Human papillomavirus testing in primary screening for the detection of high-grade cervical lesions: a study of 7932 women.

High-risk human papillomaviruses (HR-HPV) are the necessary cause of cervical carcinomas. To determine whether HPR-HPV DNA detection in primary routine screening could represent a sensitive and reliable technique for the detection of high-grade squamous intraepithelial lesions (HGSIL), laboratory analysis using 2 cytologic techniques (conventional and liquid-based), HPV testing with Hybrid Capture II assay (HC-II), followed by colposcopic examination of women with abnormal cervical finding and/or persistent HR-HPV infection, was conducted in 7932 women who had routine cervical examination. The sensitivity of HPV testing for detecting a histologically proven HGSIL was 100%, higher than that of conventional (68.1%) and liquid-based (87.8%) cytology. The low specificities of 85.6% and 87.3% of HPV testing slightly increased to 88.4% and 90.1% if HPV testing was reserved for woman >30 years old. The quantitative approach provided by the HC-II assay for the assessment of the viral load was not reliable for predicting HGSIL in normal smears. HR-HPV testing could be proposed in primary screening in association with cytology. With conventional cytology it significantly improves the detection of HGSIL. With the use of the same cervical scrape for HPV testing and liquid-based cytology, HR-HPV testing would allow to select positive samples treated in a second time for cytology which gives a good specificity.

DNA image cytometry and human papillomavirus (HPV) detection help to select smears at high risk of high-grade cervical lesions.

Three samples were submitted from women undergoing routine screening (n=910): two smears (one for routine cytology and one for DNA image cytometry) and a scrape for human papillomavirus (HPV) testing. DNA histograms were classified as suspect in cases of aneuploidy, polyploidy, and/or diploidy with a high proliferation rate. Follow-up was available in 239 cases. The primary end-point was the presence of a high-grade squamous intraepithelial lesion (HGSIL) at biopsy. Seventy women (7.7%) had a high-risk (HR) HPV infection and a suspect DNA profile. In 77 women with cytological abnormalities, 28 HGSILs were detected: four with a prior diagnosis of ASCUS (all HR-HPV infected including three with a suspect DNA profile), three with smears evocative of LGSIL (all with HR-HPV infection and a suspect DNA profile), and 21 with smears evocative of HGSIL (all with HR-HPV infection and 20 with a suspect DNA profile). During the follow-up period, out of 239 women with a cytologically normal smear at first entry, five developed a HGSIL; all were HR-HPV-positive and four had a suspect DNA profile at the first smear. HR-HPV detection alone gives a sensitivity of 100% for the detection of HGSIL, with a specificity of 84.3%, whereas DNA measurement associated with HPV testing significantly enhances the specificity to 95.4%. Thus, the combination of HPV testing and DNA measurement provides a highly sensitive and specific evaluation of the risk of HGSIL on cervical smears.

Human papillomavirus detection by the hybrid capture II assay: a reliable test to select women with normal cervical smears at risk for developing cervical lesions.

The reliability of the Hybrid Capture II (HC-II; Digene, Silver Spring, MD, U.S.A.) assay was tested in detecting 18 human Papillomavirus (HPV) types for the screening of cervical lesions. Cytology, HPV testing, colposcopy, and biopsy were used to monitor 204 women with normal smears at the first entry. The median follow-up was 15 months (range, 4-27 months). The primary endpoint was clinical progression defined as the presence of a cervical intraepithelial lesion at the biopsy. In the patient population of 204 HPV-infected women, 81 (39.7%) had a persistent HPV infection at two or three examinations with a final histologic diagnosis of 14 high-grade and 13 low-grade squamous intraepithelial lesions (SIL) within 4 to 22 months. Women with regressive HPV infection did not develop any lesion during the same period. The evaluation of the viral load of high-risk HPV by the HC-II did not represent a sensitive approach to predict the persistence or the apparition of high-grade lesions. Thus, persistent high-risk HPV infection detected with HC-II represents a reliable tool to select populations at risk for the development of high-grade cervical lesions.

Image cytometry detection of breast cancer cells with > 5C DNA content and minor DNA stemlines.

OBJECTIVE: To determine if the presence of cells having a DNA content > 5c and occurring at very low frequency is related to breast cancer outcome. STUDY DESIGN: Feulgen-stained imprints of fresh tumors used for routine standard DNA image cytometry were reanalyzed, with the aim of detecting hyperploid (> 5c) cells or minor stemlines. Specially adapted software was used. RESULTS: The new DNA analysis showed discordance of 47.3% with standard DNA cytometry. Minor stemline or rarely occurring 5c exceeding cells were found. These were not detected by the first DNA analysis. The presence of both DNA hyperploid cells occurring as rare events and a DNA hyperploid stemline was related to outcome. CONCLUSION: The detection of DNA hyperploid cells, even in very small numbers, appears essential to outcome, particularly in diploid or single DNA aneuploid breast cancers.

[Human papillomavirus typing in routine cervical smears. Results from a series of 3778 patients]. / Typage des Papillomavirus humains dans les frottis cervicaux de routine. Résultats sur une série de 3,778 patientes.

AIM: As human papillomavirus (HPV) infection is a significant risk factor for cervical cancer, the aim of this study was to assess the efficacy of HPV detection techniques in predicting the presence or the development of a high-grade squamous intra epithelial lesion. Additional reasons for carrying out this investigation were as follows. It was considered that the clinical value of HPV typing may have been underestimated in certain previous reports, which based their findings on first-generation assays. Moreover, until the present investigation most studies only investigated the cases with abnormal smear findings and did not include long-term follow-up, nor detailed follow-up of women with a normal smear but positive HPV typing, although this patient subgroup is of particular interest. The patient population included 3778 women who underwent routine cytological cervical screening and who gave their informed consent to participate in this study, consisting of a cervical smear, HPV testing via a second-generation Hybrid Capture II assay (which is more sensitive than first-generation tests, and can detect 18 different HPV types, i.e., 13 oncogenic and five non-oncogenic types); and in the case of abnormal smear findings, colposcopic examination and directed biopsies of the sites of suspected lesions. The women with cytomorphologically normal cervical smears but which who HPV-positive were reexamined six months later. RESULTS: HPV findings were positive in 66 cases where the initial smear indicated the presence of a high-grade lesion with the diagnosis confirmed by biopsy in 65 cases; in 155 cases (76.1%) where the initial smear indicated the presence of a low-grade lesion; in 44 (57.1%) out of 77 smears indicating the presence of ASCUS-type (atypical squamous cells of undetermined significance) lesions; and in 366 cases (10.5%) of apparently normal initial smears. After colposcopy and follow-up, a final diagnosis of high-grade lesion was made for 85 patients. All these patients were found to have high-risk (oncogene-positive) HPV at the first examination, but in only 65 cases (76.5%) was the initial smear indicative of a high-grade lesion. Finally, in the patient groups with low-grade or ASCUS-type smear findings or with an apparently normal smear, a high-grade lesion was only found in those patients with persistent high-risk HPV infection. In all, the sensitivity of the Hybrid Capture II assay in detecting high-grade lesions was 100% versus 85.9% for standard cytology. However, its specificity (86.3%) and positive predictive value were not as high as the latter. CONCLUSION: The results of this study indicate that HPV typing via this second-generation assay displays good sensitivity for the detection of at-risk cases, i.e., those involving the presence or development of high-grade cervical lesions. However, a number of issues have to be addressed before HPV typing is adopted in clinical practice, such as the fairly high HPV prevalence in women aged over 60 years, and whether the implications of this are the same as for younger age groups. Also, the present cost of complete typing remains too high for it to be used on a widespread scale. Nevertheless, HPV typing may have a useful role to play in the detection of cervical cancer.

Hemispheric specialization using SPECT and stimulation tasks in children with dysphasia and dystrophia.

Developmental dysphasia, a severe childhood learning disorder, is thought to result from problems in hemispheric specialization involving both left and right cerebral hemispheres. Regional cerebral blood flow (rCBF) was measured at rest and during stimulation of both hemispheres independently: dichotic listening for the left, dichaptic palpation for the right. Eight right-handed boys with expressive dysphasia, aged 8 to 12 years, were investigated using SPECT and compared with eight right-handed age-matched boys with Duchenne muscular dystrophy with reading disorders but normal speech. rCBF values at rest were also compared with those of five right-handed age-matched normal boys. In the dichotic task, children with dysphasia differed from children with dystrophia by failure to increase rCBF in the left hemisphere, in Broca's area, but rCBF increased in the right hemisphere, in the region homologous to Broca's area. In the dichaptic task, rCBF increased bilaterally for children with dysphasia whereas in children with dystrophia rCBF increased only in the right hemisphere. At rest the physiological asymmetry was reversed in favor of the right hemisphere in all areas except Broca's area. Surprisingly, the same applied at rest and for all areas in children with dystrophia. These results confirm that functional specialization of both hemispheres is impaired in developmental dysphasia. Moreover, they suggest that learning disabilities associated with Duchenne muscular dystrophy could also be related to abnormal hemispheric specialization.

[Impairment of visual recognition after a traumatic brain injury]. / Evolution des troubles de la reconnaissance visuelle à distance d'un traumatisme cérébral.

Impaired vision and cerebral blindness were observed in a patient who had suffered brain trauma. One year after the trauma, the impairment was characterized by low visual acuity, visual field restricted to central tunnel vision and impaired recognition of objects, line drawings, colors and faces. Vision improved six years after the brain trauma with more rapid recognition of objects and line drawings, increased visual acuity and broadening of the visual field. Reading was possible at this time. However, prosopagnosia remained very severe and was still the primary complaint of the patient. Improvement of visual function continuing for several years after a brain injury is discussed on the basis of cognitive and neurophysiological knowledge. The place of rehabilitation is discussed. Functional improvement is explained by extrastriate cortical afferences and the cortical network of visual pathways.

Hybrid Capture II-based human papillomavirus detection, a sensitive test to detect in routine high-grade cervical lesions: a preliminary study on 1518 women.

Hybrid Capture II (HC-II) is a commercial human papillomavirus (HPV) detection test designed to detect 18 HPV types divided into high-risk and low-risk groups. We have tested 1647 scrapes from 1518 unselected women attending routine cytological screening by this assay for the detection of histologically proven high-grade lesions. The reliability of this test was also evaluated on 117 fresh cone biopsy samples. HPV DNA has been detected in 400 scrapes (24.3%), 296 containing a high-risk HPV (18.0%). All the smears evocative of high-grade lesions were positive for high-risk HPV, and high-risk HPV were detected in all the 34 cases presenting a histologically proven high-grade lesion and in 68 (97.1%) of the 70 cone biopsy samples showing a high-grade lesion or an invasive carcinoma. Thus, the sensitivity was superior to the sensitivity of cytology (85.3%). Nevertheless, the quantitative approach provided by the HC-II assay for the assessment of the viral load could not clearly distinguish among cases with or without high-grade lesions. Thus this assay is recommended for the screening of high-grade lesions on a large scale, in association with classic cytology.

Three-dimensional reconstruction of the human central sulcus reveals a morphological correlate of the hand area.

One way to improve our understanding of cortical anatomy is to visualize the three-dimensional (3D) shape of the cerebral sulci which is normally hidden. Here, we reconstructed the 3D morphology of the central sulcus (CS) in 17 normal subjects, using conventional magnetic resonance images and dedicated software. We found that the 3D morphology was remarkably consistent in all central sulci. Our analyses revealed three different regions (upper, middle and lower), which were easily identifiable by morphological criteria and sharply interconnected in the reconstructed CS. These morphological regions appear to have a strong functional significance, since the middle region corresponded precisely to the 'hand area', as verified by hand vibration positron emission tomography activation studies in eight cases. These data suggest that the 3D anatomy of the cerebral cortex may facilitate sulcal recognition, and sulcal subdivision into smaller morphological elements, bearing remarkable relationships with functional cortical maps.

Lateralization of speech and auditory temporal processing.

To investigate the role of temporal processing in language lateralization, we monitored asymmetry of cerebral activation in human volunteers using positron emission tomography (PET). Subjects were scanned during passive auditory stimulation with nonverbal sounds containing rapid (40 msec) or extended (200 msec) frequency transitions. Bilateral symmetric activation was observed in the auditory cortex for slow frequency transitions. In contrast, left-biased asymmetry was observed in response to rapid frequency transitions due to reduced response of the right auditory cortex. These results provide direct evidence that auditory processing of rapid acoustic transitions is lateralized in the human brain. Such functional asymmetry in temporal processing is likely to contribute to language lateralization from the lowest levels of cortical processing.

DNA-EIA to detect high and low risk HPV genotypes in cervical lesions with E6/E7 primer mediated multiplex PCR.

BACKGROUND: Oncogenicity of human papillomavirus (HPV) DNA in premalignant and malignant uterine cervical diseases is mainly induced by E6/E7 open reading frame (ORF). The presence of an oncogenic HPV DNA may be a diagnostic marker for the detection of cytologically negative smears. AIMS: To evaluate an original polymerase chain reaction enzyme immunoassay (PCR-EIA) for the detection and typing of oncogenic and non-oncogenic HPV types. METHODS: The test was an original multiplex labelled PCR-EIA for the detection and typing of oncogenic and non-oncogenic HPV using three consensus sequence primers within the oncogenic E6/E7 ORF. One primer was dinitrophenyl (DNP) labelled and the DNP labelled amplimers could be further hybridised with specific biotinylated oligoprobes mixed in only two cocktails: oncogenic (16, 18, 31, 33, 35, 52, and 58) and non-oncogenic (6 and 11) HPV types in only two wells; then biotinylated oligoprobes were deposited in streptavidin-coated microplates. The PCR-EIA was validated on HPV plasmids (types 6, 11, 16, 18, 31, 35, 52, and 58) and used to evaluate cervical scrapes from 181 patients (median age 32 years) at high risk for cervical cancer. RESULTS: HPV were detected in the cervical scrapes of 88 of 181 patients (48.6%); nine with non-oncogenic HPV (5.0%) and 79 with oncogenic HPV (43.6%) including 29 coinfections with oncogenic and non-oncogenic HPV. The number of oncogenic HPV infections increased with the presence of high grade lesions: 95.8% of the cervical scrapes from patients with high grade lesions contained oncogenic HPV compared with 32.1% of the specimens from patients without any lesions detectable by colposcopy and/or by cytological examination of the cervical smears. Moreover, 60% of cervical scrapes exhibiting low grade lesions contained oncogenic HPV. CONCLUSIONS: This test is simple, specific, sensitive, safe, fast, reproducible, and easy to use in routine practice. Thus, it is possible to detect simultaneously on a simple cervical scrape, two kinds of HPV--oncogenic and non-oncogenic--in just two microplate wells with non-isotopic oligoprobes.

Comparative analysis of human papillomavirus detection by hybrid capture assay and routine cytologic screening to detect high-grade cervical lesions.

A commercial HPV detection test, Hybrid Capture (HC), designed to detect 14 HPV types divided into high-risk and low-risk groups, has been evaluated. A total of 1064 scrapes from 1028 unselected women attending routine cytologic screening were tested and results were compared with those of classic cytologic screening and cervical biopsies. The reliability of the test was also evaluated on 38 fresh conization samples. HPV DNA was detected in 108 women (10.5%), including 90 infected by a high-risk HPV (8.8%); 25 high-grade lesions were detected histologically, and high-risk HPV was found in 16 of these 25 women (64%), and in 27 (71%) of the 38 conization samples. The overall sensitivity of HC in detecting high-grade SIL on cervical scrapes and conization samples was 71.2%, while its positive predictive value was 17.8%. Classic cytologic screening appeared to be the most sensitive method (84%) for detecting high-grade SIL, with a positive predictive value of 91.3%. The lower sensitivity of HC limits its use for screening high-grade lesions on a large scale, even though it may be useful for reducing cytologically false-negative results. Moreover, the quantitative approach provided by the HC assay for assessment of the viral load cannot clearly distinguish among cases with or without high-grade lesions.

Hybrid capture II, a new sensitive test for human papillomavirus detection. Comparison with hybrid capture I and PCR results in cervical lesions.

AIM: To test a new assay for the detection of human papillomavirus (HPV) DNA, hybrid capture II (HC II), compared with the previous commercialized hybrid capture I (HC I) and polymerase chain reaction (PCR) results on cervical scrapes from fresh cone excision biopsy samples. METHODS: The three methods were used on cervical scrapes from 42 fresh cone excision biopsy samples. There were nine metaplastic and inflammatory lesions, five low grade lesions, and 28 high grade lesions. PCR was performed using the general primers GP5+/GP6+. The viral load of high risk HPV DNA was estimated by the ratio of relative light units to positive control values in the samples. RESULTS: The sensitivity of HC I for the detection of high grade lesions was 71.4%, while it was 92.8% for HC II and 96.4% for the PCR. Considering only the absence of detectable cervical in situ neoplasia, the specificity was 88.9% for HC I, 66.7% for HC II, and 66.7% for PCR. With HC II, for a ratio of cervical sample to normal control of > 200, the sensitivity for the detection of high grade lesion was only 34.6% with a specificity of 66.7%. CONCLUSIONS: HPV detection with the HC II assay is more sensitive than the previous HC I and represents a more convenient and easier test than PCR for routine use. Nevertheless the viral load estimated with this test cannot be a reliable predictive indicator of high grade lesions.

[Carcinoid thymus tumor at an advanced age: diagnostic value of mediastinal needle biopsy with computerized tomography]. / Tumeur carcinoïde du thymus à un âge avancé: intérêt diagnostique de la ponction-biopsie médiastinaie sous tomodensitométrie.

Carcinoid tumour of the thymus is a rare neuroendocrine tumour particularly at an advanced age. The authors report a case of a mediastinal mass in a man aged 85, the mass had remained asymptomatic for a long time. It was decided to achieve a diagnosis because the tumour was causing local compression: a mediastinal needle biopsy under computerised tomographic control confirmed that this was a carcinoid tumour and a study of the biopsy material using an electron microscope showed neurosecretory granules. A sternotomy enabled the tumour to be excised but a post-operative Pseudomonas pneumonia led to the death of the patient. This case underlines the diagnostic place of mediastinal needle biopsy in the presence of a mediastinal tumour. The technique can be carried out under computerised tomography or ultrasonography and this can be associated with a study of the biopsy specimen using electron microscopy which enables the diagnosis to be made before any therapeutic decisions. The treatment of choice of a carcinoid tumour of the thymus is surgery which confirms the tumour limits and also its thymic origin. Tumour excision can be completed using radiotherapy or even chemotherapy.

Determination of reliable histological features associated with early triploidy using DNA image cytometry.

In order to determine reliable histological features characterizing triploidy, the following features were examined and graded by three pathologists on 46 early abortion specimens: hydropic swelling of the villi, cisterns, villous scalloping, trophoblastic hyperplasia with syncytial vacuolization, single cytotrophoblastic cells in villous stroma, trophoblastic inclusions, microcalcifications and fibrosis. At the same time, the DNA content of the 46 specimens was quantified cytophotometrically using the CAS 200 image analyzer, in order to confirm or not the diagnosis of triploidy. Triploidy was confirmed in 45.7%, and in the triploid group, the grading of three features differed significantly from the non triploid group i.e. cisterns (p < 0.001), trophoblastic hyperplasia (p < 0.05) and trophoblastic inclusions (p < 0.05). Using these three features we were able to give a triploid score per slide which represents the sum of the grades of each of these three features. The minimum score obtained was 0, the maximum was 6. The average of these scores in the triploid group was 3.095, and 1.45 in the non triploid group (p < 0.001). This scoring method on the three significant features (cisterns, trophoblastic hyperplasia and trophoblastic inclusions) appears to be useful to classify an abortion specimen as triploid or not, and to select the specimens for which a DNA quantification may be necessary.

Time course of prefrontal lobe dysfunction in severely depressed in-patients: a longitudinal neuropsychological study.

The Stroop Colour-Word Test (SCWT) and the Verbal Fluency Test (VFT), two tests that have been suggested to be particularly sensitive to prefrontal dysfunction, were administered to 23 severely depressed in-patients. Both tests were impaired in patients at inclusion, but only verbal fluency normalized with successful treatment of depression. VFT impairment is consistent with the hypothesis of a left prefrontal cortex dysfunction in depression. Moreover, the persistence of an impaired performance on SCWT in patients at discharge suggests that a selective attention deficit may persist in patients beyond a clear clinical improvement.

Brain metabolism after recurrent insulin induced hypoglycaemic episodes: a PET study.

Neuropsychological testing was carried out and the rate of oxygen metabolism in the brain was measured by PET in 15 highly selected patients with type 1 diabetes. The aim was to investigate the impact on the brain of hypoglycaemic comas resulting from insulin treatment. No significant difference was found between nine patients with a history of more than 10 hypoglycaemic comas and six others who denied any history of such events. These data suggest that intensified insulin treatment, although increasing the frequency of hypoglycaemic coma, may not always be harmful for the brain. This may be explained by the limited duration of hypoglycaemic coma induced by conventional insulin treatment.

Delusional misidentification: a clinical, neuropsychological and brain imaging case study.

The case of a young woman with a disorder involving Capgras syndrome, Frégoli syndrome, intermetamorphosis, and the subjective-doubles syndrome is reported. Neuropsychological assessment showed a low efficiency in the complex visuospatial organization tasks and in non-verbal memory. MRI found a left lenticular hypodensity, and two PET scans performed in the symptomatic and recovered states showed significant changes and asymmetries in cerebral glucose metabolism in the frontal, parietal, and subcortical regions. These findings are discussed with respect to recent models of delusional misidentification syndromes.

Person identification and self-concept in the delusional misidentification syndrome. A case study.

This study on a delusional misidentification patient with both Frégoli symptoms and intermetamorphosis investigates the cognitive structure of others and of the self-representations with a new clustering method (HICLAS conjunctive model). Results show that this patient, free from face recognition disorders, shows severe structural anomalies in the mapping of misidentified others, and of the self. Disturbances in the cognitive structure and person identification are discussed in reference to a psychopathological explanation of the misidentification syndrome.

Changes in regional cerebral blood flow during brain maturation in children and adolescents.

Regional cerebral blood flow (rCBF) was studied by SPECT using 133Xe in 42 children, aged 2 days to 19 years, considered as neurologically normal. rCBF was measured on cortical regions and on the cerebellum and thalamus. Curves for reference values and standard deviation were defined for each region. At birth, cortical rCBFs were lower than those for adults; after birth they increased until 5 or 6 yr of age to values 50%-85% higher than those for adults and thereafter decreased, reaching adult levels between 15 and 19 yr. Neonatal values of rCBF on cerebellum and thalamus were slightly higher than adult level, but not significantly; after age 1, they followed the common pattern for cortical curves. When rCBFs were expressed in percent global CBF, they were lower at birth than adult levels in the cortex, then increased and reached a plateau corresponding to the adult value before the second year of age. The time needed to reach normal adult values differed for each cortical region. The shortest time was found on the primary cortex and the longest on the associative cortex. Cognitive development of the child seems to be related to changes in blood flow of the corresponding brain regions.