Heike Hoyer

Overview of the European and North American studies on HPV testing in primary cervical cancer screening

Several studies suggest that HPV testing is more sensitive than cytology in primary cervical screening. These studies had different designs and were reported in different ways. Individual patient data were collected for all European and North American studies in which cytology was routinely performed and HPV testing was included as an additional parallel test. More than 60,000 women were included. The sensitivity and specificity of HPV testing were compared with routine cytology, both overall and for ages <35, 35–49 and 50+. The age‐specific prevalence of high risk HPV (hr‐HPV) was also analysed. HPV testing was substantially more sensitive in detecting CIN2+ than cytology (96.1% vs. 53.0%) but less specific (90.7% vs. 96.3%). The sensitivity of HPV testing was similar in all studies carried out in different areas of Europe and North America, whereas the sensitivity of cytology was highly variable. HPV sensitivity was uniformly high at all ages, whereas the sensitivity of cytology was substantially better in women over the age of 50 than in younger women (79.3% vs. 59.6%). The specificity of both tests increased with age. Positivity rates for HPV testing in women without high‐grade CIN were region dependent. These results support the use of HPV testing as the sole primary screening test, with cytology reserved for women who test HPV positive. Large demonstration projects are needed to fully evaluate this strategy.

Screening for high‐grade cervical intra‐epithelial neoplasia and cancer by testing for high‐risk HPV, routine cytology or colposcopy

The validity of testing for high‐risk types of human papillomavirus (HPV) in cervical cancer prevention programs is undetermined. We compared the performance on primary screening of HPV DNA testing, cytology and colposcopy in detecting cervical intra‐epithelial neoplasia (CIN) grade 2 or 3 or cancer. A cohort of 4,761 women, median age 35 years, was screened by routine cytology, routine colposcopy and testing for high‐risk HPV by a PCR‐based method. Within an 8‐month period, women with abnormal findings on cytology or screening colposcopy or in whom high‐risk HPV types were detected were referred for colposcopy and biopsy. Women negative on all initial screening tests were followed by a second screening examination. To correct for work‐up bias, the true prevalence of CIN 2 or 3 or cancer was estimated by projection from histologically verified subgroups. Cervical biopsies were taken in 364 women (7.6%), of whom 114 (2.4%) showed CIN 2 (n = 34) or CIN 3 (n = 71) or cancer (n = 9). High‐risk HPV testing achieved bias‐corrected performance measures of 89.4% sensitivity, 93.9% specificity, 35.8% positive predictive value and 99.6% negative predictive value. Bias‐corrected rates of true‐ and false‐positives by high‐risk HPV testing compared to cytology (colposcopy) were about 4.5 (6.7) and 19.1 (7.4) times higher, respectively. The quality of routine cytology was controlled by computer‐assisted review, and the observed number of true‐positives more than doubled after adding automated review results. In middle‐aged women, testing for high‐risk HPV types, particularly when negative, may be used to increase the screening interval in programs for secondary prevention of cervical cancer. Int. J. Cancer 89:529–534, 2000.

Lung Ultrasound in the Diagnosis and Follow-up of Community-Acquired Pneumonia: A Prospective, Multicenter, Diagnostic Accuracy Study

BACKGROUND The aim of this prospective, multicenter study was to define the accuracy of lung ultrasound (LUS) in the diagnosis of community-acquired pneumonia (CAP). METHODS Three hundred sixty-two patients with suspected CAP were enrolled in 14 European centers. At baseline, history, clinical examination, laboratory testing, and LUS were performed as well as the reference test, which was a radiograph in two planes or a low-dose CT scan in case of inconclusive or negative radiographic but positive LUS findings. In patients with CAP, follow-up between days 5 and 8 and 13 and 16 was scheduled. RESULTS CAP was confirmed in 229 patients (63.3%). LUS revealed a sensitivity of 93.4% (95% CI, 89.2%-96.3%), specificity of 97.7% (95% CI, 93.4%-99.6%), and likelihood ratios (LRs) of 40.5 (95% CI, 13.2-123.9) for positive and 0.07 (95% CI, 0.04-0.11) for negative results. A combination of auscultation and LUS increased the positive LR to 42.9 (95% CI, 10.8-170.0) and decreased the negative LR to 0.04 (95% CI, 0.02-0.09). We found 97.6% (205 of 211) of patients with CAP showed breath-dependent motion of infiltrates, 86.7% (183 of 211) an air bronchogram, 76.5% (156 of 204) blurred margins, and 54.4% (105 of 193) a basal pleural effusion. During follow-up, median C-reactive protein levels decreased from 137 mg/dL to 6.3 mg/dL at days 13 to 16 as did signs of CAP; median area of lesions decreased from 15.3 cm2 to 0.2 cm2 and pleural effusion from 50 mL to 0 mL. CONCLUSIONS LUS is a noninvasive, usually available tool used for high-accuracy diagnosis of CAP. This is especially important if radiography is not available or applicable. About 8% of pneumonic lesions are not detectable by LUS; therefore, an inconspicuous LUS does not exclude pneumonia.

Changes in the treatment of acetabular fractures over 15 years: Analysis of 1266 cases treated by the German Pelvic Multicentre Study Group (DAO/DGU)

Epidemiological, clinical and radiological data of 1266 patients with a unilateral acetabular fracture of up to 29 hospitals was reviewed. Three time periods, 1991-1993 (Registry I; n=359), 1998-2000 (Registry II; n=503), and 2005-2006 (Registry III; n=404) were compared with regard to injury pattern and severity, fracture type, and chosen nonoperative vs. operative treatment to elucidate changes over time in the treatment of acetabular fractures. In the operatively treated group, time to operation, surgical approach, fracture fixation implants and fracture reduction quality were examined. 641 (50.6%) patients with isolated acetabular fractures, 410 (32.4%) multiple injured and 215 (17.0%) polytrauma patients with 642 (50.7%) simple and 624 (49.3%) associated acetabular fractures were evaluated. In the time period from 1991 to 2006, the rate of operative treatments increased nationwide to 77% (rho<0.001). The distribution of fracture types involving the anterior and posterior wall changed with age (rho<0.001). Across all registries, 583 (68.0%) operations were performed within 7 days, 212 (24.7%) operations between 7 and 14 days and 54 (6.3%) operations were performed later than 14 days after injury. An anatomical reduction (0-1mm displacement) was achieved in 551 (64%) acetabular fractures. The obtained reduction quality did not correlate with time to operation, was lower in associated than in simple fracture types, and also lower in patients with isolated acetabular fractures than in polytrauma patients. Most importantly, the fracture reduction quality did not improve over time despite a higher frequency of surgical interventions. The Kocher-Langenbeck approach was preferred in the nineties in nearly three quarters of all operative procedures. Currently, the Kocher-Langenbeck and the ilioinguinal approaches are used equally often. The fracture fixation did not change over time and is achieved in 51% with plates in combination with single screws. This multisurgeon series illustrates a nationwide performance in acetabular fracture management. Despite changes in the chosen approaches and an increased surgical frequency, the operative treatment of acetabular fractures of the last 15 years did not lead to an increased reduction quality. Therefore, the rarity and complexity of acetabular fractures demands further specific teaching by experienced acetabular surgeons, scientific research and clinical outcome evaluation.

Optic Edge Design as Long-term Factor for Posterior Capsular Opacification Rates

OBJECTIVE To compare the difference in posterior capsular opacification (PCO) between highly refractive silicone and hydrophobic acrylic foldable intraocular lenses (IOLs) with sharp and round edge designs 3 years after in-the-bag IOL implantation in subjects undergoing bilateral cataract surgery. DESIGN Open-label, prospective, randomized, multicenter clinical trial. PARTICIPANTS Two hundred and eighty-eight patients with bilateral surgery for senile cataract operated in German university clinics, eye hospitals, and private ophthalmic surgical centers (Aachen, Ahaus, Bad Hersfeld, Frankfurt/Main, Jena, Rosenheim, and Sulzbach/Saar). INTERVENTIONS At each center, a highly refractive index silicone IOL with a sharp optic edge (CeeOn) was intraindividually compared either with a high-refractive index silicone IOL with a round optic edge (PhacoFlex) in 108 patients or with an acrylic IOL with a sharp optic edge (AcrySof) in 139 patients. All patients received standard phacoemulsification with IOL implantation in the bag in both eyes from the same surgeon. A morphological evaluation of PCO was performed by the Evaluation of the Posterior Capsule Opacification (EPCO) system 1 to 2 weeks and 11 to 14 and 35 to 37 months after surgery. The blinded digital pictures were evaluated by an independent investigator. Posterior capsular opacification was statistically evaluated by paired comparisons of 3-year cumulative incidences of neodymium:yttrium-aluminum-garnet (Nd:YAG) laser treatment and EPCO scores. MAIN OUTCOME MEASURES Posterior capsular opacification. RESULTS The 3-year cumulative incidences of Nd:YAG laser capsulotomy were 2.1% (CeeOn), compared with 2.1% (AcrySof) (risk difference, 0%; 90% confidence interval, -3.4% to 3.4%), and 5.7% (CeeOn), compared with 17.0% (PhacoFlex) (risk difference, -11.4%; 90% confidence interval, -18.1% to -4.7%). In patients without Nd:YAG laser treatment, medians of the total area EPCO score were 0.0005 (CeeOn) versus 0.0440 (AcrySof) and 0 (CeeOn) versus 0.0700 (PhacoFlex) at 3 years. Functional results, safety, and handling did not significantly differ for the 3 lenses. CONCLUSIONS Our results suggest that modern foldable IOLs have a low incidence of PCO after 3 years. There is less PCO for sharp optic edge designs independent of IOL material.

Mutual information and phase dependencies: measures of reduced nonlinear cardiorespiratory interactions after myocardial infarction

The heart rate variability (HRV) is related to several mechanisms of the complex autonomic functioning such as respiratory heart rate modulation and phase dependencies between heart beat cycles and breathing cycles. The underlying processes are basically nonlinear. In order to understand and quantitatively assess those physiological interactions an adequate coupling analysis is necessary. We hypothesized that nonlinear measures of HRV and cardiorespiratory interdependencies are superior to the standard HRV measures in classifying patients after acute myocardial infarction. We introduced mutual information measures which provide access to nonlinear interdependencies as counterpart to the classically linear correlation analysis. The nonlinear statistical autodependencies of HRV were quantified by auto mutual information, the respiratory heart rate modulation by cardiorespiratory cross mutual information, respectively. The phase interdependencies between heart beat cycles and breathing cycles were assessed basing on the histograms of the frequency ratios of the instantaneous heart beat and respiratory cycles. Furthermore, the relative duration of phase synchronized intervals was acquired. We investigated 39 patients after acute myocardial infarction versus 24 controls. The discrimination of these groups was improved by cardiorespiratory cross mutual information measures and phase interdependencies measures in comparison to the linear standard HRV measures. This result was statistically confirmed by means of logistic regression models of particular variable subsets and their receiver operating characteristics.

Posterior capsule opacification after implantation of CeeOn Edge 911A, PhacoFlex SI-40NB, and AcrySof MA60BM lenses One-year results of an intraindividual comparison multicenter study

Purpose: To perform an intraindividual comparison of posterior capsule opacification (PCO) with 2 foldable intraocular lenses (IOLs) and a foldable acrylic IOL 1 year after in‐the‐bag implantation. Settings: Seven German ophthalmology centers. Methods: In an open prospective randomized multicenter study, each center intraindividually compared a high‐refractive‐index, sharp‐edged optic silicone IOL (CeeOn® Edge 911A, Pharmacia) with a high‐refractive‐index, round‐edged optic silicone IOL (PhacoFlex® SI‐40NB, Allergan) or a sharp‐edged optic acrylic IOL (AcrySof® MA60BM, Alcon). Of 288 randomized patients, 247 had standard phacoemulsification with in‐the‐bag IOL implantation in both eyes by the same surgeon. One eye of each patient received a CeeOn Edge IOL and the fellow eye, an AcrySof or PhacoFlex IOL. A morphologic evaluation of PCO was performed using the Evaluation of Posterior Capsule Opacification (EPCO) system 1 to 2 weeks and 11 to 14 months after surgery. The digital pictures were evaluated by an independent investigator who was blind to the type of IOL. Intraindividual differences in EPCO scores were statistically evaluated by a 1‐sided binomial test at an &agr;‐level of 5%. Results: One year after surgery, 127 patients with the AcrySof IOL and 102 patients with the PhacoFlex IOL in the control eye were reexamined. Functional results, safety, and handling were not significantly different between the 3 IOLs. All reexamined eyes had a very low PCO grade. The EPCO values revealed less PCO in eyes with the CeeOn Edge IOL than in eyes with the AcrySof or PhacoFlex IOL, but the difference was not statistically significant. A neodymium:YAG laser capsulotomy was performed in 1 eye with a CeeOn Edge IOL, 1 eye with an AcrySof IOL, and 2 eyes with a PhacoFlex IOL. Conclusions: The EPCO PCO grade was low 1 year after implantation of CeeOn Edge 911A, PhacoFlex SI‐40NB, and AcrySof MA60BM IOLs; there was no statistically significant difference between the IOLs. The impact of IOL material and edge design on PCO development might be relevant in a long‐term follow‐up of this study.

Cumulative 5‐year diagnoses of CIN2, CIN3 or cervical cancer after concurrent high‐risk HPV and cytology testing in a primary screening setting

The aim of our study was to assess the cumulative 5‐year diagnoses of CIN2, CIN3 or invasive cervical cancer (CIN2+) after concurrent screening by high‐risk HPV test and Pap smear in a primary screening setting. Four thousand thirty‐four women from Eastern Thuringia/Germany were recruited from 1996 to 1998 for baseline screening that included routine cytology, high‐risk HPV testing by consensus primer PCR GP5+/6+ and routine colposcopy. After a median of 59 months 3,153 women participated in final screening using identical methods. Women with abnormal cytology or colposcopy or a positive high‐risk HPV test at any time during the study period were recalled for expert colposcopy and histologic verification. CIN2+ was detected in 160 women resulting in a cumulative 5‐year proportion of 4.4% (95% CI: 3.7–5.0%). Of 3,702 women who were high‐risk HPV negative at baseline, 34 (1.1–95% CI: 0.7–1.4%) had either prevalent CIN2+ or developed CIN2+ within the observation period. HPV/cytology double negatives at baseline were at lowest risk for CIN2+ (1.0–95% CI: 0.7–1.4%) compared to screening positives (16.8–100% depending on combined test results). The 5‐year negative predictive value in HPV−/Cyto− women was 99.0% (95% CI: 98.6–99.3%). This suggests that a prolongation of the screening intervals in this group is feasible. However, it should be noted that 1 woman developed a microinvasive carcinoma within the observation period. Moreover, 2 women with prevalent cancer were missed by both tests. The prognostic relevance of concurrent high‐risk HPV/cytology screening needs to be verified further by randomized trials.

Human Papillomavirus distribution in cervical tissues of different morphology as determined by hybrid capture assay and PCR

Distribution of various types of genital human Papillomavirus (HPV) in smears from histologically classified cervical lesions was determined by hybrid capture assay (HCA) and was compared with a polymerase chain reaction (PCR) system using general primers (GP) in first and type specific primers (TS) in a second step. The overall agreement of high-risk HPV by HCA and the more sensitive GP/TS PCR was 80.6% (204 of 253, kappa value 0.6). Human Papillomavirus frequency by GP/TS PCR was 14–20% higher compared with HCA (p = 0.02–0.004) independent of morphology. Only one sample was positive by HCA and negative by GP/TS PCR. A significantly higher frequency was found using HCA and GP/TS PCR in smears from histologically proven cervical intraepithelial lesions (CIN) II/III compared with CIN I, tissues with minimal changes (metaplasia, cervicitis, or lack of glycogenization), or normal morphology (61% and 81% vs 8–15% and 24–34%, p ≤ 0.001). Semi-quantitative estimate of HPV DNA copies by GP-PCR coincided with estimated virus load by quantitative HCA and was significantly higher in patients with CIN II/III compared with CIN I (p < 0.001). Thus, the GP-PCR may be used to monitor the amount of HPV DNA copies in clinical samples. A direct correlation between morphologic changes and HPV detection as well as virus load was found by HCA and the more sensitive GP/TS PCR.

Colposcopic appearance of cervical intraepithelial neoplasia is age dependent

Objective: We investigated to determine whether colposcopic, histologic, and virologic parameters of cervical intraepithelial neoplasia are influenced by a patient’s age. Study Design: A cohort of 967 women with a mean age of 37.1 years underwent screening for detection of cervical intraepithelial neoplasia by colposcopy, cytologic examination, and testing for high-risk human papillomaviruses with the Hybrid Capture System (Digene, Silver Springs, Md) and a general primer and type-specific primer polymerase chain reaction system. Cervicography was used for documentation and reproducible evaluation of the colposcopic appearance of the cervix. In 86% of patients with trivial colposcopic changes of doubtful significance (100/116) and 89% of patients with colposcopic changes consistent with cervical intraepithelial neoplasia (89/99), punch biopsy specimens were taken for histologic evaluation. Results: In patients with trivial colposcopic changes of doubtful significance, histologically confirmed cervical intraepithelial neoplasia was almost as frequent (32%, 37/116) as in patients with colposcopic changes consistent with cervical intraepithelial neoplasia (43%, 43/99, difference not significant). The ratio between colposcopic evidence of cervical intraepithelial neoplasia and trivial colposcopic changes was 1.9 in patients <35 years old with cervical intraepithelial neoplasia, versus 0.5 in patients ≥35 years old with cervical intra-epithelial neoplasia (P = .005). Patients with trivial colposcopic changes of doubtful significance were older (median age 36 years) than were patients with colposcopic changes consistent with cervical intraepithelial neoplasia (median age 29 years, P = .008). In patients with cervical intraepithelial neoplasia who had no or trivial colposcopic changes, the thickness of neoplastic epithelium was smaller (P = .008) and the number of cellular layers was lower (P = .01) than in patients with cervical intraepithelial neoplasia who had colposcopic changes consistent with cervical intraepithelial neoplasia. In patients <35 years old the rate of positive results for a high-risk human papillomavirus (P < .005) and the viral load (difference not significant) were higher than in women ≥35 years old. The rate of positive results for high-risk human papillomaviruses differed independently of age among patients with normal colposcopic findings, patients with trivial colposcopic changes of doubtful significance, and patients with colposcopic changes consistent with cervical intraepithelial neoplasia (P < .005). Conclusions: In women ≥35 years old cervical lesions associated with intraepithelial neoplasia are thinner and thus less colposcopically conspicuous than those in women <35 years old. Patients ≥35 years old with acetowhite cervical lesions consistent with trivial changes of doubtful significance should therefore undergo punch biopsy for histologic evaluation. (Am J Obstet Gynecol 1998;179:1298-304.)