Simplified staging laparotomy in FIGO stage 1 epithelial ovarian cancer: follow-up and outcomes in south Wales, U.K.

We have conducted a retrospective analysis of FIGO stage 1 ovarian cancer patients in south Wales, who underwent a simplified staging laparotomy without routine nodal sampling and peritoneal biopsies. Patient records from January 2004 to December 2010 were analysed. A total of 116 patients were included in the final analysis. Adjuvant chemotherapy was offered to patients with risk factors for relapse (grade > 1, clear cell histology, or stage > Ia); overall, 89 patients (76.7%) received adjuvant single agent carboplatin (n = 54, 46.5%) or combination chemotherapy (n = 35, 30.2%). After a median follow up of 41 months (range 12-95), 18 patients have relapsed (15.5%), of these 17 had risk factors and 16 had received adjuvant chemotherapy. Eighteen patients have died, of whom 6 of non-cancer related causes without prior relapse. 5-year overall and relapse free survival were 80%. In conclusion, in situations where there are limited resources and operating time constraints, our data suggest that a simplified staging laparotomy approach may be a reasonable compromise in apparently early stage ovarian cancer: this may result in a more aggressive use of chemotherapy, but survival outcomes seem comparable to other series.

Short, natural, and extended photoperiod response in BC2F4 lines of bread wheat with different photoperiod-1 (Ppd-1) alleles.

Flowering is a critical period in the life cycle of flowering plant species, resulting in an irreversible commitment of significant resources. Wheat is photoperiod sensitive, flowering only when daylength surpasses a critical length; however, photoperiod insensitivity (PI) has been selected by plant breeders for >40 years to enhance yield in certain environments. Control of flowering time has been greatly facilitated by the development of molecular markers for the Photoperiod-1 (Ppd-1) homeoloci, on the group 2 chromosomes. In the current study, an allelic series of BC2F4 lines in the winter wheat cultivars 'Robigus' and 'Alchemy' was developed to elucidate the influence on flowering of eight gene variants from the B- and D-genomes of bread wheat and the A-genome of durum wheat. Allele effects were tested in short, natural, and extended photoperiods in the field and controlled environments. Across genetic background and treatment, the D-genome PI allele, Ppd-D1a, had a more potent effect on reducing flowering time than Ppd-B1a. However, there was significant donor allele effect for both Ppd-D1a and Ppd-B1a, suggesting the presence of linked modifier genes and/or additional sources of latent sensitivity. Development of Ppd-A1a BC2F4 lines derived from synthetic hexaploid wheat provided an opportunity to compare directly the flowering time effect of the A-genome allele from durum with the B- and D-genome variants from bread wheat for the first time. Analyses indicated that the reducing effect of Ppd-A1a is comparable with that of Ppd-D1a, confirming it as a useful alternative source of PI.

Republished paper: assessment of doctors' consultation skills in the paediatric setting: the Paediatric Consultation Assessment Tool.

OBJECTIVE: To determine the utility of a novel Paediatric Consultation Assessment Tool (PCAT). DESIGN: Developed to measure clinicians' communication behaviour with children and their parents/guardian, PCAT was designed according to consensus guidelines and refined at a number of stages. Volunteer clinicians provided videotaped real consultations. Assessors were trained to score communication skills using PCAT, a novel rating scale. SETTING: Eight UK paediatric units. PARTICIPANTS: 19 paediatricians collected video-recorded material; a second cohort of 17 clinicians rated the videos. MAIN OUTCOME MEASURES: Itemised and aggregated scores were analysed (means and 95% confidence intervals) to determine measurement characteristics and relationship to patient, consultation, clinician and assessor attributes; generalisability coefficient of aggregate score; factor analysis of items; comparison of scores between groups of patients, consultations, clinicians and assessors. RESULTS: 188 complete consultations were analysed (median per doctor = 10). 3 videos marked by any trained assessor are needed to reliably (r > 0.8) assess a doctor's triadic consultation skills using PCAT, 4 to assess communication with just children or parents. Performance maps to two factors - "clinical skills" and "communication behaviour"; clinicians score more highly on the former (mean (SD) 95% CI 0.52 (0.075)). There were significant differences in scores for the same skills applied to parent and child, especially between the ages of 2 and 10 years, and for information-sharing rather than relationship building skills (2-tailed significance < 0.001). Conclusions The PCAT appears to be reliable, valid and feasible for the assessment of triadic consultation skills by direct observation.

Assessment of doctors' consultation skills in the paediatric setting: the Paediatric Consultation Assessment Tool.

OBJECTIVE: To determine the utility of a novel Paediatric Consultation Assessment Tool (PCAT). DESIGN: Developed to measure clinicians' communication behaviour with children and their parents/guardian, PCAT was designed according to consensus guidelines and refined at a number of stages. Volunteer clinicians provided videotaped real consultations. Assessors were trained to score communication skills using PCAT, a novel rating scale. SETTING: Eight UK paediatric units. PARTICIPANTS: 19 paediatricians collected video-recorded material; a second cohort of 17 clinicians rated the videos. MAIN OUTCOME MEASURES: Itemised and aggregated scores were analysed (means and 95% confidence intervals) to determine measurement characteristics and relationship to patient, consultation, clinician and assessor attributes; generalisability coefficient of aggregate score; factor analysis of items; comparison of scores between groups of patients, consultations, clinicians and assessors. RESULTS: 188 complete consultations were analysed (median per doctor = 10). 3 videos marked by any trained assessor are needed to reliably (r>0.8) assess a doctor's triadic consultation skills using PCAT, 4 to assess communication with just children or parents. Performance maps to two factors--"clinical skills" and "communication behaviour"; clinicians score more highly on the former (mean (SD) 95% CI 0.52 (0.075)). There were significant differences in scores for the same skills applied to parent and child, especially between the ages of 2 and 10 years, and for information-sharing rather than relationship-building skills (2-tailed significance <0.001). CONCLUSIONS: The PCAT appears to be reliable, valid and feasible for the assessment of triadic consultation skills by direct observation.

Characterization of phosphorus sources in rural watersheds.

Correct identification of P sources in rural watersheds is critical for the development of cost-effective measures to combat agriculturally-driven eutrophication. The chemical composition of various storm runoff types (field surface runoff, field drain outfalls, roads, farmyards, and septic tanks) and the receiving streams in three micro (<10 km(2)) watersheds of varying agricultural intensity were monitored over a 2-yr period. Mean weekly stream soluble reactive phosphorus (SRP) and total phosphorus (TP) concentrations increased from 29 and 69 microg L(-1), respectively in the watershed with the lowest intensity agriculture to 382 and 503 microg L(-1), respectively in the watershed with high intensity agriculture and a village sewage treatment works. Concentrations of TP in storm runoff varied by up to two orders of magnitude reflecting the complex origins, routing, and composition of contributing source areas. Application of the DESPRAL test suggested field runoff TP concentrations were influenced by both P and organic matter in soil. However, runoff from impervious surfaces (farmyard and roads), and/or influenced by septic tank discharges, was significantly more concentrated (0.08-16 mg TP L(-1), mean >>1 mg L(-1)) than surface and subsurface runoff from cultivated land and pasture (0.02-3.6 mg TP L(-1), mean <1 mg L(-1)), and/or contained a significantly greater proportion (>50% vs. <50%) of P in dissolved forms. It is concluded that P sources associated with the functioning of rural communities (impervious surfaces, detergents, and wastewater) may be more ecologically relevant than those associated with agriculture and should be better quantified and controlled to avoid localized eutrophication impacts.

Survival in ovarian cancer in Wales: Prior to introduction of all Wales guidelines.

The objective of the study was to review referral practice, overall management, and survival in women with suspected ovarian cancer in Wales. This study was done prior to introduction of cancer management guidelines in the region. A confidential study questionnaire was sent to 20 participating hospitals. Data on 287 consecutive women with suspected ovarian cancer were collected, of which 250 women underwent primary laparotomy. Information was obtained on referral pattern, preoperative investigations, place of primary surgery, specialty of the primary surgeon, surgical parameters recorded at the time of operation, a final overall stage, adjuvant treatment, and survival outcome. There was a wide variation in referral practice and management of ovarian cancer in Wales. Stage of the disease, attempt at optimal debulking, residual disease, management by a cancer centre multidisciplinary team, and platinum-based chemotherapy were associated with improved overall survival and progression-free survival. More women were alive if managed in the cancer centre at 1 and 3 year after diagnosis (P = 0.022). This study has highlighted the acute issue of the standards of clinical care in the area of ovarian cancer management and will emphasize the implementation of better care pathways for ovarian cancers.

Teaching and learning consultation skills for paediatric practice.

Effective consultations with patients and their families are important for patient satisfaction, adherence to treatment, and recovery from illness. Communication problems among health professionals are common. Fortunately, the skills of effective communication can be taught and learned. This paper highlights evidence based approaches to teaching these skills with minimal resources.

Screening for familial ovarian cancer--management and outcome of women with moderate to high risk of developing ovarian cancer.

Five percent to ten percent of ovarian cancers are hereditary. Individual genetic risk of developing ovarian malignancy is discussed in women. Currently, prophylactic surgery is advised to women with a moderate to high risk of developing ovarian cancer. Workload and outcome of the multidisciplinary familial ovarian screening clinic in South Wales were assessed. This was an observational study of 145 women registered with the Familial Ovarian Screening Clinic between January 1998 and December 2003. The data were retrieved from the medical notes. Yearly follow-ups were investigated with a transvaginal scan and CA125 level. Post-surgery women were followed up with yearly CA125 estimations: 46.9% fell into moderate-risk and 50.3% into high-risk category. The median age was 42 (SD 10.4), 71.7% were pre menopausal, and 10.3% had a personal history of breast cancer and 1.4% colon cancer. Whereas 36.5% opted for surgery, the remaining women (but two) opted for annual follow-up. Histology of the women who had surgery showed three cases of malignancies (fallopian tube carcinoma, atypical ovarian epithelial cells, and metastatic breast cancer). Seven women developed breast cancer during the observation period. The follow-up period is too short to come to a final conclusion as to the benefits of yearly screening in this group of women. In our series, a significant number of patients developed malignancies, despite prophylactic surgery.

Association between glutathione-S-transferase GSTP1 genotypes, GSTP1 over-expression, and outcome in epithelial ovarian cancer.

Ovarian cancer accounts for the majority of deaths from gynaecological malignancy, and polymorphisms in genes encoding the glutathione-S-transferase (GST) GSTP1 detoxifying enzymes may lead to variation in detoxification of carcinogens. We describe a study involving 81 women with invasive epithelial ovarian cancer. A number of important clinical variables and outcome data were obtained. GSTP1 genotyping was undertaken using PCR-based techniques, and GSTP1 expression was quantified using immunohistochemistry (IHC). A Cox's proportional hazard regression model was used to analyze the effects on outcome. We also independently examined 11 women with borderline or low malignant potential (LMP) tumors using IHC only. The mean age of the women was 61.5 years +/- 12 (1 SD) (range 36-88 years), the median overall survival was 26 months, and median progression free interval (PFI) 21 months. There was a significant association between GSTP1 (Val(104)/Val(104)) genotypes, and reduced survival (P = 0.05) and the GTP1 (Ile(104)/Val(104)) genotype appeared to have the best outcome (HR = 0.34, P = 0.045, 95% CI = 0.12-0.98). There was no significant association between the GSTP1 genotypes and any clinico-pathological parameters; there were also no associations between GSTP1 genotypes and response to postoperative chemotherapy. Specific nuclear GSTP1 over-expression was associated with less residual disease (P = 0.05); specific cytoplasmic GSTP1 over-expression with more favourable performance status (P = 0.014)). We found that 10/11 (91%) of the LMP (borderline) tumors over-expressed nuclear GSTP1 compared to only 52% of the invasive tumors (chi(2) ((1)) = 5.95, P = 0.015). There was no significant association between the level of GSTP1 expression and response to postoperative chemotherapy. The overall level of GSTP1 expression and the subcellular localization of GSTP1 expression were not associated with either survival or PFI. There was a significant association between the GSTP1 (Ile(104)/Ile(104)) genotypes and increased overall GSTP1 expression (P = 0.049), and the GSTP1 (Ile(104)/Val(104)) genotypes and reduced overall GSTP1 expression (P = 0.046). We speculate that GSTP1 Ile(104)/Val(104) genotypes are associated with improved outcome because the protein/enzyme, which is expressed, may provide a better balance between the effects of detoxification of carcinogens and the effects of metabolism of chemotherapy agents. In addition, over-expression of nuclear GSTP1 appears to be associated with more favorable ovarian tumor characteristics. In our preliminary study, we also reported a relationship between overall GSTP1 expression and certain GSTP1 genotypes. As far as we are aware, this is the first time that a relationship between the GSTP1 genotypes, GSTP1 expression and outcome has been described in ovarian cancer. Whether the genotype directly determines GSTP1 expression is at present unclear and the precise mechanism of this interaction is unknown.

The prevalence of anti-acetylcholinesterase antibodies in autoimmune disease.

A robust and precise enzyme linked immunosorbent assay (ELISA) with proven sensitivity and specificity has been employed to detect human antibodies (allogenic/autogenic) to human acetylcholinesterase (AChE). The sensitivity of the method has been established using mouse monoclonal antibodies (0.8 ng/ml) and uniquely, human sera positive for anti-Yt(a) allogenic antibodies, to one phenotypic form (most common) of human AChE. The latter was also used as the positive human control to ensure functionality of the assay. The ELISA method was used to establish a normal distribution curve for absorbance values employing sera from healthy blood donors Subsequently, the ELISA was employed to investigate the prevalence of anti-AChE antibodies in patients with confirmed autoimmune disease and patients with non-autoimmune thyroid disease (diseased control). The results indicate that there is not a high prevalence of anti-AChE antibodies in patients with confirmed autoimmune disease. The lack of anti-AChE autoantibodies in patients' with clinically apparent Graves' ophthalmopathy, mitigates against there being a causal role of such antibodies in Graves' associated eye disease.

The role of clinical follow up in early stage cervical cancer in South Wales.

OBJECTIVE: To assess the effectiveness of clinical follow up after primary surgery for early stage cervical cancer. DESIGN: Retrospective analysis of clinical follow up after radical hysterectomy and node dissection for early stage cervical cancer. SETTING: Gynaecological Oncology Cancer Centre. SAMPLE: Two hundred and ninety-one patients who underwent surgery for cervical cancer. METHODS: Follow up data were collected retrospectively from hand-searched patients notes, as well as a computerised database (Information System for Clinical Organisation [ISCO]). The data were analysed using the SPSS for windows (SPSS, Chicago, Illinois) statistics package, using chi2, Kaplan-Meier life tables and Cox Linear regression analysis. MAIN OUTCOME MEASURES: To determine whether routine follow up was useful for detecting early recurrent disease. RESULTS: Two hundred and ninety-one patients treated by radical hysterectomy and node dissections were followed up. The cumulative five-year survival for all cases in our series was 80% and 53/291 patients (18.2%) were found to have recurrent disease. The median period from surgery to recurrence was 17.6 months (3.0-60.0). Seven patients with recurrence were detected at a routine follow up examination, and two out of seven of the patients were asymptomatic. Detection of the recurrence on routine follow up was not an independent prognostic factor for survival when compared with age, stage and whether the patient received post-operative adjuvant therapy. CONCLUSIONS: Routine follow up in patients following radical hysterectomy and node dissection for early stage cervical cancer is not a sensitive way of detecting recurrent disease, as a high proportion of patients were symptomatic at the time of detection. As there are other reasons for follow up, we propose alternative methods of structuring the programme.

Follow-up after negative large loop excision of the transformation zone (LLETZ) of the cervix.

We performed a retrospective analysis of 204 patients who underwent large loop excision of the transformation zone (LLETZ) to determine whether women who have a negative LLETZ (no cervical intra-epithelial neoplasia (CIN) present) are at a lower risk of developing further abnormal cytology or CIN than women whose LLETZ is positive (CIN present). Overall 69 of the LLETZ samples were negative (34%) and 135 were positive (66%). The mean duration of negative cytology during follow up was 25.4 months (negative LLETZ) and 21.2 months (positive LLETZ) (P=0.03). In the negative LLETZ group, cytology did not miss any cases of persistent CIN at the 6-month follow-up visit and 39 repeat punch biopsies were all negative. There were 3/69 cases (4.3%) in the negative LLETZ group and 13/135 (9.6%) in the positive LLETZ group of persistent disease (CIN diagnosed at or as a result of the 6-month follow-up). Following a negative 6-month review, one woman developed an abnormal smear in the negative LLETZ group (1/66=1.5%) compared with 10 women (10/122=8.1%) in the positive LLETZ group. Recurrent CIN (CIN subsequently diagnosed following a negative 6-month review) was seen in 0/69 cases (0%) in the negative LLETZ group and 4/135 (3.2%) in the positive LLETZ group. We conclude that women who undergo a negative LLETZ may represent a low-risk group for developing further cytological and histological abnormalities.

Usefulness of computed tomography and magnetic resonance in fulminant invasive fungal rhinosinusitis.

Fulminant invasive fungal rhinosinusitis is an aggressive, destructive process most commonly affecting the immunocompromised host. Although frequently fatal, prognosis is related directly to early recognition and aggressive treatment. Various reports advocate computed tomography (CT) scanning as the study of choice in evalucating suspected invasive fungal disease, reserving magnetic resonance imaging (MRI) for select cases. Others report lack of correlation between CT and surgical or pathological findings. Our aim wasq to investigate the usefulness of CT and MR in the diagnosis of invasive fungal rhinosinusitis. We retrospectively reviewed four cases of biopsy-proven invasive disease. Correlations between radiographic, endoscopic, and surgical findings were investigated. Rhizopus species were detected in three cases and mixed Mucor and Aspergillus species in another. Superimposed bacterial sinusitis was confirmed in all cases. CT findings were nonspecific, revealing pansinusitis; no bone destruction or intracranial extension was noted. Mild orbital cellulitis was noted in one case. Anterior rhinoscopy revealed nonviable tissue in two patients. Nasal endoscopy later confirmed tissue ischemia in a third patient, whereas a final patient had normal findings on both exams. Nonspecific findings resulted in delay of diagnosis by 48-72 hours in two patients with presumed bacterial sinusitis. MR revealed intracranial extension in two patients and better represented intraoperative findings. In conclusion, CT findings in invasive fungal rhinosinusitis may be nonspecific and underestimate extent of disease. A high index of suspicion and early endoscopic examination with biopsy are mandatory for evaluation. MRI may better represent disease progression and should be considered early.

Glutathione S-transferase GSTM1 and GSTT1 genotypes in ovarian cancer: association with p53 expression and survival.

The objective of this study was to determine whether the association between GSTM1 null/GSTTI null and survival in ovarian cancer is mediated by the influence of these genes on p53 expression. In 81 women with pure invasive ovarian cancer, GSTM1 null and GSTT1 null genotypes were identified using polymerase chain reaction and p53 expression was assessed using immunohistochemistry. The association of these factors with survival was examined using Cox's proportional hazards regression models. Performance status (P < 0.001), operative stage (P = 0.004), residual disease (P = 0.001), histologic subtype (P = 0.05), tumor grade (P = 0.007), and the combined GSTMI null/GSTTl null genotype (P = 0.023) were all individually associated with survival. p53 expression was not associated with survival (P = 0.45). In a multivariate analysis, the effects of GSTM1 null/GSTT1 null on survival were lost when residual disease and tumor grade were included. The effects of p53 expression on survival were unchanged when residual disease, tumor grade, operative stage, and performance score were included. GSTM1 null/GSTT1null did not influence the effects of p53 expression on survival and vice versa. The GSTM1 null/GSTT1 null genotype was associated with response to primary chemotherapy (P = 0.007) but p53 expression was not. We conclude that the association of GSTM1 null/GSTTl null with survival appears to be mediated through different mechanisms to p53 expression in ovarian cancer and in addition, may be a better predictor of outcome.

Proteasome involvement in agonist-induced down-regulation of mu and delta opioid receptors.

This study investigated the mechanism of agonist-induced opioid receptor down-regulation. Incubation of HEK 293 cells expressing FLAG-tagged delta and mu receptors with agonists caused a time-dependent decrease in opioid receptor levels assayed by immunoblotting. Pulse-chase experiments using [(35)S]methionine metabolic labeling indicated that the turnover rate of delta receptors was accelerated 5-fold following agonist stimulation. Inactivation of functional G(i) and G(o) proteins by pertussis toxin-attenuated down-regulation of the mu opioid receptor, while down-regulation of the delta opioid receptor was unaffected. Pretreatment of cells with inhibitors of lysosomal proteases, calpain, and caspases had little effect on mu and delta opioid receptor down-regulation. In marked contrast, pretreatment with proteasome inhibitors attenuated agonist-induced mu and delta receptor down-regulation. In addition, incubation of cells with proteasome inhibitors in the absence of agonists increased steady-state mu and delta opioid receptor levels. Immunoprecipitation of mu and delta opioid receptors followed by immunoblotting with ubiquitin antibodies suggested that preincubation with proteasome inhibitors promoted accumulation of polyubiquitinated receptors. These data provide evidence that the ubiquitin/proteasome pathway plays a role in agonist-induced down-regulation and basal turnover of opioid receptors.