reduced diagnostic uncertainty in all CUP cases and could be a valuable addition or alternative to current diagnostic methods for classifying uncertain primary cancers. [ABSTRACT FROM AUTHOR]

PTEN haploinsufficiency is common in hormone-sensitive prostate cancer, though the incidence of genomic deletion and its downstream effects have not been elucidated in clinical samples of hormone refractory prostate cancer (HRPC). Progression to androgen independence is pivotal in prostate cancer and mediated largely by the androgen receptor (AR). Since this process is distinct from metastatic progression, we examined alterations of the PTEN gene in locally advanced recurrent, non-metastatic human HRPC tissues. Retrospective analyses of PTEN deletion status were correlated with activated downstream phospho-Akt (p-Akt) pathway proteins and with the androgen receptor. The prevalence of PTEN genomic deletions in transurethral resection samples of 59 HRPC patients with known clinical outcome was assessed by four-colour FISH analyses. FISH was performed using six BAC clones spanning both flanking PTEN genomic regions and the PTEN gene locus, and a chromosome 10 centromeric probe. PTEN copy number was also evaluated in a subset of cases using single nucleotide polymorphism (SNP) arrays. In addition, the samples were immunostained with antibodies against p-Akt, p-mTOR, p-70S6, and AR. The PTEN gene was deleted in 77% of cases, with 25% showing homozygous deletions, 18% homozygous and hemizygous deletions, and 34% hemizygous deletions only. In a subset of the study group, SNP array analysis confirmed the FISH findings. PTEN genomic deletion was significantly correlated to the expression of downstream p-Akt ( p < 0.0001), AR ( p = 0.025), and to cancer-specific mortality ( p = 0.039). PTEN deletion is common in HRPC, with bi-allelic loss correlating to disease-specific mortality and associated with Akt and AR deregulation. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Copy Number Aberration (CNA) in myelodysplastic syndromes (MDS) study using single nucleotide polymorphism (SNP) arrays have been received increasingly attentions in the recent years. In the current study, a new Constraint Moving Average (CMA) algorithm is adopted to determine the regions of CNA regions first. In addition to large regions of CNA, using the proposed CMA algorithm, small regions of CNA can also be detected. Real-time Polymerase Chain Reaction (qPCR) results prove that the CMA algorithm presents an insightful discovery of both large and subtle regions. Based on the results of CMA, two independent applications are studied. The first one is power analysis for sample estimation. An accurate estimation of sample size needed for the desired purpose of an experiment will be important for effort-efficiency and costeffectiveness. The power analysis is performed to determine the minimum sample size required for ensuring at least 100λ% (0<λ⩽1) detected regions statistically different from normal references. As expected, power increase with increasing sample size for a fixed significance level. The second application is the distinguishment of high-grade MDS patients from low-grade ones. We propose to calculate the General Variant Level (GVL) score to integrate the general information of each patient at genotype level, and use it as the unified measurement for the classification. Traditional MDS classifications usually refer to cell morphology and The International Prognostic Scoring System (IPSS), which belongs to the classification at the phenotype level. The proposed GVL score integrates the information of CNA region, the number of abnormal chromosomes and the total number of the altered SNPs at the genotype level. Statistical tests indicate that the high and low grade MDS patients can be well separated by GVL score, which appears to correlate better with clinical outcome than the traditional classification approaches using morphology and IPSS sore at the phenotype level. [ABSTRACT FROM AUTHOR]

Background: Plasmablastic lymphoma (PL) is a subtype of diffuse large B-cell lymphoma (DLBCL). Studies have suggested that tumors with PL morphology represent a group of neoplasms with clinopathologic characteristics corresponding to different entities including extramedullary plasmablastic tumors associated with plasma cell myeloma (PCM). The goal of the current study was to evaluate the genetic similarities and differences among PL, DLBCL (AIDS-related and non AIDS-related) and PCM using array-based comparative genomic hybridization. Results: Examination of genomic data in PL revealed that the most frequent segmental gain (> 40%) include: 1p36.11-1p36.33, 1p34.1-1p36.13, 1q21.1-1q23.1, 7q11.2-7q11.23, 11q12-11q13.2 and 22q12.2-22q13.3. This correlated with segmental gains occurring in high frequency in DLBCL (AIDS-related and non AIDS-related) cases. There were some segmental gains and some segmental loss that occurred in PL but not in the other types of lymphoma suggesting that these foci may contain genes responsible for the differentiation of this lymphoma. Additionally, some segmental gains and some segmental loss occurred only in PL and AIDS associated DLBCL suggesting that these foci may be associated with HIV infection. Furthermore, some segmental gains and some segmental loss occurred only in PL and PCM suggesting that these lesions may be related to plasmacytic differentiation. Conclusion: To the best of our knowledge, the current study represents the first genomic exploration of PL. The genomic aberration pattern of PL appears to be more similar to that of DLBCL (AIDS-related or non AIDS-related) than to PCM. Our findings suggest that PL may remain best classified as a subtype of DLBCL at least at the genome level. [ABSTRACT FROM AUTHOR]

Background: Prostate cancer is characterized by heterogeneity in the clinical course that often does not correlate with morphologic features of the tumor. Metastasis reflects the most adverse outcome of prostate cancer, and to date there are no reliable morphologic features or serum biomarkers that can reliably predict which patients are at higher risk of developing metastatic disease. Understanding the differences in the biology of metastatic and organ confined primary tumors is essential for developing new prognostic markers and therapeutic targets. Methods: Using Affymetrix oligonucleotide arrays, we analyzed gene expression profiles of 24 androgen-ablation resistant metastatic samples obtained from 4 patients and a previously published dataset of 64 primary prostate tumor samples. Differential gene expression was analyzed after removing potentially uninformative stromal genes, addressing the differences in cellular content between primary and metastatic tumors. Results: The metastatic samples are highly heterogenous in expression; however, differential expression analysis shows that 415 genes are upregulated and 364 genes are downregulated at least 2 fold in every patient with metastasis. The expression profile of metastatic samples reveals changes in expression of a unique set of genes representing both the androgen ablation related pathways and other metastasis related gene networks such as cell adhesion, bone remodelling and cell cycle. The differentially expressed genes include metabolic enzymes, transcription factors such as Forkhead Box M1 (FoxM1) and cell adhesion molecules such as Osteopontin (SPP1). Conclusion: We hypothesize that these genes have a role in the biology of metastatic disease and that they represent potential therapeutic targets for prostate cancer. [ABSTRACT FROM AUTHOR]

Background: The DecisionDx-Melanoma test provides prognostic information for patients with cutaneous melanoma (CM). Using formalin-fixed paraffin-embedded primary tumor tissue, the RT-PCR-based test classifies patients into a low- (Class 1) or high-risk (Class 2) category for recurrence based on expression of 31 genes. The current study was designed to assess the analytical validity of this test. Methods: Inter-assay, inter-instrument, and inter-operator studies were performed to evaluate reliability of the 31-gene expression test results, sample stability and reagent stability. From March 2013 through June 2016, the gene expression test was performed on 8244 CM tumors. De-identified data from Pathology Reports were used to assess technical success. Results: Robust sample and reagent stability was observed. Inter-assay concordance on 168 specimens run on 2 consecutive days was 99% and matched probability scores were significantly correlated (R2 = 0.96). Inter-instrument concordance was 95%, and probability scores had a correlation R2 of 0.99 (p < 0.001). From 8244 CM specimens submitted since 2013, 85% (7023) fulfilled pre-specified tumor content parameters. In these samples with sufficient tumor requirements, the technical success of the test was 98%. Conclusion: DecisionDx-Melanoma is a robust gene expression profile test that demonstrates strong reproducibility between experiments and has high technical reliability on clinical samples. [ABSTRACT FROM AUTHOR]