Evaluation of women referred to the two-week wait gynaecology clinic with suspected ovarian cancer.

OBJECTIVES: Ovarian cancer is the leading cause of death from gynaecological cancer in the UK, making early diagnosis key. The two-week wait pathway aims to facilitate rapid referrals from primary to secondary care for suspected cancer thus increasing rates of early diagnosis. The objective of this study was to evaluate referrals made via the two-week wait pathway for suspected ovarian cancer. STUDY DESIGN: A retrospective analysis of 215 women referred on the two-week wait pathway to a tertiary centre in the United Kingdom with suspected ovarian cancer in 2018. RESULTS: Only 16% of women referred were subsequently diagnosed with gynaecological malignancy. Of those diagnosed with ovarian cancer, 78% had late stage disease at diagnosis. Pre-menopausal women made up 29% of those referred, but only 6% of those diagnosed with cancer. CONCLUSION: Despite its goal of increasing early stage diagnosis of cancer, the majority of women referred via the two-week wait pathway do not have cancer, and the majority of those who do are referred with late stage disease. These results highlight the need for an effective screening programme for ovarian cancer.

Effects of genetic background on cardiovascular anomalies in the Ts16 mouse.

To investigate the genetic contribution to phenotypic variability in aneuploidy, we generated mice with trisomy 16 (Ts16) by mating [Rb(6.16)24Lub x Rb(16.17)7Bnr]F1 males with females from four inbred strains, BALB/cJ, C3H/HeJ, C57BL/6J, and DBA/2J. Among the four Ts16 strains that were generated, there were no significant differences in survival, weight, or length relative to euploid control littermates at either embryonic day (E) 14.5 or E17.5. All Ts16 fetuses at E14.5 had edema that ranged from mild to severe, increased amniotic fluid volume, and a thickened neck. At E17.5, Ts16 fetuses exhibited two distinct phenotypes, one with an edematous morphology and the other runt-like. None of these gross morphological abnormalities was strain-specific either in occurrence or frequency. At E10.5, there were pharyngeal arch artery (PAA) anomalies in all Ts16 embryos on the C3H/HeJ background, but none in trisomics on the other three backgrounds. However, at E17.5, there was in addition to ventricular and atrioventricular septal defects, a high frequency of aortic arch defects in Ts16 fetuses, irrespective of genetic background. Taken together, these findings indicate that there are at least two mechanistic responses to the presence of three copies of mouse chromosome 16 in the modeling of the cardiovascular system: one, development of PAA defects, is strongly influenced by genetic background; but the second, development of aortic arch anomalies in the absence of preexisting PAA anomalies, is not.

The role of repeat uterine evacuation in the management of persistent gestational trophoblastic disease.

OBJECTIVE: To evaluate the role of second (and third) uterine evacuation in the management of persistent gestational trophoblastic disease (GTD). METHODS: This was an observational study of all cases registered over a 10-year period at the Trophoblastic Disease Centre at Weston Park Hospital, Sheffield. Five hundred and forty-four of 4050 women registered during 1991-2000 underwent a second uterine evacuation following a presumptive diagnosis of persistent GTD. The reason for evacuation, hCG level prior to the procedure, histological appearances of evacuated products and the clinical outcome (in terms of the need for chemotherapy) were determined. RESULTS: After a second uterine evacuation 368 patients (68%) completed the follow-up programme without further evidence of persistent disease or need for chemotherapy. If the diagnosis of persistent GTD was confirmed solely on the basis of elevated hCG levels then 171 of 282 (60%) patients did not require chemotherapy. Chemotherapy was more likely where there was histological evidence of persistent trophoblastic disease and where the urinary hCG was >1500 IU/L at the time of the repeat evacuation. Twenty-eight of 60 patients (46%) undergoing a third evacuation required chemotherapy. CONCLUSION: Second uterine evacuation can be a useful therapeutic option for patients with presumed persistent trophoblastic disease not mandating immediate chemotherapy, particularly where the hCG level is <1500 IU/L. Patients with documented persistent trophoblastic disease on histological examination of the second evacuation sample are more likely to require chemotherapy. Third evacuation is not now recommended.

The clinical presentation, treatment, and outcome of patients diagnosed with possible ectopic molar gestation.

The objective of this study was to determine the clinical presentation, treatment, and outcome of patients diagnosed with possible ectopic molar gestation registered with the Trophoblastic Disease Screening and Treatment Centre, Weston Park Hospital, Sheffield between 1986 and 2000. From the 5581 women registered, those with a diagnosis of ectopic molar pregnancy were identified from a computer database. Information regarding the relevant history of each patient and the clinical presentation, treatment, and outcomes of gestational trophoblastic disease (GTD) was determined by reviewing referral forms, case notes, and pro formas completed by the referring gynecologist. Histological review of the cases was undertaken where possible. Suspected ectopic molar gestations comprised 31/5581 (0.55%) of registrations. Known risk factors for ectopic pregnancy were identified in 79% of cases. Central histological review confirmed only six cases of GTD: three choriocarcinoma and three early complete moles. Four patients subsequently required chemotherapy. All patients are now in complete remission. We conclude that ectopic GTD is uncommon, with a UK incidence of approximately 1.5 per 1,000,000 births. Initial management is usually surgical removal of the conceptus, pathological suspicion of the diagnosis and registration with a screening center. Chemotherapy may be required and the prognosis is excellent.

Cardiomyopathy in mice with paternal uniparental disomy for chromosome 12.

Mice inheriting both copies of MMU12 either maternally or paternally demonstrate imprinting effects. Whereas maternal uniparental disomy 12 (matUPD12) fetuses are growth retarded and die perinatally, paternal UPD12 (patUPD12) fetuses die during late gestation and exhibit placentomegaly and skeletal muscle maturation defects. To examine further the developmental consequences of UPD12, we intercrossed mouse stocks heterozygous for Robertsonian translocation chromosomes (8.12) and (10.12). We report that at 13.5-14.5 dg patUPD12 hearts exhibit increased ventricular diameter, thinner, less compact myocardium, and deep intertrabecular recesses when compared to controls. These data provide evidence for cardiac failure, a lethal condition, and suggest a role for an imprinted gene(s) in normal heart development.

Over-diagnosis of hydatidiform mole in early tubal ectopic pregnancy.

AIMS: Tubal ectopic hydatidiform moles are rare lesions, and only 40 cases have been reported in the world literature. We investigated the apparently high incidence of tubal ectopic hydatidiform moles in women referred for treatment to a Supraregional Trophoblastic Tumour Screening and Treatment Centre between 1986 and 1996. METHODS AND RESULTS: Of 4261 women referred during the study period, 25 (0.6%) had a suspected tubal ectopic hydatidiform mole and paraffin-embedded tissue was available in 20 (80%) of these. Each case was reviewed by two pathologists and DNA flow cytometric analysis was undertaken when the histological diagnosis was initially deemed equivocal or suggestive of hydatidiform mole. On review, 17 cases (85%) showed no evidence of hydatidiform mole (circumferential trophoblastic proliferation, hydrops, scalloped villi, and stromal karyorrhexis). Of these, 11 cases (65%) showed features of early placentation and six (35%) showed hydropic abortion. DNA flow cytometry was performed in 14 (82%) of these cases and revealed a diploid population in each case. Three cases of molar pregnancy (15%) were identified. Each of these cases had the histological features of an early complete hydatidiform mole. Sufficient tissue was available for DNA flow cytometric analysis in two of these cases and confirmed the presence of diploidy in each. CONCLUSION: Our results show that tubal ectopic hydatidiform mole is a rare entity and demonstrate that it is over-diagnosed. Polar trophoblastic proliferation and hydropic villi are features of early placentation and of hydropic abortion. Sheets of extravillous trophoblast may be particularly prominent in tubal ectopic gestation. In the absence of circumferential trophoblastic proliferation combined with hydropic change a diagnosis of gestational trophoblastic disease should be avoided.

Mouse intestinal goblet cells expressing SV40 T antigen directed by the MUC2 mucin gene promoter undergo apoptosis upon migration to the villi.

Mucinous colorectal cancers exhibit a characteristic set of molecular genetic alterations and may be derived from progenitor cells committed to the goblet cell lineage. Previously, we demonstrated that the MUC2 mucin gene promoter drives transgene reporter expression with high specificity in small intestinal goblet cells of transgenic mice. On the basis of these experiments, we reasoned that the MUC2 promoter could be used to drive SV40 T antigen (Tag) expression in the same cell type, decoupling them from their normal antiproliferative controls. A line of mice was established (MUCTag6) that expressed Tag in intestinal goblet cells as determined by RNA blot and immunohistochemical analysis. These goblet cells were markedly involuted however, most notably in the villi. Endogenous intestinal MUC2 message levels were reduced to about one third the normal level in these mice. However, absorptive cell lineage markers were comparable with nontransgenics. Bromodeoxyuridine-positive S-phase cells are limited to crypts in nontransgenic intestine but are present in both crypts and villi in MUCTag6. In contrast, mitotic cells were not present in the villi, indicating that MUCTag6 villi goblet cells do not progress into M phase. Apoptotic cells positive for terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling were increased more than fourfold in MUCTag6 villi (P < 0.0001), and apoptotic goblet cells were evident. Electron microscopic examination of MUCTag6 intestinal villi revealed the presence of degraded cell remnants containing mucin goblets together with other cell debris, further indicating apoptosis of the goblet cell lineage. Thus, the expression of Tag in intestinal goblet cells releases them from normal antiproliferative controls, causing their inappropriate entry into S phase even after they transverse the crypt/villus junction. They do not, however, progress to M phase. Instead, they undergo apoptosis with a high degree of efficiency in S or G(2) phase. These experiments demonstrate that apoptosis effectively blocks inappropriate goblet cell proliferation in the intestine, supporting its proposed role as an antineoplastic mechanism.

Gestational trophoblastic disease: a study of mode of evacuation and subsequent need for treatment with chemotherapy.

OBJECTIVES: The aim of this study was to assess whether there was a change in the mode of evacuation of GTD over two time periods and to assess whether mode of evacuation influenced the subsequent need for chemotherapy. METHODS: A retrospective case note study of 4257 cases between 1986 and 1996, at a screening and treatment center managing GTD, was performed. RESULTS: Between the time periods 1986-1989 and 1990-1996 there was significant change in the mode of evacuation to suction curettage. The mode of evacuation was significant in determining the need for chemotherapy. The highest rate of chemotherapy was associated with medical methods of evacuation. CONCLUSIONS: Suction curettage is a safe method of uterine evacuation in GTD and its usage has increased with time. Medical methods of uterine evacuation are associated with higher rates of chemotherapy. This is probably due to a higher rate of incomplete evacuation. Medical methods of evacuation should not be used in cases of complete hydatiform mole.

Phase I open study of the effects of ascending doses of the cytotoxic immunoconjugate CMB-401 (hCTMO1-calicheamicin) in patients with epithelial ovarian cancer.

PURPOSE: We have performed a phase I study of the cytotoxic immunoconjugate CMB-401 in women with epithelial ovarian cancer (EOC). CMB-401 is a directed chemotherapy that comprises a genetically engineered human antibody against polymorphic epithelial mucin, to which is attached covalently two to three molecules, on average, of the cytotoxic antibiotic calicheamicin. The primary objectives of this two-centre study were to identify end-organ toxicities and to establish the maximum tolerated dose (MTD). PATIENTS AND METHODS: Thirty-four patients aged 37-75 years with progressive EOC not amenable to platinum/standard therapy, and with satisfactory WHO performance status (0-2) were recruited. Patients had received a mean of 3.2 previous chemotherapeutic regimens with a median interval since last chemotherapy of 182 days (range 34-1217). Patients received up to four cycles of a dual infusion of 35 mg/m2 hCTMO1 'predose' followed by doses of CMB-401 which were increased for each cohort--a regimen which minimises drug uptake in normal tissues whilst enhancing delivery to the ovarian tumour. CMB-401 dosing commenced at 2 mg/m2 and progressed via seven cohorts to 16 mg/m2. RESULTS: CMB-401 was generally well tolerated. However, transient fever and emesis occurred, necessitating routine prophylaxis, and increasingly significant malaise was reported as the dose increased. WHO grade 3-4 toxicities, irrespective of causality, included: anaemia 21%, granulocytopenia 9%, thrombocytopenia 9%, liver transaminases 3%, sepsis 3%, haemorrhage 6%, nausea/vomiting 76%; pulmonary 6%, and conscious state/somnolence 6%. The MTD was reached at 16 mg/m2. During the study four patients had a greater than 50% reduction in CA125, and three patients had radiological evidence of reduction in tumour bulk. CONCLUSIONS: CMB-401 appears to have an acceptable toxicity profile with demonstrable activity against EOC.

Measurement of community beliefs about colorectal cancer.

Few educational campaigns have focused on bowel cancer, though studies have indicated that members of the community need and want current information about relevant issues. In order to facilitate research in this area, reliable and valid measures of community attitudes are needed. Content validity of a survey instrument was obtained through use of a Delphi process with Directors of Education from the Australia Cancer Council and focus group discussions with informed members of the public. The subsequent survey of community perceptions about colorectal cancer included a broad range of content areas related to the risk of bowel cancer, preventing and coping with bowel cancer and beliefs about susceptibility and severity. The construct validity of these content areas was investigated by use of a factor analysis and confirmation of an association with related predictor variables. Two measures related to personal influence and anticipated coping responses showed favourable psychometric properties, including moderate to high levels of internal consistency and test-retest reliability. A test of the concurrent validity of these measures requires further development of instruments related to colorectal cancer or adaptation of measures from other areas of health research.

Treatment of persistent trophoblastic disease later than 6 months after diagnosis of molar pregnancy.

Of 4257 patients with gestational trophoblastic disease (GTD) registered between 1986 and 1996 with the Trophoblastic Screening and Treatment Centre, Sheffield, 231 women required chemotherapy; 28 were treated 24 weeks or more after the initial evacuation of products of conception. In 18 patients late treatment was a result of a predetermined watch and wait policy on the part of the Centre; these patients formed the study group. Patients were identified from the Centre's computer database. The time interval from first evacuation (diagnosis) to start of chemotherapy was calculated for each patient. Hospital records were reviewed when the interval of observation was 24 weeks or greater to determine patient characteristics, treatment and outcome. Eighteen women were treated 'late' (according to Centre policy), with a median age of 30 years (range 21-57 years). The interval from diagnosis to treatment ranged from 24 to, in one case, 56 weeks (median 33 weeks). Fourteen of 18 women had complete moles, 3/18 had partial moles and one had unclassified disease. All women had low-risk disease and were treated with single-agent methotrexate; 17 were cured with this regimen, one also required salvage chemotherapy. In conclusion, where a successful surveillance programme is in operation for GTD, a wait and watch policy can be adopted without compromising patients whose definitive treatment is commenced more than 6 months after the initial diagnosis.

Placental site trophoblastic tumour: a rare but potentially curable cancer.

Placental site trophoblastic tumour (PSTT) is a rare form of gestational trophoblastic disease (GTD). We have conducted an analysis of all cases of PSTT managed at the Trophoblastic Disease Screening and Treatment Centre, Sheffield, from 1984 to 1996. During this time we received 4,988 registrations for GTD and managed seven cases of PSTT. A large range of interval between antecedent pregnancy and presentation was observed - the most common presenting symptoms being irregular vaginal bleeding with or without preceding amenorrhoea. Three out of seven patients had disease confined to the uterus at diagnosis and were successfully treated by hysterectomy alone. Two out of seven patients had pulmonary metastases in addition to uterine tumour and were treated with combination chemotherapy--both are alive and well. Of the remaining two patients one had distant and the other loco-regional metastases and both died despite numerous therapeutic interventions.

Ubiquitous overexpression of CuZn superoxide dismutase does not extend life span in mice.

Oxidative damage has been implicated in the aging process and in a number of degenerative diseases. To investigate the role of oxygen radicals in the aging process in mammals, the life spans of transgenic mice on a CD-1 background expressing increased levels of CuZn superoxide dismutase (CuZnSOD), the enzyme that metabolizes superoxide radicals, were determined. Homozygous transgenic mice with a two- to five-fold elevation of CuZnSOD in various tissues showed a slight reduction of life span, whereas hemizygous mice with a 15- to 3-fold increase of CuZnSOD showed no difference in life span from that of the nontransgenic littermate controls. The results suggest that constitutive and ubiquitous overexpression of CuZnSOD alone is not sufficient to extend the life spans of transgenic mice.

A retrospective comparison of current and proposed staging and scoring systems for persistent gestational trophoblastic disease.

It is widely accepted that patients with persistent gestational trophoblastic disease (GTD) are best managed by stratifying their treatment according to recognized adverse prognostic features. We retrospectively evaluated 201 patients who had received chemotherapy for persistent low or high risk GTD at the Sheffield Center according to criteria used in established and proposed WHO scoring and FIGO staging systems to identify the numbers of patients in each risk category, the treatment they would receive, chemotherapy resistance patterns, and eventual outcome. The systems were broadly comparable and chemotherapy resistance was always greater in the high-risk groups (at least 33%), particularly when patients were divided into just two risk categories. Such a categorization led to fewer patients (less than 15%) falling into high-risk groupings, but outcome was not compromised. Mortality (3 deaths) was associated with high risk categorization in all systems evaluated. A proposal to combine revised FIGO staging and modified WHO scoring systems, with two risk groupings, is realistic and practicable.

The potential of melanoma antigen expression in cancer therapy.

A potential new therapy for cancer is active specific immunotherapy with melanoma antigen (MAGE) gene products. The MAGE gene family comprizes a series of 12 closely related genes, some of which have been shown to be expressed in a variety of tumours of different histological origin. Peptides encoded by the MAGE genes are targets for specific immunotherapy as they are presented in association with human leucocyte antigen class I molecules and are recognised by cytotoxic T lymphocytes. This article reviews the discovery, development, role and therapeutic potential of MAGE tumour-associated antigens. Knowledge in this field of study is in its early stages. Future advances can be anticipated in term of defining therapeutic relevance, antigen detection and discovery of related genes.

Beliefs about smoking cessation among out-of-school youth.

Although the majority of adolescents in the 13-18 age range are at school, there is a need to target specific groups of young smokers such as unemployed youth. For those young people who are not at school, few directed programs are available in either prevention or cessation and information is needed about the design and delivery of appropriate programs for this population. This report presents the results from a survey of unemployed youth and students at vocational colleges about various aspects of smoking cessation. The majority of out-of-school youth smokers had not tried to quit, but 52% were contemplating action to quit. Only a quarter of the smokers had quit for more than a week. Few young smokers would use a recognised program though more females would change to a lower nicotine brand, quit with the help of a friend or participate in a group quit program. The method of quitting most would recommend to peers is 'use of will power'. Incentives to quit were attractive to only a third of the smokers, and many enhancing and inhibiting factors for participation in programs were identified. In particular, efforts to quit increased their confidence in quitting, supporting the need to assist those who are contemplating action to quit. Programs need to incorporate input from youth and be tailored for them but not necessarily for different groups such as non-secondary school students and unemployed youth.

The presentation and management of post-partum choriocarcinoma.

Post-partum choriocarcinoma is a rare complication of pregnancy. We have analysed a series of nine consecutive patients presenting with choriocarcinoma after a full-term non-molar pregnancy. All patients were managed at the Supraregional Trophoblastic Disease Screening and Treatment Centre at Weston Park Hospital, Sheffield between 1987 and 1996. All presented with persistent primary or secondary post-partum haemorrhage. Treatment with multiagent chemotherapy (initially methotrexate, dactinomycin and etoposide) was successful in all cases. Early diagnosis is important because this rare condition is potentially curable with appropriate chemotherapy.

Gestational trophoblastic disease: does central nervous system chemoprophylaxis have a role?

In the UK there are standardized surveillance procedures for gestational trophoblastic disease. However, there are differences in practice between the two treatment centres in terms of definition of persistent gestational trophoblastic disease, prognostic risk assessment and chemotherapeutic regimens. The role of prophylactic chemotherapy for cerebral micrometastatic disease in persistent gestational trophoblastic disease is unclear. We have analysed the outcome of 69 patients with lung metastases who elsewhere might have received prophylactic intrathecal chemotherapy. Of the 69 patients, 67 received intravenous chemotherapy only. The other two patients had cerebral metastases at presentation. One patient who received only intravenous chemotherapy subsequently developed a cerebral metastasis, but this patient's initial treatment was compromised by non-compliance. This experience supports our current policy of not treating patients with pulmonary metastases, without clinical evidence of central nervous system (CNS) involvement, with prophylactic intrathecal therapy.

Goblet cell-specific expression mediated by the MUC2 mucin gene promoter in the intestine of transgenic mice.

The regulation of MUC2, a major goblet cell mucin gene, was examined by constructing transgenic mice containing bases -2864 to +17 of the human MUC2 5'-flanking region fused into the 5'-untranslated region of a human growth hormone (hGH) reporter gene. Four of eight transgenic lines expressed reporter. hGH message expression was highest in the distal small intestine, with only one line expressing comparable levels in the colon. This contrasts with endogenous MUC2 expression, which is expressed at its highest levels in the colon. Immunohistochemical analysis indicated that goblet cell-specific expression of reporter begins deep in the crypts, as does endogenous MUC2 gene expression. These results indicate that the MUC2 5'-flanking sequence contains elements sufficient for the appropriate expression of MUC2 in small intestinal goblet cells. Conversely, elements located outside this region appear necessary for efficient colonic expression, implying that the two tissues utilize different regulatory elements. Thus many, but not all, of the elements necessary for MUC2 gene regulation reside between bases -2864 and +17 of the 5'-flanking region.

The use of transgenic and mutant mice to study oxygen free radical metabolism.

To distinguish the role of Mn superoxide dismutase (MnSOD) from that of cytoplasmic CuZn superoxide dismutase (CuZnSOD), the mouse MnSOD gene (Sod2) was inactivated by homologous recombination. Sod2 -/- mice on a CD1 (outbred) genetic background die within the first 10 days of life (mean, 5.4 days) with a complex phenotype that includes dilated cardiomyopathy, accumulation of lipid in liver and skeletal muscle, metabolic acidosis and ketosis, and a severe reduction in succinate dehydrogenase (complex II) and aconitase (a TCA cycle enzyme) activities in the heart and, to a lesser extent, in other organs. These findings indicate that MnSOD is required to maintain the integrity of mitochondrial enzymes susceptible to direct inactivation by superoxide. On the other hand, Lebovitz et al. reported an independently derived MnSod null mouse (Sod2tmlLeb) on a mixed C57BL/6 and 129Sv background with a different phenotype. Because a difference in genetic background is the most likely explanation for the phenotypic differences, the two mutant lines were crossed into different genetic backgrounds for further analyses. To study the phenotype of Sod2tmlLeb mice CD1 background, the Sod2tmlLeb mice were crossed to CD1 for two generations before the -/+ mice were intercrossed to generate -/- mice. The life span distribution of CD1 < Sod2-/- > Leb was shifted to the left, indicating a shortened life span on the CD1 background. Furthermore, the CD1 < Sod2-/- > Leb mice develop metabolic acidosis at an early stage as was observed with CD1 < Sod2-/- > Cje. When Sod2tmlCje was placed on C57BL/6J (B6) background, the -/- mice were found to die either during midgestation or within the first 4 days after birth. However, when the B6 < Sod2 -/+ > Cje were crossed with DBA/2J (D2) for the generation of B6D2F2 < Sod2-/- > Cje mice, an entirely different phenotype, similar to that described by Lebovitz et al., was observed. The F2 Sod -/- mice were able to survive up to 18 days, and the animals that lived for more than 15 days displayed neurological abnormalities including ataxia and seizures. Their hearts were not as severely affected as were those of the CD1 mice, and neurological degeneration rather than heart defect appears to be the cause of death.