Timing of radiotherapy (RT) after radical prostatectomy (RP): long-term outcomes in the RADICALS-RT trial (NCT00541047).

BACKGROUND: The optimal timing of radiotherapy (RT) after radical prostatectomy for prostate cancer has been uncertain. RADICALS-RT compared efficacy and safety of adjuvant RT versus an observation policy with salvage RT for prostate-specific antigen (PSA) failure. PATIENTS AND METHODS: RADICALS-RT was a randomised controlled trial enrolling patients with ≥1 risk factor (pT3/4, Gleason 7-10, positive margins, preoperative PSA≥10 ng/ml) for recurrence after radical prostatectomy. Patients were randomised 1:1 to adjuvant RT ('Adjuvant-RT') or an observation policy with salvage RT for PSA failure ('Salvage-RT') defined as PSA≥0.1 ng/ml or three consecutive rises. Stratification factors were Gleason score, margin status, planned RT schedule (52.5 Gy/20 fractions or 66 Gy/33 fractions) and treatment centre. The primary outcome measure was freedom-from-distant-metastasis (FFDM), designed with 80% power to detect an improvement from 90% with Salvage-RT (control) to 95% at 10 years with Adjuvant-RT. Secondary outcome measures were biochemical progression-free survival, freedom from non-protocol hormone therapy, safety and patient-reported outcomes. Standard survival analysis methods were used; hazard ratio (HR)<1 favours Adjuvant-RT. RESULTS: Between October 2007 and December 2016, 1396 participants from UK, Denmark, Canada and Ireland were randomised: 699 Salvage-RT, 697 Adjuvant-RT. Allocated groups were balanced with a median age of 65 years. Ninety-three percent (649/697) Adjuvant-RT reported RT within 6 months after randomisation; 39% (270/699) Salvage-RT reported RT during follow-up. Median follow-up was 7.8 years. With 80 distant metastasis events, 10-year FFDM was 93% for Adjuvant-RT and 90% for Salvage-RT: HR=0.68 [95% confidence interval (CI) 0.43-1.07, P=0.095]. Of 109 deaths, 17 were due to prostate cancer. Overall survival was not improved (HR=0.980, 95% CI 0.667-1.440, P=0.917). Adjuvant-RT reported worse urinary and faecal incontinence 1 year after randomisation (P=0.001); faecal incontinence remained significant after 10 years (P=0.017). CONCLUSION: Long-term results from RADICALS-RT confirm adjuvant RT after radical prostatectomy increases the risk of urinary and bowel morbidity, but does not meaningfully improve disease control. An observation policy with salvage RT for PSA failure should be the current standard after radical prostatectomy. TRIAL IDENTIFICATION: RADICALS, RADICALS-RT, ISRCTN40814031, NCT00541047.

The natural history of low-risk non-muscle-invasive bladder cancer: a collaborative multi-centre study.

BACKGROUND: International guidelines vary in terms of their definition and recommendation for management of low-risk non-muscle-invasive bladder cancer (LRNMIBC). The ideal management for this large subset of bladder cancer patient remains unclear. OBJECTIVE: To evaluate long-term outcomes of patients with LRNMIBC. As a secondary objective, to assess for intergroup heterogeneity in disease-specific outcomes between G1 and G2LG diseases. METHODS: A multi-centre, retrospective study of patients who met the 2015 NICE definition of LRNMIBC. Timeline of diagnosis ranged from 01/01/2012 to 30/06/2016. RESULTS: A total 390 patients had available follow-up data (G1: 142, G2LG: 249). Over a median follow-up time of 36 months (IQR 25-50), 29.2% of the patients developed a recurrence. G2LG patients were statistically more likely to develop a recurrence (G1: 26.8%, G2LG: 33.7%, p < 0.05). 51.8% of recurrences occurred after 1 year of surveillance. Progression to high-grade disease occurred in 1.8% (n = 7, G1: 3, G2LG: 4) and a further 1.0% (n = 4, G1:3, G2LG: 1) of patients developed muscle-invasive bladder cancer (MIBC). CONCLUSION: The majority of recurrences occurred after 1 year of surveillance. The risk of disease progression was low; however, this was observed in a cohort of patients with regular cystoscopic follow-up. The risk may be higher if patients were pre-maturely discharged. If a 5-year surveillance programme were to be followed, 96.5% of recurrences would be captured. Lastly, there appears to be intergroup heterogeneity within LRNMIBC with G2LG patients having a statistically higher risk of recurrence compared to G1.

Addition of docetaxel to hormonal therapy in low- and high-burden metastatic hormone sensitive prostate cancer: long-term survival results from the STAMPEDE trial.

BACKGROUND: STAMPEDE has previously reported that the use of upfront docetaxel improved overall survival (OS) for metastatic hormone naïve prostate cancer patients starting long-term androgen deprivation therapy. We report on long-term outcomes stratified by metastatic burden for M1 patients. METHODS: We randomly allocated patients in 2 : 1 ratio to standard-of-care (SOC; control group) or SOC + docetaxel. Metastatic disease burden was categorised using retrospectively-collected baseline staging scans where available. Analysis used Cox regression models, adjusted for stratification factors, with emphasis on restricted mean survival time where hazards were non-proportional. RESULTS: Between 05 October 2005 and 31 March 2013, 1086 M1 patients were randomised to receive SOC (n = 724) or SOC + docetaxel (n = 362). Metastatic burden was assessable for 830/1086 (76%) patients; 362 (44%) had low and 468 (56%) high metastatic burden. Median follow-up was 78.2 months. There were 494 deaths on SOC (41% more than the previous report). There was good evidence of benefit of docetaxel over SOC on OS (HR = 0.81, 95% CI 0.69-0.95, P = 0.009) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P = 0.827). Analysis of other outcomes found evidence of benefit for docetaxel over SOC in failure-free survival (HR = 0.66, 95% CI 0.57-0.76, P < 0.001) and progression-free survival (HR = 0.69, 95% CI 0.59-0.81, P < 0.001) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P > 0.5 in each case). There was no evidence that docetaxel resulted in late toxicity compared with SOC: after 1 year, G3-5 toxicity was reported for 28% SOC and 27% docetaxel (in patients still on follow-up at 1 year without prior progression). CONCLUSIONS: The clinically significant benefit in survival for upfront docetaxel persists at longer follow-up, with no evidence that benefit differed by metastatic burden. We advocate that upfront docetaxel is considered for metastatic hormone naïve prostate cancer patients regardless of metastatic burden.

Adding abiraterone or docetaxel to long-term hormone therapy for prostate cancer: directly randomised data from the STAMPEDE multi-arm, multi-stage platform protocol.

Background: Adding abiraterone acetate with prednisolone (AAP) or docetaxel with prednisolone (DocP) to standard-of-care (SOC) each improved survival in systemic therapy for advanced or metastatic prostate cancer: evaluation of drug efficacy: a multi-arm multi-stage platform randomised controlled protocol recruiting patients with high-risk locally advanced or metastatic PCa starting long-term androgen deprivation therapy (ADT). The protocol provides the only direct, randomised comparative data of SOC + AAP versus SOC + DocP. Method: Recruitment to SOC + DocP and SOC + AAP overlapped November 2011 to March 2013. SOC was long-term ADT or, for most non-metastatic cases, ADT for ≥2 years and RT to the primary tumour. Stratified randomisation allocated pts 2 : 1 : 2 to SOC; SOC + docetaxel 75 mg/m2 3-weekly×6 + prednisolone 10 mg daily; or SOC + abiraterone acetate 1000 mg + prednisolone 5 mg daily. AAP duration depended on stage and intent to give radical RT. The primary outcome measure was death from any cause. Analyses used Cox proportional hazards and flexible parametric models, adjusted for stratification factors. This was not a formally powered comparison. A hazard ratio (HR) <1 favours SOC + AAP, and HR > 1 favours SOC + DocP. Results: A total of 566 consenting patients were contemporaneously randomised: 189 SOC + DocP and 377 SOC + AAP. The patients, balanced by allocated treatment were: 342 (60%) M1; 429 (76%) Gleason 8-10; 449 (79%) WHO performance status 0; median age 66 years and median PSA 56 ng/ml. With median follow-up 4 years, 149 deaths were reported. For overall survival, HR = 1.16 (95% CI 0.82-1.65); failure-free survival HR = 0.51 (95% CI 0.39-0.67); progression-free survival HR = 0.65 (95% CI 0.48-0.88); metastasis-free survival HR = 0.77 (95% CI 0.57-1.03); prostate cancer-specific survival HR = 1.02 (0.70-1.49); and symptomatic skeletal events HR = 0.83 (95% CI 0.55-1.25). In the safety population, the proportion reporting ≥1 grade 3, 4 or 5 adverse events ever was 36%, 13% and 1% SOC + DocP, and 40%, 7% and 1% SOC + AAP; prevalence 11% at 1 and 2 years on both arms. Relapse treatment patterns varied by arm. Conclusions: This direct, randomised comparative analysis of two new treatment standards for hormone-naïve prostate cancer showed no evidence of a difference in overall or prostate cancer-specific survival, nor in other important outcomes such as symptomatic skeletal events. Worst toxicity grade over entire time on trial was similar but comprised different toxicities in line with the known properties of the drugs. Trial registration: Clinicaltrials.gov: NCT00268476.

Low-temperature plasma treatment induces DNA damage leading to necrotic cell death in primary prostate epithelial cells.

BACKGROUND: In recent years, the rapidly advancing field of low-temperature atmospheric pressure plasmas has shown considerable promise for future translational biomedical applications, including cancer therapy, through the generation of reactive oxygen and nitrogen species. METHOD: The cytopathic effect of low-temperature plasma was first verified in two commonly used prostate cell lines: BPH-1 and PC-3 cells. The study was then extended to analyse the effects in paired normal and tumour (Gleason grade 7) prostate epithelial cells cultured directly from patient tissue. Hydrogen peroxide (H2O2) and staurosporine were used as controls throughout. RESULTS: Low-temperature plasma (LTP) exposure resulted in high levels of DNA damage, a reduction in cell viability, and colony-forming ability. H2O2 formed in the culture medium was a likely facilitator of these effects. Necrosis and autophagy were recorded in primary cells, whereas cell lines exhibited apoptosis and necrosis. CONCLUSIONS: This study demonstrates that LTP treatment causes cytotoxic insult in primary prostate cells, leading to rapid necrotic cell death. It also highlights the need to study primary cultures in order to gain more realistic insight into patient response.

DNA hypermethylation in prostate cancer is a consequence of aberrant epithelial differentiation and hyperproliferation.

Prostate cancer (CaP) is mostly composed of luminal-like differentiated cells, but contains a small subpopulation of basal cells (including stem-like cells), which can proliferate and differentiate into luminal-like cells. In cancers, CpG island hypermethylation has been associated with gene downregulation, but the causal relationship between the two phenomena is still debated. Here we clarify the origin and function of CpG island hypermethylation in CaP, in the context of a cancer cell hierarchy and epithelial differentiation, by analysis of separated basal and luminal cells from cancers. For a set of genes (including GSTP1) that are hypermethylated in CaP, gene downregulation is the result of cell differentiation and is not cancer specific. Hypermethylation is however seen in more differentiated cancer cells and is promoted by hyperproliferation. These genes are maintained as actively expressed and methylation-free in undifferentiated CaP cells, and their hypermethylation is not essential for either tumour development or expansion. We present evidence for the causes and the dynamics of CpG island hypermethylation in CaP, showing that, for a specific set of genes, promoter methylation is downstream of gene downregulation and is not a driver of gene repression, while gene repression is a result of tissue-specific differentiation.

HDAC inhibitor confers radiosensitivity to prostate stem-like cells.

BACKGROUND: Radiotherapy can be an effective treatment for prostate cancer, but radiorecurrent tumours do develop. Considering prostate cancer heterogeneity, we hypothesised that primitive stem-like cells may constitute the radiation-resistant fraction. METHODS: Primary cultures were derived from patients undergoing resection for prostate cancer or benign prostatic hyperplasia. After short-term culture, three populations of cells were sorted, reflecting the prostate epithelial hierarchy, namely stem-like cells (SCs, α2ß1integrin(hi)/CD133(+)), transit-amplifying (TA, α2ß1integrin(hi)/CD133(-)) and committed basal (CB, α2ß1integrin(lo)) cells. Radiosensitivity was measured by colony-forming efficiency (CFE) and DNA damage by comet assay and DNA damage foci quantification. Immunofluorescence and flow cytometry were used to measure heterochromatin. The HDAC (histone deacetylase) inhibitor Trichostatin A was used as a radiosensitiser. RESULTS: Stem-like cells had increased CFE post irradiation compared with the more differentiated cells (TA and CB). The SC population sustained fewer lethal double-strand breaks than either TA or CB cells, which correlated with SCs being less proliferative and having increased levels of heterochromatin. Finally, treatment with an HDAC inhibitor sensitised the SCs to radiation. INTERPRETATION: Prostate SCs are more radioresistant than more differentiated cell populations. We suggest that the primitive cells survive radiation therapy and that pre-treatment with HDAC inhibitors may sensitise this resistant fraction.

Retinoic acid represses invasion and stem cell phenotype by induction of the metastasis suppressors RARRES1 and LXN.

The mouse haematopoietic stem cell (SC) regulator Latexin (LXN) is the only known homologue of the retinoic acid receptor responder 1 (RARRES1) gene. Both genes lie adjacent on chromosome 3 and differ mostly by the presence of a transmembrane domain in RARRES1. Despite their homology, it is not known whether they possess similar regulatory mechanisms, cellular localization and function. Here, we identified RARRES1 and LXN as highly significantly downregulated genes in human prostate SCs, whose expression was induced by the pro-differentiation agent all-trans retinoic acid (atRA). AtRA induced expression in the most differentiated cells compared with the SC fraction, suggesting that this subpopulation was less responsive to atRA. Small interfering RNA suppression of RARRES1 and LXN enhanced the SC properties of primary prostate cultures, as shown by a significant increase in their colony-forming ability. Expression of both RARRES1 and LXN was co-ordinately repressed by DNA methylation in prostate cancer cell lines and inhibition of RARRES1 and LXN increased the invasive capacity of primary prostate cultures, which also fully rescued an inhibitory effect induced by atRA. Moreover, we showed that RARRES1 and LXN reside within different sub-cellular compartments, providing evidence that RARRES1 is not a plasma membrane protein as previously supposed but is located primarily in the endoplasmic reticulum; whereas LXN was detected in the nucleus of prostate epithelial cells. Thus, LXN and RARRES1 are potential tumour suppressor genes, which are co-ordinately regulated, SC-silenced genes functioning to suppress invasion and colony-forming ability of prostate cancer cells; yet the proteins reside within different sub-cellular compartments.

Use of granulated sugar therapy in the management of sloughy or necrotic wounds: a pilot study.

OBJECTIVE: To determine the in vitro antimicrobial efficacy of three types of sugar and conduct a pilot clinical study with a view to developing a protocol for a randomised controlled trial (RCT). METHOD: In the in vitro studies three types of granulated sugar (Demerara, granulated beet sugar and granulated cane sugar) were tested to determine their minimum inhibitory concentrations (MICs) against 18 Gram-negative and Gram-positive bacteria in a micro-titre broth dilution assay; growth inhibition of Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa in different concentrations of sugar (0.38-25%) was also tested over 12-hours in an agar diffusion assay. The pilot clinical study selected patients from a vascular surgical ward and a vascular outpatient department. All had acute or chronic exuding wounds, some of which were infected. White granulated sugar was applied to the wounds. The following parameters were assessed: surface area; wound characteristics including pain, malodour, appearance (slough/granulation); exudate level; pain level and bacterial load. Patients with diabetes had their blood sugar levels checked daily. All patients completed a short health questionnaire at the start and end of the study. Staff completed a satisfaction questionnaire at the end of the study. The study period was 21 days. RESULTS: In vitro tests demonstrated that sugar inhibits bacterial growth. All three types of sugars had MICs ranging from 6-25% in the bacterial strains tested. The diffusion tests showed that strains were able to grow well in low concentrations of sugar but were completely inhibited in higher concentrations. The two granulated sugars were found to be slightly more effective than Demerara sugar, so the latter was excluded from the clinical pilot study. Twenty-two patients (20 inpatients and two outpatients) with sloughy or necrotic wounds were recruited into the clinical study. Two patients had MRSA and two had Staphylococcus colonisation at baseline. Blood sugar levels remained stable in the seven patients with insulin-dependent diabetes mellitus. All wounds were clean/debrided in a mean of 11.13 days. Pain and malodour reduced markedly. Patient and staff surveys revealed overwhelming support for the sugar therapy. CONCLUSION: The pilot study achieved its aim of developing a protocol for a RCT. Preliminary data suggest that sugar is an effective wound cleansing and is safe to use in patients with insulin-dependent diabetes. In vitro studies demonstrate that sugar inhibits bacterial growth. CONFLICT OF INTEREST: None.

MRSA screening in the vascular day-case population.

INTRODUCTION: The UK Government has prioritised methicillin-resistant Staphylococcus aureus (MRSA) screening and new operational guidance has instructed that all day-case surgical patients should be screened from April 2009. We sought to identify the number of MRSA-positive patients in the vascular day-case population over a 1-year period and to profile this cohort in terms of risk-factors for MRSA. We also sought to identify whether the new guidance from the Department of Health (DH) had resulted in increased screening rates. PATIENTS AND METHODS: Electronic records and laboratory culture results were prospectively consulted to identify whether patients had been screened and if MRSA had been isolated. Consideration was given to whether any patients had a delayed discharge or subsequent admission with an MRSA-related complication. RESULTS: Six patients (2.1%) screened MRSA-positive (DH estimate 7%); five were previously known to be MRSA-positive, therefore only 0.36% patients were newly-identified as MRSA-positive. The proportion of patients screened increased from 35% to 72.5% after April 2009, in accordance with DH guidance. Successful decolonisation was proved in two patients (33.3%). CONCLUSIONS: There is dispute with several of the key assumptions behind the DH's impact assessment justifying an expanded MRSA-screening policy. It is not cost-effective to screen all vascular day-case admissions. We recommend selective screening for patients previously identified as MRSA-positive, or considered high risk.

The genetic basis of colorectal cancer in a population-based incident cohort with a high rate of familial disease.

BACKGROUND AND AIMS: Colorectal cancer (CRC) is the second most frequent cancer in developed countries. Newfoundland has the highest incidence of CRC in Canada and the highest rate of familial CRC yet reported in the world. To determine the impact of mutations in known CRC susceptibility genes and the contribution of the known pathways to the development of hereditary CRC, an incident cohort of 750 patients with CRC (708 different families) from the Newfoundland population was studied. METHODS: Microsatellite instability (MSI) testing was performed on tumours, together with immunohistochemistry analysis for mismatch repair (MMR) genes. Where indicated, DNA sequencing and multiplex ligation-dependent probe amplifications of MMR genes and APC was undertaken. DNA from all patients was screened for MUTYH mutations. The presence of the BRAF variant, p.V600E, and of MLH1 promoter methylation was also tested in tumours. RESULTS: 4.6% of patients fulfilled the Amsterdam criteria (AC), and an additional 44.6% fulfilled the revised Bethesda criteria. MSI-high (MSI-H) was observed in 10.7% (n=78) of 732 tumours. In 3.6% (n=27) of patients, CRC was attributed to 12 different inherited mutations in six known CRC-related genes associated with chromosomal instability or MSI pathways. Seven patients (0.9%) carried a mutation in APC or biallelic mutations in MUTYH. Of 20 patients (2.7%) with mutations in MMR genes, 14 (70%) had one of two MSH2 founder mutations. 17 of 28 (61%) AC families did not have a genetic cause identified, of which 15 kindreds fulfilled the criteria for familial CRC type X (FCCTX). CONCLUSIONS: Founder mutations accounted for only 2.1% of cases and this was insufficient to explain the high rate of familial CRC. Many of the families classified as FCCTX may have highly penetrant mutations segregating in a Mendelian-like manner. These families will be important for identifying additional CRC susceptibility loci.

Use of durometry in assessment of venous disease.

OBJECTIVES: Ulceration of the lower limbs is a common debilitating complication of chronic venous hypertension. Detection of preulcerative skin changes would allow for identification of high-risk patients; early active treatment may prevent ulcer formation. METHODS: Patients with isolated venous disease and volunteers attending outpatient clinics underwent assessment of their clinical, aetiological, anatomical and pathological (CEAP) classification. We employed an industrial durometer, an instrument that measures the hardness of metals and plastic, to assess skin induration. The durometer probe was rested perpendicular on their skin 15 cm above the medial malleolus in non-ulcerated tissue, with the patient and limb in recumbency. The average of four measurements was derived. RESULTS: In 107 people, 203 lower limbs (mean age 55.6 years) were assessed. A significant difference in durometry readings was demonstrated between patients with CEAP classes 0, 1 and 2, and those with classes 4, 5 and 6 (P < 0.0005). There was statistically significant evidence that age and CEAP classification correlated with durometry (P < 0.0001). CONCLUSION: Durometry is of potential value in the assessment and monitoring of preulcerative venous disease, and could help to identify high-risk patients. This would assist in the institution of timely and appropriate treatment.

Surgical treatment of the neuroischemic foot.

As many as 1% of older people in the Western world are at risk of developing a foot ulcer as a complication of diabetes mellitus. The resultant debility and disability constitutes a burden for both individuals and their health services. When peripheral arterial insufficiency complicates neuropathy there is a tenfold risk of ulceration progressing to infection, gangrene and amputation. Patient education and the vigilant implementation of preventive measures offer the best prospects for containment of the problem. Patients faced with ulceration and limb loss require access to a co-ordinated and comprehensive diabetic foot service offering detailed assessment and a full range of social, medical and surgical therapies.

Local versus general anaesthesia for varicose veins surgery: a prospective non-randomized controlled trial.

OBJECTIVE: To compare the acceptability and outcome of primary varicose vein (VV) surgery (saphenofemoral or saphenopopliteal ligation/excision) under local anaesthesia (LA) with that of general anaesthesia (GA). METHODS: A non-randomized controlled trial of consecutive patients treated between April 2004 and March 2006 was performed. After complete informed consent individual patients were asked to select their preferred form of anaesthesia (LA or GA). Preoperative disease status and co-morbidities were recorded. Outcomes were assessed perioperatively and at six weeks and six months postoperatively using patient scoring systems including the Aberdeen varicose veins severity score (AVVSS). RESULTS: Seventy-two (LA 46[62%] and GA 26[38%]) patients participated; median (range) age was 48 (21-74) years versus 36 (21-59) years (P = 0.0164), respectively. All procedures were performed as day cases. Median postoperative pain scores for LA and GA did not differ at 12 hours (4 versus 4; P = 0.48) and four days (5 versus 6; P = 0.44). Median improvement in the AVVSS at six weeks and six months for LA and GA cohorts were 5.7 versus 6.1 (P = 0.875) and 6.5 versus 8.3 (P = 0.131), respectively. Overall patient satisfaction did not show any intergroup difference at six weeks. CONCLUSIONS: Surgical treatment of VV under LA can be performed safely with comparable results to GA in self-selected patients.

The use of autologous femoral vein for the repair of the common iliac vein after resection of a pheochromocytoma.

AIM: To illustrate the use of autologous femoral vein for grafting ilio-caval vein defects following abdomino-pelvic tumour resections. METHODS: Case report and literature review. RESULTS: Durable restoration of ilio-caval patency was achieved, with minimal morbidity from graft harvesting. CONCLUSIONS: Autologous femoral vein presents a viable graft option for the immediate reconstruction of large intra-abdominal vein deficits.

Long-term results of surgical repair of popliteal artery aneurysm.

OBJECTIVE: To determine the long-term outcome of surgical repair of popliteal artery aneurysms (PAA). METHODS: A retrospective review of consecutive patients who underwent surgical PAA repair in two vascular surgery units between 1988 and 2006 was performed. Primary and secondary graft patency, limb salvage and patient survival rates were determined using Kaplan-Meier methods. RESULTS: 48 patients underwent repair of 63 PAAs (ligation and bypass=45, interposition grafting=18). The 5-year primary graft patency, secondary graft patency, limb salvage and patient survival rates were 75%, 95%, 98% and 81%, respectively. The 10-year primary graft patency rates were significantly lower for emergency cases (59%) compared with elective cases (66%) (p=0.0023). Thirteen patients (16 PAAs) required a total of 20 late re-interventions. Duplex ultrasound was available in 33 of 45 PAAs treated by ligation and bypass. Five (15%) PAAs demonstrated perfusion of the aneurysm sac at median (range) follow up of 75 (1-246) months after primary repair and two of these required emergency re-operation. CONCLUSIONS: These data demonstrate that surgical PAA repair is associated with excellent long-term durability and provide an important benchmark with which to compare results of endovascular PAA repair. Patients treated using the ligation and bypass technique should be enrolled in an aneurysm sac surveillance program.

Oesophageal substitution with free and pedicled jejunum: short- and long-term outcomes.

In children, the indications for oesophageal substitution are principally, long gap oesophageal atresia (OA), severe anastomotic disruption following primary repair of OA and severe caustic or peptic strictures. We present an outcome review of eight cases who underwent oesophageal substitution with jejunum at our institution between 1986 and 2001. The purpose of this study was to evaluate our experience with free/pedicled jejunal grafts and its long-term outcome as an oesophageal substitute. Operative and postoperative outcome with free and pedicled jejunal grafts in four cases of pure OA, two cases of OA and distal tracheo-oesophageal fistula (TOF), one patient with a high retrolaryngeal oesophageal web and one case of severe caustic oesophageal stricture. Six patients had an oesophagostomy and a gastrostomy fashioned previously. Eleven free jejunal grafts were performed in six patients (three intraoperative redo interpositions for immediate graft loss, three separate grafts in one patient and two free grafts in two patients). One patient's pedicled jejunal graft proximally required microvascular anastomosis while the other had a pedicled graft without microvascular anastomosis. Early postoperative complications included four upper anastomotic leaks (three free grafts, one pedicled with microvascular support), pneumothorax requiring prolonged ventilation and Horner's syndrome. Recurrent laryngeal nerve injury occurred in the patient who had a high retrolaryngeal oesophageal web. During follow up (5-18 years) late complications of upper anastomotic stricture in four patients and graft redundancy with subsequent kinking of the lower anastomosis were observed in one patient. Three patients established a complete oral diet; a further three patients relied on supplemental gastrostomy feeds and one patient is entirely gastrostomy fed. There were two late deaths, one from aspiration and the other from a severe asthmatic attack (5 and 7 months postoperatively, respectively). Our results indicate that there are significant complications related to the use of free jejunal grafts. Early recognition and treatment are of paramount importance in the ultimate achievement of a successful technical outcome.

Management of the gastrointestinal tract at the time of cystectomy.

Radical cystectomy impacts on the gastro-intestinal tract in several ways. Clearly there is the need for bowel mobilisation, resection and anastamosis in order to create a urinary diversion, and the use of bowel preparation or antibiotics are controversial topics. Post-operatively ileus is common and there is debate about the routine use of NG tubes. Early enteral feeding is a modern concept but not yet proven. In the long-term there can be problems such as diarrhoea and B12 deficiency. All of these issues are discussed in this review using the latest available evidence.