MLLT11 Regulates Endometrial Stroma Cell Adhesion, Proliferation and Survival in Ectopic Lesions of Women with Advanced Endometriosis.

MLLT11 is a gene implicated in cell differentiation and the development and progression of human cancers, but whose role in the pathogenesis of endometriosis is still unknown. Using quantitative RT-PCR and immunohistochemistry, we analyzed 37 women with and 33 women without endometriosis for differences in MLLT11 expression. We found that MLLT11 is reduced in the ectopic stroma cells of women with advanced stage endometriosis compared to women without endometriosis. MLLT11 knockdown in control stroma cells resulted in the downregulation of their proliferation accompanied by G1 cell arrest and an increase in the expression of p21 and p27. Furthermore, the knockdown of MLLT11 was associated with increased apoptosis resistance to camptothecin associated with changes in BCL2/BAX signaling. Finally, MLLT11 siRNA knockdown in the control primary stroma cells led to an increase in cell adhesion associated with the transcriptional activation of ACTA2 and TGFB2. We found that the cellular phenotype of MLLT11 knockdown cells resembled the phenotype of the primary endometriosis stroma cells of the lesion, where the levels of MLLT11 are significantly reduced compared to the eutopic stroma cells of women without the disease. Overall, our results indicate that MLLT11 may be a new clinically relevant player in the pathogenesis of endometriosis.

Multisystem inflammatory syndrome in children (MIS-C): Implications for long COVID.

The COVID-19 pandemic caused by the coronavirus 2 of the severe acute respiratory syndrome (SARS-CoV-2) has significantly affected people around the world, leading to substantial morbidity and mortality. Although the pandemic has affected people of all ages, there is increasing evidence that children are less susceptible to SARS-CoV-2 infection and are more likely to experience milder symptoms than adults. However, children with COVID-19 can still develop serious complications, such as multisystem inflammatory syndrome in children (MIS-C). This narrative review of the literature provides an overview of the epidemiology and immune pathology of SARS-CoV-2 infection and MIS-C in children. The review also examines the genetics of COVID-19 and MIS-C in children, including the genetic factors that can influence the susceptibility and severity of the diseases and their implications for personalized medicine and vaccination strategies. By examining current evidence and insights from the literature, this review aims to contribute to the development of effective prevention and treatment strategies for COVID-19, MIS-C, and long COVID syndromes in children.

Atezolizumab plus nab-paclitaxel for unresectable, locally advanced or metastatic breast cancer: real-world results from a single academic center in Austria.

PURPOSE: IMpassion130 led to the approval of atezolizumab plus nab-paclitaxel as first-line treatment for patients with unresectable locally advanced or metastatic triple-negative, PD-L1 immune-cell positive breast cancer (BC) by the European Medicines Agency (EMA). The objective of the present study was to investigate the implementation, safety and efficacy of this combination in the initial phase after approval. METHODS: A retrospective data analysis including all BC patients who received atezolizumab and nab-paclitaxel between 1.1.2019 and 31.10.2020 at the Department of Obstetrics and Gynecology and the Department of Medicine 1, respectively, at the Medical University of Vienna, Austria, was performed. Progression-free survival (PFS) and overall survival (OS) were estimated with the Kaplan-Maier product-limit method. Owing to the retrospective nature of this study, all statistics must be considered exploratory. RESULTS: In total 20 patients were included in the study. Median follow-up was 7.1 months (IQR 5.2-9.1). Median PFS was 3.0 months (SE = .24; 95% CI [2.5; 3.5]). Median OS was 8.94 months (SE = 2.34, 95%CI [4.35; 13.53]). No new safety signals were observed. CONCLUSION: The present study showed a considerably shorter PFS (3.0 vs. 7.5 months) and OS (8.94 vs. 25.0 months) than IMpassion130 putatively owing to the use of atezolizumab in later treatment lines, more aggressive tumors and a study population with higher morbidity compared to the pivotal trial.

Conventional versus reverse sequence of neoadjuvant epirubicin/cyclophosphamide and docetaxel: sequencing results from ABCSG-34.

BACKGROUND: Preoperative chemotherapy containing anthracyclines and taxanes is well established in early-stage breast cancer. Previous studies have suggested that the chemotherapy sequence may matter but definitive evidence is missing. ABCSG trial 34 evaluated the activity of the MUC1 vaccine tecemotide when added to neoadjuvant treatment; the study provided the opportunity for the second randomisation to compare two different anthracycline/taxane sequences. METHODS: HER2-negative early-stage breast cancer patients were recruited to this randomised multicentre Phase 2 study. Patients in the chemotherapy cohort (n = 311) were additionally randomised to a conventional or reversed sequence of epirubicin/cyclophosphamide and docetaxel. Residual cancer burden (RCB) with/without tecemotide was defined as primary study endpoint; RCB in the two chemotherapy groups was a key secondary endpoint. RESULTS: No significant differences in terms of RCB 0/I (40.1% vs. 37.2%; P = 0.61) or pathologic complete response (pCR) rates (24.3% vs. 25%, P = 0.89) were observed between conventional or reverse chemotherapy sequence. No new safety signals were reported, and upfront docetaxel did not result in decreased rates of treatment delay or discontinuation. CONCLUSION: Upfront docetaxel did not improve chemotherapy activity or tolerability; these results suggest that upfront neoadjuvant treatment with anthracyclines remains a valid option.

Aggressive B-cell lymphomas in patients with myelofibrosis receiving JAK1/2 inhibitor therapy.

Inhibition of Janus-kinase 1/2 (JAK1/2) is a mainstay to treat myeloproliferative neoplasms (MPN). Sporadic observations reported the co-incidence of B-cell non-Hodgkin lymphomas during treatment of MPN with JAK1/2 inhibitors. We assessed 626 patients with MPN, including 69 with myelofibrosis receiving JAK1/2 inhibitors for lymphoma development. B-cell lymphomas evolved in 4 (5.8%) of 69 patients receiving JAK1/2 inhibition compared with 2 (0.36%) of 557 with conventional treatment (16-fold increased risk). A similar 15-fold increase was observed in an independent cohort of 929 patients with MPN. Considering primary myelofibrosis only (N = 216), 3 lymphomas were observed in 31 inhibitor-treated patients (9.7%) vs 1 (0.54%) of 185 control patients. Lymphomas were of aggressive B-cell type, extranodal, or leukemic with high MYC expression in the absence of JAK2 V617F or other MPN-associated mutations. Median time from initiation of inhibitor therapy to lymphoma diagnosis was 25 months. Clonal immunoglobulin gene rearrangements were already detected in the bone marrow during myelofibrosis in 16.3% of patients. Lymphomas occurring during JAK1/2 inhibitor treatment were preceded by a preexisting B-cell clone in all 3 patients tested. Sequencing verified clonal identity in 2 patients. The effects of JAK1/2 inhibition were mirrored in Stat1-/- mice: 16 of 24 mice developed a spontaneous myeloid hyperplasia with the concomitant presence of aberrant B cells. Transplantations of bone marrow from diseased mice unmasked the outgrowth of a malignant B-cell clone evolving into aggressive B-cell leukemia-lymphoma. We conclude that JAK/STAT1 pathway inhibition in myelofibrosis is associated with an elevated frequency of aggressive B-cell lymphomas. Detection of a preexisting B-cell clone may identify individuals at risk.

Diffusion-weighted imaging (DWI) with apparent diffusion coefficient (ADC) mapping as a quantitative imaging biomarker for prediction of immunohistochemical receptor status, proliferation rate, and molecular subtypes of breast cancer.

BACKGROUND: Diffusion-weighted imaging (DWI) with apparent diffusion coefficient (ADC) mapping is one of the most useful additional MRI parameters to improve diagnostic accuracy and is now often used in a multiparameric imaging setting for breast tumor detection and characterization. PURPOSE: To evaluate whether different ADC metrics can also be used for prediction of receptor status, proliferation rate, and molecular subtype in invasive breast cancer. STUDY TYPE: Retrospective. SUBJECTS: In all, 107 patients with invasive breast cancer met the inclusion criteria (mean age 57 years, range 32-87) and underwent multiparametric breast MRI. FIELD STRENGTH/SEQUENCE: 3 T, readout-segmented echo planar imaging (rsEPI) with IR fat suppression, dynamic contrast-enhanced (DCE) T1 -weighted imaging, T2 -weighted turbo-spin echo (TSE) with fatsat. ASSESSMENT: Two readers independently drew a region of interest on ADC maps on the whole tumor (WTu), and on its darkest part (DpTu). Minimum, mean, and maximum ADC values of both WTu and DpTu were compared for receptor status, proliferation rate, and molecular subtypes. STATISTICAL TESTS: Wilcoxon rank sum, Mann-Whitney U-tests for associations between radiologic features and histopathology; histogram and q-q plots, Shapiro-Wilk's test to assess normality, concordance correlation coefficient for precision and accuracy; receiver operating characteristics curve analysis. RESULTS: Estrogen receptor (ER) and progesterone receptor (PR) status had significantly different ADC values for both readers. Maximum WTu (P = 0.0004 and 0.0005) and mean WTu (P = 0.0101 and 0.0136) were significantly lower for ER-positive tumors, while PR-positive tumors had significantly lower maximum WTu values (P = 0.0089 and 0.0047). Maximum WTu ADC was the only metric that was significantly different for molecular subtypes for both readers (P = 0.0100 and 0.0132) and enabled differentiation of luminal tumors from nonluminal (P = 0.0068 and 0.0069) with an area under the curve of 0.685 for both readers. DATA CONCLUSION: Maximum WTu ADC values may be used to differentiate luminal from other molecular subtypes of breast cancer. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:836-846.

AHR/CYP1A1 interplay triggers lymphatic barrier breaching in breast cancer spheroids by inducing 12(S)-HETE synthesis.

A causal link between overexpression of aryl hydrocarbon receptor (AHR) and its target cytochrome P450 1A1 (CYP1A1) and metastatic outgrowth of various cancer entities has been established. Nevertheless, the mechanism how AHR/CYP1A1 support metastasis formation is still little understood. In vitro we discovered a potential mechanism facilitating tumour dissemination based on the production of 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE). Utilising a three-dimensional lymph endothelial cell (LEC) monolayer & MDA-MB231 breast cancer cell spheroid co-culture model in combination with knock-down approach allowed elucidation of the molecular/biochemical basis of AHR/CYP1A1-induced tumour breaching through the LEC barrier. Enzyme immunoassay evidenced the potential of recombinant CYP1A1 to synthesise 12(S)-HETE in vitro and qPCR and Western blotting measured gene and protein expression in specific experimental settings. In detail, AHR induced CYP1A1 expression and 12(S)-HETE secretion in tumour spheroids, which caused LEC junction retraction thereby forming large discontinuities allowing transmigration of the tumour. This was enforced by the activating AHR ligand 6-formylindolo (3,3-b)carbazole (FICZ), or inhibited by the AHR antagonist 3,3'-diindolylmethane (DIM) as well as by siRNA against AHR and CYP1A1. AHR and NF-κB were negatively cross talking and therefore, the inhibition of AHR (but not CYP1A1) induced RELA, RELB, NFKB1, NFKB2 and the NF-κB target MMP1, which itself promotes tumour intravasation by a mechanism that is different from 12(S)-HETE. Conversely, the inhibition of NFKB2 induced AHR, CYP1A1 and 12(S)-HETE synthesis. The approved clinical drugs guanfacine and vinpocetine, which inhibit CYP1A1 and NF-κB, respectively, significantly inhibited LEC barrier breaching in vitro indicating an option to reduce metastatic dissemination.

Colon cancer cell-derived 12(S)-HETE induces the retraction of cancer-associated fibroblast via MLC2, RHO/ROCK and Ca2+ signalling.

Retraction of mesenchymal stromal cells supports the invasion of colorectal cancer cells (CRC) into the adjacent compartment. CRC-secreted 12(S)-HETE enhances the retraction of cancer-associated fibroblasts (CAFs) and therefore, 12(S)-HETE may enforce invasivity of CRC. Understanding the mechanisms of metastatic CRC is crucial for successful intervention. Therefore, we studied pro-invasive contributions of stromal cells in physiologically relevant three-dimensional in vitro assays consisting of CRC spheroids, CAFs, extracellular matrix and endothelial cells, as well as in reductionist models. In order to elucidate how CAFs support CRC invasion, tumour spheroid-induced CAF retraction and free intracellular Ca2+ levels were measured and pharmacological- or siRNA-based inhibition of selected signalling cascades was performed. CRC spheroids caused the retraction of CAFs, generating entry gates in the adjacent surrogate stroma. The responsible trigger factor 12(S)-HETE provoked a signal, which was transduced by PLC, IP3, free intracellular Ca2+, Ca2+-calmodulin-kinase-II, RHO/ROCK and MYLK which led to the activation of myosin light chain 2, and subsequent CAF mobility. RHO activity was observed downstream as well as upstream of Ca2+ release. Thus, Ca2+ signalling served as central signal amplifier. Treatment with the FDA-approved drugs carbamazepine, cinnarizine, nifedipine and bepridil HCl, which reportedly interfere with cellular calcium availability, inhibited CAF-retraction. The elucidation of signalling pathways and identification of approved inhibitory drugs warrant development of intervention strategies targeting tumour-stroma interaction.

Factors affecting the quantitative uncertainty of the estimated short-term intake. Part I-Calculation methods.

The calculation of the combined uncertainty of the international estimated short-term intake (IESTI) of ethephon residues in apples is shown as an example. The ethephon residues in apples were reported by the Joint FAO (Food and Agriculture Organization of the United Nations)/WHO (World Health Organization) Meeting on Pesticide Residues (JMPR). The apple consumption data were taken from the IESTI (international short-term intake) calculation template used by the JMPR. The IESTI was calculated with the currently used method (case 2a) and a proposed one recommended by the EFSA (European Food Safety Authority)/RIVM (Dutch National Institute for Public Health) Scientific Workshop co-sponsored by FAO and WHO. In this example, the ratio of IESTIproposed/IESTIcurrent and their combined relative uncertainty are about 2.8, and 1.7, respectively. The larger IESTI and uncertainty obtained with the proposed equation are the consequence of calculation only with the large portion (LP) instead of its combination with unit mass, and the MRL instead of the highest residue (HR). The LP is the major contributor to the combined uncertainty. Both the calculated IESTI and its combined uncertainty depend on the actual food - pesticide residue combination, and should be calculated for each case.

Candidatus Dirofilaria hongkongensis as Causative Agent of Human Ocular Filariosis after Travel to India.

We report a human case of ocular Dirofilaria infection in a traveler returning to Austria from India. Analysis of mitochondrial sequences identified the worm as Candidatus Dirofilaria hongkongensis, a close relative of Dirofilaria repens, which was only recently described in Hong Kong and proposed as a new species.

Expansion of BCR/ABL1+ cells requires PAK2 but not PAK1.

The p21-activated kinases (PAKs) are key nodes in oncogenic signalling pathways controlling growth, survival, and motility of cancer cells. Their activity is increased in many human cancers and is associated with poor prognosis. To date, PAK deregulation has mainly been studied in solid tumours, where PAK1 and PAK4 are the main isoforms deregulated. We show that PAK1 and PAK2 are the critical isoforms in a BCR/ABL1+ haematopoietic malignancy. In suspension, leukaemic cells deficient for PAK1 and PAK2 undergo apoptosis, while the loss of either protein is well tolerated. Transfer of medium conditioned by shPAK2- but not shPAK1-expressing leukaemic cells interferes with endothelial cell growth. We found that leukaemic cells produce exosomes containing PAK2. Transfer of isolated exosomes supports endothelial cell proliferation. In parallel, we found that leukaemic cells explicitly require PAK2 to grow towards an extracellular matrix. PAK2-deficient cells fail to form colonies in methylcellulose and to induce lymphomas in vivo. PAK2 might therefore be the critical isoform in leukaemic cells by controlling tumour growth in a dual manner: vascularization via exosome-mediated transfer to endothelial cells and remodelling of the extracellular matrix. This finding suggests that the PAK2 isoform represents a promising target for the treatment of haematological diseases.

Investigating the prediction value of multiparametric magnetic resonance imaging at 3 T in response to neoadjuvant chemotherapy in breast cancer.

OBJECTIVE: To explore the predictive value of parameters derived from diffusion-weighted imaging (DWI) and contrast-enhanced (CE)-MRI at different time-points during neoadjuvant chemotherapy (NACT) in breast cancer. METHODS: Institutional review board approval and written, informed consent from 42 breast cancer patients were obtained. The patients were investigated before and at three different time-points during neoadjuvant chemotherapy (NACT) using tumour diameter and volume from CE-MRI and ADC values obtained from drawn 2D and segmented 3D regions of interest. Prediction of pathologic complete response (pCR) was evaluated using the area under the curve (AUC) of receiver operating characteristic analysis. RESULTS: There was no significant difference between pathologic complete response and non-pCR in baseline size measures (p > 0.39). Diameter change was significantly different in pCR (p < 0.02) before the mid-therapy point. The best predictor was lesion diameter change observed before mid-therapy (AUC = 0.93). Segmented volume was not able to differentiate between pCR and non-pCR at any time-point. The ADC values from 3D-ROI were not significantly different from 2D data (p = 0.06). The best AUC (0.79) for pCR prediction using DWI was median ADC measured before mid-therapy of NACT. CONCLUSIONS: The results of this study should be considered in NACT monitoring planning, especially in MRI protocol designing and time point selection. KEY POINTS: • Mid-therapy diameter changes are the best predictors of pCR in neoadjuvant chemotherapy. • Volumetric measures are not strictly superior in therapy monitoring to lesion diameter. • Size measures perform as a better predictor than ADC values.

Diffusion-weighted imaging of breast lesions: Region-of-interest placement and different ADC parameters influence apparent diffusion coefficient values.

OBJECTIVES: To investigate the influence of region-of-interest (ROI) placement and different apparent diffusion coefficient (ADC) parameters on ADC values, diagnostic performance, reproducibility and measurement time in breast tumours. METHODS: In this IRB-approved, retrospective study, 149 histopathologically proven breast tumours (109 malignant, 40 benign) in 147 women (mean age 53.2) were investigated. Three radiologists independently measured minimum, mean and maximum ADC, each using three ROI placement approaches:1 - small 2D-ROI, 2 - large 2D-ROI and 3 - 3D-ROI covering the whole lesion. One reader performed all measurements twice. Median ADC values, diagnostic performance, reproducibility, and measurement time were calculated and compared between all combinations of ROI placement approaches and ADC parameters. RESULTS: Median ADC values differed significantly between the ROI placement approaches (p < .001). Minimum ADC showed the best diagnostic performance (AUC .928-.956), followed by mean ADC obtained from 2D ROIs (.926-.94). Minimum and mean ADC showed high intra- (ICC .85-.94) and inter-reader reproducibility (ICC .74-.94). Median measurement time was significantly shorter for the 2D ROIs (p < .001). CONCLUSIONS: ROI placement significantly influences ADC values measured in breast tumours. Minimum and mean ADC acquired from 2D-ROIs are useful for the differentiation of benign and malignant breast lesions, and are highly reproducible, with rapid measurement. KEY POINTS: • Region of interest placement significantly influences apparent diffusion coefficient of breast tumours. • Minimum and mean apparent diffusion coefficient perform best and are reproducible. • 2D regions of interest perform best and provide rapid measurement times.

Standardized evaluation of tumor-infiltrating lymphocytes in breast cancer: results of the ring studies of the international immuno-oncology biomarker working group.

Multiple independent studies have shown that tumor-infiltrating lymphocytes (TIL) are prognostic in breast cancer with potential relevance for response to immune-checkpoint inhibitor therapy. Although many groups are currently evaluating TIL, there is no standardized system for diagnostic applications. This study reports the results of two ring studies investigating TIL conducted by the International Working Group on Immuno-oncology Biomarkers. The study aim was to determine the intraclass correlation coefficient (ICC) for evaluation of TIL by different pathologists. A total of 120 slides were evaluated by a large group of pathologists with a web-based system in ring study 1 and a more advanced software-system in ring study 2 that included an integrated feedback with standardized reference images. The predefined aim for successful ring studies 1 and 2 was an ICC above 0.7 (lower limit of 95% confidence interval (CI)). In ring study 1 the prespecified endpoint was not reached (ICC: 0.70; 95% CI: 0.62-0.78). On the basis of an analysis of sources of variation, we developed a more advanced digital image evaluation system for ring study 2, which improved the ICC to 0.89 (95% CI: 0.85-0.92). The Fleiss' kappa value for <60 vs ≥60% TIL improved from 0.45 (ring study 1) to 0.63 in RS2 and the mean concordance improved from 88 to 92%. This large international standardization project shows that reproducible evaluation of TIL is feasible in breast cancer. This opens the way for standardized reporting of tumor immunological parameters in clinical studies and diagnostic practice. The software-guided image evaluation approach used in ring study 2 may be of value as a tool for evaluation of TIL in clinical trials and diagnostic practice. The experience gained from this approach might be applicable to the standardization of other diagnostic parameters in histopathology.

Bilateral diffusion-weighted MR imaging of breast tumors with submillimeter resolution using readout-segmented echo-planar imaging at 7 T.

PURPOSE: To evaluate the image quality, robustness, and diagnostic performance of submillimeter in-plane resolution diffusion-weighted ( DW diffusion-weighted ) magnetic resonance (MR) imaging at 7 T in the assessment of breast tumors. MATERIALS AND METHODS: Institutional review board approval and written informed consent of five volunteers and 33 patients with 33 breast lesions (31 with histopathologic confirmation, two with confirmation at follow-up) were obtained. Image quality optimization and comparisons of readout-segmented echo-planar imaging ( rs-EPI readout-segmented echo-planar imaging ) and single-shot echo-planar imaging ( ss-EPI single-shot echo-planar imaging ) with or without parallel imaging were performed in volunteers. In all patients, bilateral DW diffusion-weighted imaging was performed in 3 minutes 35 seconds by using combined rs-EPI readout-segmented echo-planar imaging and parallel imaging with 0.9 × 0.9 mm in-plane resolution with a 7-T whole-body MR imager. Image quality, lesion conspicuity, and image properties (ie, signal-to-noise ratio, contrast-to-noise ratio) were assessed. Regions of interest were drawn in the largest lesion in each patient (23 malignant lesions, 10 benign lesions) by two independent readers. Apparent diffusion coefficient ( ADC apparent diffusion coefficient ) values were used to differentiate between benign and malignant breast tumors. RESULTS: DW diffusion-weighted imaging with combined parallel imaging and rs-EPI readout-segmented echo-planar imaging reduced artifacts (ie, blurring and geometric distortions) by a calculated factor of seven when compared with DW diffusion-weighted imaging with ss-EPI single-shot echo-planar imaging , and it improved image quality from a score of 1 of 10 to a score of 8 of 10. The rs-EPI readout-segmented echo-planar imaging sequence with a b value of 0 sec/mm(2) yielded high-spatial-resolution T2-weighted MR images. An ADC apparent diffusion coefficient threshold of 1.275 × 10(-3) mm(2)/sec enabled differentiation between benign and malignant breast lesions, with sensitivity and specificity of 96% and 100%, respectively, for both independent readers. CONCLUSION: At 7 T, one DW diffusion-weighted imaging examination of less than 4 minutes yielded high-quality ADC apparent diffusion coefficient maps and high-spatial-resolution T2-weighted MR images that were used to assess tumor and breast morphology. ADC apparent diffusion coefficient quantification alone enabled excellent differentiation of benign and malignant breast lesions.

Multiparametric MR Imaging with High-Resolution Dynamic Contrast-enhanced and Diffusion-weighted Imaging at 7 T Improves the Assessment of Breast Tumors: A Feasibility Study.

PURPOSE: To ascertain whether multiparametric magnetic resonance (MR) imaging of the breast in combination with dynamic contrast material-enhanced (DCE) imaging and diffusion-weighted imaging (DWI) at 7 T is feasible and improves diagnostic accuracy. MATERIALS AND METHODS: From December 2011 to December 2013, 40 patients with suspicious breast lesions were included in this institutional review board-approved prospective study. Before bilateral multiparametric MR imaging of the breast at 7 T, all patients gave written informed consent. Lesions were classified according to Breast Imaging Reporting and Data System (BI-RADS) and assessed for apparent diffusion coefficient (ADC) values by two readers independently. For combined analysis of DCE MR imaging and DWI, the BI-RADS-adapted reading algorithm, which adapted ADC thresholds to the BI-RADS assessment category, was used. Diagnostic values of multiparametric, DCE MR imaging, and DWI were calculated. Receiver operating characteristic curve analysis was performed. Image quality and interreader agreement were assessed. Histopathologic results were used as the highest standard. RESULTS: There were 29 malignant and 17 benign lesions (range, 6-95 mm; mean, 23.3 mm). Multiparametric MR imaging yielded a sensitivity of 100% (29 of 29 lesions), a specificity of 88.2% (16 of 18 lesions), and an area under the curve of 0.941, which was greater than for DCE MR imaging (P = .003), which had a sensitivity of 100% (29 of 29 lesions), a specificity of 53.2% (nine of 17 lesions), and an area under the curve of 0.765. DWI had a sensitivity of 93.1% (27 of 29 lesions), a specificity of 88.2% (15 of 17 lesions), and an area under the curve of 0.907. Multiparametric MR imaging at 7 T of the breast eliminated all false-negative findings and reduced false-positive findings, from eight false-positive findings with DCE MR imaging to two false-positive findings. Thus, if used clinically, 7-T multiparametric MR imaging may have potentially obviated unnecessary breast biopsies in six of eight lesions (P = .031). Multiparametric MR imaging demonstrated either excellent or good image quality and interreader agreement (κ = 0.89-1.00). CONCLUSION: The clinical use of 7-T multiparametric MR imaging is feasible, provides good or excellent image quality, and has the potential to improve diagnostic accuracy.

Histopathological characterization of ulcerated breast cancer and comparison to their non-ulcerated counterparts.

Approximately 6-15 % of breast cancer patients are diagnosed with primary ulcerated breast cancer (ULBC). ULBC is known to be associated with short recurrence free and poor overall survival. Therefore, the purpose of this study was to characterize ULBC and compare the histopathological findings with those of non-ulcerative breast cancer (NULBC). A total of 152 ULBCs were evaluated and compared to 304 consecutive non-ulcerated, age-matched breast malignancies. Patients mean age was 65 years (SD = 13.0 ULBC, SD = 14.0 NULBC). ULBC was associated with a higher rate of poorly differentiated tumors (p = < 0.001), as well as larger tumor sizes (p = < 0.001). As expected, the rate of axillary lymph node involvement was higher in ULBC patients (p = <0.001). In addition to that, ULBC was associated with a higher rate of triple negative breast cancer (p = 0.002), and higher Ki67 expression (p = < 0.001). ULBC showed more aggressive histopathological features in comparison to NULBC which may contribute to the generally known poorer prognosis of women with ULBC.

Limitations in the determination of maximum residue limits and highest residues of pesticides: Part I.

The pesticide usages are controlled by comparing residue concentrations in treated commodities to legally permitted maximum levels (MRLs) determined based on supervised trials designed to reflect likely maximum residues occurring in practice following authorised use. The number of trials available may significantly affect the accuracy of estimated maximum residues. We conducted a study with synthetic lognormal distributions with mean of 1 and standard deviations of 0.8 and 1.0, which reflect the residue distributions observed in practice. The likely residues in samples were modelled by drawing random samples of size 3, 5, 10 and 25 from the synthetic populations. The results indicate that the estimations of highest residues (HR), used for calculation of short-term intake, and the MRLs, serving as legal limits, are very uncertain based on 3-5 trials indicated by the calculated HR0.975/HR0.025 and MRL0.975/MRL0.025 ratios of 12 and 9, and 13 and 10, respectively, which question the suitability of such trials for the intended purpose. As the 95% range of HR and MRL rapidly decreases with number of trials, ideally ≥15 but minimum 6-8 trials should be used for estimation of HR and MRL according to the current typical practice of Codex Alimentarius.

Estimation of sampling uncertainty for pesticide residues in root vegetable crops.

The sampling uncertainty for pesticide residues in carrots, parsley leaves and selected medium size crops was estimated with simple random sampling by applying range statistics. The primary samples taken from treated fields consisted of individual carrots or a handful of parsley leaves. The samples were analysed with QUEChERs extraction method and LCMS/MS detection with practical LOQ of 0.001 mg/kg. The results indicate that the average sampling uncertainties estimated with simple random sampling and range statistics were practically the same. The confidence interval for the estimated sampling uncertainty decreased with the number of replicate samples taken from one lot and the number of lots sampled. The estimated relative ranges of sampling uncertainty are independent from the relative standard deviation of the primary samples. Consequently the conclusions drawn from these experiments are generally applicable. There is no optimum for sample size and number of lots to be tested for estimation of sampling uncertainty. Taking a minimum of 6 replicate samples from at least 8-12 lots is recommended to obtain a relative 95% range of sampling uncertainty within 50%. The cost of sampling/analyses, the consequences of wrong decision should also be taken into account when a sampling plan is prepared.

Nature of the field-to-field distribution of pesticide residues.

The supervised trial datasets (1950), consisting of a minimum of five residue values and selected by the experts of FAO/WHO Joint Meeting on Pesticide Residues for recommending maximum residue levels between 1997 and 2011, were evaluated to obtain information on the typical spread of residue values in individual datasets. The typical relative standard deviation, CV, of field-to-field variation of pesticide residues was about 80%. The spread of residues in datasets is independent from the chemical structure of pesticides, residue level, pre-harvest interval and number of values in the datasets. The CV ranges within the Codex commodity groups and between groups overlapped and their difference were not statistically significant. The number of residues below the limit of quantification (LOQ) affects the CV at various extents depending on the ratio of LOQ/R mean. The combined uncertainty of the highest residue in a dataset significantly affects the CV of the dataset. The lowest and intermediate ones have less influence. The residues in different fields receiving the same treatment vary within large range: 55%, 72%, 78%, 86% and 89% of the 25,766 residues values were, respectively, within 3, 4, 5, 6 and 7 times the median value of the corresponding dataset.