Accuracy of the Apple Watch iECG in Children With and Without Congenital Heart Disease.

The development of smart technologies paves the way for new diagnostic modalities. The Apple Watch provides an FDA approved iECG function for users from 22 years of age. Yet, there are currently no data on the accuracy of the Apple Watch iECG in children. While arrhythmias are a frequent phenomenon in children, especially those with congenital heart disease, the increasing spread of smart watches provides the possibility to use a smart watch as mobile event recorder in case of suspected arrhythmia. This may help to provide valuable information to the treating physician, without having the patient to come to the hospital. Necessary treatment adjustments might be provided without timely delay. The aim of this study was therefore to evaluate the agreement of measured values of rate, interval, and amplitude with those obtained by a diagnostic quality ECG recording to an Apple Watch iECG in children with and without congenital heart disease. In this prospective, single-arm study, consecutive patients aged 0-16 years presenting to the Heart Center Leipzig, Department for pediatric cardiology were included. After obtaining informed consent from participants' parents, a 12-lead ECG and an iECG using an Apple Watch were performed. Cardiac rhythm was classified, amplitudes and timing intervals were measured and analyzed in iECG and 12-lead ECG for comparability. These measurements were performed blinded to the patients' history by two experienced pediatric cardiologists. Patient demographic data, medical and cardiac history were assessed. 215 children between 0 and 16 years were enrolled. Comparison of amplitudes and timing intervals between ECG and iECG showed excellent correlation (K > 0.7, p < 0.01) in all parameters except for the p-waves. Automatic rhythm classification was inferior to manual interpretation of ECG / iECG, while iECG interpretation was reliable in 94.86% of cases. The study demonstrates equal quality of the Apple Watch derived iECG compared to a lead I in 12-lead ECG in children of all age groups and independent from cardiac anatomy.

Prognostic gene expression signature for high-grade serous ovarian cancer.

BACKGROUND: Median overall survival (OS) for women with high-grade serous ovarian cancer (HGSOC) is ∼4 years, yet survival varies widely between patients. There are no well-established, gene expression signatures associated with prognosis. The aim of this study was to develop a robust prognostic signature for OS in patients with HGSOC. PATIENTS AND METHODS: Expression of 513 genes, selected from a meta-analysis of 1455 tumours and other candidates, was measured using NanoString technology from formalin-fixed paraffin-embedded tumour tissue collected from 3769 women with HGSOC from multiple studies. Elastic net regularization for survival analysis was applied to develop a prognostic model for 5-year OS, trained on 2702 tumours from 15 studies and evaluated on an independent set of 1067 tumours from six studies. RESULTS: Expression levels of 276 genes were associated with OS (false discovery rate < 0.05) in covariate-adjusted single-gene analyses. The top five genes were TAP1, ZFHX4, CXCL9, FBN1 and PTGER3 (P < 0.001). The best performing prognostic signature included 101 genes enriched in pathways with treatment implications. Each gain of one standard deviation in the gene expression score conferred a greater than twofold increase in risk of death [hazard ratio (HR) 2.35, 95% confidence interval (CI) 2.02-2.71; P < 0.001]. Median survival [HR (95% CI)] by gene expression score quintile was 9.5 (8.3 to -), 5.4 (4.6-7.0), 3.8 (3.3-4.6), 3.2 (2.9-3.7) and 2.3 (2.1-2.6) years. CONCLUSION: The OTTA-SPOT (Ovarian Tumor Tissue Analysis consortium - Stratified Prognosis of Ovarian Tumours) gene expression signature may improve risk stratification in clinical trials by identifying patients who are least likely to achieve 5-year survival. The identified novel genes associated with the outcome may also yield opportunities for the development of targeted therapeutic approaches.

Iatrogenic endometriosis harbors somatic cancer-driver mutations.

STUDY QUESTION: Does incisional endometriosis (IE) harbor somatic cancer-driver mutations? SUMMARY ANSWER: We found that approximately one-quarter of IE cases harbor somatic-cancer mutations, which commonly affect components of the MAPK/RAS or PI3K-Akt-mTor signaling pathways. WHAT IS KNOWN ALREADY: Despite the classification of endometriosis as a benign gynecological disease, it shares key features with cancers such as resistance to apoptosis and stimulation of angiogenesis and is well-established as the precursor of clear cell and endometrioid ovarian carcinomas. Our group has recently shown that deep infiltrating endometriosis (DE), a form of endometriosis that rarely undergoes malignant transformation, harbors recurrent somatic mutations. STUDY DESIGN, SIZE, DURATION: In a retrospective study comparing iatrogenically induced and endogenously occurring forms of endometriosis unlikely to progress to cancer, we examined endometriosis specimens from 40 women with IE and 36 women with DE. Specimens were collected between 2004 and 2017 from five hospital sites in either Canada, Germany or the Netherlands. IE and DE cohorts were age-matched and all women presented with histologically typical endometriosis without known history of malignancy. PARTICIPANTS/MATERIALS, SETTING, METHODS: Archival tissue specimens containing endometriotic lesions were macrodissected and/or laser-capture microdissected to enrich endometriotic stroma and epithelium and a hypersensitive cancer hotspot sequencing panel was used to assess for presence of somatic mutations. Mutations were subsequently validated using droplet digital PCR. PTEN and ARID1A immunohistochemistry (IHC) were performed as surrogates for somatic events resulting in functional loss of respective proteins. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, we detected somatic cancer-driver events in 11 of 40 (27.5%) IE cases and 13 of 36 (36.1%) DE cases, including hotspot mutations in KRAS, ERBB2, PIK3CA and CTNNB1. Heterogeneous PTEN loss occurred at similar rates in IE and DE (7/40 vs 5/36, respectively), whereas ARID1A loss only occurred in a single case of DE. While rates of detectable somatic cancer-driver events between IE and DE are not statistically significant (P > 0.05), KRAS activating mutations were more prevalent in DE. LIMITATIONS, REASONS FOR CAUTION: Detection of somatic cancer-driver events were limited to hotspots analyzed in our panel-based sequencing assay and loss of protein expression by IHC from archival tissue. Whole genome or exome sequencing, or epigenetic analysis may uncover additional somatic alterations. Moreover, because of the descriptive nature of this study, the functional roles of identified mutations within the context of endometriosis remain unclear and causality cannot be established. WIDER IMPLICATIONS OF THE FINDINGS: The alterations we report may be important in driving the growth and survival of endometriosis in ectopic regions of the body. Given the frequency of mutation in surgically displaced endometrium (IE), examination of similar somatic events in eutopic endometrium, as well as clinically annotated cases of other forms of endometriosis, in particular endometriomas that are most commonly linked to malignancy, is warranted. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by a Canadian Cancer Society Impact Grant [701603, PI Huntsman], Canadian Institutes of Health Research Transitional Open Operating Grant [MOP-142273, PI Yong], the Canadian Institutes of Health Research Foundation Grant [FDN-154290, PI Huntsman], the Canadian Institutes of Health Research Project Grant [PJT-156084, PIs Yong and Anglesio], and the Janet D. Cottrelle Foundation through the BC Cancer Foundation [PI Huntsman]. D.G. Huntsman is a co-founder and shareholder of Contextual Genomics Inc., a for profit company that provides clinical reporting to assist in cancer patient treatment. R. Aguirre-Hernandez, J. Khattra and L.M. Prentice have a patent MOLECULAR QUALITY ASSURANCE METHODS FOR USE IN SEQUENCING pending and are current (or former) employees of Contextual Genomics Inc. The remaining authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: Not applicable.

Evidence for a time-dependent association between FOLR1 expression and survival from ovarian carcinoma: implications for clinical testing. An Ovarian Tumour Tissue Analysis consortium study.

BACKGROUND: Folate receptor 1 (FOLR1) is expressed in the majority of ovarian carcinomas (OvCa), making it an attractive target for therapy. However, clinical trials testing anti-FOLR1 therapies in OvCa show mixed results and require better understanding of the prognostic relevance of FOLR1 expression. We conducted a large study evaluating FOLR1 expression with survival in different histological types of OvCa. METHODS: Tissue microarrays composed of tumour samples from 2801 patients in the Ovarian Tumour Tissue Analysis (OTTA) consortium were assessed for FOLR1 expression by centralised immunohistochemistry. We estimated associations for overall (OS) and progression-free (PFS) survival using adjusted Cox regression models. High-grade serous ovarian carcinomas (HGSC) from The Cancer Genome Atlas (TCGA) were evaluated independently for association between FOLR1 mRNA upregulation and survival. RESULTS: FOLR1 expression ranged from 76% in HGSC to 11% in mucinous carcinomas in OTTA. For HGSC, the association between FOLR1 expression and OS changed significantly during the years following diagnosis in OTTA (Pinteraction=0.01, N=1422) and TCGA (Pinteraction=0.01, N=485). In OTTA, particularly for FIGO stage I/II tumours, patients with FOLR1-positive HGSC showed increased OS during the first 2 years only (hazard ratio=0.44, 95% confidence interval=0.20-0.96) and patients with FOLR1-positive clear cell carcinomas (CCC) showed decreased PFS independent of follow-up time (HR=1.89, 95% CI=1.10-3.25, N=259). In TCGA, FOLR1 mRNA upregulation in HGSC was also associated with increased OS during the first 2 years following diagnosis irrespective of tumour stage (HR: 0.48, 95% CI: 0.25-0.94). CONCLUSIONS: FOLR1-positive HGSC tumours were associated with an increased OS in the first 2 years following diagnosis. Patients with FOLR1-negative, poor prognosis HGSC would be unlikely to benefit from anti-FOLR1 therapies. In contrast, a decreased PFS interval was observed for FOLR1-positive CCC. The clinical efficacy of FOLR1-targeted interventions should therefore be evaluated according to histology, stage and time following diagnosis.

[Diagnosis and differential diagnosis of cervical adenocarcinoma]. / Diagnose und Differenzialdiagnose des zervikalen Adenokarzinoms.

This overview summarizes pathogenetic and practical aspects of (sub-)classification of cervical glandular (pre-)neoplasias and, inter alia, calls into question the usefulness of grading. In the context of the differential diagnosis of benign "imitations", the phenotypic variability of glandular precancerous lesions and carcinomas is described as well as the use of special tests to distinguish them. With regard to carcinomas, the differential diagnosis of well-differentiated neoplasias is addressed including "minimal deviation" adenocarcinoma (MDA, malignant adenoma), carcinomas with endometrioid or villoglandular morphology, and mesonephric hyper- and neoplasias. Furthermore, knowledge of HPV-negative glandular (pre-)neoplasias is covered including "gastric-type" adenocarcinomas and diagnostic algorithms for discriminating between primary and secondary cervical adenocarcinomas. Finally, comments are offered on the difficulties in recognizing early invasive adenocarcinomas, especially also the pitfalls inherent in determining the depth of invasion.

Histotype predicts the curative potential of radiotherapy: the example of ovarian cancers.

BACKGROUND: To explore the influence of ovarian cancer histotype on the effectiveness of adjuvant radiotherapy (RT). METHODS: A review of a population-based experience included all referred women with no reported macroscopic residuum following primary surgery who underwent adjuvant platin-based chemotherapy (CT), with or without sequential RT, and for whom it was possible to assign histotype according to the contemporary criteria. RESULTS: Seven hundred and three subjects were eligible, of these 351 received RT. For those with apparent stage I and II tumors, the cohort with clear cell (C), endometrioid (E), and mucinous (M) disease who additionally received RT exhibited a 40% reduction in disease-specific mortality and a 43% reduction in overall mortality. CONCLUSIONS: The curability of those with stage I and II C-, E-, and M-type ovarian carcinomas was enhanced by RT-containing adjuvant therapy. This benefit did not extend to those with stage III or serous tumors. These findings necessitate reassessments of the role of RT and of the nonselective surgical and CT approaches that have characterized ovarian cancer care.

Case report: Hydropic leiomyoma of the uterus presenting in pregnancy: imaging features.

Uterine leiomyomas commonly undergo degenerative change, which can lead to variable imaging features. Diffuse hydropic change is an unusual form of degeneration that presents a considerable diagnostic challenge to both radiologists and pathologists, as it can mimic a malignant neoplasm on imaging and at histological analysis. We present the case of a giant diffuse hydropic leiomyoma presenting in the first trimester of pregnancy in a 36-year-old woman, the imaging features of which were suggestive of a more aggressive neoplasm. The sonographic and MRI appearances of the lesion are discussed, and the varied imaging features of leiomyomas are reviewed.

[Ovarian carcinoma. Do the subtypes reflect different diseases?]. / Ovarialkarzinome. Spiegeln die Subtypen verschiedene Erkrankungen wider?

Lack of therapeutic options and poor reproducibility of histopathological subtypes have been the reasons that ovarian carcinomas are currently treated as monolithic entity. Histopathological grading is used to identify those patients who can be spared adjuvant therapy. With slight modifications of the WHO based subtype classification we have shown that subtypes (i.e. serous, endometrioid, clear cell, mucinous) can be reproducibly used to stratify patients according to disease-specific survival. As these pathologically identifiable subtypes have different epidemiologic and genetic risk factors, precursor lesions, molecular abnormalities and clinical behaviour, screening and management strategies have to be subtype-specific.

Expression of the RNA-binding protein IMP1 correlates with poor prognosis in ovarian carcinoma.

The IMP (IGFII mRNA-binding protein) family comprises a group of three RNA-binding proteins involved in the regulation of cytoplasmic mRNA-fate. Recent studies identified IMP proteins as oncofetal factors in various neoplasias, but knowledge of a potential role in ovarian carcinomas is still lacking. The immunohistochemical analysis of 107 ovarian carcinomas, 30 serous borderline tumors of the ovary and five normal ovaries revealed de novo synthesis of IMP1 in 69% of ovarian carcinomas. Elevated IMP1 expression was observed preferentially in high-grade and high-stage cases and was a significant prognostic indicator for reduced recurrence-free and overall survival. Phenotypic studies in ovarian carcinoma-derived ES-2 cells demonstrated that IMP1 knockdown affects proliferation and cell survival. Reduced proliferation was associated with decreased c-myc mRNA half-life, suggesting IMP1 as an oncogenic factor that is involved in promoting elevated proliferation by stabilizing the c-myc mRNA in ovarian carcinoma cells.

Expression of lysophosphatidic acid acyltransferase beta (LPAAT-beta) in ovarian carcinoma: correlation with tumour grading and prognosis.

Lysophosphatidic acid acyltransferase beta (LPAAT-beta) is an enzyme involved in lipid biosynthesis whose role in tumour progression has been of emerging interest in the last few years. We investigated the expression of LPAAT-beta by reverse transcriptase-polymerase chain reaction and immunohistochemistry in 10 ovarian cell lines as well as in a cohort of 106 ovarian tumours and normal ovaries. Lysophosphatidic acid acyltransferase beta mRNA was found in all cell lines and ovarian tumours examined. Expression of LPAAT-beta protein was significantly increased in ovarian carcinomas compared to benign ovarian tissue (chi2 test P-value=0.001, Kruskal-Wallis test P-value <0.0001). Furthermore, LPAAT-beta expression was positively associated with higher tumour grade (P=0.044), higher mitotic index (P<0.0001) and tumour stage (P=0.032). Expression of LPAAT-beta was significantly linked to reduced overall survival time (P=0.024) as well as to shorter progression-free survival time (P=0.012) in patients younger than 60 years. Our study shows that LPAAT-beta is upregulated in ovarian cancer and is more prevalent in poorly differentiated tumours. In addition, LPAAT-beta expression is a predictor of a worse prognosis in patients younger than 60 years. Further studies are needed to investigate if LPAAT-beta may serve as a therapeutic target for certain subgroups of patients.

[Prognostic factors in ovarian carcinoma]. / Prognosefaktoren des Ovarialkarzinoms.

Ovarian carcinoma is the most lethal gynaecological malignancy in the western world with a five year survival rate of appr. 35 %. Unfortunately, most patients present with advanced disease, and their standard treatment is maximal surgical debulking and chemotherapy consisting of carboplatin and taxol. The most important prognostic factor in these patients is residual tumor after primary surgery. In patients with ovarian carcinoma confined to the ovary prognostic factors are important. Currently, high-grade and clear cell histology are regarded as worse prognostic factors, and these patients receive chemotherapy. Studies on prognostic factors in ovarian carcinomas are usually hampered by a low number of patients, and the lack of essential data (residual tumor, chemotherapy, and histological type), making meta-analyses impossible. For the future, prospective studies on putative prognostic factors are necessary. Moreover, for patients with advanced disease the evaluation of predictive factors (chemoresistance) as well as studies on the importance of the inflammatory background present in the tumor-seeded peritoneal cavity will get important.

Polo-like kinase isoform expression is a prognostic factor in ovarian carcinoma.

The Polo-like kinase (PLK) family comprises three serine/threonine kinases, functionally involved in signal transduction pathways essential for the accomplishment of mitosis in both normal and malignant cells. Moreover, certain PLKs have been functionally linked to cytoskeletal reorganisation. In this study, the expression of PLK1 and PLK3 was determined immunohistochemically in tissue specimen of normal ovaries (n=9), cystadenomas (n=17), borderline tumours (n=13) and ovarian carcinomas (n=77). PLK 1 and PLK3 expression was low in normal ovarian surface epithelium and borderline tumours, with moderately higher expression levels in cystadenomas. In ovarian carcinomas, 26% of cases were PLK1 positive and 50.6% of cases were PLK3 positive. A positive correlation of both PLK1 and PLK3 expression with indicators of mitotic frequency could be established. The overexpression of either isoenzyme had an impact on patient prognosis with shortened survival time for patients with tumours positive for PLK1 (P=0.02) and PLK3 (P=0.02), but only PLK1 expression remained a prognostic factor in multivariate survival analysis (P=0.03). The results of this study, if interpreted in the context of recently published functional data, suggest that inhibition of PLKs might represent an interesting new targeted approach for chemotherapy of epithelial ovarian cancer. Furthermore, this study suggests that PLK1 is a novel independent prognostic marker in ovarian carcinomas.

Interleukin-10 in serous ovarian carcinoma cell lines.

Interleukin-10, one of the most potent antiinflammatory cytokines, is expressed in ovarian carcinomas in vivo. In contrast to the high levels of IL-10 in ascites and tumour tissue, the expression of this cytokine appears to be a rare event in ovarian carcinoma cell lines in vitro. Virtually nothing is known about the regulation of IL-10 expression in ovarian carcinoma cell lines. We investigated the expression of IL-10 in four cell lines originally derived from ovarian serous adenocarcinoma: OVCAR-3, SKOV-3, CAOV-3 and OAW-42. IL-10- specific mRNA was detected in OVCAR-3 and only this cell line produced IL-10 constitutively under serum-free conditions as well as in serum-containing medium. Our studies on the regulation of IL-10 secretion in OVCAR-3 revealed that (1) proinflammatory stimuli IL-1beta and TNF-alpha, but not LPS, enhance IL-10 secretion, (2) IL-6 has no influence on the release of IL-10, (3) prostaglandin E2 influences neither the spontaneous nor the TNF-alpha- or IL-1beta-stimulated IL-10 production and (4) interferon-gamma inhibits IL-10 secretion. We conclude that only a minority of serous ovarian carcinoma cells maintain the ability to produce IL-10 in vitro. Our data on the regulation of IL-10 production in OVCAR-3 indicate that ovarian carcinoma cells share some, but not all, of the regulatory features typical for the monocytic IL-10 secretion.

Expression of cyclooxygenase 2 in human malignant melanoma.

Cyclooxygenase (COX)-2 is an inducible enzyme involved in production of prostaglandins in inflammatory processes. There is now increasing evidence that a constitutive expression of COX-2 plays a role in development and progression of malignant epithelial tumors. In the present study we investigated expression and function of COX-2 in malignant melanoma. Expression of COX-2 was determined by immunohistochemistry in 28 cases of primary skin melanoma and 4 benign nevi. We show that COX-2 was expressed in 26 cases (93%) of melanomas, with a moderate to strong expression in 19 cases (68%). Benign nevi as well as normal epithelium were negative in all cases. A constitutive expression of COX-2 mRNA and protein was found in five melanoma cell lines (A375, MeWo, SK-Mel-13, SK-Mel-28, and IGR-37) by using Northern blot as well as immunoblotting. All melanoma cell lines produced prostaglandin (PG) E2 between 468 and 3500 pg/ml as determined by ELISA. Treatment with NS-398 (50 microM), a specific inhibitor of COX-2, suppressed PGE2 production of all melanoma cell lines by 50-96%. The IC50 for inhibition of PGE2 production by NS-398 was determined as 4 microM, indicating that NS-398 acts via inhibition of the COX-2 isoenzyme. We could show that proliferation of melanoma cell lines was not influenced by treatment with NS-398 in concentrations up to 100 microM. However, NS-398 reduced Matrigel invasion of all five malignant melanoma cell lines by 50-68%. Our results indicate that COX-2 is expressed in malignant melanomas and may be involved in regulation of melanoma invasion. It remains to be investigated whether selective inhibitors of COX-2 might be useful for prevention or treatment of malignant melanoma.

The TUTOR, a software package for educational computing.

Computer Assisted Instruction (CAI) is an effective method of imparting factual knowledge relating to the practice of medicine. Unfortunately educational software remains scarse and expensive or lacks flexibility. This paper introduces a software package that permits continuing medical education and self assessment by Multiple Choice Question exercises. The questions are first written to a text file with an easy-to-use editor. The programs are written in BASIC and hardware prerequisite are a desk-top computer with 32K of CPU memory and a dual floppy disk drive.

[Accumulation of carbon dioxide in the operative field in ophthalmic interventions under local anesthesia]. / L'accumulation de CO2 sous le champ opératoire des interventions ophtalmologiques en anesthésie locale.

In eye surgery under local anaesthesia, a micro-climate develops under the operative field. Respiratory CO2 concentration, measured by an infrared capnograph, increases rapidly and becomes stable at a certain level. A three-dimensional relation has been established (CO2 concentration X weight of the patient X free space under the field). The effects of the accumulated CO2 are complex and partially depending on premedication. The air inhaled by the patient should be renewed by elimination of the excess CO2.