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Objective To evaluate intervention of structured reporting after wrong-site surgery that occurred after localization of an incorrect breast biopsy marker. Methods An IRB-exempt retrospective database review identified patients who underwent core-needle biopsy of a breast lesion from July 1, 2014 to July 1, 2020. They were divided into three cohorts: 2014 pre-intervention/pre-sentinel, 2017 pre-intervention/post-sentinel, and 2019 post-intervention of structured reports. One hundred reports per cohort were reviewed for documentation of marker and shape. Statistical analysis was performed with mixed-effects logistic regression model and chi-squared test with P Results The 2014 cohort consisted of 100 patients with 122 biopsies. Twenty-seven (22.1%) were excluded: 5/122 (4.1%) lesion resolution, 22/122 (18.0%) no documentation whether marker was/was not placed. Of the 95 biopsies remaining, 4/95 (4.2%) had no marker placed, 62/95 (65.3%) reported marker only, and 29/95 (30.5%) reported marker and shape. In the 2017 cohort, 100 patients underwent 108 biopsies. Four/108 (3.7%) were excluded: lesion resolution. Of the 104, 10/104 (9.6%) had no marker placed, 22/104 (21.2%) reported marker only, and 72/104 (69.2%) reported marker and shape. In the 2019 cohort, 100 patients underwent 114 biopsies. Two/114 (1.8%) were excluded: lesion resolution. Of the 112, 3/112 (2.7%) had no marker placed, 3/112 (2.7%) reported marker only, and 106/112 (94.6%) reported marker and shape. The predicted probability of both marker placement and shape described were statistically greater for 2019 compared to the other cohorts (P Conclusion Using structured reports facilitates and improves documentation of breast biopsy markers and may potentially reduce the risk of medical errors.

Background High-grade squamous intraepithelial lesions (HSIL) or cervical intraepithelial neoplasia (CIN) grade 2/3 lesions in human papillomavirus (HPV)–positive women Methods A European multicenter retrospective study was designed evaluating the FAM19A4/miR124-2 methylation test and HPV16/18 genotyping in cervical scrapes of 1061 HPV-positive women aged 15–29 years (690 ≤CIN1, 166 CIN2, and 205 CIN3+). A subset of 62 CIN2 and 103 CIN3 were immunohistochemically characterized by HPV E4 expression, a marker for a productive HPV infection, and p16ink4a and Ki-67, markers indicative for a transforming infection. CIN2/3 lesions with low HPV E4 expression and high p16ink4a/Ki-67 expression were considered as nonproductive, transforming CIN, compatible with advanced CIN2/3 lesions in need of treatment. Results FAM19A4/miR124-2 methylation positivity increased significantly with CIN grade and age groups ( Conclusions Compared with HPV16/18 genotyping, the FAM19A4/miR124-2 methylation test detects nonproductive, transforming CIN2/3 lesions with high specificity in women aged

Purpose: Current staging methods are imprecise for predicting prognosis of early-stage non–small-cell lung cancer (NSCLC). We aimed to develop a gene expression profile for stage I and stage II NSCLC, allowing identification of patients with a high risk of disease recurrence within 2 to 3 years after initial diagnosis.Experimental Design: We used whole-genome gene expression microarrays to analyze frozen tumor samples from 172 NSCLC patients (pT1-2, N0-1, M0) from five European institutions, who had undergone complete surgical resection. Median follow-up was 89 months (range, 1.2-389) and 64 patients developed a recurrence. A random two thirds of the samples were assigned as the training cohort with the remaining samples set aside for independent validation. Cox proportional hazards models were used to evaluate the association between expression levels of individual genes and patient recurrence-free survival. A nearest mean analysis was used to develop a gene-expression classifier for disease recurrence.Results: We have developed a 72-gene expression prognostic NSCLC classifier. Based on the classifier score, patients were classified as either high or low risk of disease recurrence. Patients classified as low risk showed a significantly better recurrence-free survival both in the training set (P < 0.001; n = 103) and in the independent validation set (P < 0.01; n = 69). Genes in our prognostic signature were strongly enriched for genes associated with immune response.Conclusions: Our 72-gene signature is closely associated with recurrence-free and overall survival in early-stage NSCLC patients and may become a tool for patient selection for adjuvant therapy.

Supplementary Data from An Immune Response Enriched 72-Gene Prognostic Profile for Early-Stage Non–Small-Cell Lung Cancer

High-grade cervical intraepithelial neoplasia (CIN2 and CIN3) represent a heterogeneous disease with varying cancer progression risks. Biomarkers indicative for a productive human papillomavirus (HPV) infection (HPV E4) and a transforming HPV infection (p16ink4a , Ki-67 and host-cell DNA methylation), could provide guidance for clinical management in women with high-grade CIN. This study evaluates the cumulative score of immunohistochemical expression of p16ink4a (score 0 - 3) and Ki-67 (score 0 - 3), referred to as the 'immunoscore' (IS), in 262 CIN2 and 235 CIN3 lesions derived from 5 European cohorts in relation to immunohistochemical HPV E4 expression and FAM19A4/miR124-2 methylation in the corresponding cervical scrape. The immunoscore classification resulted in 30 lesions within IS group 0 - 2 (6.0%), 151 lesions within IS group 3 - 4 (30.4%) and 316 lesions within IS group 5 - 6 (63.6%). E4 expression decreased significantly from CIN2 to CIN3 (p

In HPV cervical cancer screening, cytology is used as triage to counter the low specificity of HPV testing. VALID-SCREEN is a EU-multicentre, retrospective study conducted to evaluate the clinical performance of the FAM19A4/miR124-2 methylation-based molecular triage test as a substitute or addition to cytology as reflex testing of HPV screen positive women. FAM19A4/miR124-2 methylation test (QIAsure™ Methylation Test) was evaluated in 2384 HPV-positive cervical screening samples, from women 29-76 years of age, derived from four EU countries. Specimens were collected in ThinPrep or SurePath media, HPV-status, concurrent cytology, and histology diagnosis were provided by the parent institutes. The control population consisted of women with no evidence of disease within two years of follow-up. A total of 899 histologies were retrieved; 527 showed no disease, 124 CIN2 (5.2%), 228 CIN3 (9.6%) and 20 cervical cancers (0.8%); 19 of 20 screen-detected cervical cancers were found methylation-positive (sensitivity 95%). Overall specificity of FAM19A4/miR124-2 methylation test was 78.3% (n=2013; 95%CI: 76-80). The negative predictive value of hrHPV positive, methylation-negative outcomes were 99.9% for cervical cancer (N=1694; 95%CI: 99.6-99.99), 96.9% for ≥CIN3 (95%CI: 96-98), and 93.0% for ≥CIN2 (95%CI: 92-94). Overall sensitivity for CIN3 using FAM19A4/miR124-2 methylation test was 77% (n=228; 95%CI: 71-82). CIN3 sensitivity was uniform between centers independent of sample collection medias, DNA extraction methods and HPV screening tests. Being objectively reported compared to the subjectivity of cytology, equally performing across settings and screening methods, the FAM19A4/miR124-2 methylation constitute an alternative/supplement to cytology as triage method to be investigated in real-life pilot implementation. This article is protected by copyright. All rights reserved.

HSIL or CIN2/3 lesions in HPV-positive women30 years have high spontaneous regression rates. To reduce overtreatment, biomarkers are needed to delineate advanced CIN lesions that require treatment. We analysed the FAM19A4/miR124-2 methylation test and HPV16/18 genotyping in HPV-positive women30 years aiming to identify CIN2/3 lesions in need of treatment.A European multicentre retrospective study was designed evaluating the FAM19A4/miR124-2 methylation test and HPV16/18 genotyping in cervical scrapes of 1,061 HPV-positive women aged 15-29 years (690 ≤CIN1, 166 CIN2 and 205 CIN3+). A subset of 62 CIN2 and 103 CIN3 were immunohistochemically characterized by HPV E4 expression, a marker for a productive HPV infection and p16ink4a and Ki-67, markers indicative for a transforming infection. CIN2/3 lesions with low HPV E4 expression and high p16ink4a/Ki-67 expression were considered as non-productive, transforming CIN, compatible with advanced CIN2/3 lesions in need of treatment.FAM19A4/miR124-2 methylation positivity increased significantly with CIN grade and age groups (25, 25-29 and ≥30 years), while HPV16/18 positivity was comparable across age groups. FAM19A4/miR124-2 methylation positivity was HPV type independent. Methylation-positive CIN2/3 lesions had higher p16ink4a/Ki-67-immunoscores (p = 0.003) and expressed less HPV E4 (p = 0.033) compared with methylation-negative CIN2/3 lesions. These differences in HPV E4 and p16ink4a/Ki-67 expression were not found between HPV16/18-positive and non-16/18 HPV-positive lesions.Compared with HPV16/18 genotyping, the FAM19A4/miR124-2 methylation test detects non-productive, transforming CIN2/3 lesions with high specificity in women30 years, providing clinicians supportive information about the need for treatment of CIN2/3 in young HPV-positive women.

The dodo Raphus cucullatus Linnaeus, 1758, an extinct and flightless, giant pigeon endemic to Mauritius, hasfascinated people since its discovery, yet has remained surprisingly poorly known. Until the mid-19th century, almost all thatwas known about the dodo was based on illustrations and written accounts by 17th century mariners, often of questionableaccuracy. Furthermore, only a few fragmentary remains of dodos collected prior to the bird’s extinction exist. Ourunderstanding of the dodo’s anatomy was substantially enhanced by the discovery in 1865 of subfossil bones in a marsh calledthe Mare aux Songes, situated in southeastern Mauritius. However, no contextual information was recorded during earlyexcavation efforts, and the majority of excavated material comprised larger dodo bones, almost all of which wereunassociated. Here we present a modern interdisciplinary analysis of the Mare aux Songes, a 4200-year-old multitaxicvertebrate concentration Lagerst€atte. Our analysis of the deposits at this site provides the first detailed overview of theecosystem inhabited by the dodo. The interplay of climatic and geological conditions led to the exceptional preservation ofthe animal and associated plant remains at the Mare aux Songes and provides a window into the past ecosystem of Mauritius.This interdisciplinary research approach provides an ecological framework for the dodo, complementing insights on itsanatomy derived from the only associated dodo skeletons known, both of which were collected by Etienne Thirioux and arethe primary subject of this memoir.

Widespread adoption of primary human papillomavirus (HPV)‐based screening has encouraged the search for a triage test which retains high sensitivity for the detection of cervical cancer and precancer, but increases specificity to avoid overtreatment. Methylation analysis of FAM19A4 and miR124‐2 genes has shown promise for the triage of high‐risk (hr) HPV‐positive women. In our study, we assessed the consistency of FAM19A4/miR124‐2 methylation analysis in the detection of cervical cancer in a series of 519 invasive cervical carcinomas (n = 314 cervical scrapes, n = 205 tissue specimens) from over 25 countries, using a quantitative methylation‐specific PCR (qMSP)‐based assay (QIAsure Methylation Test®). Positivity rates stratified per histotype, FIGO stage, hrHPV status, hrHPV genotype, sample type and geographical region were calculated. In total, 510 of the 519 cervical carcinomas (98.3%; 95% CI: 96.7–99.2) tested FAM19A4/miR124‐2 methylation‐positive. Test positivity was consistent across the different subgroups based on cervical cancer histotype, FIGO stage, hrHPV status, hrHPV genotype, sample type and geographical region. In conclusion, FAM19A4/miR124‐2 methylation analysis detects nearly all cervical carcinomas, including rare histotypes and hrHPV‐negative carcinomas. These results indicate that a negative FAM19A4/miR124‐2 methylation assay result is likely to rule out the presence of cervical cancer., What's new? Methylation analysis of host cell genes is a promising strategy for the triage of women who test positive for high‐risk human papillomavirus (hrHPV). Its ability to consistently detect cervical cancer, however, warrants further evaluation. In this retrospective cross‐sectional study of more than 500 cervical cancer cases worldwide, methylation analysis using FAM19A4 and miR124‐2 genes successfully detected the vast majority of cervical carcinomas. Detection by FAM19A4/miR124‐2 methylation analysis was consistent regardless of multiple factors, including hrHPV status and genotype, cancer histotype, sample type, and geographical region. The findings suggest that a negative FAM19A4/miR124‐2 methylation test result is likely to rule out cervical cancer.

BACKGROUND: HPV-based cervical screening detects women at an increased risk of cervical cancer and precancer. To differentiate among HPV-positive women those with (pre)cancer, triage testing is necessary. The detection of cancer-associated host-cell DNA methylation (FAM19A4 and hsa-mir124-2) in cervical samples has shown valuable as triage test. This multicenter study from 6 collaborating European laboratories and one reference laboratory was set out to determine the intra- and inter-laboratory agreement of FAM19A4/mir124-2 DNA methylation analysis utilizing the QIAsure Methylation Test.METHODS: Agreement analysis for the QIAsure Methylation Test was assessed on high-risk HPV-positive cervical specimens (n = 1680) both at the level of the assay and at the full workflow, including bisulfite conversion.RESULTS: Intra- and inter-laboratory assay agreement were 91.4% (534/584; 95% CI 88.9-93.5; κ = 0.82) and 92.5% (369/399; 95% CI 90.0-94.7; κ = 0.83), respectively. The inter-laboratory workflow (bisulfite conversion and assay combined) agreement was 90.0% (627/697; 95% CI 87.5%-92.0%; κ = 0.76).CONCLUSION: These data show that the QIAsure Methylation Test performs robust and reproducible in different laboratory contexts. These results support the use of the QIAsure Methylation Test for full molecular screening for cervical cancer, including primary HPV testing and triage testing by methylation analysis.

MammaPrint is an FDA-cleared microarray-based test that uses expression levels of the 70 MammaPrint genes to assess distant recurrence risk in early-stage breast cancer. The prospective RASTER study proved that MammaPrint Low Risk patients can safely forgo chemotherapy, which is further subject of the prospective randomized MINDACT trial. While MammaPrint diagnostic results are obtained from mini-arrays, clinical trials may be performed on whole-genome arrays. Here we demonstrate the equivalence and reproducibility of the MammaPrint test. MammaPrint indices were collected for breast cancer samples: (i) on both customized certified array types (n = 1,897 sample pairs), (ii) with matched fresh and FFPE tissues (n = 552 sample pairs), iii) for control samples replicated over a period of 10 years (n = 11,333), and iv) repeated measurements (n = 280). The array type indicated a near perfect Pearson correlation of 0.99 (95 % CI: 0.989–0.991). Paired fresh and FFPE samples showed an excellent Pearson correlation of 0.93 (95 % CI 0.92–0.94), in spite of the variability introduced by intratumoral tissue heterogeneity. Control samples showed high consistency over 10 year's time (overall reproducibility of 97.4 %). Precision and repeatability are overall 98.2 and 98.3 %, respectively. Results confirm that the combination of the near perfect correlation between array types, excellent equivalence between tissue types, and a very high stability, precision, and repeatability demonstrate that results from clinical trials (such as MINDACT and I-SPY 2) are equivalent to current MammaPrint FFPE and fresh diagnostics, and can be used interchangeably. Electronic supplementary material The online version of this article (doi:10.1007/s10549-016-3764-5) contains supplementary material, which is available to authorized users.