Primary cervical cancer screening with HPV testing compared with liquid-based cytology: results of round 1 of a randomised controlled trial -- the HPV FOCAL Study.

BACKGROUND: Round 1 data of human papillomavirus (HPV) FOCAL, a three-arm, randomised trial, which aims to establish the efficacy of HPV DNA testing as a primary screen for cervical cancer, are presented. METHODS: The three arms are: Control arm - liquid based cytology with atypical squamous cells of unknown significance (ASC-US) triage with hrHPV testing; Intervention Arm - hrHPV at entry with liquid-based cytology (LBC) triage of hrHPV positives, with exit screen at 4 years; Safety check arm - hrHPV at entry with LBC triage of hrHPV positives with exit screen at 2 years. RESULTS: A total of 6154 women were randomised to the control arm and 12 494 to the HPV arms (intervention and safety check). In the HPV arm, the baseline cervical intraepithelial neoplasia (CIN)2+ and CIN3+ rate was 9.2/1000 (95%CI; 7.4, 10.9) and 4.8/1000 (95%CI; 3.6, 6.1), which increased to 16.1/1000 (95%CI 13.2, 18.9) for CIN2+ and to 8.0/1000 (95%CI; 5.9, 10.0) for CIN3+ after subsequent screening of HPV-DNA-positive/cytology-negative women. Detection rate in the control arm remained unchanged after subsequent screening of ASC-US-positive/hrHPV DNA-negative women at 11.0/1000 for CIN2+ and 5.0/1000 for CIN3+. CONCLUSION: After subsequent screening of women who were either hrHPV positive/cytology negative or ASC-US positive/HPV negative, women randomised to the HPV arms had increased CIN2+ detection compared with women randomised to the cytology arm.

Intention of parents to have male children vaccinated with the human papillomavirus vaccine.

BACKGROUND: Although already approved for use in males in some jurisdictions, there is little information about parental attitudes toward having their sons receive the human papillomavirus (HPV) vaccine. The goal of this study was to ascertain parental intentions to vaccinate their sons with an HPV vaccine and to determine factors that predict this intention. METHODS: Parents of children aged 8-18 years were recruited from across Canada through random digit dialling. Participants were asked to respond to a series of questions in the context of a Grade 6 (age 11/12 years old), publicly funded school-based HPV vaccine programme, including their intention to vaccinate their sons with the HPV vaccine. Parents were also asked about a series of characteristics thought to predict intention to vaccinate as well as demographic characteristics. Backwards logistic regression was conducted to calculate adjusted odds ratios (AOR) to identify the factors that are predictive of parents' intention to vaccinate their son(s) against HPV. RESULTS: Of the 1381 respondents with male children, 67.8% (95% CI 65.3 to 70.3) intend to vaccinate their son(s) against HPV. Parents who had positive attitudes toward vaccines and the HPV vaccine in particular (AOR 41.5, 95% CI 9.5 to 181.7), parents who were influenced by subjective norms (AOR 7.8, 95% CI 5.8 to 10.5), parents who felt that the vaccine had limited influence on sexual behaviour (AOR 2.3, 95% CI 1.6 to 3.3) and parents who were aware of HPV (AOR 1.4, 95% CI 1.1 to 2.0) were significantly more likely to report an intention to vaccinate boys against HPV. In contrast, residence in British Columbia compared to Atlantic Canada (AOR 0.4, 95% CI 0.2 to 0.8) and higher education (AOR 0.7, 95% CI 0.5 to 0.9) were negatively associated with intention to vaccinate. Parents who reported an intention to vaccinate their daughters were also highly likely to report an intention to vaccinate their sons (kappa = 0.9, p<0.001). DISCUSSION: The majority of Canadian parents would intend to have their male children receive the HPV vaccine in the context of a publicly funded school-based immunisation programme. Overall attitudes toward vaccine, recommendations from health professionals and impact of the vaccine on sexual practices are important predictors of intention to have a male child receive the HPV vaccine.

Serous borderline ovarian tumors in long-term culture: phenotypic and genotypic distinction from invasive ovarian carcinomas.

Serous borderline ovarian tumors (SBOTs) are differentiated, slow growing, noninvasive, and have a better prognosis than their invasive counterparts, but recurrence and progression to invasive carcinomas are common, and unlike high-grade serous carcinomas, they tend to be nonresponsive to chemotherapy. However, due to a lack of culture systems and animal models, information about the properties of SBOT and their changes with neoplastic progression is extremely limited. Our objective was to establish a cell culture model for SBOTs and to characterize their phenotype and genotype. We compared cultures derived from two SBOTs, one of which was a short-term culture containing a BRAF mutation but few other cytogenetic changes while the other culture developed into a spontaneously immortalized permanent cell line and had numerical and structural chromosomal abnormalities but lacked RAS/BRAF mutations. Both cultures formed whorl-like epithelial colonies and resembled low-grade invasive carcinomas by their secretion of CA125 and oviduct-specific glycoprotein, production of matrix metalloproteinases, E-cadherin expression, and telomerase activity. Other characteristics associated with neoplastic transformation, including invasiveness, anchorage-independent growth, and tumorigenicity, were not observed. Importantly, cell motility was reduced in both lines, likely contributing to the lack of invasiveness. The results reveal a striking phenotypic similarity between the two cell lines, regardless of their cytogenetic diversity, which suggests that their characteristic phenotype is regulated to a large degree by epigenetic and environmental factors. In conclusion, we have established the first permanent SBOT cell line, which provides a new model to elucidate the undefined relationship of SBOTs to invasive ovarian carcinomas.

A pilot phase 2 study of oregovomab murine monoclonal antibody to CA125 as an immunotherapeutic agent for recurrent ovarian cancer.

This prospective, open-label, pilot phase 2 study examined the clinical and immunologic effects of oregovomab (OvaRex) in heavily pretreated patients with recurrent ovarian cancer (OC). Thirteen women were administered intravenous oregovomab (2 mg) at weeks 0, 2, 4, 8, and 12, followed by quarterly doses for up to 2 years or disease progression. Concomitant chemotherapy was not permitted. Eligibility criteria included recurrence after one or more platinum-based chemotherapy regimens, CA125 >35 U/mL, evaluable or measurable disease. Tumor burden was evaluated by physical or radiologic methods pretreatment, weeks 12, 24, and every 24 weeks thereafter. Immune responses, including antibodies and T cells to oregovomab and CA125, were demonstrated in over half the patients. Stabilization of disease and survival >2 years was observed in 3 of 13 patients and coincided with robust immune responses. Shrinkage of marker lesions was not observed; however, four patients showed decreases in CA125 levels. Treatment was well tolerated without serious adverse events or discontinuations due to therapy. This pilot study supports immunologic activity and safety of oregovomab in recurrent OC. Further study of this agent in the consolidation and adjuvant setting is ongoing to establish its clinical utility.

Gestational trophoblastic disease.

OBJECTIVE: To provide standards for the diagnosis and treatment of patients with hydatidiform mole and gestational trophoblastic tumours (GTT). OPTIONS: Prognostic factors useful for treatment decisions in GTT are defined with patients classified as low-, medium-, and high-risk groups. OUTCOMES: Improved mortality and morbidity. EVIDENCE: Evidence was gathered using Medline for relevant studies and articles from 1980 to 2001 with specific reference to diagnosis, treatment options, and outcomes. The quality of evidence of Recommendations has been described using the Evaluation of Evidence criteria outlined in the Report of the Canadian Task Force on the Periodic Health Exam. RECOMMENDATIONS: 1. Suction curettage is the preferred method of evacuation of the hydatidiform mole (III-C). Post-operative surveillance with hCG assays is essential (II-3B). 2. Low-risk patients with both non-metastatic and metastatic disease should be treated with single-agent chemotherapy, either methotrexate or dactinomycin (II-3B). 3. Medium-risk patients should usually be treated with multi-agent chemotherapy, either MAC or EMA (III-C); single-agent chemotherapy may also be used (III-C). 4. High-risk patients should be treated with multi-agent chemotherapy EMA/CO, with selective use of surgery and radiotherapy (II-3B). Salvage chemotherapy with EP/EMA and surgery should be employed in resistant disease (III-C). 5. Placental site trophoblastic tumour that is non-metastatic should be treated with hysterectomy (III-C). Metastatic disease should be treated with chemotherapy, most commonly EMA/CO (III-C).6. Women should be advised to avoid pregnancy until hCG levels have been normal for six months following evacuation of a molar pregnancy and for one year following chemotherapy for gestational trophoblastic tumour. The combined oral contraceptive pill is safe for use by women with GTT (III-C). VALIDATION: These guidelines have been reviewed and approved by the Policy and Practice Guidelines Committee of the Society of Obstetricians and Gynaecologists of Canada (SOGC), the Gynaecologic Oncologists of Canada (GOC), the Society of Canadian Colposcopists (SCC), and by Executive and Council of the SOGC. SPONSOR: The Society of Obstetricians and Gynaecologists of Canada.

Peritoneal implantation of squamous cell carcinoma following rupture of a dermoid cyst during laparoscopic removal.

BACKGROUND: In recent years, there has been a move toward using laparoscopy in the management of presumed benign ovarian masses. This paper discusses the use of laparoscopy for ovarian masses (particularly dermoid cysts). The focus is on the implications for unexpected malignancies. CASE: We report here a case involving a dermoid cyst that was removed at laparoscopy and was subsequently found to contain a squamous cell carcinoma. Spillage of the cyst's contents occurred at the time of removal. At staging laparotomy, peritoneal implants of the tumor were found, upgrading the tumor from FIGO stage Ia to IIc. CONCLUSION: Spillage rates of dermoid cyst content with laparoscopic removal are inevitably higher than with excision at laparotomy. It remains controversial whether upstaging from FIGO stage Ia to IIc affects prognosis; however, in this case it led to aggressive adjuvant therapy which imposed significant additional morbidity, including loss of fertility, on the patient. One should be aware of the possibility of unexpected malignancy when the decision to manage an ovarian mass laparoscopically is made.

Coexpression of hepatocyte growth factor-Met: an early step in ovarian carcinogenesis?

Since autocrine regulation of HGF-Met is implicated in many forms of human cancer, we investigated whether the predisposition to develop ovarian cancer in women with hereditary ovarian cancer syndromes involves changes in the expression of HGF-Met by the tissue of origin of epithelial ovarian cancers, the ovarian surface epithelium (OSE). We compared cultures of normal OSE from women with (FH-OSE) (n=20) and with no (NFH-OSE) (n=48) family histories of ovarian cancer, SV40 Tag immortalized OSE lines (IOSE, n=5) and ovarian cancer cell lines (n=3). Cultures derived from 21/22 women with NFH-OSE and 13/13 women with FH-OSE expressed Met mRNA initially. After two to three passages, Met was downregulated in 37% of NFH-OSE cultures but persisted in 100% of FH-OSE cultures and ovarian cancer lines, like other epithelial differentiation markers that are stabilized in FH-OSE and neoplasia. HGF and Met mRNA were concomitantly expressed by NFH-OSE from only three of 32 women but in FH-OSE from eight of 13 women, and also in five of five IOSE and two of three ovarian cancer lines. Conditioned media from FH-OSE, but not NFH-OSE, contained immunoreactive HGF and induced cohort migration which was inhibited by neutralizing HGF antibody. Several signaling molecules of the PI3K pathway, including Akt2 and p70 S6K, were constitutively activated in FH-OSE from six of six women but in NFH-OSE from only four of eight women. Exogenous HGF was mitogenic in OSE, and that effect was regulated through the MAP kinase (ERK1/ERK2) and FRAP/p70 S6K pathways. The proliferative response to HGF was greater in NFH-OSE than in FH-OSE cultures. The results show that FH-OSE cultures differ from NFH-OSE by increased stability of Met expression and by HGF secretion. Constitutive phosphorylation of kinases and a diminished growth response to HGF suggest the presence of autocrine regulation in FH-OSE. In analogy with other cell types where an autocrine HGF-Met loop has been implicated in tumorigenic transformation, this change in FH-OSE may play a role in the enhanced susceptibility to ovarian carcinogenesis in women with hereditary ovarian cancer syndromes.

Clear cell carcinoma arising in extragonadal endometriosis in a caesarean section scar during pregnancy.

Malignancy arising in ectopic endometriosis is a rare event. This paper documents a case of clear cell carcinoma arising in a focus of ectopic endometrium in a low abdominal transverse scar.

Basal cell carcinoma of the vulva: clinical features and treatment results in 28 patients.

OBJECTIVE: To review our experience and that in the recent literature regarding basal cell carcinoma of the vulva to see whether current management guidelines are appropriate. METHODS: Twenty-eight women with basal cell carcinoma of the vulva were seen over 25 years at the BC Cancer Agency. The clinical-pathologic features were tabulated and the outcome was analyzed. RESULTS: The mean age was 74 years, and almost two-thirds were over the age of 70 at diagnosis. Patients typically presented with an irritation or soreness, with a symptom duration ranging from a few months to several years. Most lesions were confined to the anterior half of the vulva, and 23 of the 28 patients had T1 lesions. Wide local excision was the treatment method used most commonly. Only one patient was known to have died from disease metastasis. Ten women had other basal cell carcinomas, either before or after the diagnosis of their vulvar lesions, and in ten patients 11 other malignancies were diagnosed. CONCLUSION: Basal cell carcinoma of the vulva is an extremely uncommon tumor that rarely metastasizes or spreads. Primary treatment should consist of wide local excision and continued follow-up.

Successful term pregnancy following conservative debulking surgery for a stage IIIA serous low-malignant-potential tumor of the ovary: a case report.

Low-malignant-potential tumors of the ovary can occur in young women of childbearing age. Often these tumors are early stage and confined to the ovary at diagnosis allowing for fertility-preserving surgery. This case report describes a 25-year-old woman who presented with an advanced-stage metastatic LMP tumor and who underwent successful tumor debulking while preserving normal ovarian function. A successful spontaneous pregnancy occurred subsequently and the patient has remained well with 2 years of follow-up.

Complete hydatidiform mole coexistent with a twin live fetus: clinical course of four cases with complete cytogenetic analysis.

Twin gestations can occur in which one twin is a normal gestation (46 chromosomes: 23 maternal and 23 paternal origin) and in which the other twin is a complete hydatidiform mole (46 chromosomes all of paternal origin). Case reports of four such combined pregnancies that presented to a single institution are provided. All cases had documentation of clinical information, cytogenetic analysis, and fetal and placental pathology. Three of the four pregnancies were terminated for medical indications despite information documenting the presence of a normal fetus. All three of these patients required subsequent chemotherapy. The fourth case was followed conservatively and resulted in the birth of a normal infant at 38 weeks gestation. We speculate that the factors that led to the need for termination of the pregnancy (aggressive growth of trophoblast) may predict the need for further therapy. A true assessment of the antenatal and malignant sequelae risks associated with these rare gestations awaits the collection of a larger series of patients.

Distinction of low grade from high grade human ovarian carcinomas on the basis of losses of heterozygosity on chromosomes 3, 6, and 11 and HER-2/neu gene amplification.

We examined the frequencies of loss of heterozygosity at 13 different loci distributed on 9 chromosomes in 30 human ovarian carcinomas. The same tumors were also examined for the presence of amplification of the HER-2/neu and H-ras protooncogenes. The results confirmed earlier findings that losses of heterozygosity occurred at nonrandom frequencies on chromosomes 3, 6, and 11 in these tumors. None of the tumors examined showed amplification at the H-ras locus. The HER-2/neu gene, however, was amplified in approximately one-third of the tumors, in agreement with earlier studies from other laboratories. We subdivided our tumor specimens according to their histological grades, which can be regarded as representing different stages of tumor progression. Losses of heterozygosity on chromosomes 3 or 11 were not seen in low grade lesions, although they were present in most of the high grade tumors examined. Losses of heterozygosity on chromosome 6 as well as HER-2/neu amplification, in contrast, were present in several low grade tumors and were not more frequent in high grade lesions. We conclude that the latter two abnormalities are associated with cellular functions involved at earlier stages of ovarian tumor development, whereas inactivation of genes on chromosome 3 or 11 is associated with later steps that may be incompatible with the well differentiated phenotype.

Loss of heterozygosity on chromosomal segments 3p, 6q and 11p in human ovarian carcinomas.

The genetic events involved in human ovarian carcinoma development are still largely unknown. We have used DNA recombinant technologies to examine the genome of normal and neoplastic tissues from 12 different patients with such tumors. We used cloned DNA sequences homologous to loci showing restriction fragment length polymorphisms on chromosomal segments 3p, 5p, 6q, 11p, or 21q to determine the frequencies of losses of constitutional heterozygosity at these loci in tumor DNAs. Losses affecting loci on 3p, 6q, and 11p were found in a high percentage of the cases examined. In contrast, losses of heterozygosity were not found when we used DNA probes for the other 2 above chromosomal segments. Thus, genetic losses involving chromosomal segments 3p, 6q and 11p occurred at non-random frequencies in ovarian carcinomas, suggesting that inactivation of genes located on these chromosomes played a role in their development.

Posthysterectomy carcinoma of the fallopian tube presenting as vaginal adenocarcinoma: a case report.

The clinical and pathological features of a case of adenocarcinoma of the fallopian tube with a unique presentation are described. The 68-year-old patient presented with vaginal bleeding 25 years after a vaginal hysterectomy. Pelvic examination revealed a 0.5-cm nodule of tumor involving the mucosa of the vaginal apex. At laparoscopy, the left fallopian tube was dilated and adherent to the vaginal vault. Pathological examination of the upper vaginectomy and bilateral salpingo-oophorectomy specimen revealed a primary papillary adenocarcinoma of the left fallopian tube that had invaded directly into the mucosa of the vaginal apex. Vaginal involvement, either at the time of presentation or subsequently in the course of the disease, is very rare in patients with carcinoma of the fallopian tube.

Detection of ras point mutations by polymerase chain reaction using mutation-specific, inosine-containing oligonucleotide primers.

The use of DNA primers with 3'-ends complementary to specific genetic point mutations allowed for the rapid detection of such mutations in genomic DNA by polymerase chain reaction. The sensitivity of this approach was such that mutations could be detected in DNA samples mixed with a 10(7)-fold excess of normal non-mutated DNA. To increase the practicality of this approach for the detection of point mutations affecting all 3 of the known ras oncogenes we synthesized mutation-specific primers complementary to all 3 genes by substituting inosine residues at positions corresponding to ambiguous bases on the genes.

Isolation and characterization of the C3b-binding entity of C3b-receptor from human erythrocytes.

Applying 2 M KBr, membranes of Ehu were solubilized. By C3-affinity chromatography an activity could be isolated that inhibited the immune adherence reaction and C3b-dependent rosette formation. Since this material did not agglutinate EAC14oxy23b we termed it monovalent C3b receptor (mC3bR). PAGE and SDS-PAGE and staining with Coomassie brilliant blue and PAS reagent revealed a single glycoprotein band with a mol. wt. of 55,000-60,000 daltons and an electrophoretic mobility comparable to ovalbumin. This mC3bR proved to be antigenetically related to gp 205 [17]. The potential of mC3bR to react with C3b-carrying particles was not destroyed by heat and trypsin treatment but by neuraminidase or periodic acid treatment suggesting that mC3bR reacted by its carbohydrate moiety with C3b. As by mC3bR, immune adherence could be inhibited by D-glucose and D-galactose but not by their optical antipodes, L-glucose and L-galactose.

Differentiation of C3b receptors on human lymphocytes, phagocytes, erythrocytes and renal glomerulus cells by monoclonal antibodies.

C3b receptor protein was purified form human erythrocytes by 2 M KBr solubilization and affinity chromatography on C3-coated sepharose. This material served as antigen for raising monoclonal antibodies. To investigate the distribution and antigenetic relationship between the receptors for C3b on human erythrocytes, lymphoid and phagocytic cells, as well as kidney cells three monoclonal antibodies were selected which inhibited the binding of EAC14 degrees 23b to complement receptor-bearing cells. This could be shown for human erythrocytes by inhibiting the immune adherence reaction, for tonsil lymphocytes, Raji cells, and guinea-pig spleen cells by inhibition of rosette formation of these cells with EAC14 degrees 23b, and for human renal glomeruli by blocking of the the adherence of EAC14 degrees 23b to kidney sections. In contrast, these monoclonal antibodies were not capable of inhibiting rosette formation of human granulocytes and monocytes with EAC14 degrees 23b. The antibodies only interfered with the rosette formation, of EAC14 degrees 23bi and EAC14 degrees 23d with Raji cells and tonsil lymphocytes-if at all-at high concentrations, whereas the rosette formation of Raji cells and tonsil lymphocytes with EAC14 degrees 23b was influenced by supernatants of the selected clones up to a dilution of 1:10(3) to 1:10(5).

Description of a simple, specific, and sensitive test for the detection of detergent-solubilized C3b receptor.

The C3b receptor was isolated from detergent-solubilized human erythrocyte membranes by a previously described technique (1). The receptor glycoprotein was shown to enhance EAC14oxy23b rosette formation with Raji lymphoblastoid cells. This provided a specific and sensitive test to detect the solubilized C3b receptor either in crude or highly purified form. The property of the C3b receptor tested by this assay appears to be analogous to properties of beta 1H.