Women’s preferences regarding options for management of atypical,borderline or low‐grade cervical cytological abnormalities: a review of the evidence

M. Z. Sadique and R. Legood Women’s preferences regarding options for management of atypical, borderline or low‐grade cervical cytological abnormalities: a review of the evidence Objectives: To review the evidence on women’s preferences for and valuation of alternative management pathways following identification of low‐grade cytological abnormalities as part of routine cervical cancer screening. The aim was to identify empirical studies evaluating women’s preferences regarding alternative management pathways and to compare the impact of alternative elicitation methods on results. Methods: A systematic review of the literature was conducted using the online bibliographic information service PubMed database. Empirical studies were identified that elicited general preferences, utilities or valuations based on willingness to pay (WTP) with respect to management of low‐grade cytology results. Data were extracted on the methodology used and the empirical results. Results: Where quality of life data were elicited directly from patients that were undergoing management of low‐grade abnormalities utilizing direct elicitation techniques such as WTP, general preference questionnaires and the Euroqol, the studies tended towards a preference in favour of HPV testing (and colposcopy referral if HPV positive) rather than repeat cytology. In contrast, where studies included the general population and presented hypothetical scenarios of treatment pathways, and explicitly tried to incorporate assessment of process utility, the evidence indicated a slight tendency to favour repeat cytology. Conclusion: Consideration of patient preferences in the management of low‐grade cytology is important for designing screening protocols. The reviewed studies indicate that potentially different conclusions may be drawn depending on the elicitation methodology and selection of participants in the research.     

Atypical squamous cells and low‐grade squamous intraepithelial lesion in cervical cytology: cytohistological correlation and implication for management in a low‐resource setting

N. Gupta, R. Srinivasan, R. Nijhawan, A. Rajwanshi, P. Dey, V. Suri and L. Dhaliwal Atypical squamous cells and low‐grade squamous intraepithelial lesion in cervical cytology: cytohistological correlation and implication for management in a low‐resource setting Objectives: To perform an audit of all cervical smears reported as atypical squamous cells (ASC) and low‐grade squamous intraepithelial lesion (LSIL) as in the Bethesda system (TBS) 2001, and determine their histological follow‐up and outcome when available, in order to define the threshold for colposcopic referral. Material and methods: A total of 25 203 cervical smears were screened over a period of 3 years (January 2006 – December 2008) and all ASC and LSIL smears were reviewed with the corresponding histological follow‐up. All cervical intraepithelial neoplasia (CIN) grade 2 lesions and above (CIN2+) were considered as clinically significant lesions for analysis. Results: Out of 25 203 cervical smears, 424 (1.7%) were reported as ASC and 113 (0.4%) as LSIL. Additionally, three were reported as atypical cells, not otherwise specified. The ASC : SIL ratio was 2.18 : 1. Follow‐up histology was available in 153 (36.8%) of the ASC cases and revealed CIN2+ lesions in 22 (14.4%). Follow‐up histology was available in 50 (44.2%) of LSIL cases and revealed clinically significant abnormalities in five (10%), all of which were CIN2. CIN3 and invasive squamous carcinomas were seen in 5.9% and 1.4%, respectively, of cases of ASC, and not seen in LSIL. Reclassification of ASC smears into ASC‐US (ASC‐undetermined significance) and ASC‐H (ASC‐ high grade SIL not excluded) revealed ASC‐H in 2.6% of all ASC smears, with a clinically significant outcome in 45.4%. Conclusion: In a low‐resource setting where human papillomavirus testing is unaffordable, the threshold for colposcopic referral and follow‐up histology should be ASC rather than SIL.     

Posters. P11 Positive predictive values for high and low‐grade cytological abnormalities as surrogates for specificity and sensitivity

Introduction Positive predictive value (PPV), measuring the percentage of moderate dyskaryosis or worse confirmed as CIN2 or worse, is used as a measure of accuracy in cervical screening. However, it relates more to specificity than sensitivity because the denominator includes false positives rather than false negatives. Low values reflect over‐reporting of high‐grade dyskaryosis but high values may reflect under‐reporting. Sensitivity is impossible to measure from correlation of cytology with outcome because women with negative cytology are rarely referred for colposcopy. Rates of CIN3 resulting from referrals for low‐grade cytology may be used as a surrogate for sensitivity, as high values may reflect under‐reporting (ref). Study design Outcome of colposcopy referrals was monitored during a period of 4 years, using a fail‐safe database. Results PPV at Guy's & St Thomas rose from 54% in 1998/1999 to 69% in 2001/2002. The former was below the NHSCSP recommended range. During the same period of time CIN1 rates for moderate dyskaryosis fell from 37% to 24%, reflecting the main source of discrepancy. While specificity increased (as reflected by increasing PPV) sensitivity remained constant in that CIN3 rates for mild dyskaryosis and borderline remained below 6%: average rates in England have fallen over the last 3 years and were 7.4% in 2000/2001 (ref). CIN2 rates for mild dyskaryosis also remained constant at 11% to 12%. Conclusion Correlation of biopsy results with high‐ and low‐grade cytological abnormalities is a useful method of monitoring accuracy of cytology reporting, and can be used to measure over‐ and under‐reporting as surrogates for specificity and sensitivity.     

MAPK pathway activation and the origins of pediatric low‐grade astrocytomas

Low‐grade astrocytomas (LGAs) are the most common type of brain tumor in children. Until recently, very little was known about the underlying biology and molecular genetics of these tumors. However, within the past year a number of studies have shown that the MAPK pathway is constitutively activated in a high proportion of LGAs. Several genetic aberrations which generate this deregulation of the MAPK pathway have been identified, most notably gene fusions between KIAA1549 and BRAF. In this review we summarize these findings, discuss how these gene fusions may arise and consider possible implications for diagnosis and treatment. J. Cell. Physiol. 222: 509–514, 2010. © 2009 Wiley‐Liss, Inc.     

Review of negative and low‐grade cervical smears in women with invasive cervical cancer after the first 3 years of the national cervical screening programme in Slovenia

A. Repše‐Fokter, A. Pogačnik, V. Snoj, M. Primic‐Žakelj and M. S. Fležar
Review of negative and low‐grade cervical smears in women with invasive cervical cancer after the first 3 years of the national cervical screening programme in Slovenia Objective: The purpose of the study was to perform a national review of negative, low‐grade and inadequate smears reported during the latest screening period before cervical cancer diagnosis in 2006, after the first 3 years of the screening programme. Methods: Among 162 new cervical cancer cases there were 47 (29%) without previous cytology, 47 (29%) with one high‐grade smear prior to diagnosis and 68 (42.0%) with at least one previous negative, low‐grade, atypical or inadequate smear 1–40 months before diagnosis. Of the latter 68 cases, 37 patients with 59 smears (together with 118 control slides) were included in the review as 31 had smears reported at laboratories no longer operating. Findings were related to the last cytology report before diagnosis as well as to histological type and stage of the cancer. Results: In our study group, 19 (51%) of 37 patients had squamous cell carcinoma, 15 (41%) adenocarcinoma and 3 (8%) adenosquamous carcinoma, compared with 121 (75%), 26 (16%), 12 (7%), respectively, and 3 (2%) other types, for all carcinomas. Twenty‐one of 37 women also had high‐grade cytology prior to diagnosis of cancer. Women with previous cytology (with or without recent high‐grade smears) were more likely to have stage I cancers than those without cytology (P < 0.0001). The expert group upgraded 17/33 smears in the patients with squamous carcinomas, which was more than in those with adeno‐ and adenosquamous carcinomas (5/24, P < 0.05). Conclusion: As expected, a higher proportion of smears preceding adenocarcinomas were true negative. Under‐diagnosed smears were not related to cancer stage or last cytology report before diagnosis.     

Pathophysiological roles of chronic low‐grade inflammation mediators in polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is the most common hormonal imbalance disease in reproductive‐aged women. Its basic characteristics are ovulatory dysfunction and ovarian overproduction of androgens that lead to severe symptoms such as insulin resistance, hirsutism, infertility, and acne. Notwithstanding the disease burden, its underlying mechanisms remain unknown, and no causal therapeutic exists. In recent years, further studies showed that inflammation processes are involved in ovulation and play a key role in ovarian follicular dynamics. Visceral adipose tissue can cause inflammatory response and maintenance of the inflammation state in adipocytes by augmented production of inflammatory cytokines, monocyte chemoattractant proteins, and recruitment of the immune cell. Therefore, the PCOS can be related to a low‐grade inflammation state and inflammatory markers. Investigating the inflammatory processes and mediators that contribute to the commencement and development of PCOS can be a critical step for better understanding the pathophysiology of the disease and its treatment through inhibition or control of related pathways. In the present review, we discuss the pathophysiological roles of chronic low‐grade inflammation mediators including inflammasome‐related cytokines, interleukin‐1β (IL‐1β), and IL‐18 in PCOS development.     

Identification of novel biomarker candidates for immunohistochemical diagnosis to distinguish low‐grade chondrosarcoma from enchondroma

Chondrosarcoma is the third most common primary bone cancer, requiring surgical resection. However, differentiation of low‐grade chondrosarcoma (grade 1) from enchondroma that is benign and only requires regular follow‐up is one of the most frequent diagnostic dilemmas facing orthopedic oncologists in clinical management. Although multiple techniques are applied to make the distinction, immunohistochemistry is an important ancillary technique, especially when a histopathological stain of specimen must be obtained in order to guarantee an accurate confirmation. Currently, no adequate immunohistochemical diagnostic protein biomarkers are available to distinguish low‐grade chondrosarcoma from enchondroma. To discover novel protein biomarker candidates, an LC‐MS/MS approach was applied to directly compare formalin‐fixed, paraffin‐embedded low‐grade chondrosarcoma with enchondroma tissue samples. The proteomics analysis revealed 17 protein biomarker candidates. A principle was developed to prioritize the candidates using category and ranking. An algorithm, prioritization index of biomarker candidates for immunohistochemistry on tissue specimens, was developed to rank the candidates inside each category. Using the proteomics data and bioinformatics results, the prioritization index of biomarker candidates for immunohistochemistry on tissue revealed periostin as a top candidate. Immunohistochemical staining of periostin in 23 low‐grade chondrosarcoma and 31 enchondroma tissue specimens disclosed 87% specificity and 70% sensitivity.     

Value of computer‐assisted quantitative nuclear morphometry for differentiation of reactive renal tubular cells from low‐grade urothelial carcinoma

H. Ohsaki, E. Hirakawa, K. Kagawa, M. Nakamura, H. Kiyomoto and R. Haba Value of computer‐assisted quantitative nuclear morphometry for differentiation of reactive renal tubular cells from low‐grade urothelial carcinoma Objective: To assess whether computer‐assisted quantitative morphological parameters can be an effective tool for objectively distinguishing reactive renal tubular cells from low‐grade urothelial carcinoma cells (LG‐UCs) in voided urine. Methods: Nuclear morphometry was performed by a computer‐assisted image analyser system on Papanicolaou‐stained cytological specimens. The circumference of reactive renal tubular cells (n = 40) or LG‐UC (n = 20) nuclei were manually traced, and the following nuclear morphometric parameters were analysed: (i) area, (ii) perimeter, (iii) roundness factor, (iv) maximum length, and (v) linear factor. For each nuclear measurement, we calculated the maximum, minimum, mean and standard deviation. Results: The mean nuclear area and nuclear perimeter were higher in reactive renal tubular cells compared to the LG‐UCs. The mean of roundness and linear factors (reflecting a tendency for the nuclear outline to be regular and oval, respectively) were higher in LG‐UCs compared with reactive renal tubular cells. Among nuclear areas, the nuclear perimeter, roundness factors and maximum length did not show any significant differences between reactive renal tubular cells and LG‐UCs. On the other hand, the linear factor showed a mean higher value among LG‐UCs than reactive renal tubular cells (P = 0.023). Conclusions: Of five quantitative nuclear morphological parameters, only linear factor was statistically significant in differentiating reactive renal tubular cells in renal disease from LG‐UCs.     

Characterization of Bacillus subtilis spore inactivation in low‐pressure,low‐temperature gas plasma sterilization processes

Aims: To identify structural components of Bacillus subtilis spores serving as targets for sterilization with microwave induced low‐pressure, low‐temperature nitrogen‐oxygen plasma. Methods and Results: The inactivation of spores followed a biphasic kinetics consisting of a log‐linear phase with rapid inactivation followed by a slow inactivation phase. In the course of plasma treatment, damage to DNA, proteins and spore membranes were observed by monitoring the occurrence of auxotrophic mutants, inactivation of catalase (KatX) activity and the leakage of dipicolinic acid, respectively. Spores of the wild‐type strain showed the highest resistance to plasma treatment. Spores of mutants defective in nucleotide excision repair (uvrA) and small acid‐soluble proteins (ΔsspA ΔsspB) were more sensitive than those defective in the coat protein CotE or spore photoproduct repair (splB). Exclusion of reactive particles and spectral fractions of UV radiation from access to the spores revealed that UV‐C radiation is the most effective inactivation agent in the plasma, whereby the splB and ΔcotE mutant spores were equally and slightly less sensitive, respectively, than the wild‐type spores. Finally, the extent of damages in the spore DNA determined by quantitative PCR correlated with the spore inactivation. Conclusions: Spore inactivation was efficiently mediated by a combination of DNA damage and protein inactivation. DNA was identified to be the primary target for spore inactivation by UV radiation emitted by the plasma. Coat proteins were found to constitute a protective layer against the action of the plasma. Significance and Impact of the Study: The results provide new evidence to the understanding of plasma sterilization processes. This knowledge supports the identification of useful parameters for novel plasma sterilization equipment to control process safety.     

Endothelial function and weight loss: Comparison of low‐carbohydrate and low‐fat diets

Objective: The effect of weight loss on obesity‐associated endothelial dysfunction is not clear because of conflicting data, demonstrating both improvement and no change in endothelial function after weight loss in obese subjects. A 2‐year prospective study (n = 121) was conducted to examine: (1) the effect of obesity and weight loss (either a low‐carbohydrate or and low‐fat diet) on flow mediated vasodilatation (FMD), a measure of endothelial function. Design and Methods: Participants reduced body weight by 7.1% ± 4.4%, 8.7% ± 6.8%, 7.1% ± 7.8%, and 4.1% ± 7.7% at 3, 6, 12, and 24 months, respectively with no significant differences between the low‐fat and low‐carbohydrate groups. Results: Endothelial function was inversely correlated with waist circumference, triglyceride level, and directly correlated with leptin in obese persons prior to weight loss. These weight losses did not confer any improvements in FMD. There were no differences between the low‐fat and low‐carbohydrate diets in FMD at any time point. At 6 months (r = 0.26, P = 0.04) and 1 year (r =0.28, P = 0.03), there were positive correlations between change in FMD and change in leptin but not at 2 years. Conclusion: There was no significant improvement in endothelial function after 7.1% ± 7.8% weight loss at 1 year and 4.1% ± 7.7% at 2 years, achieved by either a low carbohydrate or a low fat diet.