Lack of effect of coumarin on unscheduled DNA synthesis in precision-cut human liver slices

OBJECTIVE: To evaluate the accuracy of cytologic screening in pregnancy through routine colposcopy and to confirm the safety of conservative management of cervical intraepithelial neoplasia (CIN) in pregnancy. STUDY DESIGN: In total, 3,658 pregnant women, screened for cervical cancer with either cytology or colposcopy, were prospectively evaluated. Patients with abnormal findings underwent colposcopically directed biopsy and, in case of CIN, repeat cytology and colposcopy. Biopsy was repeated in case of suspected progression of the lesion. Suspected microinvasion was the only reason for diagnostic conization during pregnancy. After delivery, excisional treatment provided a final specimen from all patients. Diagnostic methods were compared. RESULTS: Comparison between cytology and colposcopy showed 97.1% concordance with a few false positives (2.5%) and false negatives (0.2%). Abnormal cytology and colposcopy, as compared with histology, showed similar concordances, but the risk of underestimation by cytology was significantly higher (P < .05). Initial and final histology of the 63 cases of CIN and microinvasive carcinoma showed 88.9% concordance. Progression of the lesion was not observed. CONCLUSION: These data do not justify combined use of cytology and colposcopy to improve screening for cervical cancer in pregnancy. Delayed treatment of CIN after delivery is safe.     

Comparing two modalities of management of women with cytologic evidence of squamous or glandular atypia: early repeat cytology or colposcopy

Early repeat cytology is recommended in most screening programs for cervical cancer in subjects with squamous or glandular abnormalities not amounting to neoplasia (atypical squamous cells of undetermined significance, ASCUS), but immediate colposcopy is also recommended in some countries, especially those where there is easy access to colposcopic facilities. We evaluated the cost-effectiveness of the two procedures in a prospective study of women with cytologic ASCUS, invited to cytocolposcopic assessment after 6 months. Colposcopy-directed biopsy was assumed as the gold standard, and the accuracy of colposcopy at 6 months was assumed to be equal to that of immediate colposcopy. Out of 874 compliers, punch biopsy was performed in 303 cases (34.7%), and 19 CIN2+ lesions were detected (CIN2 = 12, CIN3 = 6, microinvasive carcinoma = 1). Detecting 13 CIN2+ lesions at colposcopy required 874 colposcopies and 303 directed biopsies: the cost per CIN2+ lesion detected with the procedure was 2,749 US$. Detecting 15 CIN2+ lesions at repeat cytology required 874 cytologic examinations, 137 colposcopies, 64 directed biopsies, and 6 diagnostic large-loop resections, the latter being performed in subjects with high-grade squamous intraepithelial lesion and less severe lesions at punch biopsy: the cost per CIN2+ lesion detected with the procedure was 1,961 US$. The policy of repeat smear was more cost-effective than immediate colposcopy. According to such results, the protocol of the Florence screening program has been modified since October 1996.     

Colposcopy and selective biopsy in patients with abnormal cervical cytology

Patients with atypical or positive findings on cervical cytology should be referred to a special colposcopy clinic as the next step in investigation. Colposcopy complements cytology, and when combined with selective biopsy of the worst-affected area allows a high level of diagnostic accuracy (90,7%). The necessity for diagnostic conization with its risks is markedly reduced. When all three modalities were used in combination, only 0,7% of invasive cancers were missed.     

2-(4-Aminophenyl)benzothiazoles: novel agents with selective profiles of in vitro anti-tumour activity

OBJECTIVE: To evaluate the results of cervical cytology screening in the National Breast and Cervical Cancer Early Detection Program and to compare the findings with results from other screening programs. METHODS: We analyzed data on 312,858 women aged 18 years and older who received one or more Papanicolaou smears, and follow-up if indicated, from October 1991 through June 1995 at screening sites across the United States providing comprehensive National Breast and Cervical Cancer Early Detection Program services. RESULTS: Of the women screened, more than half were 40 years or older; slightly less than half (44%) were of racial and ethnic minorities. During the first screening cycle, 3.8% of Papanicolaou tests were reported as abnormal (squamous intraepithelial lesion [SIL] or squamous cell cancer); proportions of abnormals decreased with increasing age. The age-adjusted rate of biopsy-confirmed cervical intraepithelial neoplasia (CIN) II or worse among women screened was 7.4 per 1000 Papanicolaou tests; rates of CIN were highest among young women, but cancer rates peaked among women in their 50s and 60s. The percentages of first screening cycle-Papanicolaou tests interpreted as high-grade SIL and squamous cell carcinoma associated with biopsy-confirmed CIN II or worse (the positive predictive value) were 56.0% for CIN II/III and 3.7% for invasive cancer. Of the 150 invasive cancers diagnosed, 54.0% were classified as local disease. CONCLUSION: Observed results emphasize the duality of cervical neoplasia-CIN in younger women and invasive cancer in older women. This finding points to the importance of reaching both younger and older women for cervical cancer screening.     

Non-surgical prevention of uterine cancer

Non surgical prevention of uterine cervical cancer relies on regular performance of Pap smears and colposcopy. Screening for cervical dysplasia allows their treatment by laser vaporisation or cone biopsy, according to their grade, and therefore the prevention of invasive carcinoma. Unfortunately, 40% of the female population does not comply to cervical screening and Pap smears entail 20% false negative results. Prevention of endometrial carcinoma is even far more difficult in that endometrial smears are seldom practised. Periodic surveillance of women receiving oestrogenic hormonal therapy, addition of progesterone in order to eventually protect the endometrium, hysteroscopic detection of irregular endometrial hyperplasia, represent the only tools available today.     

Significant reduction in the rate of false-negative cervical smears with neural network-based technology (PAPNET Testing System)

False-negative cervical Pap smears may lead to disability or death from carcinoma of the uterine cervix. New computer technology has led to the development of an interactive, neural network-based vision instrument to increase the accuracy of cervical smear screening. The instrument belongs to a new class of medical devices designed to provide computer-aided diagnosis (CADx). To test the instrument's performance, 487 archival negative smears (index smears) from 228 women with biopsy-documented high-grade precancerous lesions or invasive cervical carcinoma (index women) were retrieved from the files of 10 participating laboratories that were using federally mandated quality assurance procedures. Samples of sequential negative smears (total 9,666) were retrieved as controls. The instrument was used to identify evidence of missed cytological abnormalities, including atypical squamous or glandular cells of undetermined significance (ASCUS, AGUS), low-grade or high-grade squamous intraepithelial lesions (LSIL, HSIL) and carcinoma. Using the instrument, 98 false-negative index smears were identified in 72 of the 228 index women (31.6%, 95% confidence interval [CI]: 25% to 38%). Disregarding the debatable categories of ASCUS or AGUS, there were 44 women whose false-negative smears disclosed squamous intraepithelial lesions (SIL) or carcinoma (19.3%; 95% CI: 14.2% to 24.4%). Unexpectedly, SILs were also identified in 127 of 9,666 control negative smears (1.3%; 95% CI: 1.1% to 1.5%). Compared with historical performance data from several participating laboratories, the instrument increased the detection rate of SILs in control smears by 25% and increased the yield of quality control rescreening 5.1 times (P < 0.0001). These data provide evidence that conventional screening and quality control rescreening of cervical smears fail to identify a substantial number of abnormalities. A significant improvement in performance of screening of cervical smears could be achieved with the use of the instrument described in this report.     

Natural history of false-negative papanicolaou smears: a prospective study using screening colposcopy in addition to cytology

The regular Papanicolaou (Pap) smear is cornerstone of women's preventive healthcare. The introduction of the regular Pap smear as a screening tool for cervical cancer has markedly decreased the number of deaths from cervical cancer. During the past decade, however, the rate of death from cervical cancer has remained relatively static. This screening method is known to have a high rate of false-negative results; therefore, serial examinations are necessary for optimal sensitivity. The sensitivity of the routine pelvic examination is further increased with the addition of colposcopy to cytologic screening. Patients identified as having disease by colposcopy and biopsy but not by Pap smear (false-negative), are followed up, and the progression of their disease is documented until the Pap smear reflects the known change. A total of 276 patients whose Pap tests showed "no abnormal cells" and mild dysplasia (CIN-1 [cervical intraepithelial neoplasia]) by colposcopy and biopsy, who opted not to be treated, were followed up as a function of time. The results of the Pap test on the 276 patients progressed to a low-grade squamous intraepithelial lesion (LGSIL) or higher within 42 months. In this study, false-negative Pap tests that were identified by simultaneously performed colposcopy became positive within 42 months; therefore, careful repetitive screening is necessary. The author argues that a definitive, prospective study on the addition of colposcopy or similar adjunct procedure to the routine pelvic examination, in selected cases, is needed.     

Cytopathological analysis of sputum in patients with airflow obstruction and significant smoking histories

Advances in the understanding of lung cancer biology have led to observations that specific genetic changes occur in premalignant dysplasia. These observations have occurred predominantly in molecular studies of resected lung tumors and consequently, they may not be fully representative of those biological abnormalities characterizing premalignant lesions in individuals without overt lung cancer. Studies of premalignant epithelial cell biology and chemoprevention are needed in this patient subgroup. Such an initiative is now underway through the lung cancer Specialized Program of Research Excellence (SPORE) grant awarded to the University of Colorado Cancer Center (and affiliated institutions) by the National Cancer Institute. To identify participants for the early detection and chemoprevention trials of the Colorado SPORE, we initiated a sputum cytology screening program targeting persons with chronic obstructive pulmonary disease and smoking histories of 40 or more pack-years. During the first 26 months after activation of the screening program, sputum samples from 632 participants were evaluated. Of these, 533 (84%) of the subjects submitted specimens deemed adequate for cytopathological interpretation; 99 (16%) provided sputum samples unsuitable for cytodiagnosis. Of those participants who submitted adequate samples, 48% had cytodiagnoses of mild dysplasia, 26 % had moderate to severe dysplasia, and 2% presented with carcinoma in situ or invasive carcinoma. Logistic regression modeling was pursued to determine whether selected demographic and/or clinical status variables could be identified as statistically significant predictors of the specific cytological outcome to be expected (mild dysplasia, moderate dysplasia, and so forth). The only apparent associations found from both univariate and multivariate analyses were that the total number of pack-years of smoking history decreased with severity of cytodiagnosis and that those individuals with mild or moderate dysplasia were more likely to be ex-smokers than those with grades of regular metaplasia or lower. Based on the initial results of the Colorado SPORE sputum cytology screening program, we conclude that persons with chronic obstructive pulmonary disease and 40 or more pack-years of smoking history have a high prevalence of premalignant dysplasia detectable through sputum cytology and should be targeted for research programs focusing on lung cancer prevention, early detection, and exploratory biomarker studies.     

Osteochondritis dissecans of the humeral head

ISSUES: The colposcope was developed in 1925 and is well established in clinical gynecologic practice for defining and delineating cytologically detected lesions mainly of the cervix but also the vagina and vulva. Additionally, various endoscopic procedures in gastroenterology, pulmonary and urologic lesions enhance the cytologic detection and histologic verification of precancerous and cancerous lesions. The cost-effectiveness of all these devices and their applicability, particularly in countries with a limited health budget, is a major issue. This task force considered aspects of the present state of the art and the challenges in the 21st century. CONSENSUS POSITION: Automated cytology can interface with colposcopic examination in a number of significant ways. Automated cytologic analysis of conventional cervical smears can potentially direct colposcopic examination by predicting the nature of a lesion, assist in determining which patients should receive colposcopy and, in some settings, thereby reduce the number of colposcopies. Potentially, various combinations of automated cytology and colposcopy may be used to generate screening protocols that might result in more effective and inexpensive screening. The role of cervicography, or high-resolution cervical photography, as a screening device remains to be defined. Sensitivity for high grade lesions is generally no greater than that in cytology, and specificity appears lower. The interpretation of cervical photographs in triage of mildly abnormal cytology may prove to be useful in countries with established cytology programs. In areas of the world where cytology screening programs are not in place, the interpretation of cervical photographs may have its most dramatic effect. Cost-effectiveness analyses are needed. There are, at present, insufficient data for the evaluation of speculoscopy, a procedure using chemiluminescent illumination of the cervix for visualization of acetowhite areas. Basic training in colposcopy should be integrated into the residency programs of obstetrics and gynecology. Criteria for the adequate training of colposcopists should be developed. Continuing education programs in colposcopy should be developed when they are not already in existence. The cost-effectiveness of integrating colposcopy as a primary screening technique should be evaluated. Following a high-grade squamous intraepithelial lesion (HSIL) cytology result, colposcopically directed punch biopsy should be taken with or without endocervical curettage. This generally should precede the loop electrosurgical excision procedure (LEEP); however, in certain circumstances direct LEEP may be indicated. LEEP under colposcopic vision is an efficient way to treat an HSIL lesion of the cervix because the histologic extent and margins can be determined, unlike with laser surgery or cryosurgery. It is also more cost-effective than cold knife conization because general anesthesia and an operating room are unnecessary. Following LEEP, the endocervical canal should be examined colposcopically for any evidence of involvement. Lesions in the endocervix can then be removed with a different-shaped loop. Further research into Raman spectroscopy as a diagnostic aid in cervical pathology is needed, as is the use of micrococolpohysteroscopy for in vivo cytologic analyses, especially of the endocervical canal and transformation zone. Hysteroscopy is the most direct method for the diagnosis and treatment of intrauterine diseases. Hysteroscopic endometrial biopsy is more accurate than conventional biopsy methods. Cervical invasion of endometrial cancer can be detected by hysteroscopy. The depth of invasion, however, is more accurately determined by magnetic resonance imaging or computed tomography. ONGOING ISSUES: Many topics for ongoing research and/or implementation are mentioned under "Consensus Position," above. (ABSTRACT TRUNCATED)     

When is bacterial vaginosis not bacterial vaginosis?--a case of cervical carcinoma presenting as recurrent vaginal anaerobic infection

Vaginal anaerobic infection is the most common cause of vaginal discharge in women. We present a case of recurrent vaginal anaerobic infection and cervical carcinoma and discuss the association of the two conditions. More frequent cytology/colposcopy may be indicated in women who give a history of recurrent or persistent vaginal anaerobic infection.     

Cervex-Brush vs. spatula and Cytobrush. A cytohistologic evaluation

OBJECTIVE: To compare the efficacy of two cervical smear instruments, Cervex-Brush and spatula plus Cytobrush. STUDY DESIGN: Cervical smears were taken before laser ring biopsies in 213 women, who were randomized for the Cervex-Brush or spatula plus Cytobrush (S+C). The cytologic diagnosis was compared to the histologic diagnosis after laser ring biopsy. RESULTS: The correlation between cytology and histology showed comparable concordance (54% and 42%) for the two devices. In 130 (74 with Cervex-Brush and 56 S+C) patients, histology revealed moderate dysplasia or more advanced lesions. Those cases were further analyzed for smear failures. Negative smears were found in 13 cases (10 in the Cervex-Brush and 3 in the S+C group). This difference in favor of S+C was not, however, statistically significant. Significantly more false negative smears were found when endocervical cells were absent and in patients 30-39 years of age. CONCLUSION: Modern sampling devices, such as the Cervex-Brush and S+C, seem to be equally efficient in obtaining dysplastic squamous cells. Other factors of importance for nonrepresentative cervical smears should be studied in order to improve efficacy.     

Endoscopic ultrasonography for preoperative staging of esophageal carcinoma

OBJECTIVE: The objective was to determine the frequency with which regression or progression of disease without treatment occurred in women diagnosed with squamous cell cervical carcinoma in situ (CIS) during pregnancy. METHODS:. A retrospective chart review of all women evaluated at the University of Iowa Colposcopy Clinic diagnosed with CIS during pregnancy from 1987 through 1992 was used. Thirty-four women were evaluated during pregnancy, of which 26 also had postpartum evaluation. All pathology reports of initial cytology and biopsies, as well as colposcopic impressions, were reviewed and compared to the same evaluations postpartum. RESULTS: Of the 26 women evaluated both antepartum and postpartum, only 1 was treated (cone biopsy) during pregnancy. She had disease suspicious for microinvasion. She was disease free postpartum. Of the remaining 25, 20 (80%) had persistent disease, 2 (8%) had either missed disease or progressive disease postpartum, and 3 (12%) resolved without treatment at postpartum evaluation. No statistical significance was found between route of delivery and persistence (P = 0.34). No statistical significance was found between smoking and persistence of disease (P = 1.0). In 46% of women the initial cytology was CIN I or II, and the initial colposcopic impression was found to underestimate the severity of the disease in 35% of cases. Two women were found to have invasive disease postpartum. CONCLUSIONS: There is a high persistence rate of CIS complicating pregnancy. Given the relatively high rate of underestimation of disease severity by both cytology and colposcopic impression, the use of routine biopsy at the time of colposcopy is recommended. Invasive disease may be encountered on postpartum evaluation.     

Diagnostic conization of the uterine cervix. II. Comparison of histological diagnoses with cytological and colposcopic tentative diagnoses

This report presents colposcopic and cytologic misinterpretations in cases with a cervical intraepithelial neoplasia or early invasive carcinoma and benign cervical lesions and the accuracy of these two methods of screening for cervical cancer. The accuracy of the cytology and of the colposcopic impression in predicting the degree of cervical intraepithelial neoplasia and early invasive carcinoma was over 93 per cent. In patients showing benign cervical lesions the cytology is more accurate in predicting the correct histologic change with 94,2 per cent than the colposcopic impression with 63,1 per cent. The suspicious smears (Papanicolaou III) are discussed.     

Usefulness of early detection of uterine collum carcinoma

Systematic screening of preinvasive and invasive lesions of uterine cervix by exfoliative cytology is justified by present morphologic and physiologic knowledge of the cervical epithelium. This technically easy screening procedure should be performed by the family doctor. If the result is positive, the case should be turned over to the gynecologist. Systematic repeated screening permits nearly complete eradication of invasive cervical carcinoma.     

Comparative evaluation of abnormal cytology, colposcopy and histopathology in preclinical cervical malignancy during pregnancy

The results of a two-and-a half-year study on cytodetection of preclinical cervical malignancy during pregnancy are presented. Of 3,534 pregnant women, 125 (3.5%) had cytologic diagnoses of dysplasia, carcinoma in situ or microinvasive carcinoma of the uterine cervix. These results are compared with those obtained from colposcopy and from tissue diagnosis following biopsy, cervical conization and hysterectomy. They are also analyzed in relation to the patients' age, parity and age at first sexual intercourse. The management of these patients during pregnancy is discussed, especially with regard to the authors' experience in dealing with patients from very poor socioeconomic and cultural backgrounds.     

Academic associate program: integrating clinical emergency medicine research with undergraduate education

MATERIALS AND METHODS: The diagnostic accuracy of scintimammography with 99mTc-MDP was evaluated in 400 consecutive women with clinical or mammographic suspicion of breast cancer, candidate to surgery and/or excisional biopsy. Lateral views of both glands were acquired, in prone position, 5-10 min after the injection of 550-740 MBq of 99mTc-MDP. The scintigraphic results were compared to mammograms and classified using the histological findings as gold standard. RESULTS: Mammography was suggestive for cancer in 231 (57%), suspicious in 49 (12%) and indeterminate in 120 (31%) patients. Breast carcinoma was histologically proven in 330 women, benign breast diseases in 70. The tumor size ranged from 4 x 5 to 50 x 60 mm. 99mTc-MDP visualized as foci of increased uptake 305/330 cancers (92%). In particular, in women with indeterminate mammograms the SMM had a diagnostic accuracy of 84%, correctly characterizing 101/120 lesions. Twenty missed cancers had largest diameter < or = 10 mm, 5 < or = 15 mm. Lack of 99mTc-MDP uptake occurred in 64 out of 70 benign lesions. These lesions were classified as truly negative. Conversely, 3 fibroadenoma and 3 epithelial hyperplasia with moderate or severe atypia were falsely positive. The overall specificity was 91.5%; the accuracy was 92%, the positive and negative predictive values were respectively 98% and 72%. CONCLUSIONS: The results obtained in this study suggest that 99mTc-MDP scintimammography accurately detects breast carcinomas with largest diameter > 10 mm; it differentiates malignant from benign lesions, and it shows promising insights in characterizing breast abnormalities mammographically indeterminate.     

Immunoglobulin G responses against human papillomavirus type 16 virus-like particles in a prospective nonintervention cohort study of women with cervical intraepithelial neoplasia

BACKGROUND: Infection with cancer-linked human papillomavirus (HPV) types such as HPV type 16 (HPV16) is the most important risk factor in the development of cervical cancer. It has been shown that immunoglobulin G (IgG) antibody responses against HPV16 virus-like particles (VLPs) are specifically associated with genital HPV16 infection. PURPOSE: The aim of this study was to determine the temporal relationships between the presence of HPV16 VLP-specific IgGs, HPV16 infection patterns, and the course of premalignant cervical disease. METHODS: Plasma samples from 133 women who had been diagnosed originally with mild to moderate cervical dyskaryosis and enrolled in a prospective non-intervention cohort study conducted in Amsterdam, The Netherlands, from 1991 through 1996 were analyzed for the presence of HPV16 VLP-specific IgGs by use of an enzyme-linked immunosorbent assay. A detailed analysis was performed on 43 women with different HPV16 infection patterns during a follow-up period of 10-34 months. Progression or regression of cervical intraepithelial neoplasia (CIN) lesions was monitored by cytologic and colposcopic testing at intervals of 3-4 months. HPV typing in cervical smears was performed by use of a polymerase chain reaction-based assay. Statistical analysis of the serologic data was performed by use of the Mann-Whitney U test or 2 x 2 table analyses. RESULTS: The presence of HPV16 VLP-specific IgGs in the plasma of the patients was found to be associated with the presence of HPV16 DNA in the cervical smear. Significantly higher proportions of patients with persistent HPV16 infections (i.e., who were polymerase chain reaction positive in three to 11 consecutive tests) than of patients with cleared HPV16 infections were found to be positive for the presence of HPV16 VLP-specific IgGs (18 [69.2%] of 26 versus nine [28.1%] of 32, respectively; P = .003). HPV16 VLP-specific IgGs were consistently detected in all women (n = 11) who were persistently HPV16 DNA positive during follow-up and whose disease ultimately progressed to CIN III (histologically diagnosed severe dysplasia or carcinoma in situ). CONCLUSION: HPV16 VLP-specific IgG responses are present in the plasma of a majority of patients with persistent HPV16 infections and histologically confirmed high-grade lesions but only in a smaller subset of patients with cleared HPV16 infections and either normal cervical histology or low-grade CIN lesions. IMPLICATIONS: These results suggest that HPV16 VLP-specific antibodies are not responsible for the clearance of virally induced CIN lesions but that they might, in patients with persistent HPV16 infections, be indicative of an increased cervical cancer risk.     

Human papillomavirus in normal cervical smears from Cape Town

OBJECTIVE: To determine the prevalence of human papillomavirus (HPV) types in South African women with normal cervical cytology and to determine whether our results are comparable to what has been found elsewhere in the world. DESIGN: Cervical smears were collected from 262 women. SETTING: The Cape Town metropolitan area. PARTICIPANTS: A total of 262 women, aged 19-85 years. Eighty-five women attended the family planning clinic of the Gynaecology Department at Groote Schuur Hospital and 177 women consulted private gynaecological practices. MAIN OUTCOME MEASURES: The prevalence and types of HPV in 192 women with normal cervical cytology. RESULTS: The incidence of HPV DNA in cervical smears from Cape Town women with normal cytology was found to be 13% (25/192) using Southern blot hybridisation. The types of HPV found in normal cervical tissue from Cape Town did not differ significantly from those found elsewhere in the world. Nine per cent (17/192) were positive for "high-risk' HPV types which are associated with premalignant and malignant cervical lesions. In the age group 20-39 years, 15 of 92 (16%) were positive for HPV DNA, while in the age group above 39 years, 3 of 53 (6%) women were positive for HPV DNA. CONCLUSIONS: In this study, 25 of 192 (13%) women with normal cytology were positive for HPV.     

Abnormal cervical cytology in the teen-ager: a continuing problem

Abnormal cervical cytology is being discovered in an alarming number of sexually active teen-agers. Over an 18 month period, cytology consistent with mild dysplasia or worse was noted in 188 of 2,655 teen-agers screened. This represents a rate of 70.8 per thousand. Colposcopically directed biopsies in 65 patients revealed 15 cases of severe dysplasia-carcinoma in situ. Cryosurgery was the principle method of treatment and, combined with colposcopy, is a safe and effective means of managing these patients.