Development and Validation of a Short Version of the Metric for the Observation of Decision-Making in Multidisciplinary Tumor Boards: MODe-Lite.

BACKGROUND: Evidence-based tools are necessary for scientifically improving the way MTBs work. Such tools are available but can be difficult to use. This study aimed to develop a robust observational assessment tool for use on cancer multidisciplinary tumor boards (MTBs) by health care professionals in everyday practice. METHODS: A retrospective cross-sectional observational study was conducted in the United Kingdom from September 2015 to July 2016. Three tumor boards from three teaching hospitals were recruited, with 44 members overall. Six weekly meetings involving 146 consecutive cases were video-recorded and scored using the validated MODe tool. Data were subjected to reliability and validity analysis in the current study to develop a shorter version of the MODe. RESULTS: Phase 1, a reduction of the original items in the MODe, was achieved through two focus group meetings with expert assessors based on previous research. The 12 original items were reduced to 6 domains, receiving full agreement by the assessors. In phase 2, the six domains were subjected to item reliability, convergent validation, and internal consistency testing against the MODe-Lite global score, the MODe global score, and the items of the MODe. Significant positive correlations were evident across all domains (p < 0.01), indicating good reliability and validity. In phase 3, feasibility and high inter-assessor reliability were achieved by two clinical assessors. Six domains measuring clinical input, holistic input, clinical collaboration, pathology, radiology, and management plan were integrated into MODe-Lite. CONCLUSIONS: As an evidence-based tool for health care professionals in everyday practice, MODe-Lite gives cancer MTBs insight into the way they work and facilitates improvements in practice.

Adjuvant therapy in renal cell carcinoma: does higher risk for recurrence improve the chance for success?

The success of targeted therapies, including inhibitors of the vascular endothelial growth factor pathway or the mammalian target of rapamycin, in the treatment of metastatic renal cell carcinoma led to interest in testing their efficacy in the adjuvant setting. Results from the first trials are now available, with other studies due to report imminently. This review provides an overview of adjuvant targeted therapy in renal cell carcinoma, including interpretation of currently available conflicting data and future direction of research. We discuss the key differences between the completed targeted therapy adjuvant trials, and highlight the importance of accurately identifying patients who are likely to benefit from adjuvant treatment. We also consider reasons why blinded independent radiology review and treatment dose may prove critical for adjuvant treatment success. The implications of using disease-free survival as a surrogate end point for overall survival from the patient perspective and measurement of health benefit have recently been brought into focus and are discussed. Finally, we discuss how the ongoing adjuvant trials with targeted therapies and checkpoint inhibitors may improve our understanding and ability to prevent tumor recurrence after nephrectomy in the future.

European temporal trends in the use of lymph node dissection in patients with renal cancer.

BACKGROUND: The role of lymph node dissection (LND) in renal cell carcinoma (RCC) is still under debate. We aimed to assess the utilization rates of LND over time in Europe. METHODS: A multi-institutional database of 13,581 RCC patients who underwent radical nephrectomy (RN) or nephron sparing surgery (NSS) between 1988 and 2014 was created within an European consortium. We analysed temporal trends in the frequency of LND by using Joinpoint regression. Logistic regression models were used to identify predictors of LND. RESULTS: Overall, 5114 patients (42.7%) underwent LND. Lymph node invasion was recorded in 566 cases (11% of LND patients) which represents 4.7% of the whole study cohort. A gradual decline in the use of LND started in the 1990s. After 2008 LND decreased significantly by 21.5% per year (95%CI -33.3 to -7.5, p < 0.01) until 2011 and stabilized thereafter (Annual Percentage Change 4.9%, 95%CI -3.4 to 13.8, p = 0.2). At multivariable analyses, patient age (OR 0.98, p < 0.0001), type of surgery (RN vs. NSS: OR 5.46, p < 0.0001), surgical approach (open vs. minimally invasive: OR 1.75, p < 0.0001), T stage (T2 vs. T1: OR 1.57; T3-4 vs. T1: OR 1.44, p < 0.0001), clinical tumour size (OR 1.14, p < 0.0001), and year of surgery (OR 0.95, p < 0.0001) were associated with higher probability of LND at nephrectomy. CONCLUSIONS: A trend towards lower LND was observed over time for RCC patients who underwent RN or NSS. LND is more frequently performed in younger patients, locally advanced diseases and in case of open surgery.

Meta-analysis of the prevalence of renal cancer detected by abdominal ultrasonography.

BACKGROUND: The potential for an ultrasound-based screening programme for renal cell carcinoma (RCC) to improve survival through early detection has been the subject of much debate. The prevalence of ultrasound-detected asymptomatic RCC is an important first step to establishing whether a screening programme may be feasible. METHODS: A systematic search of MEDLINE and Embase was performed up to March 2016 to identify studies reporting the prevalence of renal masses and RCC. Two populations of patients were chosen: asymptomatic individuals undergoing screening ultrasonography and patients undergoing ultrasonography for abdominal symptoms not related to RCC. A random-effects meta-analysis was performed. Study quality was evaluated using a validated eight-point checklist. RESULTS: Sixteen studies (413 551 patients) were included in the final analysis. The pooled prevalence of renal mass was 0·36 (95 per cent c.i. 0·23 to 0·52) per cent and the prevalence of histologically proven RCC was 0·10 (0·06 to 0·15) per cent. The prevalence of RCC was more than double in studies from Europe and North America than in those from Asia: 0·17 (0·09 to 0·27) versus 0·06 (0·03 to 0·09) per cent respectively. Data on 205 screen-detected RCCs showed that 84·4 per cent of tumours were stage T1-T2 N0, 13·7 per cent were T3-T4 N0, and only 2·0 per cent had positive nodes or metastases at diagnosis. CONCLUSION: At least one RCC would be detected per 1000 individuals screened. The majority of tumours identified are early stage (T1-T2).

Matched pair analysis of laparoscopic versus open radical nephrectomy for the treatment of T3 renal cell carcinoma.

PURPOSE: The perioperative and oncological outcomes of laparoscopic radical nephrectomy (LRN) for T1-T2 renal cell carcinoma (RCC) are well established. We aim to determine whether LRN is a comparable alternative to open radical nephrectomy (ORN) in the treatment of T3 RCC using a matched pair analysis study design. METHODS: A review of a prospectively collected database at the Western General Hospital, Edinburgh, between 2000 and 2011 was conducted. Patient pairs were matched based on age at operation, gender, histological subgroup, maximal tumour diameter, TNM stage and grade. Patient demographics, operative and post-operative outcomes were compared. Overall, cancer-specific and progression-free survival [overall survival, cancer-specific survival (CSS) and progression-free survival (PFS)] were estimated using the Kaplan-Meier method. RESULTS: From 252 patients with T3 disease, 25 pairs were matched. Patients were of median age 66.2 years, 64 % male. Tumours were all clear cell RCC, were stage pT3a (32 %) or pT3b and had maximal tumour diameters of 8.7 cm for LRN and 10.0 cm for ORN. Estimated blood loss (100 ml LRN; 650 ml ORN, p < 0.001) and length of post-operative hospital stay (4 days LRN: 9 days ORN, p < 0.001) were lower in the LRN group. Operation time and post-operative complication rates were comparable. CSS and PFS were comparable with a mean CSS of 91.3 months for LRN and 88.7 months for ORN. CONCLUSION: This study reports the longest median follow-up in a T3 LRN cohort. In matched patients, LRN has been shown to have a superior perioperative profile to ORN for the treatment of pT3a/b RCC, with no adverse effect on midterm oncological outcomes.

Analysis of the pentafecta learning curve for laparoscopic radical prostatectomy.

PURPOSE: Laparoscopic radical prostatectomy (LRP) has a long learning curve; however, little is known about the pentafecta learning curve for LRP. We analysed the learning curve for a fellowship trained surgeon with regard to the pentafecta with up to 6-year follow-up. METHODS: A retrospective review was performed in 550 cases, by dividing these cases into 11 groups of 50 patients. Outcomes analysed were the following: (1) the pentafecta (complication rate, positive surgical margin (PSM) rate, continence, potency and biochemical recurrence); (2) operative time and blood loss; and (3) overall pentafecta attainment. RESULTS: The mean complication rate for the entire series was 9 %; this plateaued after 150 cases. The overall PSM rate for the series was 23.5 %, 16.3 % for pT2 and 40.5 % for pT3. PSM plateaued after 200 cases. Excluding the first 100 cases, the overall PSM rate for pT2 was 10.9 % and 37.8 % for pT3. The continence rate stabilised after approximately 250 cases. The rate of male sling/artificial urinary sphincter plateaued after 200 cases. The potency learning curve continues to improve after 250 cases of nerve-sparing (ns) endoscopic extraperitoneal radical prostatectomy (EERPE) as does the pentafecta learning curve which closely follows the pattern of the potency learning curve. The last group of nsEERPE achieved pentafecta in 63 %. CONCLUSION: This study shows multiple learning curves: an initial for peri-operative outcomes, then stabilisation of oncologic outcomes and the final for stabilisation of functional outcomes. In this series over 250 cases were required to achieve the learning curve.

A prospective evaluation of VEGF-targeted treatment cessation in metastatic clear cell renal cancer.

BACKGROUND: Vascular endothelial growth factor (VEGF)-targeted therapy is administered continuously until progression in metastatic clear cell renal cancer (mRCC). The role of intermittent therapy is under investigation. Preclinical data raise concerns about this approach. MATERIALS AND METHODS: This study combined the data from three similar phase II studies investigating VEGF-targeted therapy prior to planned nephrectomy for untreated mRCC (European Union Drug Regulating Authorities Clinical Trials 2006-004511-21, 2006-006491-38 and 2009-016675-29). The significance of progression during the planned treatment break (median 4.3 weeks) was assessed. RESULTS: Sixty-two patients had a structured treatment interruption for nephrectomy after achieving clinical benefit from treatment and restarted therapy. Twenty-three of these patients (37%) progressed (Response Evaluation Criteria In Solid Tumors v1.1) on the first scan after the treatment break. Subsequent stabilisation of disease occurred in 16 of the 23 (70%) progressing patients when the same VEGF tyrosine kinase inhibitor (TKI) was reintroduced. Baseline characteristics, such as the Memorial Sloan Kettering Cancer Centre prognostic score, did not predispose to the development of this progression. Progression during the treatment break was associated with an increased risk of death on multivariate analysis {hazard ratio (HR) 5.56; [95% confidence interval 2.29-13.5], P < 0.01}. Sequential fluorodeoxyglucose positron emission tomography showed a rebound in metabolic activity during the treatment break. CONCLUSIONS: Progression during planned VEGF TKI treatment interruptions is frequent and associated with a poor prognosis. Treatment cessation should be pursued with caution.

mRNA profiling of the cancer degradome in oesophago-gastric adenocarcinoma.

BACKGROUND: Degradation of the extracellular matrix is fundamental to tumour development, invasion and metastasis. Several protease families have been implicated in the development of a broad range of tumour types, including oesophago-gastric (OG) adenocarcinoma. The aim of this study was to analyse the expression levels of all core members of the cancer degradome in OG adenocarcinoma and to investigate the relationship between expression levels and tumour/patient variables associated with poor prognosis. METHODS: Comprehensive expression profiling of the protease families (matrix metalloproteinases (MMPs), members of the ADAM metalloproteinase-disintegrin family (ADAMs)), their inhibitors (tissue inhibitors of metalloproteinase), and molecules involved in the c-Met signalling pathway, was performed using quantitative real-time reverse transcription polymerase chain reaction in a cohort of matched malignant and benign peri-tumoural OG tissue (n=25 patients). Data were analysed with respect to clinico-pathological variables (tumour stage and grade, age, sex and pre-operative plasma C-reactive protein level). RESULTS: Gene expression of MMP1, 3, 7, 9, 10, 11, 12, 16 and 24 was upregulated by factors >4-fold in OG adenocarcinoma samples compared with matched benign tissue (P<0.01). Expression of ADAM8 and ADAM15 correlated significantly with tumour stage (P=0.048 and P=0.044), and ADAM12 expression correlated with tumour grade (P=0.011). CONCLUSION: This study represents the first comprehensive quantitative analysis of the expression of proteases and their inhibitors in human OG adenocarcinoma. These findings implicate elevated ADAM8, 12 and 15 mRNA expression as potential prognostic molecular markers.

Identification of stromally expressed molecules in the prostate by tag-profiling of cancer-associated fibroblasts, normal fibroblasts and fetal prostate.

The stromal microenvironment has key roles in prostate development and cancer, and cancer-associated fibroblasts (CAFs) stimulate tumourigenesis via several mechanisms including the expression of pro-tumourigenic factors. Mesenchyme (embryonic stroma) controls prostate organogenesis, and in some circumstances can re-differentiate prostate tumours. We have applied next-generation Tag profiling to fetal human prostate, normal human prostate fibroblasts (NPFs) and CAFs to identify molecules expressed in prostatic stroma. Comparison of gene expression profiles of a patient-matched pair of NPFs vs CAFs identified 671 transcripts that were enriched in CAFs and 356 transcripts whose levels were decreased, relative to NPFs. Gene ontology analysis revealed that CAF-enriched transcripts were associated with prostate morphogenesis and CAF-depleted transcripts were associated with cell cycle. We selected mRNAs to follow-up by comparison of our data sets with published prostate cancer fibroblast microarray profiles as well as by focusing on transcripts encoding secreted and peripheral membrane proteins, as well as mesenchymal transcripts identified in a previous study from our group. We confirmed differential transcript expression between CAFs and NPFs using QrtPCR, and defined protein localization using immunohistochemistry in fetal prostate, adult prostate and prostate cancer. We demonstrated that ASPN, CAV1, CFH, CTSK, DCN, FBLN1, FHL1, FN, NKTR, OGN, PARVA, S100A6, SPARC, STC1 and ZEB1 proteins showed specific and varied expression patterns in fetal human prostate and in prostate cancer. Colocalization studies suggested that some stromally expressed molecules were also expressed in subsets of tumour epithelia, indicating that they may be novel markers of EMT. Additionally, two molecules (ASPN and STC1) marked overlapping and distinct subregions of stroma associated with tumour epithelia and may represent new CAF markers.

The evolution of laparoscopic antireflux surgery and its influence on postoperative stay.

Laparoscopic fundoplication is an established treatment for refractory gastro-oesophageal reflux disease. This study aims to compare the outcome of two laparoscopic antireflux techniques in a regional specialist unit. A sequential audit was carried out on patients undergoing laparoscopic Nissen (LN: performed May 1994 to November 2000) or laparoscopic anterior (LA: performed March 2001 to December 2004) fundoplication. Patient satisfaction was assessed by postal questionnaire. The cohorts undergoing each operation were also divided into two chronological groups of 51 patients, to study the effect of possible learning curve progression on the number of nights spent in the hospital postoperatively. In all, 142/204 (70%) questionnaires were returned from patients with follow-up ranging from 5 to 40 months postoperation. Overall, 102/142 (72%) reported a good or excellent outcome. Patients who underwent LA had a higher rate of antacid medication use (LN 17.4% versus LA 34.2%, P = 0.036) but there was a higher score for inability to belch following LN (LN 2.03 versus LA 1.53, P = 0.034). When comparing the chronologically divided cohorts, LN was associated with a significantly longer hospital stay than LA (P < 0.001, Mann-Whitney U test). There was a significant decrease in hospital stay from the first to second group of 51 LNs (P < 0.001, Mann-Whitney U test) and a further significant reduction in hospital stay from the first 51 to second 51 LAs (P < 0.001, Mann-Whitney U test). In conclusion, both procedures provide good symptom control. Increased requirement for acid suppression following LA and inability to belch following LN, may suggest more long-term durability of the LN wrap. The decrease in the number of nights spent in hospital may be related to the procedure performed but seems more likely to be an effect of increasing volume of surgical experience.

Continuing professional development for surgeons.

With the introduction of revalidation, continuing professional development (CPD) is becoming an increasingly important part of a surgeon's professional life. There is minimal existing information describing the CPD practices and attitudes of surgeons to CPD. This review describes the current CPD expectations of the General Medical Council and the current CPD activities and attitudes of surgeons, based around the results of an on-line study performed by the Royal College of Surgeons of Edinburgh.

Variation in dermcidin expression in a range of primary human tumours and in hypoxic/oxidatively stressed human cell lines.

Dermcidin acts as a survival factor in a variety of cancer cell lines under hypoxia or oxidative stress. The aim of this study was to evaluate dermcidin expression in cell lines following simulation of tumour microenvironmental conditions and in a range of primary tumours. Tumour tissues were collected from patients with oesophageal (28 samples), gastric (20), pancreatic (five), bile duct (one) and prostatic (52) carcinomas as well as 30 benign tissue samples, for assessment of dermcidin mRNA levels using real-time PCR. Dermcidin expression was assessed in prostatic and pancreatic cancer cell lines, with and without induction of hypoxia or oxidative stress. Dermcidin mRNA expression was very low or absent in both unstressed and stressed prostate cell lines. None of the primary prostate tissue, benign or malignant, expressed dermcidin mRNA. Only two (4%) of the gastro-oesophageal cancer samples expressed moderate quantities of dermcidin mRNA. However, three (60%) of the pancreatic cancer samples and the single cholangiocarcinoma specimen had moderate/high levels of dermcidin expression. Of the two pancreatic cancer cell lines, one expressed dermcidin moderately but neither showed a response to hypoxia or oxidative stress. Expression of dermcidin in human primary tumours appears highly variable and is not induced substantially by hypoxia/oxidative stress in cell line model systems. The relationship of these findings to dermcidin protein levels and cell survival remains to be determined.

Matched pair analysis of ureteroscopy vs. shock wave lithotripsy for the treatment of upper ureteric calculi.

There is controversy over whether shock wave lithotripsy (SWL) or ureteroscopy (URS) is the best management of ureteric calculi, especially for stones located in the upper ureter. This study compares URS and SWL management of upper ureteric stones directly for the first time using a different analysis tool, the matched pair analysis study design. This method enables meaningful comparisons to be made on a small number of matched patients, using precise like-for-like matching. Adult patients undergoing primary treatment of solitary radiopaque proximal ureteric stones were identified. Patients with stents, nephrostomies or stones at the pelvi-ureteric junction were excluded. Patients had a minimum of 3 months follow-up. Patients treated by primary URS were matched using four parameters (sex, laterality, stone size and location) to patients treated on a Dornier Compact Delta Lithotriptor. A total of 1479 patients had URS or SWL from which 27 upper ureteric stone matched pairs were identified. Three-month stone free rates were 82% for URS and 89% for SWL (McNemar's test, p=0.625). Re-treatment was required in 11% and 26% following URS and SWL respectively (p=0.219). Forty-one per cent of URS patients required an ancillary treatment, such as stent removal, compared with only 22% of SWL patients (p=0.227). Introduction of a holmium:YAG laser for use with URS improved the stone free rate for URS to 100%. Using a robust like-for-like comparison of similar patients with very similar upper ureteric stones the outcomes following SWL and URS were comparable. Choice of treatment should therefore be based on parameters such as availability of equipment, waiting times and patient preference.

The molecular mechanisms of skeletal muscle wasting: implications for therapy.

Skeletal muscle wasting is an important systemic manifestation of a wide range of diseases, including trauma, sepsis and cancer. The clinical consequences of muscle wasting undoubtedly include significant patient morbidity and worsened survival. Recently, there has been important progress in our understanding of the molecular mechanisms behind muscle wasting. In this review, the common systemic mediators, intracellular signalling pathways and effector mechanisms of skeletal muscle wasting are discussed with particular reference to different models of wasting and the development of novel therapeutic strategies.

A teratoid cyst containing nephrogenic tissue in a woman with a horseshoe kidney.

A 21 year old woman presenting with flank pain and vomiting was found to have a cystic lesion associated with a horseshoe kidney. The inner aspect of the cyst wall consisted of connective tissue intermingled with colonic-type epithelium. Within the cyst wall there were multiple foci of immature and incompletely differentiated renal elements, together with fragments of urothelium, smooth muscle, bone, and neuroendocrine tissue. No immature renal blastema were found. This lesion is unique and labelled as a teratoid cyst containing nephrogenic tissue.

An analysis of urinary tract trauma in Scotland: imnpact on management and resource needs.

OBJECTIVE: We report the incidence, distribution, aetiology and outcome of urological trauma in a unique national database to provide an insight into its contemporary management. PATIENTS AND METHODS: The Scottish Trauma Audit Group prospectively collected data from severe trauma presenting to all major Scottish hospitals. We examined data from 24,666 trauma admissions from 1999 to 2002. Patients who sustained urological injuries were identified and studied in detail. RESULTS: 362 patients had urological injuries, comprising 1.5% of the trauma population, and an incidence of 1 per 45,000 head of adult population per year. Blunt injury (n = 285, 79%) was the main cause of urological trauma. Road traffic accidents were most frequent (197 patients, 54%), followed by assaults (76, 21%) and high falls (45, 12%). Renal injuries were the most common (n = 241, 67%), followed by injuries to the external genitalia (71, 20%), bladder (65, 18%), urethra (16, 4%) and ureter (3, 1%). Only 52 patients (14%) had isolated urological trauma. One hundred and fifty nine out of 310 (51%) urological patients with associated injuries were physiologically compromised on arrival in A&E, compared with only 4/52 (8%) patients with isolated urological trauma. All patients with isolated urological trauma survived, whereas 110/310 (35%) of those with associated injuries died. CONCLUSION: Urological injuries in Scotland mostly result from blunt trauma due to high-energy impacts. Isolated urological injuries are uncommon and all such patients survived. The majority of patients with urological trauma have multiple injuries and require a multi-disciplinary approach. Current urological services appear adequately distributed to cope with contemporary demands of urological trauma.

Comparison of three different procedures for antireflux surgery.

BACKGROUND: No long-term comparisons of the various open and laparoscopic antireflux procedures have been undertaken. The aim of this study was to compare symptomatic outcomes of three procedures for antireflux surgery performed at three specialist units. METHODS: Patients undergoing open Nissen fundoplication, laparoscopic Nissen fundoplication and laparoscopic anterior partial fundoplication between December 1993 and February 2001 were identified. Patient outcome was assessed by means of a postal questionnaire. This was a hypothesis-generating study. RESULTS: Three hundred and fifty-seven patients (80.0 per cent) completed the questionnaire, with no differences in response rate between centres. Overall, a mean of only 7.6 per cent of patients reported a poor outcome. Logistic regression revealed no significant differences amongst the three procedures for any symptoms, after allowing for the effect of time. There was a general increase in the DeMeester score with increasing time from operation. The incidence of revisional reflux surgery was similar in the three groups. CONCLUSION: Medium-term symptomatic outcome following all three procedures was similar. There was some recurrence of symptoms of gastro-oesophageal reflux with time for all procedures, suggesting that the effects of surgery diminish with time. The level of experience of the surgeon in a particular operation was more important than the procedure performed.

The extent of resection influences outcome following hepatectomy for colorectal liver metastases.

BACKGROUND: The acceptable indications for liver resection in patients with colorectal metastases have increased significantly in the last decade. It is thus becoming more difficult to ascertain the limitations for selection as the boundaries have been greatly extended. This has resulted in not only more extensive resections, but more atypical and bilobar resections. The aim of this study was to compare the outcome of patients undergoing different extent of liver resection in a specialist unit. METHODS: All patients undergoing liver resection for colorectal metastases at the Royal Infirmary of Edinburgh between October 1988 and April 2001 were reviewed. Patients were allocated into one of three groups: standard group, extended group, and segmental group. Patient information was collected from a prospectively completed database. RESULTS: One hundred and thirty-seven patients had liver resections for colorectal metastases during the study period. There were 69 standard hepatectomies, 41 extended resections and 27 segmental resections. CEA level was significantly lower in the segmental group(p = 0.012). There was a significant difference between the groups in terms of median operating time (p < 0.0001, Kruskal-Wallis test), operative blood loss (p = 0.006, Kruskal-Wallis test) and post-operative stay ( p = 0.036, Kruskal-Wallis test). Major post-operative complications were similar between standard and extended resections but less following segmental resection (p = 0.050. Predicted median survival was 51 months following standard resection, 23 months following extended resection and 59 months after segmental resection ( p = 0.037, log rank test), however, there was no difference between the three groups for actual 5-year survival (p = 0.662, Pearson chi-square test). CONCLUSION: Morbidity and mortality rates were comparable with other previous studies as was overall survival, although survival in patients undergoing extended resections was reduced. There was an acceptable level of morbidity and mortality for all three groups. Patients undergoing segmental resection had fewer complications, shorter length of stay, and the longest median survival suggesting adequate oncological clearance. Segmental resection has a role for favourably placed tumour deposits if oncological clearance can be ensured. Extended liver resections have a role for selected patients with bilobar colorectal metastases or large solitary deposits close to the hepatic vein confluence.