Low Arginine Plasma Levels do not Aggravate Renal Blood Flow after Experimental Renal Ischaemia/reperfusion

AbstractBackground: ischaemic renal dysfunction is present in many clinical settings, including cardiovascular surgery. Renal hypoperfusion seems to be the most important pathophysiologic mechanism. Arginine plasma levels are rate limiting for NO synthesis, and low arginine plasma levels are seen after major vascular surgery. Objective: to establish the effects of low arginine plasma levels on renal blood flow after renal ischaemia/reperfusion. Design: Wistar rats were used in this unilateral renal ischaemia/reperfusion model. After 70 min of ischaemia, the kidney was reperfused for 150 min. Arginase infusion was used to lower arginine plasma levels. Blood flow measurement was performed at the end of the experiment using radiolabelled microspheres. Additional experiments were performed for histopathology. Results: arginase efficiently decreased arginine plasma levels to about 50% of normal. There was a lower blood flow in the ischaemic kidney than the contralateral (non-ischaemic) kidney. Lowering arginine plasma levels did not reduce renal blood flow in the ischaemic kidney. Renal histopathology was not influenced by lowered arginine plasma levels. Conclusions: lowering arginine plasma levels did not affect blood flow or histology following renal ischaemia and reperfusion

Evaluation of the 2015 ATA Guidelines in Patients with Distant Metastatic Differentiated Thyroid Cancer

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Relevance of routine pathology review in cervical carcinoma

To determine the impact of pathology review on the management of patients with cervical carcinoma, 264 reports of pathology review from 230 patients referred to Erasmus MC (2010–2012) were studied retrospectively. Discrepancies between pathologic diagnoses were classified as ‘major’ if they led to changes in treatment, and as ‘minor’ where there was no change. Patient and tumor characteristics were analyzed to identify the factors influencing these discrepancies. Fifty-eight (25.2%) discrepancies were identified; 28 (12.2%) were major, these resulted frequently from missing essential information, or discordant assessment of tumor invasion. Pathology review prevented under-treatment of 3.5%, over-treatment of 1.3%, treatment for incorrect malignancy of 1.3%, and enabled definitive treatment of 6.1% of patients. This highlights the importance of pathology review for appropriate management. Major discrepancies were rare (1%) for patients with macroscopic tumor and histologic diagnosis of squamous cell carcinoma (n = 100). For these patients, yield of pathology review may be limited

Evaluation of the 2015 ATA Guidelines in Patients With Distant Metastatic Differentiated Thyroid Cancer

CONTEXT: Current American Thyroid Association (ATA) Management Guidelines for the treatment of differentiated thyroid cancer (DTC) stratify patients to decide on additional radioiodine (RAI) therapy after surgery, and to predict recurring/persisting disease. However, studies evaluating the detection of distant metastases and how these guidelines perform in patients with distant metastases are scarce. OBJECTIVE: To evaluate the 2015 ATA Guidelines in DTC patients with respect to 1) the detection of distant metastases, and 2) the accuracy of its Risk Stratification System in patients with distant metastases. PATIENTS AND MAIN OUTCOME MEASURES: We retrospectively included 83 DTC patients who were diagnosed with distant metastases around the time of initial therapy, and a control population of 472 patients (312 low-risk, 160 intermediate-risk) who did not have a routine indication for RAI therapy. We used the control group to assess the percentage of distant metastases that would have been missed if no RAI therapy was given. RESULTS: Two hundred forty-six patients had no routine indication for RAI therapy of which 4 (1.6%) had distant metastases. Furthermore, among the 83 patients with distant metastases, 14 patients (17%) had excellent response, while 55 (67%) had structural disease after a median follow-up of 62 months. None of the 14 patients that achieved an excellent response had a recurrence. CONCLUSIONS: In patients without a routine indication for RAI therapy according to the 2015 ATA Guidelines, distant metastases would initially have been missed in 1.6% of the patients. Furthermore, in patients with distant metastases upon diagnosis, the 2015 ATA Guidelines are an excellent predictor of both persistent disease and recurrence

Increased expression of the EZH2 polycomb group gene in BMI-1-positive neoplastic cells during bronchial carcinogenesis.

Polycomb group (PcG) genes are responsible for maintenance of cellular identity and contribute to regulation of the cell cycle. Recent studies have identified several PcG genes as oncogenes, and a role for PcG proteins in human oncogenesis is suspected. We investigated the expression of BMI-1 and EZH2 PcG oncogenes in human bronchial squamous cell carcinomas (SCCs) and bronchial premalignant precursor lesions (PLs). Whereas normal bronchial epithelium was associated with widespread expression of BMI-1 in resting EZH2-negative cells, neoplastic cells in lung carcinomas displayed altered expression of both BMI-1 and EZH2. Two patterns of abnormal PcG expression were observed: increased expression of BMI-1 in dividing neoplastic cells of PLs and SCCs, and enhanced expression of EZH2 and Ki-67 in BMI-1-positive cells according to severity of the histopathologic stage. We propose that altered expression of BMI1 and EZH2 is an early event that precedes high rates of proliferation in lung cancer. Because PcG complexes are normally involved in the maintenance of cell characteristics, abnormal PcG expression may contribute to loss of cell identity

Comparing SurePath, ThinPrep, and conventional cytology as primary test method: SurePath is associated with increased CIN II+ detection rates

Purpose: Within the last decade, SurePath and ThinPrep [both liquid-based cytology (LBC) tests] have replaced conventional cytology (CC) as primary test method in cervical cancer screening programs of multiple countries. The aim of our study was to examine the effect in the Dutch screening program. Methods: All primary smears taken within this program from 2000 to 2011 were analyzed using the nationwide registry of histo- and cytopathology (PALGA) with a follow-up until March 2013. The percentage of smears classified as borderline/mildly dyskaryotic (BMD) and >BMD as well as CIN and cervical cancer detection rates were compared between SurePath and ThinPrep versus CC by logistic regression analyses (adjusted for age, screen region, socioeconomic status, and calendar time). Results: We included 3,118,685 CC, 1,313,731 SurePath, and 1,584,587 ThinPrep smears. Using SurePath resulted in an increased rate of primary smears classified as >BMD [odds ratio (OR) = 1.12 (95% confidence interval (CI) 1.09–1.16)]. CIN I and II+ detection rates increased by 14 % [OR = 1.14 (95% CI 1.08–1.20)] and 8 % [OR = 1.08 (95% CI 1.05–1.12)]. Cervical cancer detection rates were unaffected. Implementing ThinPrep did not result in major alterations of the cytological classification of smears, and it did not affect CIN detection rates. While not significant, cervical cancer detection rates were lower [OR = 0.87 (95% CI 0.75–1.01)]. Conclusions: The impact of replacing CC by LBC as primary test method depends on the type of LBC test used. Only the use of SurePath was associated with increased CIN II+ detection, although it simultaneously increased the detection of CIN I

FAM19A4/miR124-2 methylation analysis as a triage test for HPV-positive women: cross-sectional and longitudinal data from a Dutch screening cohort

Objectives: The aim was to evaluate the cross-sectional and long-term triage performance of FAM19A4/miR124-2 methylation analysis in human papillomavirus (HPV)-based cervical screening. Methods: We conducted a post hoc analysis within a Dutch population-based HPV-positive study cohort of women aged 30–60 years (n = 979). Cross-sectional cervical intraepithelial neoplasia (CIN) 3+ sensitivity, specificity, positive predictive value and negative predictive value as well as cumulative CIN3+ or cervical cancer risks after 9 and 14 years were compared for three baseline triage strategies: (1) cytology, (2) FAM19A4/miR124-2 methylation analysis and (3) combined FAM19A4/miR124-2 methylation with cytology. Results: CIN3+ sensitivity of FAM19A4/miR124-2 methylation analysis was similar to that of cytology (71.3% vs 76.0%, ratio 0.94, 95% CI 0.84 to 1.05), at a lower specificity (78.3% vs 87.0%, ratio 0.90, 95% CI 0.86 to 0.94). Combining FAM19A4/miR124-2 methylation analysis with cytology resulted in a CIN3+ sensitivity of 84.6% (95% CI 78.3 to 90.8) at a specificity of 69.6% (95% CI 66.5 to 72.7). Similar 9- and 14-year CIN3+ risks for baseline cytology-negative women and baseline FAM19A4/miR12

Precursor lesions of vulvar squamous cell carcinoma – histology and biomarkers: A systematic review

The precursor lesion of vulvar squamous cell carcinoma (VSCC), namely vulvar intraepithelial neoplasia (VIN), is classified as: human papillomavirus (HPV)-related high grade squamous intraepithelial lesion (HSIL), and HPV-independent differentiated VIN (dVIN). Traditionally, histology and immunohistochemistry (IHC) have been the basis of diagnosis and classification of VIN. HSIL shows conspicuous histological atypia, and positivity on p16-IHC, whereas dVIN shows less obvious histological atypia, and overexpression or null-pattern on p53-IHC. For both types of VIN, other diagnostic immunohistochemical markers have also been evaluated. Molecular characterization of VIN has been attempted in few recent studies, and novel genotypic subtypes of HPV-independent VSCC and VIN have been identified. This systematic review appraises the VSCC precursors identified so far, focusing on histology and biomarkers (immunohistochemical and molecular). To gain further insights into the carcinogenesis and to identify additional potential biomarkers, gene expression omnibus (GEO) datasets on VSCC were analyzed; the results are presented