High Discordance Rate Research Articles

Mild dermatoglyphic deviations in adolescents with autism spectrum disorders and average intellectual abilities as compared to typically developing boys.

Dermatoglyphics, ridge constellations on the hands and feet, are permanently formed by the second trimester of pregnancy. Consequently, they are considered “fossilized” evidence of a specific prenatal period. A high frequency of dermatoglyphic anomalies, or a high rate of dermatoglyphic asymmetry (discordance), is an indication of developmental instability (prenatal disturbances) prior to 24-week gestation. Most dermatoglyphic studies in psychiatry focus on adult schizophrenia. Studies on dermatoglyphic deviances and autism are sparse, include severely disturbed and intellectually retarded patients with autism, and are carried out mainly in non-Western European populations. In this study, finger print patterns, atd-angles, and palmar flexion crease patterns (PFCs) are compared between Western European adolescent teenage males, of average intellect, with Autism Spectrum Disorders (ASD; n = 46) and typically developing adolescent teenage males (TD; n = 49). Boys with ASD had a higher rate of discordance in their finger print patterns than TD boys. Thus, the hypothesized prenatal disturbances that play a role in the etiology of schizophrenia and severe autism might not be specific to these severe psychiatric disorders but might also be involved in the etiology of varying degrees of ASD.

Endobronchial Ultrasound–guided Transbronchial Needle Aspiration for Lymphoma: The Final Frontier

Endobronchial Ultrasound–guided Transbronchial Needle Aspiration for Lymphoma: The Final Frontier

Prospective clinical experience with research biopsies in breast cancer patients

There are ethical concerns regarding the performance of biopsies in patients for research purposes. We examined our single-institution experience regarding acceptance, safety, and success rate with research biopsies in patients with breast cancer. Among patients with data from paired samples, receptor status agreement between primary and metastatic samples was examined, either on first recurrence or after progression on one or more lines of therapy. An IRB-approved prospective study at the Dana-Farber Cancer Institute collects research biopsies as additional passes at the time of a clinical biopsy (AB, additional biopsy) or as a separate procedure for banking purposes (RPOB, research purposes only biopsy). Biopsies are not linked to a specific therapeutic or correlative trial. Grade 2–5 adverse events are prospectively collected. 151 patients were included in the analytic cohort (total procedures = 161); 80.8 % underwent AB, 17.2 % underwent RPOB, and 2.0 % underwent both AB and RPOB. Most patients were white (88.7 %) with a performance status of 0–1 (94.0 %). 96.0 % of patients underwent a biopsy in the setting of known or suspected metastatic disease. Receptor status between primary cancer and recurrent research biopsies differed in 43.2 % of patients with available data (18.8 % among patients who underwent the research biopsy before any systemic treatment, 48.1 % after treatment). Tissue was successfully collected in 92.3 % of patients undergoing AB and 100 % patients undergoing RPOB. Only three (2.0 %) patients had adverse events ≥grade-2: one grade-2 pain; one grade-2 pneumothorax; and one grade-3 pain. Our experience suggests research biopsies can be performed safely with a high rate of successful tissue collection. Consistent with previous reports we found a high rate of discordance between primary and metastatic samples, which was even higher among treated patients. This supports continued efforts to study tissue samples at multiple points in a patient’s disease course.

Pathologic Discordance of Differentiation Between Endoscopic Biopsy and Postoperative Specimen in Mucosal Gastric Adenocarcinomas

Tumor differentiation is a major determinant of endoscopic resection in mucosal gastric cancers, and the treatment decision is usually based on a preoperative endoscopic biopsy. However, in a proportion of patients, the pathologic assessment of differentiation differs between the endoscopic biopsy and postgastrectomy specimen. This discrepancy is important in that it may lead to an additional radical gastrectomy after endoscopic resection or unnecessary operation for patients who could have been treated with endoscopic resection. This study aimed to investigate the frequency of such cases and to identify risk factors for discordance in patients with mucosal gastric adenocarcinoma. The clinicopathologic characteristics of 1,326 patients who underwent curative gastrectomy for mucosal gastric cancer at Asan Medical Center from 2007 to 2011 were retrospectively reviewed. The overall discordance was 21.5 % (285 cases), and clinically significant discordant rate was 11.9 % (157 cases). Ninety-nine tumors (7.5 %) with differentiated histology on preoperative biopsy were found to be undifferentiated on postoperative pathology. Additionally, 58 patients (4.4 %) with undifferentiated histology on preoperative biopsy exhibited differentiated histology postoperatively. Multivariate analysis revealed that age, sex, tumor location, size, and gross pattern were associated with overall pathologic discordance. In patients with clinically significant discordance, only tumor location (cardia) and size ([2 cm) were independent factors for discordance. Considering a high discordance rate of differentiation between biopsy samples and resected specimens in mucosal cancer in cardia, performing endoscopic resection for confirmative diagnosis of differentiation before total gastrectomy can be a good option.

Alterations in the EGFR pathway coincide in colorectal cancer and impact on prognosis

Alterations of the downstream effectors of the epidermal growth factor receptor (EGFR) are common events in colorectal cancer (CRC) carcinogenesis. Since EGFR serves as a target for therapy and some downstream effectors of EGFR have predictive and prognostic impact, reliable information on the frequency and concordance of alterations in the signaling pathway has become clinically significant. We, therefore, determined the frequency and coincidence of mutations in the EGFR pathway. We also analyzed the concordance of these alterations between primary tumor and distant metastases. Furthermore, we assessed their prognostic relevance for the development of metastasis. Mutations of KRAS exon 2, BRAF exons 11 and 15, AKT exon 3, and PIK3CA exons 9 and 20 were analyzed by pyrosequencing in 171 primary CRC samples as well as in 63 corresponding metastases. Furthermore, the expression of PTEN and EGFR was assessed by immunohistochemistry. Of the 171 tumors investigated, 60.2% showed mutations in one or more genes of pathways downstream of EGFR. KRAS exon 2 and BRAF exon 15 mutations were detected in 40.9 and 11.1% of cases, respectively, and were mutually exclusive. Mutations in exons 9 and 20 of the PIK3CA gene (18.7%) largely overlapped with exon 2 KRAS mutations (16 of 32 cases; 50.0%) and, to a lesser extent, with exon 15 mutations of BRAF (2 of 32 cases; 6.3%). Only one case had simultaneous mutations of AKT exon 3 (0.6%) and BRAF exon 15. Mutation analysis for KRAS exon 2, BRAF exon 15, PIK3CA exon 20, and AKT exon 3 in primary tumors and in their corresponding metastases revealed 100% concordance. In one case, a PIK3CA exon 9 mutation in the primary tumor could not be detected in the matched distant metastases (κ = 0.9). Three different scores were applied for the evaluation of EGFR immunohistochemistry, and the range of positive cases varied between 8.8 and 52.6%. Loss of PTEN expression was detected in 38.6%. Although the expression of both markers does coincide with KRAS exon 2, BRAF exon 15, AKT exon 3, and PIK3CA exons 9 and 20 mutations, high discordance rates were found. The presence of at least one alteration in downstream effectors of the EGFR pathway was associated with a higher rate of distant metastases (p = 0.002). PIK3CA exons 9 and 20 mutations overlap with KRAS exon 2 and BRAF exon 15 mutations, and BRAF exon 15 and AKT exon 3 mutations co-occur in a single tumor, whereas KRAS exon 2 and BRAF exon 15 mutations are mutually exclusive. This suggests that mutations in the PIK3CA/PTEN/AKT branch of the EGFR pathway are less important than those of the RAS/RAF/MAPK branch for the progression of CRC. We found no difference in the mutational status of KRAS exon 2, BRAF exon 15, and AKT exon 3 between primary tumor and distant metastasis, validating both for diagnostic purposes. PIK3CA exons 9 and 20 mutations can be discordant between primary tumor and distant metastasis, and therefore, the lesion which is targeted for therapy should be tested. Protein expression of PTEN and EGFR using current protocols yields highly discordant results, and better standardization is needed before these markers can be used for diagnostic purposes.

High discordance rates between sub-areolar and peri-tumoural breast lymphoscintigraphy

To test the hypothesis that sub-areolar (SA) lymphoscintigraphy (LSG) identifies the same sentinel node as peri-tumoural (PT) injections. It is commonly believed that all LSG techniques will identify the same sentinel lymph nodes (SLN) draining the breast. Hybrid imaging technology (SPECT/CT) allows accurate identification of the exact location of SLNs. Using SPECT/CT SA and PT LSG techniques were compared. In a multi-centre trial 39 patients sequentially underwent LSG (SA followed by PT) separated by 2-7 days. Patients were referred by 4 surgeons to 3 LSG centres, with standardization of isotope (99mTc-antimony sulfide colloid), LSG and SPECT/CT evaluation techniques. LSG were evaluated for SLN concordance and degree of discordance in the axilla and internal mammary nodes (IMN). 39 eligible patients, median age 62 years, were recruited. Successful axillary SLN mapping for SA and PT injection techniques was 87% and 95% respectively. Successful internal mammary SLN mapping occurred with SA and PT LSG in 5% and 36% respectively. Discordance was identified in the IMN (39%) and axilla (21%), with an overall rate of discordance between SA and PT LSG of 56%. There is a high level of discordance in the localization of SLN by these commonly used LSG injection techniques. This discordance has implications for accuracy of axillary and extra-axillary staging and could impact on patient outcome.

Use of flow cytometry during induction chemotherapy to determine outcomes in acute myeloid leukemia.

7104 Background: The use of MRD to predict outcome in AML is controversial. We sought to determine concordance between FC and BM biopsy morphology on day 14 (D14BM) and CR bone marrow (CRBM) specimens and whether MRD detected by FC predicted for inferior outcomes. Methods: We performed a retrospective analysis of adult AML patients treated between 2005 and 2010 with standard induction chemotherapy. Based upon BM morphology and FC, patients were designated as BM+FC+, BM+FC-, BM-FC+, or BM-FC-. Outcomes assessed included induction failure, RFS and OS. Results were adjusted for age at diagnosis, NCCN risk classification, and secondary AML status. Results: Of 287 evaluable patients, 74 had D14 BM and FC results and 98 had CR BM and FC results. Using BM morphology as the gold standard, discordance rates for the presence and absence of disease for the D14 BM by FC were 29% and 23% respectively. Multivariate analysis revealed that patients categorized as BM-FC+ at D14 were more likely to experience induction failure (HR 8.62, CI 0.36-208) and had lower RFS and OS (HR 1.47, 1.95 CI 0.40-5.41, 0.52-7.36 respectively). Analysis of the CR BM samples showed similar results. Conclusions: In this retrospective study there was a high discordance rate between FC and BM morphology on D14 BM and CR BM. While there was a trend toward inferior patient outcomes when disease was detected by FC but not morphology, this was not statistically significant. Limitations of our study include the retrospective nature of the analysis, paucity of patient samples that had a FC evaluation, lack of data to see if positive FC at D14 or CR changed clinician therapy choices and interpretation bias by pathologists as a result of access to FC results during BM morphology interpretation. Larger prospective studies are needed to evaluate whether MRD detected by FC as early as D14 during AML therapy affects clinical outcomes.

Differences in the Receptor Status between Primary and Recurrent Breast Cancer - The Frequency of and the Reasons for Discordance

Objective: Receptor discordances between primary and recurrent breast cancer have been described for years, but only a few analyses have elucidated the factors that influence receptor changes. Methods: Explorative analyses of prospective data from a breast cancer database of a tertiary breast cancer unit. Results: Recurrent tumours that had expressed oestrogen (ER) and progesterone receptors (PR) and human epidermal growth factor receptor 2 (HER2) as primary tumours were negative for the respective receptor in 22.8, 41.4 and 40.8% of cases. ER, PR and HER2 expression was found in 19.8, 16.7 and 11.5% of recurrent tumours, although no expression had been observed in primary tumours. Receptor discordances in recurrent disease leading to different therapeutic approaches were noted in 126 of 411 patients (30.7%). In patients with tumours expressing primary ER and HER2, independent factors associated with discordance were endocrine therapy and treatment with trastuzumab. Conclusion: High rates of receptor discordance were found. The impact of factors that influence receptor changes is small so that no subgroup of patients with recurrent breast cancer should be excluded from biopsy. Whenever possible, a biopsy should be taken to confirm the diagnosis of a possible relapse as well as the receptor status of patients with breast cancer.

Hepatitis E: Clinical Presentation in Disease-Endemic Areas and Diagnosis

Infection with hepatitis E virus (HEV), mostly genotype 1, is endemic in several developing countries. It can be asymptomatic, be associated with acute hepatitis or fulminant hepatic failure, or present as acute-on-chronic liver disease. Pregnant women are at particular risk of serious outcomes and death. Chronic HEV infection has not been reported from these areas. Diagnosis of acute hepatitis E depends on detection of IgM anti-HEV antibodies or HEV RNA. Current assays for IgM anti-HEV are suboptimal, with high rates of interassay discordance. Though they perform reasonably well in disease-endemic areas, positive test results in low-endemicity areas require confirmation using HEV RNA testing. Detection of IgG anti-HEV antibodies indicates exposure to HEV, either recent or remote. Assays for these too have low concordance, making comparisons of seroprevalence rates using different assays difficult to interpret. There is an urgent need to develop better assays for markers of HEV infection and exposure.

Discordance of community and hospital ultrasound reports for urological abnormalities

In Ontario, community ultrasound clinics do not require the on-site presence of a radiologist at the time of imaging. In hospitals, a radiologist is always present for this step. We compared the discrepancy rate of community and hospital ultrasound reports in a urology practice. We retrospectively reviewed the charts of patients who had abdominal ultrasound performed in the community and in the hospital between April 1, 2001 and June 30, 2005. Reports were examined for indication, findings and whether there was a discrepancy. A medical student, a resident, and a staff physician each independently reviewed the findings. One hundred and twenty-two patients had abdominal ultrasound performed in the community and were followed up with hospital imaging. Sixty-nine patients had a community ultrasound followed by hospital ultrasound, with a discordance rate of 52.2%. Fifty-three patients had a community ultrasound and then a hospital CT scan, with a discordance rate of 43.3%. Of patients with discordant ultrasound reports, 23 had an additional CT scan in which all findings were consistent with the hospital ultrasound findings. We found a very high discordance rate between community and hospital ultrasound reports. This is consistent with a study showing that the active role of the radiologist in ultrasound imaging is very important for accurate reporting. Ultrasound reports form the community in patients referred to our urology practice have a high discrepancy rate when compared with ultrasound or CT scan reports from the hospital setting. We found no discordance between ultrasound and CT scan findings from imaging performed in hospital. We recommend standardization of abdominal ultrasound imaging protocols across Canada to include the presence of a radiologist at all times.

Uncertainty in ultrasound reporting

Chung and colleagues present an interesting study on the high discordance rate between community and hospital ultrasound reports for urologic abnormalities.1 This retrospective chart review found a discordance rate of 52.2% in community ultrasound reports followed by hospital ultrasound findings. A discordance rate of 43.3% was found with community ultrasound reports followed by hospital CT scans. In total, the discrepancy rate between hospital and community studies was 48.4%. Conversely, the discordance rate between hospital ultrasound and hospital CT scan reports was 0%; that is, hospital CT scan findings agreed with hospital ultrasound findings in all cases. The authors acknowledge the limitations of the study, including temporal bias, as the hospital studies were all performed after the community studies. There is variation in quality and expertise of the community ultrasound sites and technologists, which was not stratified. In many provinces, such as Alberta and Quebec, it is mandated that a radiologist be on site at all times during the provision of ultrasound. This is not a requirement in Ontario (where the study was performed) in that a radiologist has to be available but not on site at the time of the ultrasound examination. However, in this study it is assumed that the radiologist was not present during any of the community ultrasounds, when in fact a radiologist may have been called in for at least some of these community ultrasounds. The variability in ultrasound technician experience in these community centres may also have a profound impact. This does not diminish the surprising discordance between community ultrasound examinations and hospital examinations in this study. This up to 48% discordance creates not a trivial increase in cost to the system associated with repetition of radiologic studies, anxiety and confusion for patients and doctors over uncertain results. To correct this discordance, it remains to be proven whether the confounding factors are lack of quality equipment, ultrasound technician experience or the presence of an on-site radiologist. Certainly this discordance between community and hospital radiology centres is unacceptable and requires further study.

Different metastatic pattern according to the KRAS mutational status and site-specific discordance of KRAS status in patients with colorectal cancer

BackgroundWe evaluated the association between a KRAS mutational status and various clinicopathologic features including the metastatic pattern in patients with metastatic or recurrent colorectal cancer (MRCRC). The concordance rates of the KRAS status between primary tumor sites and paired metastatic organs were also analyzed.MethodsThe KRAS mutational status in codons 12, 13, and 61 from formalin-fixed sections of both primary tumors and related metastases was determined by sequencing analysis. One hundred forty-three Korean patients with MRCRC with available tissues (resection or biopsy) from both primary tumors and related metastatic sites were consecutively enrolled.ResultsThe KRAS mutation rate was 52.4% (75/143) when considering both the primary and metastatic sites. When the relationship between the KRAS status and initial metastatic sites at the time of diagnosis of MRCRC was analyzed, lung metastasis was more frequent as the initial metastatic site in patients with the KRAS mutation than in patients without the KRAS mutation (45.3% vs. 22.1%; P = 0.003). However, liver (37.3% vs. 70.6%; P < 0.001) or distant lymph node metastases (6.7% vs. 19.1%; P = 0.025) were less frequent as the initial metastatic organ in patients with the KRAS mutation than in patients without the KRAS mutation. The discordance rate of KRAS mutational status between primary and paired metastatic sites other than the lung was 12.3% (13/106). Compared with primary tumor sites, the KRAS discordance rate was significantly higher in matched lung metastases [32.4% (12/37)] than in other matched metastatic organs (P = 0.005).ConclusionsOrgans initially involved by distant metastasis were different according to the KRAS mutational status in MRCRC patients. The concordance rate (87.7%) of the KRAS mutation status at metastatic sites other than the lung was generally high compared with primary tumor sites; however, lung metastasis had a high rate of KRAS discordance (32.4%).

Risk factors associated with perineural invasion in prostate cancer

Abstract Objectives The prognostic importance of perineural invasion (PNI) in prostate cancer (PC) has been postulated by some authors. Few studies have investigated the risk factors associated with PNI. The aim of this study was to identify factors associated with PNI in PC. Patients and methods The study group of 113 patients diagnosed with PC during the period 2005–2010 consisted of 66 who underwent radical prostatectomy (RP) and 66 who did not. Each group was further divided into those with and without PNI. The association between clinicopathological parameters and PNI in prostate biopsy (Pbx) and RP specimens was investigated using t -test and logistic regression analysis. Discordance in PNI prevalence and PNI up-migration between Pbx and RP specimens were also studied. Results In patients who did not undergo RP, Pbx Gleason score (GS) ≥ 7 was a significant predictor for the presence of PNI. In patients who underwent RP, Pbx GS > 7 increased the risk of PNI in Pbx and RP samples, while a high RP GS predicted PNI in the RP specimen. The discordance rate for PNI in Pbx and RP specimens was 27.3%. Up-migration to a PNI positive cancer between Pbx and RP specimens was seen in 45.5% of cases and RP GS was the only factor associated with PNI up-migration. Conclusion The association of PNI with a high GS and the high rate of discordance between Pbx and RP specimens indicate that in patients with a high GS on Pbx, the pathologist should look more carefully for PNI, and the surgeon should be aware of sampling errors and the unreliability of Pbx specimens in detecting PNI.

Concordância entre core biopsy e exame anatomopatológico da peça cirúrgica em pacientes com câncer de mama

INTRODUÇÃO: A core biopsy (CB) tem ganhado espaço cada vez mais importante no diagnóstico e no manejo do câncer de mama devido a seu baixo custo e alta acurácia. Entretanto, devemos nos perguntar se esse método realmente é adequado para a caracterização do tipo histológico e do grau de diferenciação tumoral, uma vez que a região biopsiada pode não ser representativa do tumor como um todo. OBJETIVO: Avaliar a concordância entre o anatomopatológico da biópsia e o encontrado na peça cirúrgica. MATERIAL E MÉTODOS: Realizamos um estudo retrospectivo envolvendo todos os pacientes com câncer de mama submetidos à mastectomia radical modificada ou à quadrantectomia em nosso serviço, entre janeiro de 2007 a dezembro 2009, analisando a taxa de concordância entre o resultado da CB do tumor de mama e o anatomopatológico da peça cirúrgica. Estudamos como variáveis o tipo histológico e o grau de diferenciação tumoral e de invasão linfovascular. RESULTADOS: Os resultados mostraram taxa de concordância para tipo histológico de 76% entre os métodos. Já a concordância para o grau tumoral foi de 50%, observando-se uma tendência da CB a subestimar o grau. Em relação à presença de invasão linfovascular, ocorreram 62,09% de concordância, sendo 100% seu valor preditivo positivo (VPP), mas com baixa sensibilidade (29%). CONCLUSÃO: Esses achados sugerem que a CB seja o método adequado para o diagnóstico histológico do câncer de mama, porém apresenta alta taxa de discordância para grau tumoral e invasão linfovascular com o exame anatomopatológico da peça cirúrgica, tendendo a subestimar a agressividade do tumor.

Researchers find discordance between standard human epidermal growth factor receptor 2 (HER2) testing and HER2 status reported on Oncotype DX

Researchers find discordance between standard human epidermal growth factor receptor 2 (HER2) testing and HER2 status reported on Onco<i>type</i> DX

Differences in Bone Mineral Density between the Right and Left Hips in Postmenopausal Women

Bone mineral density (BMD) using dual energy radiography absorptiometry are commonly used for the diagnosis of osteoporosis. It is usually measured at the spine and also at one hip joint. Controversy still exists regarding the use of bilateral hip scanning. We analyzed the difference of BMD at bilateral hips in 384 postmenopausal women, retrospectively. The concordance and discordance rates of the lowest T-score and BMD between both hips were evaluated. The BMDs of the femoral neck and trochanter were significantly different between both hips (P < 0.05). There were also discrepancies between the lowest T-scores of both hips (P < 0.05). The discordance rates were about 30%. Due to significant differences in BMD between both hips at the femoral neck and trochanter and high discordance rate, bilateral hip measurements using DEXA are recommended to avoid underestimating osteoporosis.

Epigenetics and the Developmental Origins of Inflammatory Bowel Diseases

The gut microbiota, the intestinal mucosa and the host immune system are among the large biological networks involved in the development of inflammatory bowel disease (IBD), which includes Crohn disease (CD) and ulcerative colitis (UC). Host genetics and environmental factors can significantly modulate the interactive relationships among these biological systems and influence predilection toward IBD. High monozygotic twin discordance rates and the rapid rise in the prevalence of IBD indicate that environmental influences may be as important or even more important in their pathogenesis than genetic susceptibility. However, the nature and timing of environmental factors critical for inducing IBD remain largely unknown. The molecular mechanisms and the key biological component(s) that may be affected by such factors are also in question. Epigenetic changes, such as DNA methylation (the methylation of cytosines followed by a guanine in CpG dinucleotides) can be modified by environmental influences during finite developmental periods and have been implicated in the pathogenesis of IBD. Mucosal DNA methylation can also react to changes in the commensal microbiota, underscoring the intercalating relationships among the large biological systems involved in gastrointestinal disorders. Therefore, transient environmental influences during specific periods of development may induce critical change(s) in an isolated or concomitant fashion within the intestinal biomic networks and lead to increased susceptibility to IBD. The present review focuses on the emerging paradigm shift considering IBD to originate from critical environmental effects during pre- and postnatal development.

P4-07-14: Circulating Tumor Cells (CTCs) Detection and HER2 Profiling by CellSearch® in Non-Metastatic Breast Cancer: An International Ring Study To Assess Inter-Reader Variability.

Abstract Background: Preliminary results from the Success and Remagus trials showed that CTC detection by CellSearch® has adverse prognostic value in non-metastatic breast cancer. Moreover, several investigators have characterized HER2 expression on CTCs in early breast cancer. Since the majority of CTC-positive women with non-metastatic breast cancer have only 1 CTC detected / blood volume analyzed, we wanted to evaluate the inter-reader variability in this setting. This is a crucial step before moving forward with multi-lab/multi-center prospective testing of the clinical utility of the CellSearch® technology in non-metastatic breast cancer. Methods: Five galleries of CellSearch® images from 3 European and one US institution (a total of 307 images) were mailed to 22 independent readers from 14 European and US academic laboratories and 8 readers from two CellSearch® Veridex laboratories in a blinded fashion. These images came mainly from studies on CTC and/or HER2−positive CTC detection in breast cancer and included healthy women (negative controls), women with metastatic (positive controls) and non-metastatic disease (Pierga et al SABCS 2010, Pierga et al ASCO 2011, Riedthorf et al CCR 2010, Ignatiadis et al PLoS ONE 2011). Each reader reported the images as either CTC-negative or CTC-positive/HER2−negative or CTC-positive/HER2−positive. Kappa statistics were used to assess inter-reader agreement. The 8 Veridex readers were summarized by a majority voting system to derive a gold standard in order to compare each independent reader using discordance rates. Results: Kappa statistics showed moderate to good agreement between independent readers depending on the gallery evaluated (gallery 1 K: 0.55, gallery 2 K:0.57 gallery 3 K:0.64, gallery 4 K:0.72, gallery 5 K:0.85). These differences were attributed to differences in scoring difficulty of each gallery. Discordances in CTC-positive vs CTC-negative events between each reader and the gold standard ranged from 2.3%-31.3% with 7 readers showing discordance rates &amp;lt;5%, 11 readers between 5–10%, 10 readers between 10–14% and only 2 readers showing discordance rates &amp;gt;14% as compared to the gold standard (median discordance rate: 9.3%). Image analysis showed that investigators with high discordance rates compared to the Veridex gold standard were not always taking into account “morphological characteristics” for defining an event as CTC-positive. Discordant results between readers were mainly due to discordance in CTC definition and to a lesser extent in the definition of HER2−positivity. Indeed, discordances in assigning a CTC-positive event as either HER2−negative or HER2−positive ranged from 0.3−13.7% with 19 readers showing discordance rates &amp;lt;5%, 7 readers between 5–10% and 4 readers with discordance rates &amp;gt;10% (median discordance rate: 3.9%). Conclusion: In non-metastatic breast cancer, we observed low discordance between most independent readers and the gold standard for defining a CellSearch® event as CTC with very few readers showing high discordance rates. Concordance can be improved through appropriate training and the use of all the tools provided by the CellSearch® system for image interpretation. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-07-14.

P3-07-15: Sequential Peri-Areolar and Peri-Tumoural SPECT/CT Lymphoscintigraphy Has Identified High Rates of Discordance in Both Axillary and Internal Mammary Sentinel Lymph Node Mapping.

Abstract Introduction: The release of the MA20 intergroup trial results has confirmed the importance of locoregional radiation on local and distant disease control and survival. Sentinel lymph node (SLN) evaluation is the gold standard for regional lymph node evaluation and radiation oncologists continue to utilize the nodal staging to plan adjuvant locoregional therapy. Despite over a decade of experience in SLN evaluation there persists a common belief that the lymphatic drainage of the whole breast is to anteropectoral axillary lymph nodes. Several different lymphoscintigraphy injection techniques are in use with claims that they all identify the same axillary sentinel nodes. However this is not based on a high level of evidence. The evolution of SPECT/CT has led to the accurate anatomic identification of SLN, hence the different lymphoscintigraphy techniques can now be directly compared. Method: 38 patients underwent double sequential lymphoscintigraphy (peri-areolar followed by peri-tumoural) separated by 1–7 days. Patients were referred by 4 surgeons to 3 separate lymphoscintigraphy centres with standardisation of tracer substance (99mTc-antimony sulfide colloid), lymphoscintigraphy and SPECT/CT evaluation techniques. The degree of discordance in sentinel node evaluation was defined as: Type 1 - One study demonstrates SLN(s) in a nodal basin [axilla or internal mammary chain (IMC)] and the other study demonstrates none. Type 2 - Both studies identified SLN(s) in a nodal basin however the SLN(s) are all different. Type 3 - Both studies identified SLNs in a nodal basin, however some SLN(s) are identical and others not. Results: Notably 21 patients (55%) had either axilla or IMC lymphoscintigraphy discordance. Two patients had both axilla and IMC lymphoscintigraphy discordance. The majority of discordance was identified in the IMC. In the concordant IMC lymphoscintigraphies neither study demonstrated IMC SLN. There were no studies that identified identical IMC nodes in both PA and PT lymphoscintigraphy. Discordant axillary drainage was more evident in patients with lateral sector tumours compared to IM discordance with medial sector tumours. Conclusions: Accurate lymphoscintigraphy is the road map to assist a surgeon identify lymph node metastases. In turn accurate staging will determine appropriate adjuvant therapy decisions particularly regional node irradiation. This study demonstrates a high degree of discordance between PA and PT lymphoscintigraphy techniques in 55% of patients. Inadequate lymphoscintigraphy can result in unrealized false negative results, which could impact patient outcomes and clinical trial results. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-07-15.

Sampling variability of transient elastography according to probe location

Heterogeneity of fibrosis throughout the liver has been reported. However, the need for several measurements when using transient elastography was not thoroughly investigated. The aim was to find out whether measurement of liver stiffness varies according to the probe location. Six hundred and twenty-five consecutive patients with chronic liver diseases referred for transient elastography were enrolled. All patients underwent successive liver stiffness measurements at three different sites. Representative measurements were acquisitions with a success rate greater than 60% and an interquartile range lower than 30% of the median. The sample included 371 eligible patients with three representative measurements. Comparing the three successive measurements categorized to fibrosis stages F0-F4, 68.2% of patients had agreement between all three sites. Discordance of one stage was noted in 28.3% of the patients, in 7% for two stages, and in 1.4% for three stages.The κ for comparing the maximal versus the minimal results was 0.43. There was no significant difference in the characteristics of patients with discordance and patients without discordance including age, sex, waist circumference, BMI, and etiology of liver disease. The stage of fibrosis was associated with discordance between measurements (P<0.001), demonstrating low discordance rate in patients with stages F0-F1 or F4 and high discordance rate in patients with stages F2 and F3. Sampling variability according to probe location is seen in transient elastography in approximately 30% of patients. Therefore, it may be suggested to perform transient elastography from various sites to minimize the sample error.