Upper gastrointestinal training in the UK and Ireland: a Roux Group Study.

INTRODUCTION: Surgical training programmes in the United Kingdom and Ireland (UK&I) are in a state of flux. This study aims to report the contemporary opinions of trainee and consultant surgeons on the current upper gastrointestinal (UGI) training model in the UK&I. METHODS: A questionnaire was developed and distributed via national UGI societies. Questions pertained to demographics, current training evaluation, perceived requirements and availability. RESULTS: A total of 241 responses were received with representation from all UK&I postgraduate training regions. The biggest discrepancies between rotation demand and national availability related to advanced/therapeutic endoscopy and robotic surgery, with 91.7% of respondents stating they would welcome greater geographical flexibility in training. The median suggested academic targets were 3-5 publications (trainee vs consultant <3 vs 3-5, p<0.001); <3 presentations (<3 vs 3-5, p=0.002); and 3-5 audits/quality improvement projects (<3 vs 3-5, p<0.001). Current operative requirements were considered achievable (87.6%) but inadequate for day one consultant practice (74.7%). Reassuringly, 76.3% deemed there was role for on-the-job operative training following consultant appointment. Proficiency in diagnostic endoscopy was considered a minimum requirement for Certificate of Completion of Training (CCT) yet the majority regarded therapeutic endoscopy competency as non-essential. The median numbers of index UGI operations suggested were comparable with the current curriculum requirements. Post-CCT fellowships were not considered necessary; however, the majority (73.6%) recognised their advantage. CONCLUSIONS: Current CCT requirements are largely consistent with the opinions of the UGI community. Areas for improvement include flexibility in geographical working and increasing national provisions for high-quality endoscopy training.

The impact of ileal pouch-anal anastomosis on graft survival following liver transplantation for primary sclerosing cholangitis.

BACKGROUND: Liver transplantation is the only life-extending intervention for primary sclerosing cholangitis (PSC). Given the co-existence with colitis, patients may also require colectomy; a factor potentially conferring improved post-transplant outcomes. AIM: To determine the impact of restorative surgery via ileal pouch-anal anastomosis (IPAA) vs retaining an end ileostomy on liver-related outcomes post-transplantation. METHODS: Graft survival was evaluated across a prospectively accrued transplant database, stratified according to colectomy status and type. RESULTS: Between 1990 and 2016, 240 individuals with PSC/colitis underwent transplantation (cumulative 1870 patient-years until first graft loss or last follow-up date), of whom 75 also required colectomy. A heightened incidence of graft loss was observed for the IPAA group vs those retaining an end ileostomy (2.8 vs 0.4 per 100 patient-years, log-rank P = 0.005), whereas rates between IPAA vs no colectomy groups were not significantly different (2.8 vs 1.7, P = 0.1). In addition, the ileostomy group experienced significantly lower graft loss rates vs. patients retaining an intact colon (P = 0.044). The risks conferred by IPAA persisted when taking into account timing of colectomy as related to liver transplantation via time-dependent Cox regression analysis. Hepatic artery thrombosis and biliary strictures were the principal aetiologies of graft loss overall. Incidence rates for both were not significantly different between IPAA and no colectomy groups (P = 0.092 and P = 0.358); however, end ileostomy appeared protective (P = 0.007 and 0.031, respectively). CONCLUSION: In PSC, liver transplantation, colectomy + IPAA is associated with similar incidence rates of hepatic artery thrombosis, recurrent biliary strictures and re-transplantation compared with no colectomy. Colectomy + end ileostomy confers more favourable graft outcomes.

Transplantation of Declined Liver Allografts Following Normothermic Ex-Situ Evaluation.

The demand for liver transplantation (LT) exceeds supply, with rising waiting list mortality. Utilization of high-risk organs is low and a substantial number of procured livers are discarded. We report the first series of five transplants with rejected livers following viability assessment by normothermic machine perfusion of the liver (NMP-L). The evaluation protocol consisted of perfusate lactate, bile production, vascular flows, and liver appearance. All livers were exposed to a variable period of static cold storage prior to commencing NMP-L. Four organs were recovered from donors after circulatory death and rejected due to prolonged donor warm ischemic times; one liver from a brain-death donor was declined for high liver function tests (LFTs). The median (range) total graft preservation time was 798 (range 724-951) min. The transplant procedure was uneventful in every recipient, with immediate function in all grafts. The median in-hospital stay was 10 (range 6-14) days. At present, all recipients are well, with normalized LFTs at median follow-up of 7 (range 6-19) months. Viability assessment of high-risk grafts using NMP-L provides specific information on liver function and can permit their transplantation while minimizing the recipient risk of primary graft nonfunction. This novel approach may increase organ availability for LT.

Liver Transplantation Using Grafts From Donors After Circulatory Death: A Propensity Score-Matched Study From a Single Center.

The use of livers from donation after circulatory death (DCD) is increasing, but concerns exist regarding outcomes following use of grafts from "marginal" donors. To compare outcomes in transplants using DCD and donation after brain death (DBD), propensity score matching was performed for 973 patients with chronic liver disease and/or malignancy who underwent primary whole-liver transplant between 2004 and 2014 at University Hospitals Birmingham NHS Foundation Trust. Primary end points were overall graft and patient survival. Secondary end points included postoperative, biliary and vascular complications. Over 10 years, 234 transplants were carried out using DCD grafts. Of the 187 matched DCDs, 82.9% were classified as marginal per British Transplantation Society guidelines. Kaplan-Meier analysis of graft and patient survival found no significant differences for either outcome between the paired DCD and DBD patients (p = 0.162 and p = 0.519, respectively). Aspartate aminotransferase was significantly higher in DCD recipients until 48 h after transplant (p < 0.001). The incidences of acute kidney injury and ischemic cholangiopathy were greater in DCD recipients (32.6% vs. 15% [p < 0.001] and 9.1% vs. 1.1% [p < 0.001], respectively). With appropriate recipient selection, the use of DCDs, including those deemed marginal, can be safe and can produce outcomes comparable to those seen using DBD grafts in similar recipients.

The Royal College of Radiologists' audit of prostate brachytherapy in the year 2012.

AIMS: This audit provides a comprehensive overview of UK prostate brachytherapy practice in the year 2012, measured against existing standards, immediately before the introduction of new Royal College of Radiologists (RCR) guidelines. This audit allows comparison with European and North American brachytherapy practice and for the impact of the RCR 2012 guidelines to be assessed in the future. MATERIALS AND METHODS: A web-based data collection tool was developed by the RCR Clinical Audit Committee and sent to audit leads at all cancer centres in the UK. Standards were developed based on available guidelines in use at the start of 2012 covering case mix and dosimetry. Further questions were included to reflect areas of anticipated change with the implementation of the 2012 guidelines. Audit findings were compared with similar audits of practice in Europe, the USA and Latin America. RESULTS: Forty-nine of 59 cancer centres submitted data. Twenty-nine centres reported carrying out prostate brachytherapy; of these, 25 (86%) provided data regarding the number of implants, staffing, dosimetry, medication and anaesthesia and follow-up. Audit standards achieved excellent compliance in most areas, although were low in post-implant dosimetry and in post-implant scanning at 30 days. CONCLUSION: This audit provides a comprehensive picture of prostate brachytherapy in the UK in 2012. Patterns of care of prostate brachytherapy are similar to practice in the USA and Europe. The number of prostate brachytherapy implants carried out in the UK has grown significantly since a previous RCR audit in 2005 and it is important that centres maintain minimum numbers of cases to ensure that experience can be maintained and compliance to guidelines achieved.

A gene expression profiling approach assessing celecoxib in a randomized controlled trial in prostate cancer.

BACKGROUND: We performed a pilot study, looking at the COX-2 inhibitor celecoxib, on newly diagnosed prostate cancer patients in the neo-adjuvant setting using DNA microarray analysis. PATIENTS AND METHODS: This was a single-blinded, randomized controlled phase II presurgical (radical prostatectomy) 28-day trial of celecoxib versus no drug in patients with localized T1-2 N0 M0 prostate cancer. cDNA microarray analysis was carried out on prostate cancer biopsies taken from freshly obtained radical prostatectomy samples. Results were confirmed by qPCR analysis of a selection of genes. RESULTS: Multiple genes were differentially expressed in response to celecoxib treatment. Statistical analysis of microarray data indicated 24 genes were up-regulated and 4 genes down-regulated as a consequence of celecoxib treatment. Gene changes e.g. survivin, SRP72kDa, were associated with promoting apoptotic cell death, enhancement of antioxidant processes and tumour suppressor function (p73 and cyclin B1 up-regulation). CONCLUSION: Celecoxib at 400 mg b.i.d. for 4 weeks perioperatively gave rise to changes in gene expression in prostate cancer tissue consistent with enhancement of apoptosis and tumour suppressor function. Given the short time interval for the duration of this study, the data are encouraging and provide a good rationale for conducting further trials of celecoxib in prostate cancer.

Metabolic syndrome and prostate cancer: a review.

Androgen deprivation therapy is widely used in a number of different settings in the treatment of prostate cancer. This overview will look at the current evidence for the potential development of metabolic syndrome and cardiovascular disease as a consequence of this therapy, and highlight strategies aimed at their prevention. The relationship between metabolic syndrome and prostate cancer development will also be examined.

Biochemical relapse-free survival in 400 patients treated with I-125 prostate brachytherapy: the Guildford experience.

A total of 1200 patients had undergone I-125 prostate brachytherapy (BXT) in our centre. We present prospective outcome data for the first 400 treated patients. Data were analysed from a prospective database of 400 consecutive patients treated with permanent prostate BXT between March 1999 and December 2003. Patients were stratified into low (49%), intermediate (36%) and high (15%) risk as defined by the Memorial Sloan-Kettering Prognostic Index. Patients received 145 Gy BXT alone (41%), BXT with 3 months neoadjuvant androgen deprivation (NAAD) (39%), 45 Gy external beam radiotherapy (EBRT) with 110 Gy BXT (3%) or a combination of NAAD, 45 Gy EBRT and 110 Gy BXT (17%). Biochemical relapse-free survival (bRFS) and prostate-specific antigen (PSA) nadirs were analysed for treatment received in each risk group. Median follow-up was 54 months (range, 38-96 months) with a mean patient age of 63 years. Prostate cancer-specific survival was 99.5%. Twenty-eight patients (7%) experienced biochemical failure according to the 2006 Radiation Therapy Oncology Group-American Society for Therapeutic Radiology and Oncology (RTOG-ASTRO) Phoenix Consensus definition (PSA nadir plus >or=2 ng ml(-1)): nine low-, fourteen intermediate- and five high-risk patients. When stratified by treatment group for low-, intermediate- and high-risk groups, the 5-year actuarial bRFS was 98, 89 and 100% for BXT; 91, 87 and 88% for NAAD and BXT; 100, 80 and 100% for EBRT and BXT; and 100, 92 and 88% for NAAD, EBRT and BXT, respectively. Overall 4- and 5-year PSA

State-of-the-art: prostate LDR brachytherapy.

This article on low dose rate (LDR) prostate brachytherapy reviews long-term results, patient selection and quality of life issues. Mature results from the United States and United Kingdom are reported and issues regarding definitions of biochemical failure are discussed. Latest data comparing brachytherapy with radical prostatectomy or no definitive treatment and also the risk of secondary malignancies after prostate brachytherapy are presented. Urological parameters of patient selection and quality of life issues concerning urinary, sexual and bowel function are reviewed. The position of prostate brachytherapy next to surgery as a first-line treatment modality is demonstrated.

COX-2 inhibition: a possible role in the management of prostate cancer?

There is mounting evidence to support a role for cyclooxygenase-2 (COX-2) inhibitors (coxibs) in the management of prostate cancer. This review considers the current evidence base for the use of coxibs in prostate cancer as well as their adverse event profile. A systematic literature review using the search terms 'cyclooxygenase', 'COX-2', 'coxibs', 'cardiovascular risk', and 'prostate cancer' was performed using Medline. Celecoxib appears safer in terms of cardiovascular toxicity than other coxibs, and this may relate to its lower selectivity for the COX-2 enzyme. This lower selectivity also provides rationale for its putative broader anti-cancer effects, via non-COX-2-dependent pathways that affect cell cycle regulation, angiogenesis, and hypoxic modulation. There are also interacting relationships between COX-2, chronic inflammation, and prostate cancer. There is much promise for the coxibs as anti-cancer agents. The future might be to pharmacologically adapt these agents to exert their COX-2 independent mechanisms of action while minimizing their COX-2-dependent adverse cardiovascular effects.

Interstitial low dose rate brachytherapy for prostate cancer--a focus on intermediate- and high-risk disease.

AIMS: To investigate the role of brachytherapy in intermediate- and high-risk prostate cancer. We report our results and a review of published studies. MATERIALS AND METHODS: Between March 1999 and April 2003, 300 patients were treated with low dose rate 1-125 interstitial prostate brachytherapy and followed prospectively. The patients were stratified into low-, intermediate- and high-risk groups and received brachytherapy alone or in combination with external beam radiotherapy (EBRT) and/or neoadjuvant androgen deprivation (NAAD). One hundred and forty-six patients were classified as low risk, 111 as intermediate risk and 43 as high risk. Biochemical freedom from disease and prostate-specific antigen (PSA) nadirs were analysed for risk groups and for treatment received in each risk group. RESULTS: The median follow-up was 45 months (range 33-82 months) with a mean age of 63 years. Actuarial 5-year biochemical relapse-free survival for the low-risk group was 96%, 89% for the intermediate-risk group and 93% for the high-risk group. When stratified by treatment group, low-risk patients had a 5-year actuarial biochemical relapse-free survival of 94% for brachytherapy alone (n=77), 92% for NAAD and brachytherapy (n=66) and 100% for NAAD, EBRT and brachytherapy (n=3). In the intermediate-risk patients, biochemical relapse-free survival was 93% for brachytherapy alone (n=15), 94% for NAAD and brachytherapy (n=67), 75% for EBRT and brachytherapy (n=4) and 92% for NAAD, EBRT and brachytherapy (n=25). In the high-risk group, biochemical relapse-free survival was 100% for brachytherapy alone (n=2), 88% for NAAD and brachytherapy (n=7), 80% for EBRT and brachytherapy (n=5) and 96% for NAAD, EBRT and brachytherapy (n=29). Overall 3- and 4-year PSA = 0.5 ng/ml were achieved by 71 and 86%, respectively, and a 4-year PSA = 0.2 ng/ml was achieved by 63%. CONCLUSION: Although the role of combination treatment with pelvic EBRT and androgen therapy is not clear, our early results show that many patients with intermediate- and high-risk disease have excellent results with brachytherapy.

Gleason scoring varies among pathologists and this affects clinical risk in patients with prostate cancer.

AIMS: To investigate whether our practice of specialist review of all diagnostic biopsies was necessary to prevent misgrading of referred prostate cancer patients, and whether this misclassification, if any, would have resulted in misclassification of clinical risk grouping (Seattle Risk Grouping [SRG]) and subsequent treatment strategy and prognosis. MATERIALS AND METHODS: Important prognostic indicators for prostate cancer include the presenting prostate-specific antigen (PSA), clinical stage and Gleason sum of the tumour. These three variables are incorporated into the SRG cohorts to establish treatment strategy. Patients with prostate cancer referred for brachytherapy had their prostate biopsies reviewed by a reference pathologist (PD) with a special interest in prostate cancer. We compared the agreement between the scoring of the referring pathologists with that of PD, and evaluated if any differences changed the SRG and therefore the clinical risk and treatment strategy for the patients. RESULTS: In only 52% (43/83) of cases, was there total agreement between the two sets of pathologists. The inter-rater agreement was statistically 'fair' (unweighted kappa statistic 0.27). In 90% (36/40) of cases with disagreement, PD assigned higher Gleason sums. In 40% (16/40) of cases with disagreement, the change in Gleason sum altered the SRG; in one out of 16 cases, the SRG was downgraded from 'intermediate' to 'low' risk disease; in six out of 16 cases, it was upgraded from 'low' to 'intermediate' risk, and, in nine out of 16, from 'intermediate' to 'high' risk. CONCLUSION: Our findings confirm previous reports of only limited correlation between pathologists in reporting Gleason sums. In this study, 19% (16/83) of cases had their grading changed to a level that altered clinical risk, almost always (94%; 15/16) to one that worsened prognosis. This would have significantly affected treatment strategy for these patients, and thus we recommend that all centres ensure accurate Gleason grading by the use of pathologists with special interests in prostate cancer.

Neoadjuvant vinorelbine/epirubicin (VE) versus standard adriamycin/cyclophosphamide (AC) in operable breast cancer: analysis of response and tolerability in a randomised phase III trial (TOPIC 2).

BACKGROUND: Vinorelbine is active and well tolerated against advanced breast cancer but there are no published efficacy studies in early breast cancer. We have therefore carried out a randomised phase III neoadjuvant trial in operable breast cancer. PATIENTS AND METHODS: Patients with > or =3 cm operable breast carcinoma were randomised to receive either vinorelbine 25 mg/m(2) on days 1 and 8 and epirubicin 60 mg/m(2) on day 1, 3 weekly for six cycles (VE) or doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) i.v. on day 1, 3 weekly for six cycles (AC), prior to standard local therapy, and adjuvant endocrine therapy as appropriate. RESULTS: A total of 451 patients were randomised. Results for AC and VE, respectively, were: overall clinical response 73% and 74%, complete clinical remission 20% and 24%, pathological complete remission 12% and 12%, mastectomy rate 52% and 55%. None of these differences were significant. Dose reduction was required in 8% for AC and 20% for VE (P <0.001) (GSCF support not used). Significantly more grade 3/4 toxicity for nausea, vomiting and alopecia (despite scalp cooling) was seen for AC compared with VE but significantly less grade 3/4 thrombophlebitis and neuropathy. CONCLUSIONS: Neoadjuvant VE is as effective as AC in early breast cancer and was better tolerated except for thrombophlebitis and neuropathy.

Iodine seed prostate brachytherapy: an alternative first-line choice for early prostate cancer.

This article on permanent iodine-125 seed prostate brachytherapy reviews the techniques, results, and patient selection issues for early prostate cancer. The long-term 10 y results of brachytherapy from Seattle, and their reproducibility in other centres both in the USA and UK are reported. The use of hormone therapy in brachytherapy and the value of combining external beam radiotherapy with a brachytherapy implant are discussed. Reviewed comparative data show the similarity of biochemical survival in patients treated with brachytherapy, radical prostatectomy, and external beam radiotherapy. The role of brachytherapy as a first-line treatment option for patients with prostate cancer is demonstrated.

Toxicity and early biochemical outcomes from 125iodine prostate brachytherapy in the UK. A prospective study.

AIMS: Transperineal interstitial prostate brachytherapy is increasingly available to patients with early prostate cancer in the U.K., but limited data are available about the toxicity and early results in the U.K. prostate cancer population. We describe our experience and results from prostate brachytherapy to date. MATERIALS AND METHODS: Two hundred and fifty-five patients were treated at St Luke's Cancer Centre, Guildford, U.K., between March 1999 and November 2002. Of these, over 3 months of follow-up data were available for 216 patients. Patients were assessed at 6 weeks and then at 3, 6, 9 and 12 months after implant, and at 6 monthly intervals thereafter. Prostate-specific antigen (PSA), International Prostate Symptom Score (IPSS) and toxicity, including catheter use, was recorded prospectively. RESULTS: Median PSA at 1, 2 and 3 years was 0.5, 0.4 and 0.1 ng/ml, respectively. Ninety-five per cent of patients experienced temporary deterioration in their urinary symptoms, which persisted at clinically significant levels (IPSS increase >3 points) for 9 months after implant. The severity of urinary symptoms (IPSS) after implant was most closely related to IPSS at presentation (P<0.001). Acute urinary retention (AUR) occurred in 20 (9.3%) patients, with a further 26 (12.1%) patients using clean intermittent self-catheterisation (CISC) to reduce voiding frequency associated with chronic retention. Median duration of catheter use was 4 weeks. Multivariate analysis revealed that urodynamic status, prostate volume and IPSS score were independently significant (P<0.05) predictors of post-implant catheter use. Twelve patients (5.6%) reported either rectal urgency or mild, self-limiting rectal bleeding. CONCLUSION: Brachytherapy was tolerated well, with self-limiting urinary, bowel and sexual toxicity in most patients. Postoperative catheter use in our population is closely linked to pre-implant IPSS score, baseline prostate volume and urodynamic obstruction status. This work confirms the prognostic value of urodynamic assessment, which adds useful prognostic information to assessment of known risk factors such as prostate volume and IPSS.

A novel continuous infusional 5-fluorouracil-based chemotherapy regimen compared with conventional chemotherapy in the neo-adjuvant treatment of early breast cancer: 5 year results of the TOPIC trial.

BACKGROUND: To compare the efficacy of continuous infusional 5-fluorouracil (5-FU)-based chemotherapy against conventional bolus chemotherapy in the preoperative treatment of patients with large operable early breast cancer. PATIENTS AND METHODS: Four hundred and twenty-six women with histologically proven 3 cm invasive early breast cancer were randomised to receive pre-operative infusional 5-FU 200 mg/m(2) by daily 24 h continuous infusion via a Hickman line for 18 weeks with epirubicin 60 mg/m(2) intravenous (i.v.) bolus on day 1 and cisplatin 60 mg/m(2) i.v. bolus on day 1, both repeating 3-weekly (infusional ECisF), or conventional bolus doxorubicin 60 mg/m(2) i.v. on day 1 and cyclophosphamide 600 mg/m(2) i.v. on day 1, both repeating 3-weekly (AC), both schedules for six courses. Patients subsequently had local therapy (surgery or radiotherapy or both) and tamoxifen 20 mg orally daily as appropriate. RESULTS: The 5 year results for AC and infusional ECisF, respectively, were as follows: overall response, 75% and 77%; complete clinical remission, 31% and 34%; pathological complete remission (pathCR), 16% for both; and pathCR with residual ductal carcinoma in situ (DCIS), 25% and 24%. Mastectomy rates were 37% and 34%, respectively. Five-year overall survival was 74% for AC and 82% for infusional ECisF (hazard ratio 0.76, 95% confidence interval 0.51-1.13; P = 0.18). Both treatments were well tolerated. Grade III/IV lethargy, vomiting, alopecia and plantar-palmar erythema were significantly greater for infusional ECisF; grade III/IV leucopenia was significantly greater for AC. CONCLUSIONS: Preoperative continuous infusional 5-FU-based chemotherapy is no more active than conventional AC for early breast cancer; with a median 5 year follow-up, the infusion-based schedule shows a non-significant trend towards improved survival.

Is bicalutamide equivalent to goserelin for prostate volume reduction before radiation therapy? A prospective, observational study.

INTRODUCTION: We compare the cytoreductive efficacy of bicalutamide or goserelin with no hormonal manipulation in prostate cancer before brachytherapy. MATERIALS AND METHODS: Transrectal ultrasound volume estimations were performed in clinic and during the brachytherapy-planning scan. Between volume estimations, patients received no hormonal treatment, bicalutamide 150 mg once daily or goserelin 3.6 mg every 28 days. RESULTS: Patients receiving no hormonal manipulation had a volume increase of 8% compared with an 8% volume reduction in the bicalutamide group and a 26% reduction in the goserelin group. As initial prostate volume was not equivalent in the three groups, a subgroup analysis was performed on patients who received active treatment for more than 3 months who had initial prostate volume less than 55 cm3. In this subgroup, a mean fall in prostate volume of 7%, occurred in the bicalutamide group compared with 21% in the goserelin group. In both the original and subgroup analysis, the cytoreductive efficacy of goserelin was significantly greater than bicalutamide (P < 0.0001). CONCLUSION: In the absence of data from randomised trials, comparing the efficacy of these agents, luteinising hormone-releasing hormone (LHRH) analogues remain the gold standard for cytoreduction before prostate brachytherapy. If the neoadjuvant efficacy of hormonal manipulation in external beam radiotherapy is dependent on prostate volume reduction, then LHRH analogues may also prove more effective in this neoadjuvant role.