Population-based study of human papillomavirus infection and cervical neoplasia in rural Costa Rica.

BACKGROUND: Human papillomavirus (HPV) is the main cause of cervical neoplasia. Because few population-based studies have investigated the prevalence of type-specific infection in relation to cervical disease, we studied a high-risk population, estimating the prevalence of HPV infection and the risk associated with various HPV types. METHODS: We screened 9175 women in Guanacaste, Costa Rica, to obtain a referent standard final diagnosis, and tested 3024 women for more than 40 types of HPV with a polymerase chain reaction-based system. RESULTS: Among women with normal cytology, HPV infections peaked first in women younger than 25 years, and they peaked again at age 55 years or older with predominantly non-cancer-associated types of HPV and uncharacterized HPV types. Low-grade squamous intraepithelial lesions (LSILs) (n = 189) decreased consistently with age. The prevalence of high-grade squamous intraepithelial lesions (HSILs) (n = 128) peaked first around age 30 years and again at age 65 years or older. Seventy-three percent of LSILs were HPV positive, with HPV16 being the predominant type (16% of positive subjects). HPV was found in 89% of HSILs and 88% of cancers, with HPV16 being strongly predominant (51% and 53% of positive subjects). Virtually all HSILs and cancers had cancer-associated HPV types, with high odds ratios (ORs) and attributable fractions around 80%. Risk for HPV16 was particularly high (OR for HSILs = 320, 95% confidence interval [CI] = 97-1000; OR for cancer = 710, 95% CI = 110-4500). CONCLUSIONS: We confirm the early decline of HPV infection with age but note increased prevalence after menopause, which could be related to a second peak of HSILs, an observation that warrants further investigation. At least 80% of HPVs involved in cervical carcinogenesis in this population have been characterized. Polyvalent vaccines including the main cancer-associated HPV types may be able to prevent most cases of cervical disease in this region.

Failure of 1H nuclear magnetic resonance spectroscopy of blood plasma to detect malignancy.

Water-suppressed proton nuclear magnetic resonance (NMR) of plasma was proposed as a technique for detecting malignant tumors. In that analysis, bloods drawn from cancer patients at the Beth Israel Hospital (BIH; Boston, MA), were easily distinguished from normal subjects by measuring and averaging the proton NMR methyl and methylene line widths of plasma lipoproteins. We collected blood at the Massachusetts General Hospital (MGH), including from normal controls, patients with untreated and treated malignant tumors, and patients with nontumor diseases. The plasma NMR analyses were carried out blind. The code was not broken until all patient charts and pathology records were reviewed, plasma analyses were completed, and patients had been divided into appropriate clinical groups. Analysis of these data showed no differences between the means of the study groups (false-positive and false-negative frequencies 46% and 57%, respectively). An inverse correlation of methyl/methylene line widths with age (P less than .01), and a correlation with nitrate-requiring cardiovascular disease (P less than .05) was, however, evident. This test cannot be validly used to detect malignancy.

Atrial pacing for the prevention of atrial fibrillation after cardiovascular surgery.

OBJECTIVE: The purpose of this study was to determine the efficacy of atrial pacing in the prevention of atrial fibrillation following cardiovascular surgery. BACKGROUND: Although pharmacologic therapy has been used to help prevent postoperative atrial fibrillation, it suffers from limited efficacy and adverse effects. In the nonoperative setting, novel pacing strategies have been shown to reduce recurrences of atrial fibrillation and prolong arrhythmia-free periods in patients with paroxysmal atrial arrhythmias. METHODS: A total of 154 patients (115 men; mean age, 65 +/- 10 years; ejection fraction, 53 +/- 10%) undergoing cardiac surgery (coronary artery bypass surgery, 88.3%; aortic valve replacement, 4.5%; coronary bypass + aortic valve replacement, 7.1%) had right and left atrial epicardial pacing electrodes placed at the time of surgery. Patients were randomized to either no pacing, right atrial (RAP), left atrial (LAP) or biatrial pacing (BAP) for 72 h after surgery. Beta-adrenergic blocking agents were administered concurrently to all patients following surgery. RESULTS: There was a reduction in the incidence of postoperative atrial fibrillation from 37.5% in patients receiving no postoperative pacing to 17% (p < 0.005) in patients assigned to one of the three pacing strategies. The length of hospital stay was reduced by 22% from 7.8 +/- 3.7 days to 6.1 +/- 2.3 days (p = 0.003) in patients assigned to postoperative atrial pacing. The incidence of atrial fibrillation was lower in each of the paced groups (RAP, 8%; LAP, 20%; BAP, 26%) compared with patients who did not receive postoperative pacing (37.5%). CONCLUSION: Postoperative atrial pacing, in conjunction with beta-blockade, significantly reduced both the incidence of atrial fibrillation and the length of hospital stay following cardiovascular surgery. Additional studies are needed to determine the most effective anatomic pacing site.

Evaluation of self-collected cervicovaginal cell samples for human papillomavirus testing by polymerase chain reaction.

As human papillomavirus (HPV) becomes accepted as the central cause of cervical cancer, longitudinal studies are shifting focus away from causality to a more detailed investigation of the natural history of HPV infections. These studies commonly require repeated samples for HPV testing over several years, usually collected during a pelvic exam, which is inconvenient to the participants and costly to the study. To alleviate the inconvenience and cost of repeated clinic visits, it has been proposed that women collect cervicovaginal cells themselves, hopefully increasing participation in the natural history studies. We evaluated the technical feasibility of self-collection of cervicovaginal cells using a Dacron swab for HPV DNA detection. We compared the self-collected swab sample and two clinician-administered swab samples (one from the endocervix and another from the ectocervix) from a total of 268 women participating in a case-control study of adenocarcinoma and squamous cell carcinomas of the uterine cervix (111 cases and 157 controls). HPV DNA was detected and genotyped using an L1 consensus PCR assay. The overall agreement between the clinician- and self-collected swabs was excellent [88.1%; kappa = 0.73 (95% confidence interval (CI), 0.61-0.85)]. The correlation was highest between the two clinician-administered swabs [kappa = 0.81 (95% CI, 0.69-0.93)] but was still excellent when comparing either clinician-administered swab to the self-administered sample [kappa = 0.75 (95% CI, 0.63-0.87) and 0.67 (95% CI, 0.55-0.79) for ectocervix and endocervix, respectively]. The type-specific agreement between samples was higher for high-risk, or cancer-associated, HPV genotypes than for low risk, noncancer-associated HPV genotypes when comparing the self-administered swab sample to the clinician-administered swab sample (kappa = 0.78 for high-risk versus 0.66 for low-risk HPV infections, t = -1.45, P = 0.15). The decrease in agreement for low risk types was largely attributable to an increased detection of these types in the self-administered sample (McNemar's chi2 = 6.25, P = 0.01 for clinician- versus self-administered swab comparisons). The agreement did not vary significantly by age, menopausal status, case status, or clinic center. We have demonstrated that a self-collected Dacron swab sample of cervicovaginal cells is a technically feasible alternative to clinician-administered cervical cell collection in natural history studies of HPV and cervical cancer.

Oral contraceptives as risk factors for cervical adenocarcinomas and squamous cell carcinomas.

To assess the hypothesis that oral contraceptives (OCs) increase the risk of cervical adenocarcinomas, we conducted a six-center case-control study of 124 patients with adenocarcinomas, 139 with squamous cell carcinomas, and 307 population controls. Women between the ages of 18 and 69 who were newly diagnosed with cervical adenocarcinomas between 1992 and 1996 were eligible. Healthy female controls and a second case group of incident cervical squamous cell carcinomas were matched to the adenocarcinoma cases. All participants were interviewed regarding OCs, other risk factors for cervical carcinoma, and utilization of cytological screening, and a PCR-based test determined HPV genotype of cervical samples for both case groups and controls. Use of OCs was positively and significantly associated with adenocarcinomas and positively but weakly associated with squamous cell carcinomas. Associations between OCs and invasive adenocarcinomas (n = 91), squamous cell carcinoma in situ (n = 48), and invasive squamous cell carcinomas (n = 91) disappeared after accounting for HPV infection, sexual history, and cytological screening, but a positive association remained between current use of OCs and cervical adenocarcinoma in situ (n = 33). This association persisted after stratification by screening and sexual history and after restriction according to HPV status, but small numbers made it difficult to exclude detection bias, selection bias, or residual confounding by HPV as potential explanations Current OC use was associated with cervical adenocarcinomas in situ, but we saw no other evidence that OCs independently increase the risk of cervical carcinomas.

Amiodarone versus a beta-blocker to prevent atrial fibrillation after cardiovascular surgery.

BACKGROUND: Both amiodarone and beta-blockers have been shown to decrease the incidence of atrial fibrillation after cardiovascular surgery. However, the superior agent has not been identified. METHODS: We performed a pilot study on 102 patients (68 men, mean age 65 +/- 10 years, mean left ventricular ejection fraction 0.53 +/- 0.12) undergoing cardiovascular surgery (94 coronary artery bypass grafting [CABG], 5 valvular surgery only, and 3 CABG + valvular surgery). The patients were randomized to receive amiodarone (1 g/d intravenously x 48 hours, then 400 mg/d orally until discharge) or propranolol (1 mg intravenously every 6 hours x 48 hours, then 20 mg orally four times a day until discharge). Atrial fibrillation was defined as lasting longer than 1 hour or resulting in hemodynamic compromise. RESULTS: The incidence of postoperative atrial fibrillation was 16.0% (8/50) in the amiodarone group and 32.7% (17/52) in the propranolol group (P =.05). The mean length of stay was 8.8 +/- 3.5 days for amiodarone-treated patients and 8.4 +/- 2.7 days for propranolol-treated patients (P not significant). Serious adverse events were uncommon and similar in each group. CONCLUSION: Early intravenous amiodarone, followed by oral amiodarone, appears to be superior to propranolol in the prevention of postoperative atrial fibrillation. It is well tolerated and can be started at the time of surgery. However, the use of amiodarone did not result in a reduction in the length of hospital stay.

Human papillomavirus infection of the cervix: relative risk associations of 15 common anogenital types.

During the years 1982-1989, 2627 women were recruited into eight studies analyzing the relationship between human papillomavirus (HPV) infection and cervical neoplasia. Subsequently, each individual was assigned as either a case or control, and each cervical sample was rescreened for HPV DNA by low-stringency Southern blot hybridization. Positive samples were retested at high stringency with specific probes for HPVs 6/11, 16, 18, 31, 33, 35, 42, 43, 44, 45, 51, 52, 56, and (in most instances) 58. Most cases (153 cancers, 261 high-grade and 377 low-grade squamous intraepithelial lesions) had target or cone biopsies; all 270 borderline atypia subjects and more than 85% of the 1566 normal controls had cytology plus colposcopy/cytology. Scientists performing HPV testing were masked to the clinical diagnoses. Human papillomavirus DNA was detected in 79.3% of specimens from women with definite cervical disease (627 of 791), in 23.7% of borderline atypia subjects (64 of 270), and in 6.4% of normal subjects (101 of 1566). Graphic analysis of odds ratios at each point in the diagnostic spectrum defined four categories: 1) "low risk" (HPVs 6/11, 42, 43, and 44), present in 20.2% (76 of 377) of low-grade lesions but absent in all 153 cancers; 2) "intermediate risk" (HPVs 31, 33, 35, 51, 52, and 58), detected in 23.8% (62 of 261) of high-grade squamous intraepithelial lesions but only 10.5% (16 of 153) of cancers; 3) "high risk/HPV 16," associated with 47.1% of both high-grade intraepithelial lesions (123 of 261) and cancers (72 of 153); and 4) "high risk/HPV 18" (HPVs 18, 45, and 56), found in 26.8% (41 of 153) of invasive carcinomas but only 6.5% (17 of 261) of high-grade intraepithelial lesions. The presence of an oncogenic HPV type conferred relative risks ranging at 65.1-235.7 for the occurrence of a high-grade lesion and 31.1-296.1 for an invasive cancer.

Superficial laser vulvectomy. IV. Extended laser vaporization and adjunctive 5-fluorouracil therapy of human papillomavirus-associated vulvar disease.

Although most human papillomavirus infections can be managed satisfactorily by office methods, extensive, refractory, and dysplastic vulvar disease poses frustrating problems. This observational cohort study evaluated the efficacy of extended laser ablation (vaporization of both clinically apparent and adjacent subclinical changes) among 160 women drawn from 1000 referrals between 1982-1987. During the final 2 years, the protocol incorporated two different 5-fluorouracil (5-FU) regimens: routine once-weekly applications as prophylaxis against postoperative recurrence, and twice-weekly dosing to avoid further laser surgery among patients with early but diffuse failures. One hundred seven patients (66.9%) were controlled by a single operation. Subsequent therapy for the remaining 53 women involved 44 additional superficial photovaporizations, 38 courses of therapeutic 5-FU, four deep laser destructions with skin grafting, and six trials of systemic alpha-interferon. Eventually, 158 patients (98.7%) entered stable clinical remission. Adjuvant 5-FU improved success rates among the 76 women with two or more adverse prognostic factors (87.5 versus 55.8%; P less than .01) but had no prophylactic value in the other 84 women. In contrast, the therapeutic 5-FU regimen was generally effective, avoiding the need for further surgery in 22 (57.9%) of 38 inevitable failures, compared with only four successes (10.3%) among 39 historic controls managed with caustic agents (chi 2 = 19.5; P less than .001). Improvements in laser technology had no impact upon outcome, but more sophisticated heat containment strategies reduced postoperative pain, healing time, and morbidity. Given adequate technique and an appropriate indication, we find extended laser ablation to be an excellent primary control method. However, the availability of an effective adjuvant regimen would be a valuable complement.

A double-blind, randomized trial of 0.5% podofilox and placebo for the treatment of genital warts in women.

Patient-applied formulations of 0.5% podofilox (podophyllotoxin) were evaluated for the treatment of external genital warts in a double-blind, placebo-controlled study. Seventy-two women were enrolled and, using a randomized, computer-generated list, assigned to receive either active drug or placebo in a 2:1 ratio. Patients were instructed to apply the medication to their external warts twice each day for 3 consecutive days, followed by 4 days without treatment. This cycle was repeated at weekly intervals for a maximum of 4 weeks (and a minimum of 2 weeks). Patients were evaluated weekly for the first month and then at weeks 6 and 10. The number of warts present was recorded and the overall improvement was assessed. The treated area was examined, the patients were questioned about any adverse effects, and standard hematologic/biochemical studies were conducted. The final results showed that podofilox cleared 74% of the total wart count, compared with an 18% regression in the placebo group (P less than .001). The investigators' assessments of improvement correctly distinguished active drug from placebo at every observation point. Local untoward effects were minor and transient. There was no evidence of systemic effects. It is concluded that patient-applied podofilox is a safe and effective therapy for genital condylomata in women. When available, this drug will simplify the treatment of genital warts by providing a patient-applied alternative therapy.

Safety and efficacy of 0.5% podofilox gel in the treatment of anogenital warts.

OBJECTIVE: To determine the safety and efficacy of a new gel formulation of podofilox in the treatment of anogenital warts. DESIGN: Double-blind, randomized, multicenter, vehicle-controlled investigation. SETTING: Private dermatology practices, university clinics (dermatology, gynecology, and infectious diseases), and contract research organizations. PATIENTS: Three hundred twenty-six patients with anogenital warts. MAIN OUTCOME MEASURE: Number of patients with clearing of all treated warts (treatment success). RESULTS: The 0.5% podofilox gel was significantly better than vehicle gel for successfully eliminating and reducing the number and size of anogenital warts. In the intent-to-treat population, 62 (37.1%) of 167 patients treated with 0.5% podofilox gel had complete clearing of the treated areas (treatment successes) compared with 2 (2.3%) of 86 patients who had clearing of warts with the vehicle gel (P < .001) after 4 weeks. Nineteen additional patients treated with 0.5% podofilox gel and 2 patients treated with vehicle gel had clearing of warts with continued treatment up to 8 weeks. After 8 weeks, 35.9% of the baseline anogenital warts treated with 0.5% podofilox gel remained; this was significantly fewer than in the vehicle-treated group (88.4% of the baseline number) (P = .001). The 0.5% podofilox gel was generally well tolerated, with predominantly mild or moderate local adverse reactions occurring in the majority of patients. Only 7 patients (3.2%), all receiving 0.5% podofilox gel, discontinued study treatment because of drug-related local reactions. CONCLUSIONS: The results demonstrated that 0.5% podofilox gel is safe and significantly more effective than vehicle gel in the treatment of anogenital warts.

A meta-analysis of antidepressant outcome under "blinder" conditions.

A meta-analysis of 22 studies of antidepressant outcome assessed the level of medication effects under conditions thought to be less subject to clinician bias than those in the typical double-blind drug trial. Studies were included only if, in addition to a newer antidepressant group, they also contained both standard antidepressant and placebo control groups. Effect sizes were quite modest and approximately one half to one quarter the size of those previously reported under more transparent conditions. Effect sizes that were based on clinician outcome ratings were significantly larger than those that were based on patient ratings. Patient ratings revealed no advantage for antidepressants beyond the placebo effect. Effect sizes were unrelated to sample sex ratios, patient age, inpatient or outpatient status, dosage level, and treatment duration. Findings highlight the fragility of the antidepressant effect.

Sexually transmitted papillomaviral infection in men.

Clinical experience gained from the assessment of 291 men over the last 8 years is analyzed to determine the clinical features of sexually transmitted papillomaviral infection in males, the patterns of anatomic distribution, the results of follow-up, the types of HPV associated with specific disease patterns, and the outcome of different methods of therapy.

Cervicography as an adjunct to cytologic screening.

Cervicography is not a surrogate for colposcopy. Its easy availability and economy maximize the predictive potential of the existing screening test, the Pap smear. It can also be used as a triage tool for women "at risk" for cervical HPV infections, such as women with a history of vulvar condylomata. It is not colpophotography, as the magnification and focus are stable, and the operator cannot manipulate the position of the cervix and change focus and light settings. Cervicography cannot replace Pap smears in detection programs, but can augment the predictive value of screening when used in tandem. Stafl cautions gynecologic practitioners to use the two in partnership and that the duo can push cervical cancer detection rates closer to 100%. What Cervicography does provide is a screening tool with great potential and a way to attack the troubling death rates from cervical cancer still facing us in the 21st century.

The management of genital condylomas in pregnant women.

Genital condylomas complicating pregnancy pose several management problems for the obstetrician, including the issues of mechanical difficulties in women with large lesions and possible viral transmission to the fetus during delivery. Although respiratory papillomatosis is infrequent, this complication can be catastrophic and produce significant long-term morbidity in affected children. Hence, we believe that condylomas in pregnancy should not be ignored. In view of the precision, high success rate, and low risk of complications, CO2 laser surgery appears to offer the best option in patients with extensive condylomas and those whose disease proves resistant to simpler therapies.

Clinical manifestations and natural history of genital human papillomavirus infections.

Over the past decade, the ever-increasing volume of evidence implicating HPV types in genital neoplasia has stimulated much research interest into all aspects of the biology of this interesting group of viruses. This research has led to the identification of growing heterogeneity of HPV types. It is not surprising, therefore, that the clinical profile of disease associated with genital HPV types is much broader than previously recognized. Knowledge of this clinical spectrum is mandatory to the understanding of the possible role of specific HPV types in human carcinogenesis.

Accelerated dobutamine stress testing: safety and feasibility in patients with known or suspected coronary artery disease.

BACKGROUND: Dobutamine pharmodynamics require approximately 10 min to reach steady state. Despite this, standard dobutamine stress echo typically uses 3-min stages of advancing dobutamine doses because of safety concerns. HYPOTHESIS: In patients with a high pretest probability of coronary artery disease (CAD), a continuous infusion of high-dose dobutamine is a feasible and safe method for performing a dobutamine stress test. METHODS: Forty-seven consecutive patients (mean age 64 +/- 11 years) with 3.0 +/- 1.4 cardiac risk factors underwent dobutamine stress testing utilizing a single, high-dose (40 mcg/kg/min), continuous dobutamine infusion. The 40 mcg/kg/min infusion was continued for up to 10 min or until a test endpoint had been reached. If a test endpoint was not achieved, atropine (up to 1.0 mg) was added. RESULTS: Heart rate rose from 71 +/- 12 to 137 +/- 18 beats/min at peak (p<0.0001) with a concomitant change in systolic blood pressure (143 +/- 35 vs. 167 +/- 38 mmHg; p = 0.001) but no change in diastolic blood pressure (74 +/- 19 vs. 75 +/- 18 mmHg; p = NS). Target heart rate was achieved in 20 of 47 (43%) patients with accelerated dobutamine alone and in 34 of 47 (72%) with the addition of atropine. An average of 11.6 +/- 3.7 min was required to obtain target heart rate. Subjective sensations from the dobutamine occurred in 49% of patients (palpitations 21%, nausea 6%, chest pain 6%, headache 6%, dizziness 13%), mild arrhythmia in 48% of patients (ventricular premature beats 38%, supraventricular tachycardia 10%), and one patient had nonsustained ventricular tachycardia. CONCLUSION: A single, high-dose (40 mcg/kg/min) dobutamine-atropine protocol provides an efficient means of performing dobutamine stress echocardiography with a similar symptom profile as conventional dobutamine infusion protocols in patients with a high pretest probability of CAD. Randomized, controlled studies will be necessary to assess the sensitivity and specificity of this accelerated dobutamine echo protocol.

Evaluation of the patient with blunt chest trauma: an evidence based approach.

The patient who has sustained blunt trauma to the chest can present a diagnostic challenge to the emergency physician. There are several diagnostic modalities available for treating life-threatening injuries to these patients. The authors review published studies to support the use of these tests in diagnosing injuries from blunt thoracic trauma. The article focuses chiefly on two current areas of controversy, the diagnosis of blunt aortic and blunt myocardial injury. Finally, the authors make recommendations for the use of various tests based on the available evidence.

Colposcopic findings in women with vulvar pain syndromes. A preliminary report.

Of 105 women referred for vulvar discomfort, 77 had idiopathic vulvodynia (pain, dyspareunia, burning or pruritus not explicable by a standard diagnosis). Physical examination showed that patients with those complaints fell into one of two categories: (1) diffuse, irritative acetowhitening of both the cutaneous and mucosal surfaces (42 patients), and (2) painful vestibular erythema, with or without acetowhitening (35 patients). The physical findings appeared to be predictive of therapeutic response. Among women with only diffuse, irritative acetowhitening, low-dose topical 5 fluorouracil was about 75% effective in milder cases, while CO2 laser photovaporization controlled 77% of cases with moderate and severe symptomatology. In contrast, medical regimens succeeded in just 8% of women with painful vestibular erythema, and only 59% were cured by hymenal resection. Several of the remaining cases have responded to selective argon laser photocoagulation of the hyperemic blood vessels within symptomatic areas.

Reid's Colposcopic Index.

Reid's Colposcopic Index (RCI) is a systematic, objective method of colposcopically grading the severity of premalignant cervical lesions. The index considers four colposcopic signs: lesion margin, color of acetowhitening, blood vessels, and iodine staining. The RCI can accurately predict the histologic grade of cervical disease, readily permitting differentiation between low-grade cervical disease and high-grade disease. Hence, use of the index helps direct the clinician to perform a biopsy of the most significant abnormal cervical lesions and enhances the formulation of the colposcopic impression.