Vitamin D treatment induces in vitro and ex vivo transcriptomic changes indicating anti-tumor effects.

Vitamin D deficiency is associated with risk of several common cancers, including colorectal cancer (CRC). Here we have utilized patient derived epithelial organoids (ex vivo) and CRC cell lines (in vitro) to show that calcitriol (1,25OHD) increased the expression of the CRC tumor suppressor gene, CDH1, at both the transcript and protein level. Whole genome expression analysis demonstrated significant differential expression of a further six genes after 1,25OHD treatment, including genes with established links to carcinogenesis GADD45, EFTUD1 and KIAA1199. Furthermore, gene ontologies relevant to carcinogenesis were enriched by 1,25OHD treatment (e.g., 'regulation of Wnt signaling pathway', 'regulation of cell death'), with common enriched processes across in vitro and ex vivo cultures including 'negative regulation of cell proliferation', 'regulation of cell migration' and 'regulation of cell differentiation'. Our results identify genes and pathways that are modifiable by calcitriol that have links to CRC tumorigenesis. Hence the findings provide potential mechanism to the epidemiological and clinical trial data indicating a causal association between vitamin D and CRC. We suggest there is strong rationale for further well-designed trials of vitamin D supplementation as a novel CRC chemopreventive and chemotherapeutic agent.

Diagnostic evaluation of upper tract urothelial carcinoma: can we safely omit diagnostic ureteroscopy?

OBJECTIVE: To identify clinicopathological or radiological factors that may predict a diagnosis of upper urinary tract urothelial cell carcinoma (UTUC) to inform which patients can proceed directly to radical nephroureterectomy (RNU) without the delay for diagnostic ureteroscopy (URS). PATIENTS AND METHODS: All consecutive patients investigated for suspected UTUC in a high-volume UK centre between 2011 and 2017 were identified through retrospective analysis of surgical logbooks and a prospectively maintained pathology database. Details on clinical presentation, radiological findings, and URS/RNU histopathology results were evaluated. Multivariate regression analysis was performed to evaluate predictors of a final diagnosis of UTUC. RESULTS: In all, 260 patients were investigated, of whom 230 (89.2%) underwent URS. RNU was performed in 131 patients (50.4%), of whom 25 (9.6%) proceeded directly without URS - all of whom had a final histopathological diagnosis of UTUC - and 15 (11.5%) underwent RNU after URS despite no conclusive histopathological confirmation of UTUC. Major surgery was avoided in 77 patients (33.5%) where a benign or alternative diagnosis was made on URS, and 14 patients (6.1%) underwent nephron-sparing surgery. Overall, 178 patients (68.5%) had a final diagnosis of UTUC confirmed on URS/RNU histopathology. On multivariate logistic regression analysis, a presenting complaint of visible haematuria (hazard ratio [HR] 5.17, confidence interval [CI] 1.91-14.0; P = 0.001), a solid lesion reported on imaging (HR 37.8, CI = 11.7-122.1; P < 0.001) and a history of smoking (HR 3.07, CI 1.35-6.97; P = 0.007), were predictive of a final diagnosis of UTUC. From this cohort, 51 (96.2%) of 53 smokers who presented with visible haematuria and who had a solid lesion on computed tomography urogram had UTUC on final histopathology. CONCLUSION: We identified specific factors which may assist clinicians in selecting which patients may reliably proceed to RNU without the delay of diagnostic URS. These findings may inform a prospective multicentre analysis including additional variables such as urinary cytology.

High-sensitivity cardiac troponin and the diagnosis of myocardial infarction in patients with kidney impairment.

The benefit and utility of high-sensitivity cardiac troponin (hs-cTn) in the diagnosis of myocardial infarction in patients with kidney impairment is unclear. Here, we describe implementation of hs-cTnI testing on the diagnosis, management, and outcomes of myocardial infarction in patients with and without kidney impairment. Consecutive patients with suspected acute coronary syndrome enrolled in a stepped-wedge, cluster-randomized controlled trial were included in this pre-specified secondary analysis. Kidney impairment was defined as an eGFR under 60mL/min/1.73m2. The index diagnosis and primary outcome of type 1 and type 4b myocardial infarction or cardiovascular death at one year were compared in patients with and without kidney impairment following implementation of hs-cTnI assay with 99th centile sex-specific diagnostic thresholds. Serum creatinine concentrations were available in 46,927 patients (mean age 61 years; 47% women), of whom 9,080 (19%) had kidney impairment. hs-cTnIs were over 99th centile in 46% and 16% of patients with and without kidney impairment. Implementation increased the diagnosis of type 1 infarction from 12.4% to 17.8%, and from 7.5% to 9.4% in patients with and without kidney impairment (both significant). Patients with kidney impairment and type 1 myocardial infarction were less likely to undergo coronary revascularization (26% versus 53%) or receive dual anti-platelets (40% versus 68%) than those without kidney impairment, and this did not change post-implementation. In patients with hs-cTnI above the 99th centile, the primary outcome occurred twice as often in those with kidney impairment compared to those without (24% versus 12%, hazard ratio 1.53, 95% confidence interval 1.31 to 1.78). Thus, hs-cTnI testing increased the identification of myocardial injury and infarction but failed to address disparities in management and outcomes between those with and without kidney impairment.

Differential genetic influences over colorectal cancer risk and gene expression in large bowel mucosa.

Site-specific variation in colorectal cancer (CRC) incidence, biology and prognosis are poorly understood. We sought to determine whether common genetic variants influencing CRC risk might exhibit topographical differences on CRC risk through regional differences in effects on gene expression in the large bowel mucosa. We conducted a site-specific genetic association study (10 630 cases, 31 331 controls) to identify whether established risk variants exert differential effects on risk of proximal, compared to distal CRC. We collected normal colorectal mucosa and blood from 481 subjects and assessed mucosal gene expression using Illumina HumanHT-12v4 arrays in relation to germline genotype. Expression quantitative trait loci (eQTLs) were explored by anatomical location of sampling. The rs3087967 genotype (chr11q23.1 risk variant) exhibited significant site-specific effects-risk of distal CRC (odds ratio [OR] = 1.20, P = 8.20 × 10-20 ) with negligible effects on proximal CRC risk (OR = 1.05, P = .10). Expression of 1261 genes differed between proximal and distal colonic mucosa (top hit PRAC gene, fold-difference = 10, P = 3.48 × 10-57 ). In eQTL studies, rs3087967 genotype was associated with expression of 8 cis- and 21 trans-genes. Four of these (AKAP14, ADH5P4, ASGR2, RP11-342M1.7) showed differential effects by site, with strongest trans-eQTL signals in proximal colonic mucosa (eg, AKAP14, beta = 0.61, P = 5.02 × 10-5 ) and opposite signals in distal mucosa (AKAP14, beta = -0.17, P = .04). In summary, genetic variation at the chr11q23.1 risk locus imparts greater risk of distal rather than proximal CRC and exhibits site-specific differences in eQTL effects in normal mucosa. Topographical differences in genomic control over gene expression relevant to CRC risk may underlie site-specific variation in CRC. Results may inform individualised CRC screening programmes.

The effect of vitamin D supplementation on survival in patients with colorectal cancer: systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: Low circulating vitamin D levels are associated with poor colorectal cancer (CRC) survival. We assess whether vitamin D supplementation improves CRC survival outcomes. METHODS: PubMed and Web of Science were searched. Randomised controlled trial (RCTs) of vitamin D supplementation reporting CRC mortality were included. RCTs with high risk of bias were excluded from analysis. Random-effects meta-analysis models calculated estimates of survival benefit with supplementation. The review is registered on PROSPERO, registration number: CRD42020173397. RESULTS: Seven RCTs (n = 957 CRC cases) were identified: three trials included patients with CRC at outset, and four population trials reported survival in incident cases. Two RCTs were excluded from meta-analysis (high risk of bias; no hazard ratio (HR)). While trials varied in inclusion criteria, intervention dose and outcomes, meta-analysis found a 30% reduction in adverse CRC outcomes with supplementation (n = 815, HR = 0.70; 95% confidence interval (CI): 0.48-0.93). A beneficial effect was seen in trials of CRC patients (progression-free survival, HR = 0.65; 95% CI: 0.36-0.94), with suggestive effect in incident CRC cases from population trials (CRC-specific survival, HR = 0.76; 95% CI: 0.39-1.13). No heterogeneity or publication bias was noted. CONCLUSIONS: Meta-analysis demonstrates a clinically meaningful benefit of vitamin D supplementation on CRC survival outcomes. Further well-designed, adequately powered RCTs are needed to fully evaluate benefit of supplementation in augmenting 'real-life' follow-up and adjuvant chemotherapy regimens, as well as determining optimal dosing.

High-Sensitivity Cardiac Troponin and the Risk Stratification of Patients With Renal Impairment Presenting With Suspected Acute Coronary Syndrome.

BACKGROUND: High-sensitivity cardiac troponin testing may improve the risk stratification and diagnosis of myocardial infarction, but concentrations can be challenging to interpret in patients with renal impairment, and the effectiveness of testing in this group is uncertain. METHODS: In a prospective multicenter study of consecutive patients with suspected acute coronary syndrome, we evaluated the performance of high-sensitivity cardiac troponin I in those with and without renal impairment (estimated glomerular filtration rate <60mL/min/1.73m2). The negative predictive value and sensitivity of troponin concentrations below the risk stratification threshold (5 ng/L) at presentation were reported for a primary outcome of index type 1 myocardial infarction, or type 1 myocardial infarction or cardiac death at 30 days. The positive predictive value and specificity at the 99th centile diagnostic threshold (16 ng/L in women, 34 ng/L in men) was determined for index type 1 myocardial infarction. Subsequent type 1 myocardial infarction and cardiac death were reported at 1 year. RESULTS: Of 4726 patients identified, 904 (19%) had renal impairment. Troponin concentrations <5 ng/L at presentation identified 17% of patients with renal impairment as low risk for the primary outcome (negative predictive value, 98.4%; 95% confidence interval [CI], 96.0%-99.7%; sensitivity 98.9%; 95%CI, 97.5%-99.9%), in comparison with 56% without renal impairment (P<0.001) with similar performance (negative predictive value, 99.7%; 95% CI, 99.4%-99.9%; sensitivity 98.4%; 95% CI, 97.2%-99.4%). The positive predictive value and specificity at the 99th centile were lower in patients with renal impairment at 50.0% (95% CI, 45.2%-54.8%) and 70.9% (95% CI, 67.5%-74.2%), respectively, in comparison with 62.4% (95% CI, 58.8%-65.9%) and 92.1% (95% CI, 91.2%-93.0%) in those without. At 1 year, patients with troponin concentrations >99th centile and renal impairment were at greater risk of subsequent myocardial infarction or cardiac death than those with normal renal function (24% versus 10%; adjusted hazard ratio, 2.19; 95% CI, 1.54-3.11). CONCLUSIONS: In suspected acute coronary syndrome, high-sensitivity cardiac troponin identified fewer patients with renal impairment as low risk and more as high risk, but with lower specificity for type 1 myocardial infarction. Irrespective of diagnosis, patients with renal impairment and elevated cardiac troponin concentrations had a 2-fold greater risk of a major cardiac event than those with normal renal function, and should be considered for further investigation and treatment. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01852123.

Intravenous heparin during ruptured abdominal aortic aneurysmal repair.

BACKGROUND: There have been enormous advances in the screening, diagnosis, intervention and overall prognosis of abdominal aortic aneurysms (AAAs) in the last decade, but despite these, ruptured AAAs (rAAAs) still cause around 3500 to 6000 deaths in England and Wales each year. Open repair remains standard treatment for rAAA in most centres but increasingly endovascular aneurysm repair (EVAR) is being adopted. This has a 30-day postoperative mortality of 40%. This has remained static despite surgical, anaesthetic and critical care advances.One significant change to current practice for elective repairs of AAAs, as opposed to emergency repairs of rAAAs, has been the introduction of intravenous heparin. This provides a protective effect against cardiac and thrombotic disease in the postoperative period. This practice has not gained widespread acceptance for emergency repairs of rAAA even though a reduction in mortality and morbidity has been demonstrated in elective repairs. OBJECTIVES: The primary objective was to assess the effect of intravenous heparin on all-cause mortality in ruptured abdominal aortic aneurysm (rAAA) management in people undergoing an emergency repair.The secondary objectives were to assess the effect of intravenous heparin in rAAA management on the incidence of general arterial disease, for example, cardiovascular, cerebral, pulmonary and renal pathologies, in people undergoing emergency repair. SEARCH METHODS: The Cochrane Vascular Information Specialist (CIS) searched the Specialised Register (December 2015). In addition the CIS searched CENTRAL;2015, Issue 11). The CIS searched clinical trials registries for details of ongoing or unpublished studies. SELECTION CRITERIA: We sought all published and unpublished randomised controlled trials (RCTs) and controlled clinical trials (CCTs) of intravenous heparin in rAAA repairs (including parallel designs). DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies identified for potential inclusion in the review. We used standard methodological procedures in accordance with the Cochrane Handbook for Systematic Review of Interventions. MAIN RESULTS: We identified no RCTs or CCTs that satisfied the inclusion criteria. AUTHORS' CONCLUSIONS: We identified no RCTs or CCTs of intravenous heparin in rAAA repairs (including parallel designs). Therefore, we were unable to assess the effect of intravenous heparin on all-cause mortality and incidence of general arterial disease, for example, cardiovascular, cerebral, pulmonary and renal pathologies in rAAA management in people undergoing an emergency repair. It is clear that an RCT is needed to address this question in rAAA management as there is no high quality evidence.

Matched-pair analysis of open versus laparoscopic nephroureterectomy for upper urinary tract urothelial cell carcinoma.

OBJECTIVE: Laparoscopic nephroureterectomy (LNU) offers a superior morbidity profile compared with open nephroureterectomy (ONU) in treating upper urinary tract urothelial cell carcinoma. Evidence of oncological equivalence between LNU and ONU is limited. We compare operative and oncological outcomes for LNU and ONU using matched-pair analysis. METHODS: Of 159 patients who underwent a nephroureterectomy at a single institution between April 1992 and April 2010, 13 pairs of ONU and LNU patients were matched for gender, age, tumour location, tumour grade and stage. Operative details, post-operative characteristics and recurrences were collated and survival rates analysed using the Kaplan-Meier method. RESULTS: There was no significant difference in mean operation time between LNU (191 min) and ONU (194 min, p=0.92). There was no significant difference in the 5-year survival rate between LNU and ONU (overall survival 59.1% vs. 73.5%, p=0.18; progression-free survival 24.0% vs. 56.0%, p=0.14; cancer-specific survival 60.9% vs. 73.5%, p=0.56; bladder cancer recurrence-free survival 8.7% vs. 0.0%, p=0.09). CONCLUSION: Amidst limited RCT and comparative studies, this study presents further evidence of oncological equivalence between LNU and ONU. There was a trend towards poorer outcomes following LNU though, which merits further study.

Surgical training 2.0: How contemporary developments in information technology can augment surgical training.

BACKGROUND: The current surgical trainee is faced with reduced training time compared to predecessors as a result of changes in working practices. The past decade has seen marked developments in the information technology sector. This editorial will review how modern technological innovations could augment current surgical training. METHODS: We review the literature and summarize important developments in information technology that could assist the modern surgical trainee. We also look at some of the challenges faced by use of this technology. FINDINGS: Developments in mobile internet connectivity will improve access to online resources for the surgical trainee. Web 2.0 will revolutionise the way trainees interact with textbooks, journals, webpages and each other. Simulators could help to fill gaps created by reduced operating hours. To maximize the effectiveness of these resources they need to be accessible and incorporated into training in a structured way, ensuring patient safety and accuracy of information. CONCLUSION: Contemporary developments in technology offer benefits to the surgical trainee and could fill gaps left by reduced operating times. In order to ensure efficient use of technology and patient safety, bodies such as the Royal Colleges and Training Programmes must embrace these developments.

Transcriptional dynamics of colorectal cancer risk associated variation at 11q23.1 correlate with tuft cell abundance and marker expression in silico.

Colorectal cancer (CRC) is characterised by heritable risk that is not well understood. Heritable, genetic variation at 11q23.1 is associated with increased colorectal cancer (CRC) risk, demonstrating eQTL effects on 3 cis- and 23 trans-eQTL targets. We sought to determine the relationship between 11q23.1 cis- and trans-eQTL target expression and test for potential cell-specificity. scRNAseq from 32,361 healthy colonic epithelial cells was aggregated and subject to weighted gene co-expression network analysis (WGCNA). One module (blue) included 19 trans-eQTL targets and was correlated with POU2AF2 expression only. Following unsupervised clustering of single cells, the expression of 19 trans-eQTL targets was greatest and most variable in cluster number 11, which transcriptionally resembled tuft cells. 14 trans-eQTL targets were found to demarcate this cluster, 11 of which were corroborated in a second dataset. Intra-cluster WGCNA and module preservation analysis then identified twelve 11q23.1 trans-eQTL targets to comprise a network that was specific to cluster 11. Finally, linear modelling and differential abundance testing showed 11q23.1 trans-eQTL target expression was predictive of cluster 11 abundance. Our findings suggest 11q23.1 trans-eQTL targets comprise a POU2AF2-related network that is likely tuft cell-specific and reduced expression of these genes correlates with reduced tuft cell abundance in silico.

Study on the feasibility of provision of distance learning programmes in surgery to Malawi.

Medical educational opportunities and resources are considerably limited in the developing world. The expansion of computing and Internet access means that there exists a potential to provide education to students through distance learning programmes. This study investigated the feasibility of providing distance learning course in surgery in Malawi. The study investigated the user requirements, technical requirements and Internet connections in two teaching hospitals in Malawi. In addition the appropriateness of current course material from the Edinburgh Surgical Sciences Qualification to Malawi trainees was assessed. The study found a high degree of interest from Malawian trainees in distance learning. The provision of basic science modules such as anatomy and physiology and the ability to access journals were considered highly desirable. The current ESSQ course would require extensive re-modelling to make it suitable to an African trainee's requirements. Internet speeds remain slow and access is currently expensive. There is considerable interest in distance learning programmes in Malawi but access to them is limited partly because of slow and expensive Internet access. Understanding the needs of trainees in countries such as Malawi will allow better direction of educational aid and resources to support surgical training.

Leibovich score is the optimal clinico-pathological system associated with recurrence of non-metastatic clear cell renal cell carcinoma.

PURPOSE: To determine the optimal post-operative risk stratification system associated with survival following surgery for clear cell renal cell carcinoma (ccRCC): tumour grade, tumour stage, Leibovich 2003, Leibovich 2018, Kattan, Stage, size, grade and necrosis (SSIGN) or UCLA Integrated Staging System (UISS) scores. METHODS: 542 patients with non-metastatic ccRCC who underwent nephrectomy 2008-2018 were reviewed. Primary outcome was recurrence-free survival (RFS), with secondary outcomes cancer-specific survival (CSS) and overall survival (OS). RESULTS: All systems were significantly associated with RFS, CSS and OS by Kaplan-Meier and unadjusted Cox-regression. ROC analysis identified that Leibovich 2003, Leibovich 2018A or B and SSIGN were optimally association with 5year RFS (AUC (Area under curve) 0.87, 0.86, 0.86 and 0.86), but Leibovich 2003 or 2018A offered additional information on adjusted regression analysis (HR 1.24, P = 0.02; HR 1.17, P = 0.04). ROC analysis identified that Leibovich 2018B, Leibovich 2003, SSIGN and UISS were equally associated with 5 year OS (AUC 0.76, 0.74, 0.73 and 0.72). UISS added additional explanation of the variance in OS on adjusted regression analysis (HR 1.96, P = 0.002). A novel combination of Leibovich 2003 score and Eastern Co-operative Oncology Group (ECOG) performance status improved 5 year OS association compared to the Leibovich 2003 alone (AUC 0.78, P = 0.001), without affecting association with 5year RFS (AUC 0.87, P = 0.75). CONCLUSIONS: All systems were robust tools associated with RFS, CSS and OS in ccRCC. In our cohort, the Leibovich 2003 and Leibovich 2018A scores may be better associated with RFS compared to other strategies. The UISS, Leibovich 2018B or Leibovich 2003 combined with ECOG performance status may stratify OS better than other modalities.

Gene Co-Expression Network Analysis Identifies Vitamin D-Associated Gene Modules in Adult Normal Rectal Epithelium Following Supplementation.

Colorectal cancer (CRC) is a common, multifactorial disease. While observational studies have identified an association between lower vitamin D and higher CRC risk, supplementation trials have been inconclusive and the mechanisms by which vitamin D may modulate CRC risk are not well understood. We sought to perform a weighted gene co-expression network analysis (WGCNA) to identify modules present after vitamin D supplementation (when plasma vitamin D level was sufficient) which were absent before supplementation, and then to identify influential genes in those modules. The transcriptome from normal rectal mucosa biopsies of 49 individuals free from CRC were assessed before and after 12 weeks of 3200IU/day vitamin D (Fultium-D3) supplementation using paired-end total RNAseq. While the effects on expression patterns following vitamin D supplementation were subtle, WGCNA identified highly correlated genes forming gene modules. Four of the 17 modules identified in the post-vitamin D network were not preserved in the pre-vitamin D network, shedding new light on the biochemical impact of supplementation. These modules were enriched for GO terms related to the immune system, hormone metabolism, cell growth and RNA metabolism. Across the four treatment-associated modules, 51 hub genes were identified, with enrichment of 40 different transcription factor motifs in promoter regions of those genes, including VDR:RXR. Six of the hub genes were nominally differentially expressed in studies of vitamin D effects on adult normal mucosa organoids: LCN2, HLA-C, AIF1L, PTPRU, PDE4B and IFI6. By taking a gene-correlation network approach, we have described vitamin D induced changes to gene modules in normal human rectal epithelium in vivo, the target tissue from which CRC develops.

Shockwave Lithotripsy Is an Efficacious Treatment Modality for Obese Patients with Upper Ureteral Calculi: Logistic Regression and Matched-Pair Analyses from a Dedicated Center Comparing Treatment Outcomes by Skin-to-Stone Distance.

Objectives: To assess the association of skin-to-stone distance (SSD) and stone-free rates following extracorporeal shockwave lithotripsy (SWL) using two statistical methods: logistic regression and a matched-pair analysis approach. Patients and Methods: Patients with a solitary radio-opaque upper ureteral calculus diagnosed on noncontrast computed tomography were included. Patients were treated with a Sonolith I-Sys Lithotripter (focal depth 17 cm). Stone treatment success was defined as stone free (fragments ≤3 mm) at 3 months. Failure was defined as persistent fragments beyond 3 months or requirement for intervention with ureteroscopy. The outcome was assessed by a plain kidney, ureter, and bladder radiograph (KUB) at 2 weeks. Logistic regression was used to determine association of patient and stone factors with treatment failure. The patient cohort was divided into tertiles by SSD, and matched-pair analysis was undertaken between individuals from the top and bottom tertiles (SSD ≤12 cm and SSD ≥14 cm). Matching criteria consisted of age, sex, maximum stone diameter (±2 mm), and stone density (±250 HU). Results: From a database of 2849 patients who underwent SWL, 397 patients were identified who had treatment of a single upper ureteral stone. Age (odds ratio [OR]: 1.03, 95% confidence interval [CI]: 1.01-1.04, p = 0.007), SSD (OR: 1.16, 95% CI: 1.03-1.32, p = 0.02), stone side (OR: 1.65, 95% CI 1.01-2.73, p = 0.05), stone diameter (OR: 1.09, 95% CI: 1.00-1.19, p = 0.05), and multiple sessions (OR: 4.65, 95% CI: 2.61-8.29, p < 0.001) were significantly associated with treatment failure by logistic regression univariable analysis. Multiple sessions was the only factor significantly associated with treatment failure on multivariable analysis (OR: 4.03, 95% CI: 2.18-7.42, p < 0.001). From a cohort of 141 patients with SSD ≥14 cm and 174 patients with a SSD ≤12 cm, 66 matches were identified (132 patients). Forty-nine patients (74.2%) with SSD ≥14 cm were deemed stone free at follow-up vs 51 patients (77.3%) with SSD ≤12 cm (p = 0.85). Conclusion: This study demonstrates by two statistical methods that SWL can provide efficacious treatment of upper ureteral stones in obese patients and that the upper threshold of SSD for SWL with Sonolith I-SYS could be revised to allow these patients the benefits of SWL.

Comparison of two patients presenting with the clear cell variant of urothelial cell carcinoma of the urinary bladder: laser-assisted partial cystectomy for local disease versus chemotherapy for locally advanced disease.

A 43-year-old woman and a 73-year-old man were referred separately from primary care to the urology service with short histories of frank haematuria. In both cases, histology from transurethral resection of their bladder tumours demonstrated the rare clear cell variant of urothelial/transitional cell carcinoma. Staging scans found the former patient had low-volume local disease, and the latter had locally advanced disease. The former patient went on to have partial cystectomy and pelvic lymph node dissection (with the endoscopic portion of the partial cystectomy undertaken by holmium:YAG laser), while the latter was found to have inoperable disease, and proceeded to chemotherapy. The former patient was alive with no evidence of disease recurrence at 45 months, while the latter was alive but with extensive lymph nodal recurrence at 45 months.

A Comprehensive Study of the Effect on Colorectal Cancer Survival of Common Germline Genetic Variation Previously Linked with Cancer Prognosis.

BACKGROUND: Germline genetic variants may influence pathways of tumor progression common to multiple cancer types. Here, we investigated the association between survival after colorectal cancer diagnosis and 128 common genetic variants previously associated with prognosis in genome-wide association studies in different cancer types. METHODS: We studied survival outcomes in a large well-documented, prospective, population-based cohort (5,675 patients with colorectal cancer) with up to 20 years' follow-up. RESULTS: None of the 128 variants were significantly associated with overall or colorectal cancer-specific survival (P < 5 × 10-4, Bonferroni-corrected threshold). We observed suggestive evidence (P < 0.05) for eight variants (rs17026425, rs17057166, rs6854845, rs1728400, rs17693104, rs202280, rs6797464, and rs823920) in all colorectal cancer and two variants (rs17026425 and rs6854845) in rectal cancer that were concordant with previous reports. CONCLUSIONS: Given good statistical power (>0.80 for 75% of variants), this study indicates that most previously reported variants associated with cancer survival have limited influence on colorectal cancer prognosis. IMPACT: Although small effects cannot be excluded, clinically meaningful germline influences on patients with colorectal cancer as a group are unlikely.

A Cross-sectional Study of Current Doctors' Performance in a Modified Version of a Medical School Admission Aptitude Test: The UKCAT.

The 2-hour long United Kingdom Clinical Aptitude Test (UKCAT) is used by many universities in the United Kingdom as part of their selection process for undergraduate medical and dentistry degrees. We aimed to compare the performance of senior doctors in primary and secondary care and across a range of specialties, in a modified version of the medical school entrance examination-the mUKCAT. Lay people were also included in the study. Despite its widespread use, this is the first study that examines the performance of senior clinicians in the UKCAT.The study used a prospective cross-sectional design. It used mock questions from the UKCAT website to generate an mUKCAT that was anticipated to take 15 minutes to complete. In all, 167 doctors at consultant, general practitioner (GP), or specialty trainee grade and 26 lay people took part.The overall mean mUKCAT score of all participants was 2486 (69.1%). Of the total cohort, 126 (65.3%) scored above our designated threshold of 2368 and were deemed to have passed the mUKCAT. Excluding lay people, 113 (67.7%) of the 167 doctors scored above that threshold. Medical specialty was associated with overall score (P = 0.003), with anesthetists/intensive care physicians scoring highest (n = 20, mean score 2660) and GPs scoring lowest (n = 38, mean score 2302). Academics outperformed nonacademics (mean score of academics, n = 44 vs nonacademics, n = 123: 2750 vs 2406; P < 0.001). Those clinicians in senior management positions scored lower than those in "standard" roles (mean score of senior management, n = 31 vs standard roles, n = 136: 2332 vs 2534, mean difference 202, 95% confidence interval 67-337, P = 0.004).In the situational judgement section, there was no evidence that specialty was associated with score (P = 0.15). Academics exhibited greater situational judgement than their nonacademic colleagues (academics vs nonacademics: 69.8 vs 63.6%; P = 0.01).The majority of senior clinicians passed our mUKCAT. Academics and anesthetists were found to be the best performers, with GPs and those in senior management positions performing the worst.

Analysis of Factors' Association with Risk of Postoperative Urosepsis in Patients Undergoing Ureteroscopy for Treatment of Stone Disease.

INTRODUCTION: To investigate which patient, stone, infective, and surgical factors were most likely to increase the risk of postoperative urosepsis within 28 days of ureteroscopy (URS) and laser stone fragmentation for ureteral or renal stones. METHODS: Data were collected prospectively in a single National Health Service institution. A logistic regression model was used to assess the association of factors with postoperative urosepsis. Two matched-pair analyses were used to assess the risk of postoperative urosepsis in patients with (a) an emergency presentation to hospital with urosepsis in the 90 days preceding URS and (b) a positive midstream sample of urine (MSSU) identified, but who were asymptomatic at preoperative assessment, who then received an appropriate course of antibiotics. RESULTS: Four hundred sixty-two consecutive patients were included in the study. Thirty-four patients (7.4%) had an episode of urosepsis within 28 days of their operation. A positive preoperative MSSU was significantly associated with postoperative urosepsis on multivariable analysis, despite appropriate treatment with a preoperative course of antibiotics: odds ratio (OR) 4.88, 95% confidence interval (CI) 2.11, 11.31, p < 0.001. The presence of diabetes mellitus, presence of ischemic heart disease, patient American Society of Anesthesiologists score, same-session bilateral URS, and stone volume were the other variables significantly associated with postoperative infection on univariable analysis, but these ceased to be significantly associated on multivariable analysis. Subgroup analysis found that a positive MSSU in both patients with a preoperative ureteral stent and those without was significantly associated with postoperative urosepsis, however, the OR was much lower for the stented group (OR 3.23 vs OR 16.67). On matched-pair analysis, patients with a positive preoperative MSSU were significantly more likely to have postoperative urosepsis compared to controls (OR 17.46, 95% CI 2.18, 139.80, p = 0.007). There was no significant difference in the OR of postoperative urosepsis in patients who had a preceding urine infection requiring hospital admission in the 90 days preceding URS (OR 0.60, 95% CI 0.19, 1.92, p = 0.39). CONCLUSIONS: Positive preoperative MSSU was significantly associated with postoperative urosepsis by logistic regression and matched-pair analysis. These higher risk patients should be counseled appropriately before surgery, and should be the focus of vigilant postoperative monitoring. The study suggests particular caution in patients with a positive preoperative MSSU without a preoperative ureteral stent.