Triage of women with equivocal or low-grade cervical cytology results: a meta-analysis of the HPV test positivity rate

Introduction Methods Results Discussion Conclusion Abstract Consistent evidence underlines the utility of human papillomavirus (HPV) DNA testing in the management of women with equivocal cervical cytological abnormalities, but not in case of low-grade lesions. We performed a meta-analysis including studies where the high-risk probe of the Hybrid Capture-II is used to triage these two cytological categories. The triage test-positivity rate reflects the colposcopy referral workload.Data were pooled on the HPV test positivity rate in women with atypical squamous cells of undetermined significance (ASCUS/ASC-US) or low-grade squamous intraepithelial lesions (LSIL), derived from different cytological classification systems. The meta-analysis was restricted to studies, published between 1991 and 2007. A random-effect model was applied for meta-analytical pooling and the influence of covariates on the HPV positivity rate was analyzed by meta-regression. The variation by age was assessed within individual studies since age strata were not defined uniformly. On an average, 43% (95% CI: 40-46%) of women with ASCUS/ASC-US were high-risk HPV positive (range 23-74%). In women with LSIL, the pooled positivity rate was 76% (95% CI: 71-81%; range 55-89%). In spite of considerable inter-study heterogeneity, the difference in HPV positivity between the two triage groups was large and highly significant: 32% (95% CI: 27-38%). HPV rates dropped tremendously as age and cutoffs of test positivity increased. Other factors (cytological classification system, country, continent, collection method and year of publication) had no statistically significant impact, except in LSIL triage where HPV positivity was significantly lower in European compared to American studies. Women with LSIL, especially younger women, have high HPV positivity rates suggesting limited utility of reflex HPV triaging these cases. Research is needed to identify more specific methods to triage women with low-grade squamous cervical lesions

Εκδηλώσεις παρανεοπλασματικών συνδρόμων στο νεφρικό παρέγχυμα

Ο Auche περιέγραψε το 1890 για πρώτη φορά παρανεοπλασματικό συνδρόμο με συμμετοχή του περιφερικού νευρικού συστήματος σε ασθενείς με καρκίνο. Ωστόσο ο ορισμός «παρανεοπλασματικό» χρησιμοποιήθηκε για πρώτη φορά το 1949 από τους Guichard και Vignon όταν συζήτησαν την διαφορική διάγνωση ενός ασθενή με κεντρική και περιφερική νευροπάθεια που προκλήθηκε από μετάσταση καρκίνου του τραχήλου της μήτρας. Στην εποχή μας η έκφραση «παρανεοπλασματικό σύνδρομο» ορίζεται ως μια ομάδα συμπτωμάτων που μπορούν να αναπτυχθούν όταν ουσίες που απελευθερώνονται από καρκινικά κύτταρα διαταράσσουν την φυσιολογική λειτουργία των περιβαλλόντων κυττάρων και ιστών. Οι νεφρικές εκδηλώσεις των παρανεοπλασματικών συνδρόμων είναι παθήσεις οι οποίες έμμεσα μεταβάλλουν την σωληναριακή και σπειραματική λειτουργία μέσω ηλεκτρολυτικών διαταραχών, όγκων που παράγουν ορμόνες ή εναποθέσεων συμπλεγμάτων αντιγόνων-αντισωμάτων στα σπειράματα. Η νεφρική λειτουργία μπορεί να επηρεαστεί από αρκετά παρανεοπλασματικά σύνδρομα, ενώ μπορεί να παρατηρηθεί υπερκαλιαιμία σε κακοήθειες, σύνδρομο λύσης όγκου, όγκους που παράγουν ρενίνη και παρανεοπλασματικές σπειραματοπάθειες. Μια έγκαιρη διάγνωση και μια αποτελεσματική θεραπεία μπορεί να βελτιώσει την ποιότητα ζωής και να αλλάξει την πρόγνωση αυτών των ασθενειών.Auche described in 1890 the first report of paraneoplastic syndrome with involvement of the peripheral nervous system in patients with cancer. However the word “paraneoplastic” was first used only in 1949 by Guichard and Vignon, when they discussed the differential diagnosis of a patient with central and peripheral neuropathies caused by metastasis of a cervical neoplasia. Nowdays the expression “paraneoplastic syndrome” is defined as a group of symptoms that may develop when substances released by some cancer cells disrupt the normal fuction of surrounding cells and tissue. Paraneoplastic renal symdromes are diseases that indirectly compromise tibular and glomerular fuction by electrolyte imbalance, hormone-producing tumors or deposition of antigen-antibody complexes in the glomeruli. Renal function can be affected by many paraneoplastic syndromes causing hypercalcemia in malignancies, tumor lysis syndrome, renin-producing tumors and paraneoplastic glomerulopathies. An early diagnosis and effective treatment might improve quality of life and change prognosis of these patients

Ανάλυση ούρων στον υπερτασικό ασθενή-ανασκόπηση

Η βασική ανάλυση ούρων είναι μια εύκολη και γρήγορη μέθοδος για τη λήψη διαγνωστικών πληροφοριών σχετικά με ασθένειες που επηρεάζουν τον ανθρώπινο οργανισμό. Ο σκοπός της εξέτασης ούρων είναι να ανιχνεύσει ασυμπτωματικά, χαμηλού κινδύνου άτομα, να διαγνώσει τον συμπτωματικό ασθενή και να βοηθήσει στη θεραπευτική παρακολούθηση διάφορων καταστάσεων-παθήσεων. Η αξία της ανάλυσης ούρων έγκειται στην ευκολία λήψης δειγμάτων και στον ταχύ προσδιορισμό των χημικών συστατικών με τη χρήση ταινιών μέτρησης. Στην παρούσα ανασκόπηση αξιολογείται η χρήση της ανάλυσης ούρων ως εργαλείο, που δίνει σημαντικές πληροφορίες και κατευθύνει σε απαιτούμενες θεραπευτικές παρεμβάσεις ατόμων που παρουσιάζουν υπέρταση. Πραγματοποιήθηκε συστηματική αναζήτηση στο Pubmed και το Google scolar και συμπεριλήφθησαν μελέτες που αναφέρονταν στην ανάλυση της γενικής ούρων, την χρησιμότητα της για την αξιολόγηση του ασθενούς και την συσχέτιση που μπορεί να παρουσιάσει σε υπερτασικούς ασθενείς. Γίνεται αναφορά στον ενδεδειγμένο τρόπο συλλογής ούρων, τα φυσικά, τα χημικά χαρακτηριστικά των ούρων καθώς και την μικροσκοπική εξέταση των ούρων. Παρουσιάζεται η ερμηνεία των κύριων ευρημάτων του ιζήματος των ούρων και ποια είναι τα ευρήματα που παρατηρούνται στην γενική ούρων υπερτασικών ατόμων.Basic urinalysis is an easy and quick method to obtain diagnostic information about diseases affecting the human body. The purpose of urinalysis is to detect asymptomatic, low-risk individuals, diagnose the symptomatic patient, and assist in the therapeutic monitoring of various disease states. The value of urinalysis lies in the ease of sampling and the rapid determination of chemical constituents using test strips. The present review evaluates the use of urinalysis as a tool, which gives important information and directs to required therapeutic interventions in people with hypertension. A systematic search of Pubmed and Google scholar was performed and included studies that referred to the analysis of general urinalysis, its utility in patient evaluation and the correlation it may present in hypertensive patients. Reference is made to the appropriate method of urine collection, the physical and chemical characteristics of urine as well as the microscopic examination of urine. The interpretation of the main findings of the urine sediment and what are the findings observed in the general urine of hypertensive individuals is presented

Decreased D2-40 and increased p16INK4A immunoreactivities correlate with higher grade of cervical intraepithelial neoplasia

<p>Abstract</p> <p>Background</p> <p>D2-40 has been shown a selective marker for lymphatic endothelium, but also shown in the benign cervical basal cells. However, the application of D2-40 immunoreactivity in the cervical basal cells for identifying the grade of cervical intraepithelial neoplasia (CIN) has not been evaluated.</p> <p>Methods</p> <p>In this study, the immunoreactive patterns of D2-40, compared with p16^INK4A, which is currently considered as the useful marker for cervical cancers and their precancerous diseases, were examined in total 125 cervical specimens including 32 of CIN1, 37 of CIN2, 35 of CIN3, and 21 of normal cervical tissue. D2-40 and p16^INK4Aimmunoreactivities were scored semiquantitatively according to the intensity and/or extent of the staining.</p> <p>Results</p> <p>Diffuse D2-40 expression with moderate-to-strong intensity was seen in all the normal cervical epithelia (21/21, 100%) and similar pattern of D2-40 immunoreactivity with weak-to-strong intensity was observed in CIN1 (31/32, 97.2%). However, negative and/or focal D2-40 expression was found in CIN2 (negative: 20/37, 54.1%; focal: 16/37, 43.2%) and CIN3 (negative: 22/35, 62.8%; focal: 12/35, 34.3%). On the other hand, diffuse immunostaining for p16^INK4Awas shown in 37.5% of CIN1, 64.9% of CIN2, and 80.0% of CIN3. However, the immunoreactive pattern of D2-40 was not associated with the p16^INK4Aimmunoreactivity.</p> <p>Conclusions</p> <p>Immunohistochemical analysis of D2-40 combined with p16^INK4Amay have a significant implication in clinical practice for better identifying the grade of cervical intraepithelial neoplasia, especially for distinguishing CIN1 from CIN2/3.</p

Novel dual-function CellDetect® staining technology: wedding morphology and tinctorial discrimination to detect cervical neoplasia

<p>Abstract</p> <p>Background</p> <p>A persistent goal of oncologic histochemistry is to microscopically identify neoplasia tinctorially. Consequently, the newly developed CellDetect^®staining technology, that appears to exhibit this property, warrants clinical evaluation. The objective of this study was to compare the diagnostic results using CellDetect^®to the outcomes of standard microscopic examination based on hematoxylin and eosin (H&E) staining for the recognition of different squamous epithelial phenotypes of the uterine cervix.</p> <p>Methods</p> <p>Pairs of adjacent sections were made from 60 cervical biopsy cases that were diagnosed originally as either normal or neoplastic (CIN, SCC). One section of the pair was stained for H&E; the second section, with CellDetect^®. Based on the examination of these pairs by two experienced pathologists, we investigated the following issues:(1) diagnostic agreement between the pathologists on each pair; (2) agreement between H&E and CellDetect^®for each pair (3) tinctorial characteristics in micro-regions (n = 130) evaluated as either normal, reactive or neoplastic.</p> <p>Results</p> <p>Qualitatively, CellDetect^®-stained preparations displayed cyto-morphological detail comparable to H&E images. Tinctorially, <it>non-neoplastic </it>cells appeared green/blue when stained withCellDetect^®, contrasting with cytologically <it>neoplastic </it>foci, where cells of every grade were red/magenta in color. Due to these tinctorial characteristics, even small foci of neoplasia could be readily distinguished that were inconspicuous on H&E at low magnification. In some instances, this prompted re-examination of the H&E and revision of the diagnosis. Quantitatively, we found that despite diagnostic variation between pathologists, in about 3% of the cases, each pathologist made the same diagnosis regardless of whether CellDetect^®or H&E was used, i.e. there was 100% self-agreement for each pathologist between stains. Particularly noteworthy was the finding of a 0% false negative rate, coupled with a 10-15% false positive rate. Regarding specificity, the performance in <it>reactive </it>squamous processes was similar to that observed for morphologically normal squamous epithelium.</p> <p>Conclusions</p> <p>In this first order assessment of clinical applicability, CellDetect^®staining technology was at least comparable to results using H&E, and perhaps surperior. CellDetect^®provided a uniquely useful tinctorial clue for the detection of neoplasia, which exhibited an impressive 0% false negative rate. A more extensive, blinded study is needed to confirm these promising findings.</p

Eurogin Roadmap 2017: triage strategies for the management of HPV-positive women in cervical screening programmes

Cervical cancer screening will rely, increasingly, on HPV testing as a primary screen. The requirement for triage tests which can delineate clinically significant infection is thus prescient. In this EUROGIN 2017 roadmap, justification behind the most evidenced triages is outlined, as are challenges for implementation. Cytology is the triage with the most follow-up data; the existence of an HR-HPV-positive, cytology-negative group presents a challenge and retesting intervals for this group (and choice of retest) require careful consideration. Furthermore, cytology relies on subjective skills and while adjunctive dual-staining with p16/Ki67 can mitigate inter-operator/-site disparities, clinician-taken samples are required. Comparatively, genotyping and methylation markers are objective and are applicable to self-taken samples, offering logistical advantages including in low and middle income settings. However, genotyping may have diminishing returns in immunised populations and type(s) included must balance absolute risk for disease to avoid low specificity. While viral and cellular methylation markers show promise, more prospective data are needed in addition to refinements in automation. Looking forward, systems that detect multiple targets concurrently such as next generation sequencing platforms will inform the development of triage tools. Additionally, multistep triage strategies may be beneficial provided they do not create complex, unmanageable pathways. Inevitably, the balance of risk to cost(s) will be key in decision making, although defining an acceptable risk will likely differ between settings. Finally, given the significant changes to cervical screening and the variety of triage strategies, appropriate education of both health care providers and the public is essential

Human papillomavirus testing versus repeat cytology for triage of minor cytological cervical lesions

Background: A typical squamous cells of undetermined significance (ASCUS) and low-grade squamous intra-epithelial lesions (LSIL) are minor lesions of the cervical epithelium, detectable by cytological examination of cells collected from the surface of the cervix of a woman. Usually, women with ASCUS and LSIL do not have cervical (pre-) cancer, however a substantial proportion of them do have underlying high-grade cervical intra-epithelial neoplasia (CIN, grade 2 or 3) and so are at increased risk for developing cervical cancer. Therefore, accurate triage of women with ASCUS or LSIL is required to identify those who need further management. This review evaluates two ways to triage women with ASCUS or LSIL: repeating the cytological test, and DNA testing for high-risk types of the human papillomavirus (hrHPV) - the main causal factor of cervical cancer. Objectives Main objective: To compare the accuracy of hrHPV testing with the Hybrid Capture 2 (HC2) assay against that of repeat cytology for detection of underlying cervical intraepithelial neoplasia of grade 2 or worse (CIN2+) or grade 3 or worse (CIN3+) in women with ASCUS or LSIL. For the HC2 assay, a positive result was defined as proposed by the manufacturer. For repeat cytology, different cut-offs were used to define positivity: Atypical squamous cells of undetermined significance or worse (ASCUS+), low-grade squamous intra-epithelial lesions or worse (LSIL+) or high-grade squamous intra-epithelial lesions or worse (HSIL+). Secondary objective: To assess the accuracy of the HC2 assay to detect CIN2+ or CIN3+ in women with ASCUS or LSIL in a larger group of reports of studies that applied hrHPV testing and the reference standard (coloscopy and biopsy), irrespective whether or not repeat cytology was done. Search methods: We made a comprehensive literature search that included the Cochrane Register of Diagnostic Test Accuracy Studies; the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE (through PubMed), and EMBASE (last search 6 January 2011). Selected journals likely to contain relevant papers were handsearched from 1992 to 2010 (December). We also searched CERVIX, the bibliographic database of the Unit of Cancer Epidemiology at the Scientific Institute of Public Health (Brussels, Belgium) which contains more than 20,000 references on cervical cancer. More recent searches, up to December 2012, targeted reports on the accuracy of triage of ASCUS or LSIL with other HPV DNA assays, or HPV RNA assays and other molecular markers. These searches will be used for new Cochrane reviews as well as for updates of the current review. Selection criteria: Studies eligible for inclusion in the review had to include: women presenting with a cervical cytology result of ASCUS or LSIL, who had undergone both HC2 testing and repeat cytology, or HC2 testing alone, and were subsequently subjected to reference standard verification with colposcopy and colposcopy-directed biopsies for histologic verification. Data collection and analysis: The review authors independently extracted data from the selected studies, and obtained additional data from report authors. Two groups of meta-analyses were performed: group I concerned triage of women with ASCUS, group II concerned women with LSIL. The bivariate model (METADAS-macro in SAS) was used to assess the absolute accuracy of the triage tests in both groups as well as the differences in accuracy between the triage tests. Main results: The pooled sensitivity of HC2 was significantly higher than that of repeat cytology at cut-off ASCUS+ to detect CIN2+ in both triage of ASCUS and LSIL (relative sensitivity of 1.27 (95% CI 1.16 to 1.39; P value < 0.0001) and 1.23 (95% CI 1.06 to 1.4; P value 0.007), respectively. In ASCUS triage, the pooled specificity of the triage methods did not differ significantly from each other (relative specificity: 0.99 (95% CI 0.97 to 1.03; P value 0.98)). However, the specificity of HC2 was substantially, and significantly, lower than that of repeat cytology in the triage of LSIL (relative specificity: 0.66 (95% CI 0.58 to 0.75) P value < 0.0001). Authors' conclusions: HPV-triage with HC2 can be recommended to triage women with ASCUS because it has higher accuracy (significantly higher sensitivity, and similar specificity) than repeat cytology. When triaging women with LSIL, an HC2 test yields a significantly higher sensitivity, but a significantly lower specificity, compared to a repeat cytology. Therefore, practice recommendations for management of women with LSIL should be balanced, taking local circumstances into account

Η ΑΡΧΗ ΤΗΣ ΠΑΓΚΟΣΜΙΑΣ ΔΙΚΑΙΟΣΥΝΗΣ

Παρουσιάζεται και αναλύεται η αρχή της παγκόσμιας δικαιοσύνης ως μια βάση ποινικής δικαιοδοσίας. Αναφέρονται τα εγκλήματα που μπορεί να εφαρμοστεί και παρατίθεται το άρθρο 8 του ελληνικού ΠΚ, στο οποίο θεμελιώνεται η αρχή αυτή.In this thesis, it is presented the principle of universal jurisdiction as a basis of criminal jurisdiction and the article in which greek legislation has cited this principle (article 8