The role of HPV DNA in the evaluation and follow-up of asymptomatic male sexual partners of females with CIN3.

PURPOSE: To determine whether and how asymptomatic sexual partners of females with high-grade cervical intraepithelial neoplasia (CIN3) lesions should be examined. METHODS: Sexual partners of females with CIN3 were evaluated for HPV-related lesions by scraping samples for high-risk HPV DNA and androscopy (colposcopic inspection of the penis, scrotum and peri-anal area). Abnormal androscopically detected lesions were sampled for cytology by Pap smears. RESULTS: 74 partners of 87 females were studied and underwent androscopy, and 17 (22.9%) had abnormal findings: 11/74 had clinical genital condyloma acuminata and 6/74 had aceto-white lesions on the penile shaft or scrotum. Cytology of the 17 abnormal androscopies showed that six smears were normal and 11 had atypia and koilocytosis. Positive high-risk HPV DNA indicated that 13/74 (17.5 %) were infected with HPV. Two partners (2/74, 2.8%) had concomitant HPV DNA 16. CONCLUSIONS: Male sexual partners of females with CIN3 should undergo androscopy and cytology of colposcopically detected abnormal areas.

Clinical and economic benefit of HPV-load testing in follow-up and management of women postcone biopsy for CIN2-3.

This study aimed to evaluate the clinical and economic implications of integrating human papilloma virus (HPV) load testing into the follow-up and management protocol of women postconisation for high-grade cervical intraepithelial neoplasia (CIN2-3). We evaluated 130 suitable women: 63 were screened biannually by Pap smears ('conventional approach') and 67 also had HPV-load testing ('HPV approach'). More stringent criteria for undergoing colposcopy or reconisation were observed by the former group compared to the latter. Both approaches were analysed for cost effectiveness. There were 33 out of 67 (49.2%) colposcopic referrals and 24 out of 67 (35.8%) reconisation/hysterectomies with the 'conventional approach' compared to 9 out of 63 (14.2%) and 7 out of 63 (11.1%) with the 'HPV approach'. Cervical intraepithelial neoplasia 2-3 residual disease was detected in 7 out of 67 (10.5%) and 7 out of 63 (11.1%) women. The 'conventional approach' had more negative colposcopic biopsies and more negative reconisation/hysterectomy histologies than the 'HPV approach'. The respective cost per detection of one case of residual disease was US$3573 and US$3485. The 'HPV approach' required fewer colposcopic and reconisation procedures to detect one case of residual CIN2-3. Its higher positive predictive value than that of cytology provided a significant decrease in false positive rates and a reduction of US$88 per detected case.

Contribution of human papillomavirus testing by hybrid capture in the triage of women with repeated abnormal pap smears before colposcopy referral.

OBJECTIVE: The purpose of this work was to evaluate the ability of testing for high-risk human papillomavirus (HPV) types using the hybrid capture technique to predict the presence of cervical intraepithelial neoplasia (CIN) II,III in patients with repeated atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesion (LGSIL) on Pap smears. METHODS: Hybrid capture testing and tissue biopsy were performed on 503 consecutive women with ASCUS or LGSIL on repeated Pap smears who were referred for colposcopy. RESULTS: A highly significant association (P < 0.0001) was found between a positive test for high-risk HPV types and CIN II,III, with an 87.0% positive predictive value and a 95.7% negative predictive value. In 226 women with ASCUS on repeated Pap smears, a positive test for high-risk HPV types had a 85.7% sensitivity and a 97% specificity for CIN II,III. In 277 patients with LGSIL on repeated Pap smears, a positive test for high-risk HPV types had an 88.2% sensitivity and a 94.7% specificity for CIN I,II. Reserving colposcopy examination for women who were positive for high-risk HPV types would have reduced the number of referrals for colposcopy to 24.6% and maintained a sensitivity of 87.0% for CIN II,III. CONCLUSIONS: A positive hybrid capture test for high-risk HPV types was highly sensitive and specific for the presence of CIN II,III in patients with ASCUS and LGSIL on repeated Pap smears. We believe that improved methodology will eventually enable more selective colposcopy referrals without affecting patient safety among these women.

Patients with double primary tumors in the breast and ovary- clinical characteristics and BRCA1-2 mutations status.

OBJECTIVE: The aim of this study was to define the prevalence, clinical characteristics, and BRCA1-2 mutation carrier status of ovarian cancer (OvC) patients with a previous primary malignancy in the breast (PPMBr). METHODS: The study population comprised 1240 consecutive Jewish Israeli women with pathologically confirmed epithelial OvC diagnosed between March 1, 1994, and December 31, 1997. Demographic and clinical data were obtained from medical files and from a detailed questionnaire taken through a nationwide epidemiological case-control study on OvC. Blood samples and tumor tissues were collected for analysis of the three predominant germline BRCA1-2 Jewish founder mutations (185delAG, 5382insC, and 6174delT). RESULTS: Fifty nine (4.7%) patients with OvC had a PPMBr. The median age at diagnosis of OvC was 60 years. The mean interval between the two diagnoses was 104 months (range 0-363 months). In the majority of the patients (n = 53), the diagnosis of breast cancer (BrC) preceded the OvC by more than 1 year. The ovarian tumors were diagnosed in 47% of the cases following investigation of patients' symptoms. In 41%, diagnosis was made as a consequence of check-up exams performed during the routine follow-up of BrC survivors. Patients with PPMBr were more likely to present with FIGO ovarian stage III-IV, compared to women with solitary OvC (73% vs 60. 3%, P < 0.05), and less likely to have borderline tumors (3.4% vs 17. 9%, P = 0.007). Family history of OvC/BrC was recorded in 26% of this group of patients compared to 10.5% among patients with solitary OvC (P = 0.003). Patients with PPMBr had an exceptionally high prevalence of BRCA1-2 mutations (57%), irrespective of family history. CONCLUSIONS: Patients with PPMBr present with more advanced disease and invasive-type epithelial ovarian tumors when compared to cases associated with solitary OvC. The rate of BRCA1-2 mutations in Jewish women with OvC who had PPMBr is at least twice as high as in Jewish women with OvC as the solitary disease.

p53 and WAF1 polymorphisms in Jewish-Israeli women with epithelial ovarian cancer and its association with BRCA mutations.

OBJECTIVE: To investigate whether polymorphic p53 and WAF1 alleles are associated with clinical, demographic and histopathological features and BRCA mutation in women with ovarian cancer. DESIGN: A cross-sectional study. POPULATION: Two hundred and twenty-one nonselected Israeli women with epithelial ovarian cancer. METHODS: DNA was analysed for known polymorphisms in intron 3 (a 16 nucleotide single repeat) and intron 6 (a G to A change at nucleotide 13,494) of the p53 gene, the S31R polymorphism in the WAF1 gene, and for three predominant Jewish mutations in the BRCA genes (185delAG and 5382insC in BRCA1, and 6174delT in BRCA2). MAIN OUTCOME MEASURE: The rate of polymorphic p53 and WAF1 alleles and their association with BRCA mutation, ethnic origin, age and stage at diagnosis, and family history of cancer. RESULTS: Of the tested women, 72 (32.6%) were either BRCA1 (n = 57) or BRCA2 (n = 15) mutation carriers. Sixty-eight of 213 (31.9%) were heterozygous for intron 3 polymorphism, 67/193 (34.7%) for intron 6 polymorphism, and 22/154 (14.3%) for S31R of the WAF1 gene. The p53 and WAF1 polymorphism rate did not differ between BRCA mutation carriers and noncarriers. No significant association between specific p53 or WAF1 genotypes, and clinical, histopathological or demographic variables was observed. CONCLUSION: In Jewish-Israeli women with sporadic and familial ovarian cancer, p53 or WAF1 polymorphisms do not seem to affect the phenotype.

Combined colposcopy, loop conization, and laser vaporization reduces recurrent abnormal cytology and residual disease in cervical dysplasia.

OBJECTIVES: Loop electrosurgical excision of the transformation zone (LEETZ) was recently associated with relatively high failure rates. We evaluated whether the combination of LEETZ with laser vaporization is superior to LEETZ alone in reducing the rates of recurrent abnormal cytology and residual disease. METHODS: The study population included 426 women with histologic diagnosis of cervical intraepithelial neoplasia (CIN) 2-3, of whom 289 (study group) were treated by LEETZ followed by laser vaporization of the crater base and walls and 137 (control group) were treated by LEETZ alone. All women were followed scrupulously at regular intervals for recurrent abnormal cytology and residual disease. The mean follow-up periods were 43 and 59 months for the study and control groups, respectively. RESULTS: Both groups were derived from the same community and were similar in epidemiologic characteristics and disease severity. Although the incidence of positive surgical margins was similar in both groups (10.4 and 9.5% for the study and control groups, respectively), recurrent abnormal cytology (10.2% vs 5.5%, P = 0.07) and histologic residual disease (21.4% vs 0%, P = 0.05) were more frequent among women in the control group. This applied to women with both negative and positive surgical margins. Both study and control women with positive surgical margins, especially at the endocervix, were at higher risk for recurrence. CONCLUSION: The addition of laser vaporization to LEETZ may improve outcome of both women with positive margins and women with negative margins. Our results support conservative management for all treated women, regardless of cone margin status.

Vascular cell adhesion molecule-1 in normal, failed, and ectopic pregnancy.

PROBLEM: Vascular cell adhesion molecule-1 (VCAM-1) is involved in early pregnancy establishment. This study sought to determine whether soluble VCAM-1 (sVCAM-1) serum levels differ among normal, failed, and ectopic pregnancy, its capacity to serve as a marker for pregnancy viability or ectopic pregnancy, and its correlation with serum progesterone and beta human chorionic gonadotrophin (PHCG) levels. METHOD OF STUDY: Maternal serum samples were obtained from 20 women with ectopic, 10 with normal, and 10 with failed intra-uterine pregnancy, all of comparable gestational age. Samples were assayed for sVCAM-1, progesterone, and betaHCG by specific assays. RESULTS: The median serum level of sVCAM-1 was comparable between the three pregnancy types (normal: 578.3 ng/mL, range 434.4-699.5 ng/mL; failed: 567.8 ng/mL, range 401.9 669.5 ng/mL; and ectopic: 470.7ng/mL range, 328.2-1151.1 ng/mL). Serum levels sVCAM-1 were not significantly correlated with betaHCG or progesterone levels. CONCLUSION: sVCAM-1 is not appropriate to serve as a marker for pregnancy viability or ectopic pregnancy.

Levels of vascular endothelial growth factor are elevated in patients with ectopic pregnancy: is this a novel marker?

OBJECTIVE: To determine serum levels of vascular endothelial growth factor (VEGF) and evaluate their capacity to serve as a marker for the diagnosis of ectopic pregnancy (EP). DESIGN: Prospective, case-controlled study. SETTING: A tertiary care center. PATIENT(S): Twenty women with EP, 10 women with normal intrauterine pregnancy, and 10 women with abnormal intrauterine pregnancy, all at comparable stages of gestation. INTERVENTION(S): Serum samples were obtained from all women. MAIN OUTCOME MEASURE(S): All samples were analyzed for VEGF, progesterone, and beta-hCG by specific methods. RESULT(S): Women with EP had higher serum levels of VEGF than women with normal intrauterine pregnancy and women with abnormal intrauterine pregnancy (median levels, 226.8 pg/mL, 24.4 pg/mL, and 59.4 pg/mL, respectively). With a cutoff level of 200 pg/mL, serum VEGF could distinguish intrauterine from extrauterine pregnancy with a sensitivity of 60%, specificity of 90%, and positive predictive value of 86%. CONCLUSION(S): The increased serum VEGF levels in women with EP may facilitate this challenging diagnosis and reduce maternal morbidity and mortality.

Phase II study of carboplatin and etoposide as salvage treatment for patients with metastatic breast cancer.

A phase II study of carboplatin and etoposide as salvage polychemotherapy in metastatic, infiltrating breast carcinoma was carried out with 25 multiply pretreated patients. Six of 25 patients (24%) had a partial response that lasted an average of 3.5 months; of the six responders, four had undergone either four or five previous chemotherapeutic treatments. Eight of 25 patients (32%) had stable disease, and 11 (44%) manifested disease progression. The median survival from time of entry to the salvage protocol was 8 months. There were treatment responses in lung, chest wall, liver, and skeleton. The most common side effects were leukopenia (68% of 25 patients), thrombocytopenia (56%), anemia (40%), fever (28%), and weakness (16%). Carboplatin combined with etoposide may be an effective and tolerable salvage regimen in advanced breast cancer.

Bone scan and bone biopsy in the detection of skeletal metastases.

This study provides the first quantitative indication of the limits of sensitivity of a bone scan with technetium (99Tc-MDP) in detecting skeletal metastases and thereby also helps to explain the fact that bone scans may be negative when metastases are present in the bone marrow. Since 99Tc-MDP remains the least noxious and most widely used isotope for bone scanning, these results have direct clinical relevance in the evaluation of patients with solid tumors and possible metastatic spread.

Does typing of human papillomavirus assist in the triage of women with repeated low-grade, cervical cytologic abnormalities?

OBJECTIVE: To evaluate the ability of testing for high-risk human papillomavirus (HPV) using the hybrid capture technique to detect cervical intraepithelial neoplasia (CIN) in patients with repeated low-grade cervical cytologic abnormalities and an adequate and normal colposcopy. METHODS: Hybrid capture testing and LEETZ were performed on 166 women with repeated low-grade cervical cytologic abnormalities who were referred for colposcopy which was to be adequate and normal. RESULTS: A highly significant correlation (P < 0.0001) was found between a positive test for high-risk HPV types and the finding of CIN II,III. In 67 women with atypical squamous cells of undetermined significance on repeated cytologic studies, a positive test for high-risk HPV types had a sensitivity and specificity of 90 and 96.5%, respectively, for detecting CIN II,III. In 99 patients with low-grade squamous intraepithelial lesions found on repeated cytologic study, a positive test for high-risk HPV types identified all patients as having CIN II,III on cone biopsy (sensitivity, 100%), with a specificity of 86.4%. Restriction of tissue sampling to women who were positive for high-risk HPV types would have reduced the number of tissue samplings performed to 20.4%, while identifying 20 of 21 patients with biopsy-confirmed CIN II, III. CONCLUSION: A positive hybrid capture test for high-risk HPV types is highly sensitive and specific for detecting CIN II,III in patients with repeated low-grade cervical cytologic abnormalities and an adequate and normal colposcopy and may be used in the triage of these women before performing tissue sampling.

Intrauterine irrigation with prostaglandin F2-alpha for management of severe postpartum hemorrhage.

BACKGROUND: Severe postpartum hemorrhage is a significant contributor to maternal morbidity and mortality. The use of prostaglandin F2-alpha to control severe postpartum hemorrhage may avert surgery for the control of bleeding. METHODS: After ruling out the possibility of genital tract injuries, 18 patients with severe postpartum hemorrhage caused by uterine atony were enrolled in the study. None of the patients responded to treatment with oxytocin, methylergonovine, or uterine massage. A Foley catheter was introduced into the uterine cavity and the balloon was inflated with 5 ml sterile saline solution. The catheter was connected to an infusion line of 500 ml saline solution containing 20 mg prostaglandin F2-alpha. The solution was infused at a rate of 3-4 ml/minute for the first 10 min, and then reduced to 1 ml/minute for a period of 12 24 hours. RESULTS: In 17 patients (94.4%) bleeding ceased within several minutes of initiation of intrauterine prostaglandin F2-alpha infusion, the uterus was firmly contracted and uterine bleeding did not recur. In one patient with placenta increta bleeding continued and hysterectomy was performed. None of the patients had any side effects. CONCLUSIONS: Intrauterine irrigation with low concentrations of prostaglandin F2-alpha is a simple, rapid and effective treatment for severe postpartum hemorrhage and facilitates constant and continuous hemostasis. Moreover, the minute dosage used eludes potentially complicating side effects.

The role of routine pelvic lymph node sampling in patients with stage I endometrial carcinoma: second thoughts.

BACKGROUND AND METHODS: The cases of 245 patients diagnosed during 1980-1989 with stage I endometrial carcinoma were retrospectively reviewed in order to assess the contribution of lymph node sampling (LNS) to both course of treatment and outcome. The 183 women treated by gyneco-oncologic surgeons had undergone the standard surgical procedure of total abdominal hysterectomy (TAH), bilateral salpingo-oophorectomy (BSO) and pelvic lymph node sampling (LNS). Sixty-two other women, treated by gynecologists, received only TAH and BSO. Of women who had received TAH+BSO+LNS, 105 (57.4%) were referred for adjuvant radiotherapy on the basis of one or any combination of high grade histology (G2 or G3), myometrial invasion to a depth of 50% or more and LNS positivity. Of the group who had not had LNS, 37 (59.7%) likewise received adjuvant radiotherapy but on the bases of histology and/or depth of invasion. RESULTS AND CONCLUSIONS: Recurrence and survival over a mean follow-up period of 7.5 years (range 5-15 years) showed no significant differences between the patients who underwent LNS and those who did not. Of 43 recurrences, six were among 'low risk' women (those with both minimal invasion and low grade histology), suggesting a special need among this group for the additional staging information which LNS may provide.

Taking a satisfactory cervical cytologic smear. Is it really an easy procedure?

OBJECTIVE: To evaluate the correlation between the experience of the cervical cytologic smear provider and the quality of the smears in terms of the percentages of satisfactory smears and contribution of the various factors affecting the smear's adequacy. STUDY DESIGN: A newly available quality control system was used to evaluate the adequacy of 4,000 smears. RESULTS: Of 4,000 smears, 660 (16.5%) were classified as "satisfactory but limited" or "unsatisfactory." Technical factors contributed 1.0%, while 15.5% were due to sampling factors, considered human errors. Thus, human error accounted for 90% of the total number of unsatisfactory smears. CONCLUSION: Greater experience with smear sampling is associated with fewer unsatisfactory smears. The results correlate directly with the total number of smears taken annually. Sampling skill improves in steps, with improvement limited beyond a certain point.

Treatment of bilateral multiple primary ovarian leiomyomas during pregnancy by way of conservative surgery: a case report.

Primary ovarian leiomyoma is a rare, unilateral and solitary, benign tumour. We report a unique case of bilateral, multiple, primary ovarian leiomyomas diagnosed incidentally during caesarean section. As opposed to previously reported cases, conservative surgery was performed which resulted in preservation of ovarian function and anatomy.

A case of severe hyperandrogenism, acanthosis nigricans and over diabetes: the use of non-invasive methods for diagnosis, pathogenesis and management.

Hyperandrogenism is characterized clinically by hirsutism, acne, androgens-dependent alopecia and elevated serum concentrations of androgens (testosterone and androstenedione). Polycystic ovary syndrome is the most frequent cause of hyperandrogenism. Nevertheless, the differential diagnosis includes androgen-secreting tumors of the ovary or adrenal gland. Although rare, it is important to consider this diagnosis in patients with serum testosterone concentrations greater than 7 nmol/l. A 35-year-old woman who presented with hirsutism, amenorrhea and acanthosis nigricans is described. The endocrine abnormalities included a serum testosterone concentration of 9 nmol/l and overt type II diabetes mellitus. Imaging studies, including magnetic resonance imaging and Doppler ultrasonography, did not disclose a secreting tumor. After cyproterone acetate was prescribed the serum testosterone concentration returned to normal. The recent application of modern, high-resolution diagnostic ultrasonography and magnetic resonance imaging enabled a morphologically based diagnosis in a case of severe hyperandrogenism, with no need for invasive procedures. The therapeutic response to antiandrogens is reassuring.

The effects of tamoxifen treatment on the endometrium.

OBJECTIVE: To investigate the association between tamoxifen and endometrial cancer. BACKGROUND: Tamoxifen is a nonsteroidal antiestrogenic drug that has been used successfully for 15 years in the treatment of all stages of breast carcinoma. In light of the positive results, several studies are now being conducted to test prolonged tamoxifen treatment as a prophylaxis against breast cancer in high-risk women. Although tamoxifen was thought to have only a few side effects, reports indicate that it is associated with an increased incidence of proliferative and neoplastic changes in the endometrium. As the current trend is to administer tamoxifen for prolonged periods and for more indications, the detrimental effects on the endometrium have vast implications. METHODS: Review of the current literature. RESULTS: Tamoxifen treatment is associated with an increased incidence of proliferative and neoplastic changes in the endometrium, with a 1.3 to 7.5 relative risk of developing endometrial carcinoma. CONCLUSIONS: The results of tamoxifen treatment in breast carcinoma override the risk of developing endometrial carcinoma. Any vaginal bleeding in women treated with tamoxifen should be investigated carefully and promptly. In the future it may be necessary to advise these women to undergo routine uterine cavity examination.

Sensitivity and specificity of sonohysterography for the evaluation of the uterine cavity in perimenopausal patients.

Sonohysterography is a technique for evaluating the uterine cavity by the instillation of sterile saline solution through an 8 Fr Foley catheter, before performing an ultrasonographic evaluation. The sensitivity and specificity of the procedure were evaluated in comparison to hysteroscopy. In a prospective double-blind study, 47 postmenopausal patients were evaluated first by sonohysterography, and within 1 week by hysteroscopy. After comparing the hysteroscopic and sonohysterographic results, sonohysterography showed a sensitivity of 86% and specificity of 100%. Sonohysterography is an accurate mode of diagnosis for pathologic intrauterine processes in perimenopausal patients.

Are Israeli women in a low risk group for developing squamous cell carcinoma of the uterine cervix?

OBJECTIVE: Invasive cervical squamous cell carcinoma is not a common disease among Jewish women. In the present study an attempt was made to find what is the distribution of the known risk factors in this population. METHODS: Three hundred and ninety-one patients with various cervical cytological abnormalities comprised the study group. They were compared to 350 Israeli women with negative cytology. The risk factors were extracted from an anonymous questionnaire. The results were statistically analyzed and compared to the equivalent figures published in the literature pertaining to non-Jewish women. RESULTS: The prevalence of abnormal cytology among the Israeli women was almost the same as that of the non-Jewish group: 24/1000 and 26/1000, respectively. Significant statistical differences were found between the following risk factors: number of sexual partners, age at first intercourse, age at first pregnancy. Women in the study group were younger when they became sexually active and at first pregnancy, they had a larger number of sexual partners, fewer of them were married and fewer of them were observant of Jewish ritual practices. In addition, they had achieved higher academic levels than the women in the control group. CONCLUSIONS: It was found that the distribution of the known risk factors among the study group was practically the same as those in the non-Jewish population. Moreover, it was found that there was an increase of 29.2% (from 17/1000 to 24/1000) in the prevalence of cervical premalignant lesions among the Israeli women. We believe that this population can no longer be considered as being at low risk for this disease.