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.

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.

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.

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.

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.

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.

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.

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.

Fractionated stereotactic external beam radiotherapy in the management of brain metastases.

24 patients with 28 brain metastases were treated with fractionated stereotactic radiotherapy (SRT). Doses ranged from 10 Gy in two fractions to 20 Gy in two fractions. 13 patients received SRT boost after whole brain radiotherapy (WBRT), 5 were treated with SRT alone and 6 were treated at the time of recurrence following WBRT. The median progression-free survival at the treated site was 18 months and the median survival was 18 months. All patients were treated without admission to hospital. Toxicity of fractionated SRT was minimal and patients treated without WBRT did not suffer significant alopecia. Fractionated SRT offers a non-toxic non-invasive alternative to excision surgery in patients with solitary brain metastases. The optimum fractionation schedule and the role of whole brain irradiation remain to be determined.

Hypofractionated stereotactic radiotherapy in the management of recurrent glioma.

PURPOSE: This study aimed to assess the efficacy and toxicity of hypofractionated stereotactic radiotherapy (SRT) in the management of patients with recurrent glioma. METHODS AND MATERIALS: From January 1989 to July 1994, 36 patients with glioma were treated at the time of recurrence. Twenty-nine had recurrent high-grade astrocytoma, 3 high-grade oligodendroglioma, 1 high-grade ependymoma, and 3 pilocytic astrocytoma. Hypofractionated stereotactic radiotherapy was given using either three noncoplanar arcs or four to six noncoplanar fixed beams at 5 Gy/fraction, to doses ranging from 20 to 50 Gy initially on a dose escalation program. Two patients received 20 Gy, 8 received 30 Gy, 10 received 35 Gy, 10 received 40 Gy, 5 received 45 Gy, and 1 received 50 Gy, treating 5 days/week. RESULTS: The median survival of 29 patients with recurrent high-grade astrocytoma was 11 months from the time of SRT. This compared to a median survival of 7 months for a cohort matched for age, performance status, and initial histologic grade who received nitrosourea-based chemotherapy at recurrence (p < 0.05). Initial low-grade astrocytoma histology was the only favorable prognostic factor for survival on univariate analysis. Three patients with recurrent oligodendroglioma remain alive 11, 23, and 34 months after SRT. Three children treated for recurrent pilocytic astrocytoma remain alive 14, 41, and 55 months following SRT. Presumed radiation damage, defined as reversible steroid-dependent toxicity, was observed in 13 patients (36%) and required reoperation in 2 (6%). A total dose of >40 Gy was a major predictor of radiation damage (p < 0.005). CONCLUSION: Hypofractionated SRT is a noninvasive, well-tolerated, outpatient-based method of delivering palliative, high-dose, focal irradiation.

Quality assurance in fractionated stereotactic radiotherapy.

The recent development of fractionated stereotactic radiotherapy (SRT), which utilises the relocatable Gill-Thomas-Cosman frame (GTC 'repeat localiser'), requires comprehensive quality assurance (QA). This paper focuses on those QA procedures particularly relevant to fractionated SRT treatments, and which have been derived from the technique used at the Royal Marsden Hospital. They primarily relate to the following: (i) GTC frame fitting, initially in the mould room, and then at each imaging session and treatment fraction; (ii) checking of the linear accelerator beam geometry and alignment lasers; and (iii) setting up of the patient for each fraction of treatment. The precision of the fractionated technique therefore depends on monitoring the GTC frame relocation at each fitting, checking the accuracy of the radiation isocentre of the treatment unit, its coincidence with the patient alignment lasers and the adjustments required to set the patient up accurately. The results of our quality control checks show that setting up to a mean radiation isocentre using precisely set-up alignment lasers can be achievable to within 1 mm accuracy. When this is combined with a mean GTC frame relocatability of 1 mm on the patient, a 2-mm allowance between the prescribed isodose surface and the defined target volume is a realistic safety margin for this technique.

Efficacy and toxicity of fractionated stereotactic radiotherapy in the treatment of recurrent gliomas (phase I/II study).

Twenty-two patients with recurrent glioma have been treated on a dose escalation protocol with fractionated stereotactic external beam radiotherapy (SRT). All had previously received radical radiotherapy (median dose 55 Gy) as part of the initial treatment. The dose of SRT was increased from 30 Gy in six fractions to 50 Gy in ten fractions. Median survival from the date of SRT was 9.8 months. There was no significant acute morbidity but five patients who received > or = 40 Gy developed steroid responsive neurological deterioration assumed to represent late radiation damage. The survival and toxicity in patients with recurrent glioma are comparable with interstitial therapy. Fractionated SRT is a noninvasive form of localised radiation which may be a suitable alternative to interstitial therapy in this group of patients.

Stereotactic radiotherapy of irregular targets: a comparison between static conformal beams and non-coplanar arcs.

Stereotactic radiotherapy using a linear accelerator is usually equated with the technique of delivery using multiple non-coplanar arcs, which achieves a spherical dose distribution. As the majority of intracranial lesions are not spherical, a range of schematized tumour shapes were planned to assess the role of static conformal beams in the treatment of irregular lesions. A sphere and 2 ellipsoids, ranging from 20 to 50 mm maximum diameter located intracranially were planned using 3, 4, and 6 non-coplanar static beams with conformal blocks and were compared with four 120 degree non-coplanar arcs. Comparison of the plans was made by the relative sparing of normal tissue outside the target volume using three-dimensional dose-volume distributions. Non-coplanar arcs spared more normal tissue at low isodoses and achieved the best high dose sparing for spherical targets. For the majority of irregular targets, 3 and 4 static beams spared more tissue at doses > or = 50% and > or = 80% than the arc technique. For all irregular volumes, maximum sparing of normal tissue to isodoses > or = 50% and > or = 80% of the treatment isodose was obtained with 6 static conformal beams. We conclude that irregularly shaped tumours suitable for stereotactic radiotherapy with a linear accelerator are better treated with conformal static non-coplanar beams rather than with the multiple arc technique.

Thorotrast granuloma: an unexpected diagnosis.

An example of a Thorotrast granuloma (thorotrastoma) occurred in the neck of a patient 44 years after a carotid angiogram in which Thorotrast was used as radiological contrast medium. The lesion had produced a "cold" abscess and the patient was undergoing treatment for retropharyngeal tuberculosis. Thorotrast leakage can produce unusual clinical symptoms and signs which are frequently misdiagnosed.

Feasibility of new prognostic classification for rectal cancer.

Sixty slides from 60 blocks taken from 30 colonic carcinomas were circulated twice to six histopathologists of varying experience. Five of the six pathologists showed a good to excellent intraobserver agreement for assessment of the character of the invasive margin (0.44 less than kappa less than 0.82), which was not significantly affected by sampling (0.40 less than kappa less than 0.56, comparing both slides from each tumour) or observer (five of six pathologists agreeing on 46 of 60 slides). Pathologists were unreliable in assessing peritumoural lymphocytic infiltrates, with only two pathologists achieving moderate levels of intraobserver agreement (-0.03 less than kappa less than 0.52). The interobserver agreement for peritumoural lymphocytic infiltrates was also low (kappa less than 0.29) between the three most experienced pathologists. The assessment of peritumoural lymphocytic infiltrates was significantly affected by sampling, the two pathologists with the lowest intraobserver variation achieving kappa values of 0.21 and 0.10 between the 30 paired slides from each tumour. The character of the invasive margin was reliably assessed, was not dependent on sample, and added useful prognostic information, but peritumoural lymphocytic infiltration is not a reproducible observation and may therefore not add useful prognostic information in routine use.

Failure of conventionally fractionated radiotherapy to decrease the risk of hemorrhage in inoperable arteriovenous malformations.

Twenty-six patients with arteriovenous malformations (AVMs) were treated between 1965 and 1986 with conventional fractionated radiotherapy at the Royal Marsden Hospital. There were 14 male patients and 12 female, aged 11 to 57 years (median, 24 yr). Twenty-five patients completed radiotherapy with a localized treatment target volume of a dose of 40 to 54 Gy. The median follow-up was 14.5 years. Eleven patients had an additional hemorrhage. The actuarial annual risk of bleeding was 2.3%, which is similar to that found in untreated patients. Follow-up angiograms were performed in 11 patients, and 10 showed persistence of AVM. The results suggest that fractionated radiotherapy in conventional doses does not make a large impact on the risk of hemorrhage in patients with inoperable AVMs, and, where possible, stereotactic external beam radiotherapy/radiosurgery should be employed.

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.

Feasibility of patient immobilization for conventional cranial irradiation with a relocatable stereotactic frame.

The precision of patient repositioning and the firmness of immobilization are among the major determinants of the accuracy of radiation treatment delivery. A relocatable Gill-Thomas localizer (GTL) developed for neurosurgery and stereotactic radiotherapy achieves highly accurate relocation and immobilization and has been used successfully for fractionated stereotactic radiotherapy of intracranial lesions. The feasibility of using GTL for immobilization in conventional fractionated external beam radiotherapy was assessed by comparison with conventional Cabulite shell head fixation. The GTL was well tolerated at the time of preparation and during a 5 week course of radiotherapy. The principal advantage was superior relocation accuracy maintained throughout the course of treatment, high precision of field set-up and markedly reduced production time. In addition the time taken to position the patient in the treatment room was also marginally shortened. GTL is therefore a feasible method of head fixation for conventional cranial irradiation providing patients have adequate dentition. With further development the relocatable method of immobilization originally designed for stereotactic radiotherapy may become the preferred technique particularly in situations where high accuracy is desirable, such as stereotactically guided conformal radiotherapy.