Treatment of Experimental Candida Sepsis with a Janus Kinase Inhibitor Controls Inflammation and Prolongs Survival.

Janus kinases (JAK) are intracellular tyrosine kinases that transduce cytokine-mediated signals to the nucleus, promoting gene expression. Cytokines play a major role in microbial sepsis, which is often associated with uncontrolled inflammation leading to death. JAK inhibitors have been used for the treatment of several autoimmune diseases by modulating immune response, but they have never been tested against microbial sepsis. Ruxolitinib is a small-molecule inhibitor of JAK1/2 proteins, which are involved in the downstream signaling pathway of the vast majority of proinflammatory and anti-inflammatory cytokines. We therefore studied the effect of ruxolitinib in a mouse model of sepsis due to Candida albicans. When ruxolitinib therapy (50 mg/kg [of body weight]/day) was started 1 day before infection, the median survival time was reduced by 3 days, the fungal loads in all organs were higher, the inflammation was significantly less, and serum tumor necrosis factor alpha (TNF-α) and interleukin 10 (IL-10) levels and IL-10/TNF-α ratios were higher than in controls. When ruxolitinib therapy (50 to 1.5 mg/kg/day) was started 1 day after infection, an inverted-U relationship was found, with 6.25 mg/kg/day prolonging median survival time by 6 days, resulting in similar fungal loads, less inflammation, and similar cytokine levels but higher IL-10/TNF-α ratios than the controls. The optimal dose of ruxolitinib controlled infection and prolonged survival with less inflammation than in control animals. Administration of JAK inhibitors may be a promising therapeutic adjunct that needs further investigation.

Galectin-3, Carotid Plaque Vulnerability, and Potential Effects of Statin Therapy.

OBJECTIVES: Galectin-3, a member of galectines, a family of b-galactoside-specific lectins, has been reported to propagate vascular inflammation. The role of galectin-3 in carotid atherosclerosis is controversial. The aim of this study was to investigate the relationship of galectin-3 with plaque vulnerability in patients with high grade carotid stenosis. METHODS: This was a cross sectional study of patients undergoing carotid endarterectomy (CEA). Carotid plaques obtained from 78 consecutive patients (40 symptomatic [SG], 38 asymptomatic [AG]) undergoing CEA were histologically analyzed for galectin-3, macrophages (CD68) and laminin. Pre-operatively the biochemical profile and plaque echogenicity (gray-scale median, GSM) score were determined. RESULTS: There were no significant differences in clinical and demographic parameters between SG and AG(p > .05). The SG had a lower GSM score (44.21 ± 18.24 vs. 68.79 ± 28.79, p < .001) and a smaller positive stained area for galectin-3 (4.89 ± 1.60% vs. 12.01 ± 5.91%, p < .001) and laminin (0.88 ± 0.71% vs. 3.46 ± 2.12%, p < .001) than the AG. On the other hand, intra-plaque macrophage content was increased in SG (p < .001). For the whole cohort, symptomatic status was independently associated with intra-plaque contents of both galectin-3 (OR=0.634, p < .001), and GSM score (OR=0.750, p < .001). Notably, patients on long term statin treatment had elevated galectin-3 and lowered macrophage intra-plaque concentrations compared with those on short term treatment (p < .05). CONCLUSIONS: A low galectin-3 intra-plaque concentration seems to correlate with clinically and ultrasonically defined unstable human carotid plaques. Long term statin treatment may induce increase of intra-plaque galectin-3 concentration mediating plaque stabilization.

γ -H2AX: A Novel Prognostic Marker in a Prognosis Prediction Model of Patients with Early Operable Non-Small Cell Lung Cancer.

Cancer is a leading cause of death worldwide and the prognostic evaluation of cancer patients is of great importance in medical care. The use of artificial neural networks in prediction problems is well established in human medical literature. The aim of the current study was to assess the prognostic value of a series of clinical and molecular variables with the addition of γ -H2AX-a new DNA damage response marker-for the prediction of prognosis in patients with early operable non-small cell lung cancer by comparing the γ -H2AX-based artificial network prediction model with the corresponding LR one. Two prognostic models of 96 patients with 27 input variables were constructed by using the parameter-increasing method in order to compare the predictive accuracy of neural network and logistic regression models. The quality of the models was evaluated by an independent validation data set of 11 patients. Neural networks outperformed logistic regression in predicting the patient's outcome according to the experimental results. To assess the importance of the two factors p53 and γ -H2AX, models without these two variables were also constructed. JR and accuracy of these models were lower than those of the models using all input variables, suggesting that these biological markers are very important for optimal performance of the models. This study indicates that neural networks may represent a potentially more useful decision support tool than conventional statistical methods for predicting the outcome of patients with non-small cell lung cancer and that some molecular markers, such as γ -H2AX, enhance their predictive ability.

Fine needle aspiration cytology of nodular thyroid lesions: a 2-year experience of the Bethesda system for reporting thyroid cytopathology in a large regional and a university hospital, with histological correlation.

OBJECTIVE: Thyroid fine needle aspiration (FNA) contributes to the appropriate management of nodular thyroid lesions. The introduced categories in the Bethesda system for reporting thyroid cytopathology (TBSRTC) are associated with an implied cancer risk, providing a clinical management guideline. This study aims to evaluate the reproducibility of this implied risk and to compare the results from two different cytopathology departments. METHODS: Five hundred histologically confirmed FNAs, studied since the introduction of TBSRTC, were obtained from 4208 and 3587 FNAs performed in a large regional hospital in Herakleion, Crete (group A) and a university hospital in Athens (group B), respectively. Reports were issued according to TBSRTC. Aspirates were prepared with ThinPrep(®) and evaluated by two experienced cytopathologists. The reproducibility and accuracy were evaluated. RESULTS: The proportion test for suspicious for malignancy (SFM) and malignant (M) cytology reports (P < 0.0001), and the number of malignancies on histology (P < 0.0001), were significantly higher in group A than in group B, consistent with a higher incidence of thyroid carcinomas in southern Greece. Although the malignancy rates were higher in group A than in group B for all categories, except M (A, 99.3%; B, 100%), the difference was only significant for benign aspirates (P = 0.0303). Malignancy rates for all categories in group A were above the TBSRTC recommended range, but were consistent with an increased prevalence of malignancy in that centre, differences in reporting practice and the variable ranges reported in the literature. There was lower sensitivity (P = 0.019) and overall accuracy (P = 0.003) in group A relative to group B, but no difference in specificity. CONCLUSIONS: TBSRTC provides valuable information for the appropriate management of nodular thyroid lesions, both in a university and a large regional hospital.

H2AX a promising biomarker for lung cancer: a review.

Histone's H2A variant (H2AX) phosphorylation is an early indicator of DNA double-strand breaks formation and DNA damage response. Thus, it may act as a novel biomarker to monitor genotoxic events that can drive cancer development and tumor progression. This review will focus on the possible applications of H2AX as a key regulator of DNA damage response in lung cancer and as a biomarker of: sensitivity of lung tumors to chemotherapy and radiotherapy, treatment with PARP inhibitors, bystander effect, multistep lung carcinogenesis, environmental smoking, and chemical genotoxicity, chemoprevention, prognosis, and also as therapeutic targets in lung cancers.

The role of ThinPrep cytology in the investigation of ki-67 index, p53 and HER-2 detection in fine-needle aspirates of breast tumors.

PURPOSE: The aim of the current study was to compare the immunocytochemical expression of ki-67, HER-2 and p53 on ThinPrep (TP)-processed smears, obtained by preoperative fine-needle aspiration (FNA) biopsies from primary breast carcinoma with the immunohistochemical results obtained on the corresponding surgical samples. METHODS: FNA biopsies were collected from 119 female patients during a 31-month period. Subsequently, these patients underwent surgical resection of the tumors. RESULTS: The overall accuracy (OA) of the TP cytology for ki-67, p53 and HER-2 expression was 96, 99 and 97%, respectively. There was a strong positive correlation between immunohistochemistry and immunocytochemistry results for ki-67 (Spearman's test 0.875) for p53 (Cramer's phi test 0.965) and HER-2 (Kendall's tau test 0.891). CONCLUSION: This pilot study demonstrates that it is possible to monitor multiple molecular markers by using the TP cytology. Sample collection and storage is simple and permits the assortment of the FNA sample for both morphologic diagnosis and ancillary studies. The accuracy of TP technique in the evaluation of ki-67, p53 and HER-2 expression is comparable to those of the histological evaluation, and could be of paramount importance for the preoperative planning of treatment.

Liquid based cytology and HPV DNA testing in a Greek population compared to colposcopy and histology.

Screening for cervical cancer in Greece is still unorganised and based on self- motivation. The purpose of this study was to evaluate the accuracy of cytological findings from a large observational population sample, originating from Western Athens, in association with reflex DNA test, colposcopic estimation, and final histologic diagnosis. The rate of invasive carcinoma, both squamous cell and adenocarcinoma, is indicative of a largely unscreened population. In this study, the estimated overall prevalence of human papilloma virus (HPV) was 41.1%, with HPV positivity at 37.4% of cytologically normal women. HPV testing did not seem to improve sensitivity of cytology for atypical squamous cells of undetermined significance (ASC-US) and low-grade squamous intraepithelial lesion (LGSIL) cases in identifying CIN 2+ lesions, but outperformed cytology in detecting CIN3+ for cytological high-grade squamous intraepithelial lesion (HGSIL) cases. For HGSIL cases sensitivity of colposcopy for detecting CIN3+ was comparable to cytology.

Evaluation of viral co-infections in hospitalized and non-hospitalized children with respiratory infections using microarrays.

The impact of viral co-infections and recently discovered viruses on the epidemiology of respiratory infections in children is still unclear. To simultaneously detect viruses that are involved in the aetiology of respiratory infections, we used a DNA/RNA microarray assay that identifies 17 different viruses or viral subtypes. Rhinopharyngeal washes were taken from 611 children (aged 1 month to 14 years) who presented in the emergency department with respiratory infections from June 2010 to June 2011 and were treated as outpatients (299, 48.9%) or hospitalized (312, 51.1%). Lower respiratory tract infection was diagnosed more often in hospitalized children (68% versus 36%, p 0.001). Of 397 children in which microarrays detected viral infection (70.1%), a single virus was found in 228 (57.4%) and two or more viruses in 169 (42.5%). The most prevalent viruses among children with positive samples were respiratory syncytial virus (RSV) in 225 (56.6%), parainfluenza virus (PIV) in 118 (29.7%), rhinovirus (RV) in 73 (18.4%), followed by influenza in 56 (14.1%), adenoviruses in 31 (7.8%), bocavirus in 25 (6.3%), human metapneumovirus in 15 (3.7%) and enteroviruses in 12 (3%). Most common viral co-infections were RSVA-RSVB in 46 children (27.2%), RSV-Influenza in 20 (11.8%), RSV-RV in 18 (10.6%) and PIV-RV in 13 (7.7%). Multiple logistic regression analysis revealed that viral co-infections were associated with increased probability for hospitalization (OR 1.52, 95% CI 1.01-2.29, p 0.04), and previous pneumococcal vaccination was associated with decreased probability for hospitalization (OR 0.52, 95% CI 0.33-0.81, p 0.004). We conclude that viral co-infections are involved in a significant proportion of children with an acute respiratory infection and may increase the severity of clinical presentation and the risk for hospitalization.

Association between plaque echogenicity and embolic material captured in filter during protected carotid angioplasty and stenting.

OBJECTIVES/DESIGN: The aim of the study was to investigate debris captured in filter embolic protection devices (EPDs) during carotid artery stenting (CAS) and its possible correlation with plaque echogenicity and other risk factors. MATERIALS/METHODS: Between June 2010 and March 2011, 51 consecutive CAS patients (11 females, mean age 71.2 ± 7, 10 symptomatic) who underwent 53 procedures were included in this prospective study. Ultrasonographic Gray-Weale plaque type (I-V, echolucent to echogenic) characterisation was obtained in all cases. The same type of stent and filter EPD was used. Filters were collected and, after macroscopic evaluation, they were examined using the Thin-Prep(®) liquid-based cytology (LBC) technique. RESULTS: Technical success was 100%. Thirty-day stroke and death rates were 1.8% (1/53) and 0%, respectively. Visible debris was detected in eight (15%) filters, whereas LBC revealed the presence of embolic material particles in 30 filters (56.6%). The presence of embolic material into the filter EPD was 2.38-fold increased for every category change from type IV to type I carotid plaques (OR = 2.38, 95%CI = 1.15-4.93). This association remained robust even after adjustment for age, gender and known atherosclerotic disease risk factors (OR = 2.26, 95%CI = 1.02-5.02). In multivariate analysis for risk factors, hypertension was associated with increased presence of embolic material detection in filter EPD (OR = 20.4, 95%CI = 1.28-326.1). The time distance from symptom to CAS was inversely correlated with debris quantity in EPD (Spearman rho -0.716; p = 0.02). CONCLUSIONS: Echolucent plaques, smaller time frame from last symptom and hypertension were associated with increased presence of embolic material.

The use of an immunocytochemical double-labeling staining can display the distribution of Bcl-2/Ki-67 cells in endometrial adenocarcinomas as well as in normal endometrium.

BACKGROUND: Endometrial adenocarcinoma is the most common gynecologic malignancy and is the fifth most frequently diagnosed cancer in women. The objective of the present study was to determine the expression of a proliferation marker, Ki-67 and an apoptosis inhibitor, Bcl-2, by double-label staining in endometrial adenocarcinomas and in normal endometrium samples, to evaluate the differences in the immunocytochemical expression of Ki-67 and Bcl-2, and finally to correlate the results with tumor grade and stage. METHODS: This study was carried on 270 endometrial samples, collected during a 27 month period, freshly resected from women who underwent total abdominal hysterectomy. RESULTS: Ki-67 and Bcl-2 expressions were studied by immunocytochemistry. Bcl-2 expression was strong and homogeneous in normal (proliferative, secretory and atrophic) endometrium and more frequent in low-grade endometrioid carcinomas. Completely negative staining of Bcl-2 was found to be strictly related to high-grade endometrioid carcinomas. Ki-67 expression was higher in patients with high-grade endometrioid carcinomas. Proliferative endometrium showed inconclusive Ki-67 expression levels and in the secretory endometrium Ki-67 positive cells were remarkably diminished and even disappeared. Completely negative staining of Ki-67 was found to be strictly related to atrophic endometrium. CONCLUSIONS: Immunocytochemical double-label staining can be used to display the distribution of Bcl-2 and Ki-67 cells in endometrioid carcinomas as well as normal endometrium, and, in addition to cytomorphologic features, contributes to its accurate diagnosis.

The role of p16(INK4a) immunostaining in the risk assessment of women with LSIL cytology: a prospective pragmatic study.

BACKGROUND: The detection of high-grade cervical intraepithelial neoplasia (CIN2 or worse) among patients with low-grade cytology (LSIL) is challenging. The aim of this study was to assess the efficacy of p16(INK4a) in the risk assessment of women with LSIL cytology. METHODS: Consecutive liquid-based cytology specimens of 95 LSIL smears were selected and stained for p16(INK4a). All patients had colposcopically directed punch biopsies or large loop excision of the transformation zone of the cervix. The endpoint was detection of a biopsy-confirmed CIN2 or worse. RESULTS: The overall sensitivity and specificity of p16(INK4a) for diagnosis of CIN2+ among LSIL smears were 41% and 86%, respectively. The positive predictive value of the biomarker was 62% and the negative predictive value 72%. CONCLUSIONS: The study shows that p16(INK4a) has low sensitivity but acceptable specificity for evaluation of LSIL smears harbouring high-grade lesions. The marker needs to be further assessed as an adjunct to other tests in an attempt to improve the triage of LSIL cytology smears.

Molecular epidemiology of HPV infection using a clinical array methodology in 2952 women in Greece.

The molecular epidemiology of human papillomavirus (HPV) infection in a sample of Greek women (n = 2952, mean age 42.2 ± 13.3 years) was examined. HPV prevalence was 50.7% (95% confidence interval, 48.8-52.6). The most frequent HPV types were HPV 53, 51 and 66 (10.2%, 9.4% and 9.3%, respectively). HPV positivity was associated with age, age of sexual debut, number of sexual partners and duration of sexual relationship, while marriage or multiparity protected against infection (all p <0.001). Follow-up of this cohort will assist in predicting the effect of vaccination with the new HPV vaccines on future screening with HPV-based tests for cervical cancer.

Alterations in human papillomavirus-related biomarkers after treatment of cervical intraepithelial neoplasia.

OBJECTIVE: This study aims to assess the alterations in various HPV-related biomarkers 6 months post-treatment and how these relate to various risk factors and individual characteristics; their role for the prediction of treatment failure was also evaluated. DESIGN: Prospective observational study. POPULATION: Women planning to undergo treatment for cervical intraepithelial neoplasia. INTERVENTION: A liquid-based cytology sample was taken pre-operatively. This was tested for HPV genotyping, Nucleic Acid Sequence Based Amplification, flow cytometric evaluation and p16 immunostaining. A repeat LBC sample was obtained 6 months post-treatment and was tested for the same biomarkers. OUTCOMES: The alterations of the biomarkers 6 months post-treatment were recorded. Their relation to individual characteristics and risk factors (age, smoking, sexual history, use of condom, CIN grade, excision margin status, crypt involvement) as well as their role for the prediction of residual/recurrent disease were assessed. ANALYSIS: The accuracy parameters (sensitivity, specificity, positive and negative predictive value and the likelihood ratios) of each biomarker for the prediction of recurrent/residual CIN were calculated. RESULTS: A total of 190 women were recruited. All biomarkers had significantly higher negativity rates post-treatment compared to pre-treatment ones. Multivariate analysis demonstrated that consistent condom use post-treatment significantly reduces the high-risk HPV positivity rates in comparison to no use (OR=0.18; 95% CI: 0.09-0.38). Sensitivity and specificity for all high risk HPV DNA testing were 0.5/0.62, respectively; the relevant values for only type 16 or 18 DNA typing were 0.5/0.92, for NASBA 0.5/0.94, for flow 0.5/0.85 and for p16 0.25/0.93. CONCLUSION: CIN treatment reduces positivity for all HPV-related biomarkers. Consistent condom use significantly reduces high-risk HPV positivity rates. More cases of treatment failures are required in order to specify whether different combinations of HPV-related biomarkers could enhance the accuracy of follow up, possibly in the form of a Scoring System that could allow tailored post-treatment surveillance.

High-risk human papillomavirus DNA test and p16(INK4a) in the triage of LSIL: a prospective diagnostic study.

OBJECTIVE: The detection of high-grade cervical intraepithelial neoplasia (CIN) amongst patients with low-grade cytology (LSIL) is challenging. This study evaluated the role of high-risk HPV (HR-HPV) DNA test and p16(INK4a) immunostaining in identifying women with LSIL cytology at risk of harboring CIN2 or worse (CIN2+) and the role of p16(INK4a) in the triage of a population of HR-HPV positive LSIL. METHODS: We conducted a prospective study including women with LSIL cytology. Detection of HR-HPV was carried out by means of a polymerase chain reaction based assay. p16(INK4a) immunostaining was performed using the Dako CINtec cytology kit. All patients had colposcopically directed punch biopsies or large loop excision of the transformation zone of the cervix. The endpoint was detection of a biopsy-confirmed CIN2+. RESULTS: A series of 126 women with LSIL cytology were included. HR-HPV test had sensitivity 75% and specificity 64% for an endpoint of CIN2+. p16(INK4a) had significantly higher specificity of 89% (p=0.0000) but low sensitivity of 42%. The role of p16(INK4a) immunostaining in the triage of LSIL positive for HR-HPV was also evaluated. p16(INK4a) triage had 70% positive predictive value (PPV); however, this was not significantly higher than the PPV (56%) of HR-HPV test alone (p=0.4). CONCLUSIONS: The results indicate that HR-HPV or p16(INK4a) cannot be used as solitary markers for the assessment of LSIL. The addition of p16(INK4a) immunostaining led to an increase in HR-HPV specificity; however, the biomarker needs to be assessed further to establish its role as an adjunct test in the triage of LSIL.

Biweekly vinorelbine and gemcitabine as second-line and beyond treatment in ovarian cancer.

PURPOSE: To evaluate the activity and tolerance of vinorelbine (VRL) in combination with gemcitabine (GEM) in pre-treated patients with refractory ovarian cancer. PATIENTS AND METHODS: Seventeen patients with ovarian cancer who had disease progression after a carboplatin and taxane front-line regimen were treated with VRL 30 mg/m(2) IV over 10 min followed by GEM 1,200 mg/m(2) IV over 30 min on days 1 and 15 of each 28 days cycle. Chemotherapy was given in a initial prospective plan of six cycles, unless disease progression or unacceptable toxicity was seen, giving more cycles as consolidation therapy in the case of CR, PR or SD. The median age of patients was 67 years old, and the performance status (WHO) was 1 for 13 and 2 for 4 patients. The treatment was second-line for 11 (65%) and >third-line for 6 (35%) patients. RESULTS: One complete and one partial response were observed (ORR:11%). Stable disease was seen in 4 (24%) patients and progressive disease in 11 (65%). The median time to tumor progression was 4 months (range 2-11), and the median survival has not yet been reached. Myelotoxicity was rare. Grade 1 neutropenia was observed just in one patient and grade 2/3 anemia in four patients (24%). Thrombocytopenia was absent. Non-hematologic toxicity was also predictable and easily manageable. CONCLUSION: The vinorelbine plus gemcitabine combination at the present doses and schedule is a safe but ineffective regimen, and therefore, is not recommended as second-line and beyond treatment in patients with refractory ovarian cancer.

Diagnostic terminology for reporting thyroid fine needle aspiration cytology: European Federation of Cytology Societies thyroid working party symposium, Lisbon 2009.

A European Federation of Cytology Societies (EFCS) working party of 28 members from 14 European countries met at the European Congress of Cytology in Lisbon in September 2009, with two observers from the USA, to discuss the need for standardising thyroid FNA nomenclature in the light of the National Institute of Cancer (NCI) recommendations resulting from the State of the Science conference in Bethesda in 2007. The data were obtained through two questionnaires sent by email and a transcript of the live discussion at the congress, which is presented in full. The surveys and discussion showed that there were currently no national terminologies for reporting thyroid FNA in the different European countries except in Italy and the UK. Personal, 'local', surgical pathology and descriptive terminologies were in use. All but one of the working party members agreed that thyroid FNA reporting should be standardised. Whilst almost a third would adopt the NCI Bethesda terminology, which offers the advantages of a 'risk of cancer' correlation and is linked to clinical recommendations, more than half favoured a translation of local terminology as the first step towards a unified nomenclature, as has been done recently in the UK. There was some disagreement about the use of: a) the six-tiered as opposed to four or five-tiered systems, b) the use of an indeterminate category and c) the 'follicular neoplasm' category, which was felt by some participants not to be different from the 'suspicious of malignancy' category. The conclusions will be passed to the different national societies of cytology for discussion, who will be asked to map their local terminologies to the Bethesda classification, observe its acceptance by clinicians and audit its correlation with outcome.

Biweekly vinorelbine and gemcitabine as second-line treatment and beyond in non-small cell lung cancer.

BACKGROUND: To evaluate the activity and tolerance of gemcitabine (GEM) in combination with vinorelbine (VRL) in pretreated patients with advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Fifteen patients with advanced NSCLC who had disease progression after a cisplatin- or taxane-based front-line regimen were enrolled into a 2-stage design trial and were treated with VRL 30 mg/m² i.v. for 10 min followed by GEM 1,200 mg/m² i.v. for 30 min on days 1 and 15 of each 28-day cycle. Chemotherapy was given for 6 cycles unless disease progression or unacceptable toxicity was seen. The patients' median age was 64 years and the performance status (WHO) was 0 (n = 7), 1 (n = 5), and 2 (n = 3). The treatment was second line for 10 (67%) and third line or more for 5 (33%) patients. RESULTS: No complete or partial responses were observed. Stable disease was seen in 4 (27%) patients and progressive disease in 11 (73%). The median time to tumor progression was 3 months (range 1-12) and the median survival was 4 months (range 2-31). Severe myelotoxicity was infrequent. Grade 2 neutropenia was observed in 2 (13%) patients, grade 2 thrombocytopenia in 1 (7%), and grade 2 anemia in 3 (20%). Nonhematologic toxicities were very mild and easily manageable. CONCLUSION: The GEM plus VRL combination at the present doses and schedule is a safe but ineffective regimen; therefore, it is not recommended as second-line treatment in patients with advanced NSCLC.

Clinical management of HPV-related disease of the lower genital tract.

Cytology remains the mainstay for cervical screening. The need to achieve effective management, limit complications, and preserve reproductive function led to the popularity of local treatment. Although the cure rates for ablative and excisional methods are similar, the excisional method provides a more reliable histopathological diagnosis. Recent evidence revealed increased perinatal morbidity after treatment that appears to be related to the proportion of cervix removed. The human papillomavirus (HPV) DNA test appears to enhance the detection of disease in primary screening, in the triage of minor cytological abnormalities, and in follow-up. Further research on the clinical application of a scoring system is ongoing. The vaccines are now available and appear to be safe, well tolerated, and highly efficacious in HPV naive women. A synergy of vaccination and screening will be required. Treatment for early cervical cancer is increasingly shifting toward more fertility-sparing surgical techniques. Careful selection of patients is essential.

Proportion of excision and cervical healing after large loop excision of the transformation zone for cervical intraepithelial neoplasia.

OBJECTIVE: To determine how the proportion of the cervical volume excised affects cervical regeneration. DESIGN: Prospective observational study. SETTING: University Hospital. POPULATION: Women planning to undergo excisional treatment for cervical intraepithelial neoplasia who wish to have future pregnancies. METHODS: The cervical volume (and dimensions) is calculated with magnetic resonance imaging (MRI) before treatment. The volume (and dimensions) of the cone is assessed before fixation by a volumetric tube and a ruler; the percentage (%) of excision is computed. Cervical regeneration is estimated by repeat MRI at 6 months. MAIN OUTCOME MEASURES: Cervical regeneration in relation to proportion of excision. Statistical analysis was performed by box plots and analysis of variance. RESULTS: A total of 48 women have been recruited; 29 have completed 6 months follow up. Both the total cervical volume (from MRI) before treatment and the volume of the excised/ablated cone varied substantially. The estimated proportion of excision varied significantly between 4% and 39% (median 11%). Multivariate linear regression revealed that the proportional deficit at 6 months post-treatment was determined mainly by the proportion of the excised volume. CONCLUSIONS: Careful assessment of risks and benefits of treatment is essential when deciding to treat women who wish to have future pregnancies. Assessment of the proportion of the cervical volume and length excised might identify those that need further surveillance during future pregnancy.