Differences between those who panic by day and those who also panic by night.

This study examined the characteristics, correlates, background demographic, and personality variables associated with panic among those who panic exclusively from a waking state and those who also panic out of sleep. Participants were recruited through advertising in print media and through anxiety/panic support groups. Some group differences in the characteristics of panic and the associations between panic and other variables were found. Specifically, levels of anxiety sensitivity were higher, panic duration was longer, and panic was less strongly related to catastrophic cognitions for the group that experienced nocturnal panic. These differences are cautiously interpreted as not supporting a "strong" cognitive theory of panic initiation.

Safety and efficacy of low anterior en bloc resection as part of cytoreductive surgery for patients with ovarian cancer.

OBJECTIVE: To examine the feasibility and safety of a low anterior resection of the rectosigmoid plus adjacent pelvic tumour as part of primary cytoreduction for ovarian cancer. METHODS: This study included 65 consecutive patients with primary ovarian cancer who had debulking surgery from 1996 through 2000. All patients underwent an en bloc resection of ovarian cancer and a rectosigmoid resection followed by an end-to-end anastomosis. Parameters for safety and efficacy were considered as primary statistical endpoints for the aim of this analysis. RESULTS: Postoperative residual tumour was nil, <1 cm, and >1 cm in 14, 34, and 14 patients, respectively. The median postoperative hospital stay was 11 days (range, 6 to 50 days). Intraoperative complications included an injury to the urinary bladder in one patient. Postoperative complications included wound complications (n = 14, 21.5%), septicemia (n = 9, 13.8%), cardiac complications (n = 7, 10.8%), thromboembolic complications (n = 5, 7.7%), ileus (n = 2, 3.1%), anastomotic leak (n = 2, 3.1%), and fistula (n = 1, 1.5%). Reasons for a reoperation during the same admission included repair of an anastomotic leak (n = 1), postoperative hemorrhage (n = 1), and wound debridement (n = 1). Wound complications, septicemia, and anastomotic leak formation were more frequent in patients who had a serum albumin level of < or =30 g/L preoperatively. There was one surgically related mortality in a patient who died from a cerebral vascular accident 2 days postoperatively. CONCLUSIONS: An en bloc resection as part of primary cytoreductive surgery for ovarian cancer is effective and its morbidity is acceptably low.

Hormone replacement therapy and risk of epithelial ovarian cancer.

It has been suggested that oestrogen replacement therapy is associated with risk of epithelial ovarian cancer of the endometrioid type. Using data from an Australian population-based case-control study, the relation between unopposed oestrogen replacement therapy and epithelial ovarian cancer, both overall and according to histological type, was examined. A total of 793 eligible incident cases of epithelial ovarian cancer diagnosed from 1990 to 1993 among women living in Queensland, New South Wales and Victoria were identified. These were compared with 855 eligible female controls selected at random from the electoral roll, stratified by age and geographic region. Trained interviewers administered standard questionnaires to obtain detailed reproductive and contraceptive histories, as well as details about hormone replacement therapy and pelvic operations. No clear associations were observed between use of hormone replacement therapy overall and risk of ovarian cancer. Unopposed oestrogen replacement therapy was, however, associated with a significant increase in risk of endometrioid or clear cell epithelial ovarian tumours (odds ratio (OR) 2.56; 95% confidence interval (CI) 1.32-4.94). In addition, the risk associated with oestrogen replacement therapy was much larger in women with an intact genital tract (OR 3.00; 95% CI 1.54-5.85) than in those with a history of either hysterectomy or tubal ligation. Post-menopausal oestrogen replacement therapy may, therefore, be a risk factor associated with endometrioid and clear cell tumours in particular. Additionally, the risk may be increased predominantly in women with an intact genital tract. These associations could reflect a possible role of endometriosis in the development of endometrioid or clear cell ovarian tumours.

The treatment of uterine papillary serous carcinoma (UPSC): are we doing the right thing?

Tay EH, Ward BG. The treatment of uterine papillary serous carcinoma (UPSC): are we doing the right thing? In an earlier study(1) of 21 patients with uterine papillary serous carcinoma (UPSC), Ward et al. found a poor 3-year survival, even for patients with surgically documented localized disease, and a high rate of recurrence outside the field of treatment. Eight years later, we performed a retrospective study on 67 patients who were treated initially by surgery, which included the 21 patients previously reported, to evaluate any changes in the management approach since 1990 and its impact on the survival of such patients. The clinical characteristics of patients treated before and after 1990 were similar. However, after 1990, more patients had omentectomy and complete surgical staging (42% vs. 17%); chemotherapy was more widely used (63% vs. 33%); all chemotherapies were platinum-based regimens and less radiotherapy was administered (47% vs. 83%). The overall 3-year survival was 43% and 5-year survival was 35%, with a median survival period of 31 months. There was no significant difference in the survival outcome between patients managed before and after 1990, after adjusting for stage and spread of disease. Based on the results of this retrospective study, it appears that the current treatment strategy has not resulted in an improvement in the survival of patients with UPSC.

Fertility and ovarian function after conservative surgery for germ cell tumours of the ovary.

Malignant ovarian germ cell tumours (MOGCT) principally occur in girls and young women and are generally unilateral. Effective combination chemotherapy with conservative surgery has seen a dramatic improvement in survival rates. This increase has shifted the focus to long-term fertility and reproductive outcome. The present study describes 45 patients with MOGCT treated with conservative surgery to preserve fertility, with or without the addition of chemotherapy. The age range was 10 to 32 years with a mean of 20 years. The majority of the subjects had Stage 1 tumours; 44 underwent unilateral salpingo-oophorectomy and 1 patient ovarian cystectomy. Adjuvant chemotherapy was administered in 29 patients. Overall mean follow-up was 58.7 months. There were 4 recurrences and 2 deaths. Survival of those with Stage 1 disease was 97% and for advanced stages 87%. During chemotherapy 50% became amenorrhoeic but 96% resumed normal menstrual function on completion. Seven healthy babies were recorded in the chemotherapy group and no documented birth defects occurred in any of these. There was no case of persistent infertility; 3 patients experienced temporary problems. It is concluded that conservative fertility-sparing surgery is the treatment of choice in these young women and advanced disease is not necessarily a contraindication. The majority can anticipate normal menstrual function and fertility.

Microinvasive adenocarcinoma of the cervix.

We evaluated the management of patients with microinvasive adenocarcinoma of the cervix (MIAC), in particular, to determine the place of conservative surgery, and determine if the FIGO classification for MIAC is valid and equivalent to the classification as it applies to microinvasive squamous cancer. A review was undertaken of the database of the Queensland Centre for Gynaecological Cancer (QCGC) from January, 1986 to October, 1998. The records of all patients recorded as having MIAC were retrieved. Microinvasion was defined according to the 1995 FIGO classification as a depth of invasion of no greater than 5 mm and a horizontal dimension of no greater than 7 mm 30 patients were found to have been treated for MIAC. The vast majority (29) were asymptomatic, disease being discovered at the time of routine Papanicolaou smear. There was a 43% incidence of coexisting squamous intraepithelial neoplasia. Multifocal disease was found in 17% of patients and lymph-vascular positivity in 7%. Eighteen patients were treated with radical surgery and 13 with conservative surgery. There were no recurrences over a follow-up interval of 3-116 months. Of the 18 patients treated with radical surgery, none was found to have occult microscopic disease in the parametria or nodal metastases. A total of 27 ovaries were removed, all of which were free of disease. In this small study, MIAC appears to behave in a manner similar to the squamous equivalent. The results provide some justification for the FIGO classification of a microinvasive glandular neoplasm of the cervix. There is some support for a role for conservative surgery in managing this condition, but there is insufficient worldwide experience to make definitive recommendations.

Antibodies reactive with the protein core of MUC1 mucin are present in ovarian cancer patients and healthy women.

Antibodies reactive with peptide epitopes on the core protein of MUC1 epithelial mucin have been demonstrated in some patients with adenocarcinomas. Because these epitopes can be exposed on MUC1 in the serum of healthy women, we measured concentrations of MUC1-reactive antibodies in the serum of healthy pregnant and non-pregnant women, and in patients with benign and malignant ovarian tumours. Antibodies were measured in an enzyme-linked immunosorbent assay utilising a synthetic peptide corresponding to a 105-amino-acid segment of the MUC1 tandem repeat region (5.25 repeats). MUC1-reactive antibodies were always of an IgM isotype and concentrations were highest in young healthy women and declined progressively with age (P=0.0006) concomitantly with increasing serum MUC1 levels (P=0.003). Regardless of age, antibody levels were lower in cancer patients than in healthy women (P<0.0001), but MUC1 levels were much higher in cancer patients (P<0.0001). Although high antibody levels were associated with greater survival in ovarian cancer (P=0.015), multivariate regression analysis showed that this was not a significant independent prognostic indicator after consideration of the International Federation of Gynaecology and Obstetrics (FIGO) stage, histological type, serum MUC1 levels and age. Serial measurement of MUC1 and MUC1 antibodies during treatment in 18 patients with ovarian cancer and throughout pregnancy in 10 women showed a negative correlation between alterations in MUC1 and MUC1 antibodies. These results show that MUC1-peptide-reactive antibodies are present in the serum of healthy women and women with cancer and that they probably form immune complexes with MUC1, but provide no evidence for an augmentation of the humoral immune response to MUC1 in ovarian cancer

No evidence for microsatellite instability from allelotype analysis of benign and low malignant potential ovarian neoplasms.

UNLABELLED: The genetic events that lead to the development of benign and low malignant potential (LMP) tumors from normal ovarian surface epithelium are not well understood. In contrast to invasive ovarian neoplasms, loss of heterozygosity (LOH) is not common in these tumors except on the X chromosome, but one report has suggested that an alternative genetic mechanism, microsatellite instability (MSI), might be an important pathogenic mechanism for LMP ovarian tumors. OBJECTIVE: To determine the frequency of MSI in LMP tumors and to detect novel regions of LOH in benign and LMP ovarian tumors. METHODS: Sixty-nine microsatellite markers were analyzed in 23 benign and 31 LMP ovarian tumors. RESULTS: No evidence of MSI was found in any of the tumors studied, nor were any novel regions of LOH identified. CONCLUSIONS: This suggests that new approaches may be necessary to understand the genetic basis of benign and LMP ovarian neoplasms since neither LOH nor MSI appears to play a major role.

Peritoneal fluid from ovarian cancer patients stimulates MUC1 epithelial mucin expression in ovarian cancer cell lines.

The MUC1 epithelial mucin is a transmembrane glycoprotein that is frequently but variably over-expressed by adenocarcinomas. It is used as a diagnostic serum tumour marker and is a candidate target for tumour immunotherapy. Peritoneal fluid (PF) samples from ovarian cancer patients were investigated for their ability to modulate MUC1 expression in 6 ovarian cancer cell lines which showed a range from very low to high endogenous MUC1 expression. Cell lines were cultured in 20% PF for 4 days, fixed in situ and MUC1 assayed by ELISA. MUC1 expression was stimulated by some PF samples in 5 of 6 lines tested. MUC1 expression in the PE04 cell line (very low endogenous expression) was increased by 35 of 36 PFs tested (p < 0.05); stimulation varied between PFs but was greater than with 100 IU/mL hu-r-gamma-interferon. Western blotting confirmed the stimulation of MUC1 in PE04 cells and FACS showed an increase in the proportion of cells expressing MUC1. The active factor was partially purified by gel filtration and was shown to stimulate PE04 cells in a dose-dependent manner. Concentrations of IL1beta, IL4, IL6, IL8, IL10, TNF-alpha, TGF-beta and GM-CSF were often very high in PF and varied substantially between different PF samples but did not correlate with the degree of MUC1 stimulatory activity.

Progesterone stimulates production and secretion of MUC1 epithelial mucin in steroid-responsive breast cancer cell lines.

The effects of oestrogen and progesterone on expression of the MUC1 epithelial mucin were examined in MCF7 and ZR-75-1 breast cancer cells grown in steroid-free medium. Oestrogen caused an increase in cell growth and both cellular and secreted MUC1 in both cell lines. However, after correcting for increases in cellular protein, there was no clear changes. Progesterone, in combination with oestrogen, caused significant increases (over 2-fold, P<0.01) in cellular and secreted MUC1 when compared with oestrogen alone in both cell lines despite no or small increases in cellular protein. Growth of ZR-75-1 cells in a competitive inhibitor of O-glycosylation demonstrated that the increased detection by ELISA was not due to altered glycosylation. Progesterone may modulate expression of MUC1 in steroid-responsive breast cancer cells.

Early steps in the biosynthesis of MUC2 epithelial mucin in colon cancer cells.

Expression of the MUC2 mucin has been demonstrated in normal gastrointestinal and respiratory epithelium and in carcinomas of the gastrointestinal and respiratory tracts, breast, ovary, and bladder using RNA probes and (or) monoclonal antibodies reactive with peptide epitopes on the 23 amino acid tandem repeat. Mouse monoclonal antibodies 4F1 and 3A2 were previously obtained by immunization with mucin derived from the LS174T colon cancer cell line and a KLH conjugate of a synthetic MUC2 VNTR peptide. These antibodies react with distinct epitopes on synthetic VNTR peptides and with normal and malignant epithelial tissues. In the present study, we examined the biosynthesis of MUC2 in LS174T colon cancer cells, using these antibodies to immunoprecipitate labelled mucin. A very high molecular mass protein was immunoprecipitated following 1 min pulse labelling with [3H]threonine and [3H]proline. A slight increase in molecular mass was observed over the next 16 min; however, unlike the MUC1 mucin, there was no large difference in apparent molecular mass between the MUC2 protein precursor and fully processed mucin using separation by SDS-PAGE. O-Glycosylation began within 1 h of synthesis of the protein core. Mucin secretion into the culture medium was detected in the 2nd hour following synthesis and was largely completed within 4 h of synthesis. Secreted mucin was far less reactive with these monoclonal antibodies than the precursor protein.

Heterogeneity in production, secretion and glycosylation of MUC1 epithelial mucin by primary cultures of ovarian carcinoma.

The MUC1 mucin produced by many adenocarcinomas has functions that may be of biological significance and is of importance clinically as a serum tumour marker and as a candidate target for immunotherapy. Previous studies of MUC1 production by ovarian cancers have been limited to immunohistochemical studies of tumour specimens and in vitro studies using cell lines. In this study the biosynthesis, secretion and glycosylation of MUC1 were studied in primary cultures of tumour cells obtained from 35 patients with stage 3 ovarian cancer. Although 34 of the 35 tumours produced MUC1 in vitro, the concentrations of intracellular and secreted MUC1, as measured by an ELISA using core protein-reactive antibodies, varied over a wide range. In addition, the amount of secreted MUC1 as a proportion of the intracellular concentration varied between tumours. Pulse/chase amino acid labelling studies of MUC1 biosynthesis also demonstrated variation in secretion rates. Multivariate regression analysis showed that of the variables tumour size, histological type, grade, ploidy status and intracellular and secreted MUC1 concentrations in vitro, only mucin secretion rate was significantly associated with serum mucin concentrations (p < 0.001). Culture of tumour cells for 4 days in the presence or absence of a competitive inhibitor of O-glycosylation, BAG, showed that the degree of glycosylation of MUC1 varied between tumours and that under-glycosylation was not correlated with production or secretion rates. Our study has shown heterogeneity in the production, secretion and glycosylation of MUC1 and a strong correlation between the secretion rate in vitro and the concentration in the serum of patients.

CA15-3, CASA, MSA, and TPS as diagnostic serum markers in breast cancer.

This is the first comparison of the three mucin based tests CA15-3, CASA, and MSA, and the cytokeratin-related TPS assay in breast cancer. The mucin markers were superior to TPS in receiver-operator analysis, though no marker was of use in the diagnosis of malignancy due to low sensitivity. Using cutpoints that gave 95% specificity in benign disease (n = 83), corresponding sensitivities in pre-treatment breast cancer (n = 123: 13 in situ, 54 stage I, 45 stage II, 4 stage III, 7 stage IV) were 17% (CA15-3), 16% (CASA), 13% (MSA), and 8% (TPS), with a strong relationship between marker levels and disease stage. These assays did not always detect the same patients, and the use of CA15-3 combined with CASA gave the highest sensitivity (23%), though this was not significantly better than the use of CA15-3 alone. Despite detecting similar antigens, these assays can show markedly different responses in some patients, indicating that one mucin-based test cannot be substituted for another.

Predictive value of the combination of serum markers, CA125, CASA and TPS in ovarian cancer.

The serum markers CA125, CASA and TPS were compared, with particular reference to the clinical applications of these tumor markers in the management of patients with ovarian cancer (discrimination of benign and malignant disease; indicating prognosis; predicting preclinical recurrence), (i) Using recommended cut-off points, CASA (>/=4 U ml-1 and TPS (>/=80 U l-1 showed similar sensitivities in ovarian carcinoma (56% and 57% respectively), though these were lower than with CA125 (85% >/= 35 U ml-1). The combined use of CA125 with either CASA or TPS at higher cut-off points excluding benign disease (CA125> 345 U ml-1; CASA> 6 U ml-1; TPS> 359 U l-1) improved the discrimination of ovarian cancer from benign adnexal masses (100% positive predictive value with 65% of ovarian cancers detected with CA125-CASA, 61% with CA125-TPS vs 46% with CA125 alone). The combined preoperative use of these markers may therefore assist the general gynecologist in avoiding potentially difficult oncologic surgery. (ii) TPS was the best preoperative indicator of prognosis, possibly due to its association with cell proliferation, while CASA was superior as a postoperative prechemotherapeutic prognostic indicator, possibly due to it being a more accurate indicator of residual disease than the other markers, or the surgeons' assessment. Similarly, CASA gave the best differentiation of patients with minimal residual disease (<1 cm) into those with a good or poor prognosis, (iii) CA125 and CASA each detected preclinical recurrence after surgery and adjuvant therapy in seven of 11 patients (mean lead times 4.6 and 3.1 months respectively) while TPS detected four of these patients (mean lead time 2.4 months). The combined use of CA125 with either assay led to the preclinical detection of eight of 11 patients, with the mean lead time increased to 5.3 months with the CA125-CASA combination.

Prognostic significance of MUC1 epithelial mucin expression in breast cancer.

The epithelial mucin produced by the MUC1 gene is present in the apical cell membrane of normal breast epithelial cells and is highly expressed in many breast cancers. Several studies have provided conflicting evidence regarding the relationship between MUC1 expression and survival in breast cancer patients. In this study a detailed immunohistological analysis of MUC1 expression was performed using monoclonal antibody BC2 and was related to other tumor characteristics and patient survival. Patients whose tumors showed MUC1 expression in greater than 75% of tumor cells had significantly poorer disease-free and overall survival (P < .05). The proportion of cells showing cytoplasmic MUC1 expression was prognostically significant, but the proportion of cells that lined gland spaces showing apical membrane staining was of no prognostic significance. A high level of MUC1 expression was significantly associated with the presence of axillary node metastases and estrogen receptors but not with other tumor characteristics.

Effect of interferon-gamma and TNF-alpha on MUC1 mucin expression in ovarian carcinoma cell lines.

In view of the potential uses of cell surface tumour associated antigens in novel anticancer treatment, a study was designed to investigate whether the biological response modifiers interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha) could effect the expression of an epitope on the tumour associated MUC1 epithelial mucin. Four ovarian carcinoma cell lines showing high (OAW42 and GG) and low (JAM and PE01) basal expression of MUC1 were treated with 10-1000 U/mL of IFN-gamma or TNF-alpha for one or five days. Changes in MUC1 expression in cells exposed to IFN-gamma or TNF-alpha were monitored using an ELISA technique with the monoclonal antibody BC2 which reacts with a core protein epitope on the MUC1 mucin, and then corrected for the number of viable cells present. TNF-alpha had little effect on MUC1 expression, but one or five days exposure to IFN-gamma significantly increased MUC1 expression (p < 0.01) in all cell lines including the two cell lines that initially showed little or no expression.

Effect of interferon gamma and tumour necrosis factor alpha on sensitivity to cisplatin in ovarian carcinoma cell lines.

This study aimed to investigate whether the biological response modifiers (BRM) interferon gamma (IFN gamma) and tumour necrosis factor alpha (TNF alpha) could enhance the cytotoxic action of cisplatin on ovarian tumour cells in vitro. The sensitivity of four cell lines (OAW42, GG, JAM and PE01) to drugs and drug combinations was tested by a radiolabelled-thymidine incorporation assay. Cell lines demonstrated a range of sensitivity to cisplatin and the innate cytotoxic effect of each of the BRM. When IFN gamma was used in combination with cisplatin, a significant enhancement of cisplatin toxicity occurred in three of four cell lines. TNF alpha demonstrated such an effect in two cell lines but diminished the toxicity of cisplatin in one cell line. A purely additive effect of the agents may explain the enhanced toxicity of cisplatin in some of these cases. However, in one cell line at least (PEO1), both TNF alpha and IFN gamma demonstrated a clearly synergistic effect with cisplatin. These BRM used in conjunction with cisplatin may provide better antitumour regimen than cisplatin alone in some patients with ovarian cancer, but the response is likely to be heterogeneous between patients.

Randomized prospective intervention study of human cervical wart virus infection.

Between February, 1988, and January, 1991, 222 women with histologically proven cervical wart virus infection without dysplasia were randomized to be managed by 1 of 4 protocols. Group 1 acted as control, Group 2 were asked to use condoms for 6 months, Group 3 underwent local ablative therapy and Group 4 were asked to use condoms after ablative therapy. Assessment at 2 and 3 years of follow-up showed no statistically significant superiority for treatment over observation. Defaulters from follow-up were over 50% by the completion of the study.

Are CASA and CA125 concentrations in peripheral blood sourced from peritoneal fluid in women with pelvic masses?

BACKGROUND: The Cancer associated serum antigen (CASA) and CA125 assays used in the management of ovarian cancer measure distinct high molecular weight glycoproteins. The mechanisms of secretion of these molecules into the peripheral circulation are not clearly understood. METHODS: Concentrations of CASA and CA125 were assessed in peripheral blood, blood from veins draining ovarian and omental tumors, and peritoneal fluid in 20 women with pelvic masses. RESULTS: There was a near perfect correlation between peripheral vein and ovarian vein concentrations for both markers; concentrations in omental veins were higher than in peripheral veins in only a small proportion of cases, whereas the concentration in peritoneal fluid was universally much higher than in blood. CONCLUSIONS: These studies suggest a similar route of entry into the peripheral circulation and a similar half-life for these glycoproteins. These data provide no support for the hypothesis that a significant contribution to CA125 concentrations comes from peritoneal release by mesothelial cells rather than tumor cells, because the relative CA125 concentrations between compartments were similar to those of CASA within patients. The lack of a gradient between CASA levels in peripheral blood and tumor draining veins suggests that the CASA half-life is much longer than that predicted in animal studies. CA125 and CASA in peripheral blood are probably derived from markers secreted into peritoneal fluid and lymph, rather than directly into the bloodstream.

Serum markers CASA and CA 15-3 in ovarian cancer: all MUC1 assays are not the same.

The serum MUC1 markers CASA and CA 15-3 were compared with CA 125 in the serum of patients with ovarian cancer and in pregnant women. Used individually, CASA and CA 15-3 gave sensitivities of 54 and 56% in pre-operative ovarian carcinoma (n = 50), though these were lower than with CA 125 (84%). CASA levels were elevated in 3 women with a negative CA 125, while CA 15-3 was elevated in 2 of these women. The combined use of CA 125 with CASA or CA 15-3 led to the preclinical detection of recurrence in 4/5 patients, with mean lead times of 3.6 and 4.3 months, respectively. Of particular interest was the marked difference in reactivity observed with CASA and CA 15-3 in some patients, despite both assays utilising monoclonal antibodies (MAbs) that react with the MUC1 mucin. CA 15-3 and CASA showed a lower than expected correlation in patients with ovarian cancer (r = 0.70), with some patients having high concentrations of one mucin marker and low concentrations of another. Furthermore, different marker profiles were observed when monitoring the progress of patients with these markers. Marked differences between CA 15-3 and CASA were also observed in the serum of pregnant women (n = 10), where CASA showed marked elevation (mean 33.6 times cutpoint) and CA 15-3 did not (mean 0.88 times cutpoint). These data suggest that the specificities of the MAbs used in these assays affect the glycoform of MUC1 detected, and that it should not be assumed that all MUC1 assays will behave in the same manner.