The sustainability of exercise following colorectal surgery: A qualitative study of participants in the PREPARE-ABC trial.

OBJECTIVE: This study aimed to explore perceptions regarding the sustainability of exercise following participation in a pre- and post-colorectal surgery exercise intervention trial (PREPARE-ABC). DESIGN: Qualitative interview study. Data were analysed using framework analysis and independently coded by two researchers. SETTING: Six United Kingdom National Health Service Trusts. PARTICIPANTS: Eighteen interviews (hospital-based exercise n = 9, home-based exercise n = 3, standard care n = 6) were conducted with patients 12-15 months after being randomised in the trial, after their 12 month appointment. INTERVENTION: Individuals who participated in one of two exercise intervention groups (hospital-supervised or home-supported exercise) or a standard care control group of the PREPARE-ABC trial were invited to interview. RESULTS: The exercise interventions were reported to influence participants' recovery and future sustainability of exercise behaviour change. Several participants continued to engage in exercise over a year after their surgery. Reasons for this included being engaged with exercise prior to diagnosis, psychological benefits of exercise and wanting to be engaged with something to help recovery. Perceptions about the sustainability of active lifestyles were influenced by confidence to engage in structured exercise or physical activity and beliefs about its potential to promote future wellness. CONCLUSIONS: Sustainability varies among individuals and early assessment of physical activity engagement could be beneficial. Physical activity interventions immediately following surgery may be important for future engagement.

Serial tests of T-cell function predict long-term survival in an elderly cohort from a Scottish general practice.

INTRODUCTION The care of the elderly presents serious challenges to general practice. In 1979, the first author took over the care of a general practice in Scotland where 21% of registered patients were elderly. This resulted in a high workload and prompted research into how this might be mitigated. AIM To measure serial tests of T-cell function in these individuals in order to identify those whose immune response was impaired and assess the effect of this in a long term follow up. METHODS This research comprised two phases. In the assessment phase (1979-82), patients were invited to have a 3-monthly visit from a research nurse where clinical measurements were made and blood taken for immunological tests of lymphocyte proliferation after culture with phytohaemagglutinin (PHA). For each patient, all records were surveyed and problems identified. In the follow-up phase (post 1982), all deaths were assessed with complete life-long follow up. RESULTS Of 405 people originally invited to participate in this research, 314 (78%) agreed and 246 (153 female, 93 male) entered the follow-up phase and were followed for 36.5 years. Factors significantly associated with lower survival were age, male sex, diastolic blood pressure, current smoking and poor immune function, as demonstrated by the percentage of negative responses in at least six PHA tests. Considered in four groups by percentage of failing tests, the lowest group had a life span 4 years shorter than the highest (P<0.01). The four groups did not differ significantly in general practitioner workload, diagnosed problems or causes of death. DISCUSSION Poor cellular immune function was associated with poor survival over lifetime follow up of >30 years. A sensitive, specific and longitudinally consistent measure of T-cell function is required to predict who may be at risk of poorer survival within our practices.

The impact of HPV cervical screening on negative large loop excision of the transformation zone (LLETZ): A comparative cohort study.

OBJECTIVE: To determine the incidence and predictors of negative large loop excision of the transformation zone (LLETZ) following the introduction of Human Papillomavirus (HPV) cervical screening. METHOD: A retrospective cohort study. Two independent cohorts, who attended for a LLETZ procedure, before and after the introduction of HPV cervical screening were compared. For each cohort, 401 individuals were randomly selected from a colposcopy database. Clinical and colposcopic variables were extracted. The incidence of negative LLETZ was estimated in each cohort. Regression analysis was used to adjust for potential confounders and explore predictors of negative LLETZ. RESULTS: Eighty women (19.9%) from the pre-HPV testing cohort and 54 women (13.4%) from the post-HPV cohort were negative for cervical intraepithelial neoplasia (RR 0.75, CI: 0.55 to 0.93). In the post-HPV testing cohort, independent predictors of negative LLETZ were low grade cytology (RR 3.60, CI: 2.18-5.97) and a type 3 transformation zone (TZ) (RR 2.88, CI: 1.76-4.72). Women with both low grade cytology and a TZ type 3 were 10.4 times more likely to have a negative LLETZ (absolute risk 40%, 95% CI: 27-54%). CONCLUSIONS: Despite a 25% reduction in negative LLETZ following the introduction of HPV cervical screening, the incidence is still high. These results highlight the importance of continuing to improve the specificity of cervical intraepithelial neoplasia screening; this should include the use of biomarkers that detect HPV-transforming infections and techniques that sample an entirely endocervical transformation zone.

Modeling non-syndromic autism and the impact of TRPC6 disruption in human neurons.

An increasing number of genetic variants have been implicated in autism spectrum disorders (ASDs), and the functional study of such variants will be critical for the elucidation of autism pathophysiology. Here, we report a de novo balanced translocation disruption of TRPC6, a cation channel, in a non-syndromic autistic individual. Using multiple models, such as dental pulp cells, induced pluripotent stem cell (iPSC)-derived neuronal cells and mouse models, we demonstrate that TRPC6 reduction or haploinsufficiency leads to altered neuronal development, morphology and function. The observed neuronal phenotypes could then be rescued by TRPC6 complementation and by treatment with insulin-like growth factor-1 or hyperforin, a TRPC6-specific agonist, suggesting that ASD individuals with alterations in this pathway may benefit from these drugs. We also demonstrate that methyl CpG binding protein-2 (MeCP2) levels affect TRPC6 expression. Mutations in MeCP2 cause Rett syndrome, revealing common pathways among ASDs. Genetic sequencing of TRPC6 in 1041 ASD individuals and 2872 controls revealed significantly more nonsynonymous mutations in the ASD population, and identified loss-of-function mutations with incomplete penetrance in two patients. Taken together, these findings suggest that TRPC6 is a novel predisposing gene for ASD that may act in a multiple-hit model. This is the first study to use iPSC-derived human neurons to model non-syndromic ASD and illustrate the potential of modeling genetically complex sporadic diseases using such cells.

The role of cytological follow-up after radical vaginal trachelectomy for early-stage cervical cancer.

OBJECTIVES: To identify whether recurrences were picked up by cytology alone after radical vaginal trachelectomy and to determine the false-positive rate of abnormal cytology. METHODS: Retrospective collection of patients from the cancer registry since radical vaginal trachelectomy was first performed in Bristol in 1999. All cytology results were collated and re-reviewed by a senior consultant cellular pathologist at the cytopathology centre in Southmead Hospital, Bristol. Cytology results and pathology and survival data are discussed, and any downgrading or upgrading of reports is reviewed. RESULTS: Eighteen women were identified and 80 isthmic cytology samples were reviewed. Only one recurrence has occurred. Lower uterine segment sampling was apparent in 25 samples and other endometrial cells in 21 samples: thus 58% showed endometrial cell sampling. Odd metaplastic cells from the newly formed transformation zone were found in 25 samples (31%). Fifteen (19%) showed significant inflammation, two with actinomyces. After cytology review, seven of 80 reports were changed: two between negative and inadequate, two borderline changes in endocervical cells and one mild dyskaryosis were downgraded to negative, and two cases reported as ?glandular neoplasia were changed to squamous cell carcinoma and negative, respectively. CONCLUSIONS: Cytology reporting may be challenging after trachelectomy. Cytology in our series did not add to the diagnosis of recurrence in the one case in which it occurred. We propose a pragmatic follow-up regime, and discuss the importance of the centralization of cytology reporting in these patients.

Hormone replacement therapy after endometrial cancer.

Endometrial cancer is the fourth most common female cancer in the UK and the most common gynaecological cancer. Quality of life and symptom control needs to be considered in women who enter a surgically induced menopause. Hormone replacement in this population has been controversial to date. The current evidence regarding the safety of estrogen only and combined hormone replacement therapy is discussed in this review. The use of topical vaginal therapies, alternate therapies and the current data regarding testosterone use for symptom control is also outlined.

Risk of epithelial ovarian cancer in asymptomatic women with ultrasound-detected ovarian masses: a prospective cohort study within the UK collaborative trial of ovarian cancer screening (UKCTOCS).

OBJECTIVE: To estimate the risk of primary epithelial ovarian cancer (EOC) and slow growing borderline or Type I and aggressive Type II EOC in postmenopausal women with adnexal abnormalities on ultrasound. METHODS: This was a prospective cohort study in the ultrasound group of the UK Collaborative Trial of Ovarian Cancer Screening of postmenopausal women with ultrasound-detected abnormal adnexal (unilocular, multilocular, unilocular solid and multilocular solid, solid) morphology on their first scan. Women were followed up through the national cancer registries and by postal questionnaires. Absolute risks of EOC and borderline, Type I and Type II EOC within 3 years of initial scan were calculated. RESULTS: Of 48 053 women who underwent ultrasound examination and had complete scan data, 4367 (9.1% (95% CI, 8.8-9.3%)) had abnormal adnexal morphology. Median follow-up was 7.09 (25(th) -75(th) centiles, 6.03-7.92) years. Forty-seven (32 borderline or Type I, 15 Type II) were diagnosed with EOC. The overall absolute risk of EOC associated with abnormal adnexal morphology was 1.08% (95% CI, 0.79-1.43%); for borderline and Type I it was 0.73% (95% CI, 0.5-1.03%); and for Type II it was 0.34% (95% CI, 0.33-0.79%). In the subgroup (n = 741) with solid elements (unilocular solid, multilocular solid and solid) overall absolute risk was 4.45% (95% CI, 3.08-6.20%), for borderline and Type I it was 3.1% (95% CI, 1.9-4.6%) and for Type II it was 1.3% (95% CI, 0.6-2.4%). 11 982 women had both ovaries visualized and normal annual scans throughout the 3-year follow-up period. In this group, no borderline or Type I and eight Type II cancers were diagnosed. CONCLUSION: Asymptomatic postmenopausal women with ultrasound-detected adnexal abnormalities with solid elements have a 1 in 22 risk for EOC. Despite the higher prevalence of Type II EOC, the risk of borderline or Type I cancer in women with ultrasound abnormalities seems to be higher than does the risk of Type II cancer. This has important immediate implications for patients with incidental adnexal findings as well as for any future ultrasound-based screening.

Delays in treating endometrial cancer in the South West of England.

BACKGROUND: Poor cancer survival rates in the United Kingdom are often blamed on delayed medical care. A local audit of endometrial cancer revealed a variety of preventable delays. We surveyed practice in the South West of England to see if this was an isolated or widespread problem. METHODS: All 15 hospitals in the South West of England collected information prospectively from all women with endometrial cancer over 3 months in the spring of 2009. RESULTS: There were delays in all stages of the uterine cancer pathway. Excluding extraneous cases, 52% of women waited more than a month and 12% waited more than 6 months to see their GP from the onset of symptoms. Almost half the cases said they were unaware that abnormal bleeding was a symptom of cancer. Only a quarter of women had treatment within 31 days from the outpatient visit to first definitive treatment and 18% waited more than the target of 62 days for their treatment. CONCLUSIONS: Significant treatment delays occur because women do not report bleeding. If this is replicated throughout Britain, approximately 1000 women per year will delay presentation for at least 3 months and 600 will wait for more than 6 months.

Clinical decision-making in a multidisciplinary gynaecological cancer team: a qualitative study.

OBJECTIVE: To explore the factors that influence treatment decision-making in a gynaecological cancer team (MDT). DESIGN: Qualitative study using interviews and observations. SETTING: Gynaecological cancer MDT meetings and participants' offices. SAMPLE: A gynaecological cancer MDT and members of that team. METHODS: Observations of ten MDT meetings and semistructured interviews with 16 team members. Data analysis using the constant comparison technique of grounded theory and ethnography. MAIN OUTCOME MEASURES: Factors affecting treatment decisions in the MDT meetings. RESULTS: Disease-centred information was central to decision-making, whereas patient-centred factors such as patient choice and co-morbidity were more peripheral. This was partly due to variation in team members' type and level of participation: senior clinicians occupied the most dominant roles in discussions and decision-making, whereas nurses contributed less but were more likely to focus on patient-related factors. Three main decision-making pathways emerged: a short discussion followed by a clear decision, a prolonged discussion ending in a definite treatment plan, and a lengthy discussion with no clearly stated decision at the end. The type of pathway followed depended on a case's complexity and the extent of agreement among team members. CONCLUSIONS: The process of treatment decision-making was not consistent for all women but was affected by factors such as the complexity of the case, which team members participated, and the extent of team members' agreement. Improvements are needed to ensure patient-centred information is included for all women and that clear decisions are reached and recorded in all cases.

The impact of improving outcomes guidance on surgical management of vulval squamous cell cancer in southwest England (1997-2002).

OBJECTIVE: The objective of this study was to assess the impact of reorganisation of gynaecological services in southwest England following adoption of regionally agreed evidence-based guidelines and publication of the National Improving Outcomes Guidance in 1999. DESIGN: Prospective audit with cross-checking against histological reports. SETTING: All 19 acute hospitals in the four Cancer Networks of southwest England. SAMPLE: All subjects with squamous or verrucous vulval cancer diagnosed between 1997 and 2002. METHOD: A one-page minimum data set proforma agreed by the South West Gynaecology Tumour Panel was completed by surgeons after treatment of each patient, and was sent to South West Cancer Intelligence Service for entry, collation and analysis. Data are presented for the years 1997 to 2002 inclusive, and comparisons were made between each of the three 2-year cohorts. MAIN OUTCOME MEASURES: These are standards derived from the guidance. RESULTS: There were 436 squamous or verrucous vulval cancers registered. Recording of staging was missing in 20% of subjects. The percentage of subjects operated upon by lead gynaecological cancer surgeons increased from 78% in cohort 1 to 93% in cohort 3 (P < 0.001). There is a trend towards more conservative operations, which have lower co-morbidity. High activity surgeons achieved better rates of tumour-free skin margins, but even these were adequate only in 49% of operations. Lymphadenectomy rates did not follow guidance. CONCLUSION: Centralisation of care of this rare cancer should continue, but specialists need to increase their efforts to ensure adequate skin margins and lymphadenectomy rates while balancing morbidity and the likelihood of recurrence in both fit and frail patients.

Laparoscopically assisted radical vaginal hysterectomy (Coelio-Schauta): A comparison with open Wertheim/Meigs hysterectomy.

The objective of this study was to compare the safety, efficacy, and short-term benefits of the Coelio-Schauta procedure with open Wertheim/Meigs radical abdominal hysterectomy. We retrospectively analyzed records of our first 35 consecutive patients undergoing laparoscopically assisted radical vaginal hysterectomy (LARVH) for early cervical cancer and 32 consecutive patients of open radical hysterectomy (ORH) performed between 1999 and 2005 in our institution. We analyzed patient age, bodyweight, previous abdominal surgery, operating time, blood loss, perioperative complications, postoperative bladder dysfunction, other postoperative complications, and histologic type. The FIGO stage, excision margins, node count and node status, follow-up, and recurrence rates were also taken into account. We excluded stage IA and stage II disease patients to reduce the impact of tumor size on the outcome of the surgery. This left 27 patients with stage IIB disease who had LARVH and 28 patients with stage IB disease who had ORH. These patients formed the study group. The cohorts were similar in age, bodyweight, previous abdominal surgery, histologic subtype, FIGO stage, resection margins, node count and node status, length of follow-up, and recurrence. There were statistically significant differences between LARVH and ORH for duration of surgery (mean 160 vs 132 min), intraoperative blood loss (479 vs 715 mL), hospital stay (mean 5 vs 9.3 days), postoperative complications (6 vs 20 patients), and duration of bladder catheterization (mean 4.4 vs 8.8 days). Four LARVH patients and no ORH patients had urinary tract injury that was repaired. None had long-term sequelae. Our data confirm that LARVH is a suitable alternative to ORH hysterectomy for small-volume stage IB1 cervical cancer with similar clinical efficacy and a superior postoperative recovery and postoperative morbidity profile. Urinary tract trauma is a clear risk in the early stages of the learning curve.

Stage III and IV ovarian cancer in the South West of England: five-year outcome analysis for cases treated in 1998.

This study evaluates the 5-year outcome data for the management of advanced ovarian cancer in the South West of England. Anonymized data for 361 stage III and IV ovarian cancers registered between January 1, 1998, and December 31, 1998, were obtained from the central gynecological tumor database. The following data were identified: age at diagnosis, FIGO stage, American Society of Anesthesiologists (ASA) grade, tumor differentiation, treating network and surgeon, amount of residual disease after debulking surgery, current life status, and date of death if applicable. Survival analysis was performed using Kaplan-Meier crude survival for univariate analysis, and multivariate analysis was performed by Cox regression. In our data the 5-year survival for patients with stage III was 16% and with stage IV was 10%. Survival analysis demonstrated that patients in whom the disease was debulked to less than 1 cm were more likely to be alive 5 years after diagnosis than those with a 2-cm residuum (P < 0.0001). There was no significant survival difference for those patients operated on by subspecialist surgeons despite these surgeons being twice as likely to achieve optimal debulking. Therefore, there must be other variables influencing survival apart from cytoreductive surgery. While there is near-complete data collection about ovarian cancer surgery, our database on chemotherapy is incomplete. This is clearly crucial for a complete view of cancer care in our region.

Pain on medical wards in a district general hospital.

BACKGROUND: Little attention has been paid to pain on medical wards, with publications limited to the management of surgical patients. We wanted to establish the prevalence and severity of pain in the general medical setting, and how this compared with other clinical specialties. METHODS: All consenting adult in-patients were assessed daily for 5 days. Patients recorded the occurrence and severity of pain, and whether their pain was bearable. The pain team reviewed patients with unbearable pain. RESULTS: 1594 questionnaires were completed, representing 54% of the target population. 887 patients reported pain, 17% with pain scores over 6, and 10% with unbearable pain. The distribution of pain was similar for all ward types with 52% of patients on medical wards reporting pain. Of these, 20% reported severe pain and 12% unbearable pain. When patients with pain scores over 6 were analysed by consultant specialty, elderly care, general medicine, and general surgery scored highest. In each specialty 20-25% of patients with pain reported a pain score over 6. In patients reviewed by the pain team, reasons for poor analgesia included inadequate information, pain assessment, analgesic prescribing, and administration and patient reporting. CONCLUSION: Patients in all hospital specialities experience pain. Until the issue of pain management in medical patients is fully addressed the situation will not improve.

Chronic fatigue syndrome. The patient centred clinical method--a guide for the perplexed.

BACKGROUND: Chronic fatigue states are common in general practice and over the past 20 years there has been considerable worldwide consensus developed on the criteria for chronic fatigue syndrome (CFS) also commonly known as myalgic encephalomyelitis (ME). Chronic fatigue syndrome is an illness characterised by the new onset of disabling fatigue, accompanied by cognitive, musculoskeletal and sleep symptoms. There are no specific diagnostic tests or biological markers and the diagnosis is made by ruling out other causes of fatigue. The pathophysiology of CFS is still unclear. OBJECTIVE: This article discusses the application of the patient centred clinical method to the diagnosis and treatment of CFS. DISCUSSION: There is no new breakthrough in the diagnosis or management of CFS in spite of much research and controversy. There is considerable evidence that the best place to manage CFS is in primary care under the care of the patient's own general practitioner, but it has been suggested that doctors feel unable to deal with the problem. The patient centred clinical method offers a constructive guide to management. The author considers that the best hope for sufferers is self management guided by a supportive and helpful health professional, preferably the patient's own GP.

The management of women with apparent early ovarian cancer in the south-west region of England.

This study investigated the management of women with apparent early ovarian cancer in the South West region of England. This was retrospective review of prospectively collected data supplement by case note review. All women registered with stage 1 ovarian cancer in the 2 years from January 1997 to December 1998 were identified from the database of the Regional Cancer Organisation (RCO). Data on staging and subsequent management were obtained from the RCO database. Additional information was collected from the patients' casenotes. We considered the accuracy of staging, consideration of fertility-sparing surgery, evidence of multidisciplinary approach to management, appropriateness of oncological referral and adjuvant therapy. Of 222 cases of stage 1 ovarian cancer identified from the RCO database, 168 casenotes were available for inspection. Eighty-seven cases were confirmed as FIGO stage 1 but the substage was amended in 21 cases. There were insufficient data available in 75 cases to confirm the stage assigned. Six cases were re-staged to FIGO stage 3a. Fertility-sparing surgery was considered in four of 10 nulliparous patients of reproductive age. Thirty-nine patients with disease more advanced than FIGO stage 1b were not referred for onco1 logical opinion. Even after Calmine-Hine guidelines are implemented, women with early ovarian cancer may still be treated in general hospitals. There is an urgent need to provide clear local guidelines for the management of these patients.

A critical evaluation of current protocols for the follow-up of women treated for gynecological malignancies: a pilot study.

This retrospective review was undertaken to determine the efficacy of routine follow-up in the detection and management of recurrent cancer. The case notes of all women attending a regional cancer center who were diagnosed with cancer in 1997 were reviewed. Of 81 new cancers followed up for a median of 42 months (range 36-48), 14 have recurred after curative treatment and there were six cases of persistent disease. The median number of clinic visits per patient was 3.5 (range 1-16). Eight recurrences (57.1%) were diagnosed at scheduled outpatient appointments, three (2 l.4%) presented to the general practitioner (GP), and three were seen as emergencies in hospital. Seventeen patients with persistent/recurrent disease have died and three are alive with disease. The median time from initial presentation to disease recurrence was 12 months (range 5-25) and the median time from recurrence to death was 5 months (range 1-20). The longest interval between onset of symptoms and diagnosis of recurrence (4 months) occurred in those presenting at scheduled outpatient clinics. This study demonstrates that the current follow-up protocol is associated with delays in diagnosing recurrence, because symptomatic patients postpone seeking help until their scheduled visit. We have therefore commenced a prospective study evaluating other models of follow-up.

The surgical management of women with ovarian cancer in the south west of England.

The surgical management of epithelial ovarian cancer in the South West of England was studied in the two years 1997-1998 in order to determine the factors that influence the outcome of surgery and to provide a baseline from which to assess the effect of centralisation of cancer services. All hospitals in the South West region of England participating in the Regional Cancer Organisation's longitudinal study of outcomes in gynaecological malignancies are included. Six hundred and eighty-two patients with epithelial ovarian cancer were registered with the RCO in the two-year study period. Five hundred and ninety-five women were offered primary cytoreductive surgery of which 438 were said to be optimally cytoreduced. Applying multivariate models to analyse the outcome of surgery, older patients (OR = 0.82 per 5-year increase in age, P = 0.0003), patients treated in hospitals managing fewer than ten cases of ovarian cancer per year (OR = 1.92, P = 0.02) and patients with FIGO stage 3 (OR = 0.02, P < 0.0001) or 4 (OR = 0.002, P < 0.0001) disease were less likely to be optimally cytoreduced. Gynaecological oncologists were 2.06 times more likely to attain optimal cytoreduction when compared to general gynaecologists and this was statistically significant (P = 0.01). The results from this study support the argument that limiting surgery for ovarian malignancy to specialised surgeons improves the extent of cytoreductive surgery.

Cardiac malformations, adrenal agenesis, neural crest defects and exencephaly in mice lacking Cited2, a new Tfap2 co-activator.

The protein EP300 and its paralog CREBBP (CREB-binding protein) are ubiquitously expressed transcriptional co-activators and histone acetyl transferases. The gene EP300 is essential for normal cardiac and neural development, whereas CREBBP is essential for neurulation, hematopoietic differentiation, angiogenesis and skeletal and cardiac development. Mutations in CREBBP cause Rubinstein-Taybi syndrome, which is characterized by mental retardation, skeletal abnormalities and congenital cardiac defects. The CBP/p300-interacting transactivator with ED-rich tail 2 (CITED2) binds EP300 and CREBBP with high affinity and regulates gene transcription. Here we show that Cited2-/- embryos die with cardiac malformations, adrenal agenesis, abnormal cranial ganglia and exencephaly. The cardiac defects include atrial and ventricular septal defects, overriding aorta, double-outlet right ventricle, persistent truncus arteriosus and right-sided aortic arches. We find increased apoptosis in the midbrain region and a marked reduction in ErbB3-expressing neural crest cells in mid-embryogenesis. We show that CITED2 interacts with and co-activates all isoforms of transcription factor AP-2 (TFAP2). Transactivation by TFAP2 isoforms is defective in Cited2-/- embryonic fibroblasts and is rescued by ectopically expressed CITED2. As certain Tfap2 isoforms are essential in neural crest, neural tube and cardiac development, we propose that abnormal embryogenesis in mice lacking Cited2 results, at least in part, from its role as a Tfap2 co-activator.