Identification of pathologically insignificant prostate cancer is not accurate in unscreened men.

BACKGROUND: Identification of men harbouring insignificant prostate cancer (PC) is important in selecting patients for active surveillance. Tools have been developed in PSA-screened populations to identify such men based on clinical and biopsy parameters. METHODS: Prospectively collected case series of 848 patients was treated with radical prostatectomy between July 2007 and October 2011 at an English tertiary care centre. Tumour volume was assessed by pathological examination. For each tool, receiver operator characteristics were calculated for predicting insignificant disease by three different criteria and the area under each curve compared. Comparison of accuracy in screened and unscreened populations was performed. RESULTS: Of 848 patients, 415 had Gleason 3+3 disease on biopsy. Of these, 32.0% had extra-prostatic extension and 50.2% were upgraded. One had positive lymph nodes. Two hundred and six (24% of cohort) were D'Amico low risk. Of these, 143 had more than two biopsy cores involved. None of the tools evaluated has adequate discriminative power in predicting insignificant tumour burden. Accuracy is low in PSA-screened and -unscreened populations. CONCLUSIONS: In our unscreened population, tools designed to identify insignificant PC are inaccurate. Detection of a wider size range of prostate tumours in the unscreened may contribute to relative inaccuracy.

Bcl-2 and ß1-integrin predict survival in a tissue microarray of small cell lung cancer.

INTRODUCTION: Survival in small cell lung cancer (SCLC) is limited by the development of chemoresistance. Factors associated with chemoresistance in vitro have been difficult to validate in vivo. Both Bcl-2 and ß(1)-integrin have been identified as in vitro chemoresistance factors in SCLC but their importance in patients remains uncertain. Tissue microarrays (TMAs) are useful to validate biomarkers but no large TMA exists for SCLC. We designed an SCLC TMA to study potential biomarkers of prognosis and then used it to clarify the role of both Bcl-2 and ß(1)-integrin in SCLC. METHODS: A TMA was constructed consisting of 184 cases of SCLC and stained for expression of Bcl-2 and ß(1)-integrin. The slides were scored and the role of the proteins in survival was determined using Cox regression analysis. A meta-analysis of the role of Bcl-2 expression in SCLC prognosis was performed based on published results. RESULTS: Both proteins were expressed at high levels in the SCLC cases. For Bcl-2 (n=140), the hazard ratio for death if the staining was weak in intensity was 0.55 (0.33-0.94, P=0.03) and for ß(1)-integrin (n=151) was 0.60 (0.39-0.92, P=0.02). The meta-analysis showed an overall hazard ratio for low expression of Bcl-2 of 0.91(0.74-1.09). CONCLUSIONS: Both Bcl-2 and ß(1)-integrin are independent prognostic factors in SCLC in this cohort although further validation is required to confirm their importance. A TMA of SCLC cases is feasible but challenging and an important tool for biomarker validation.

Generation and validation of a revised classification for oesophageal and junctional adenocarcinoma.

BACKGROUND: Oesophageal adenocarcinoma is the commonest oesophageal malignancy in the West, but is staged using a system designed for squamous cell carcinoma. The aim was to develop and validate a staging system for oesophageal and junctional adenocarcinoma. METHODS: Patients with oesophageal adenocarcinoma (Siewert types I and II) undergoing oesophagectomy with curative intent were randomly assigned to generation (313 patients) and validation (131) data sets. Outcome in the generation data set was associated with histopathological features; a revised node (N) classification was derived using recursive partitioning and tested on the validation data set. RESULTS: A revised N classification based on number of involved lymph nodes (N0, none; N1, one to five; N2, six or more) was prognostically significant (P < 0.001). Patients with involved nodes on both sides of the diaphragm, regardless of number, had the same outcome as the N2 group. When applied to the validation data set, the revised classification (including nodal number and location) provided greater discrimination between node-positive patients than the existing system (P < 0.001). CONCLUSION: A revised N classification based on number and location of involved lymph nodes provides improved prognostic power and incorporates features that may be useful before surgery in clinical management decisions.

Effect of margin status on cervical intraepithelial neoplasia recurrence following LLETZ in women over 50 years.

OBJECTIVE: To establish the effect of margin status on recurrence following large loop excision of the transformation zone (LLETZ) in women over 50 years. STUDY DESIGN: Prospectively collected data of women over 50 years, who underwent LLETZ for suspected cervical intraepithelial neoplasia between 1998 and 2003, were analysed. Women were followed up for up to over 6 years. SETTING: District colposcopy service based at a gynae-oncology cancer centre. MAIN OUTCOME MEASURES: The main outcome measure included histologically detected recurrence. Any abnormal cytology on follow up was also documented. METHODS: Prospectively collected data were analysed from the colposcopy database. Recurrence was analysed using Kaplan-Meir plots and Cox regression. Fisher's exact test was used to determine the association between margins and grade. The Kruskal-Wallis and Mann-Whitney U tests were used to compare age and duration of follow up between groups. RESULTS: A total of 118 women underwent LLETZ and 92 were included in the final analysis. Margins were designated as clear (n = 62), involved (n = 22) or uncertain (n = 8). Histological recurrence occurred in 12 while abnormal cytology was demonstrated in 17 women. One woman with involved margins developed cervical cancer. Individuals with clear margins were less likely to have recurrence than those with involved margins (Hazard Ratio (HR) 0.18, 95% CI: 0.06-0.59). Involved margins were more common with high-grade than low-grade lesions (P = 0.002). CONCLUSION: The data show an association between disease recurrence and the finding of involved margins in this cohort.

Treatment of anal human papillomavirus-associated disease: a long term outcome study.

Treatment for human papillomavirus (HPV)-associated anal canal disease has been unsatisfactory. The objective of our study was to determine the treatment outcome in our cohort with anal HPV disease. Overall, 181 patients were evaluated over a median period of 19.1 months (range = 2.8-125.5). Eighty-eight patients (48.6%) with high-grade anal intraepithelial neoplasia (AIN) and 82 patients (45.3%) with low-grade AIN underwent treatment. One hundred and forty-one patients (77.9%) received laser ablative treatment as an outpatient procedure. The treatment yielded cure, defined as a disease-free state at 12 months after treatment, in 63.0% (114/181). Median time to cure for the cohort was 31.5 months (95% confidence interval: 23.0-40.0). Treatment outcome showed no evidence of being affected by age, sexual preference, history of smoking or presence of high-grade disease. Median time to cure was significantly affected by a positive HIV status (P = 0.02) and the extent (volume) of the disease (P = 0.01). Contrary to the current view that treatment of HPV-related anal disease is difficult, unrewarding due to recurrences and may lead to substantial morbidity, we demonstrate that effective treatment is possible for both low- and high-grade AIN. These findings should help with the general desire to introduce screening for AIN for at-risk groups.

Practical issues in the implementation of image-guided radiotherapy for the treatment of prostate cancer within a UK department.

AIMS: To study the feasibility of using implanted gold seeds in combination with a commercial software system for daily localisation of the prostate gland during conformal radiotherapy, and to assess the effect this may have on departmental workload. MATERIALS AND METHODS: Six patients had three gold radio-opaque seeds implanted into the prostate gland before starting a course of radiotherapy. The seeds were identified on daily portal images and an automated online system provided immediate vector analysis of discrepancies between the planned and actual daily position of the intraprostatic seeds. In total, 138 interfractional displacements were analysed. The workload impact for the department was assessed using the basic treatment equivalence model, by comparing measurements of daily treatment session durations with a control group of patients receiving standard conformal radiotherapy, matched for treatment complexity. RESULTS: No acute complications of seed insertion were observed. A number of developmental issues required solutions to be identified before clinical implementation was possible. The standard deviations of the set-up and organ motion systematic errors in the left-right, superior-inferior and anterior-posterior directions were 2.4, 3.0 and 2.5 mm, respectively. The standard deviations of the set-up and organ motion random errors calculated were 2.5, 2.9 and 3.7 mm. The mean treatment session duration with this daily prostate localisation system was increased by 3 min compared with matched controls using standard imaging practice. If all radical prostate patients in our department were to receive image-guided radiotherapy in this way, this would increase machine workload time by 2.2 h/day. CONCLUSIONS: The implementation of this image-guided system is feasible. No additional linear accelerator modification is required and standard imaging devices can be used. It would be a useful addition to any department's image-guided radiotherapy developmental strategy.

Endoscopic sinus surgery for 'sinus headache'.

The relationship between sinus disease and headache is complicated. We undertook a prospective study to examine the success of endoscopic sinus surgery for the alleviation of headache in a defined group of individuals. In particular we wished to discover whether the presence of asthma, nasal polyposis and purulent rhinosinusitis indicated that surgical intervention achieved any greater relief of symptoms compared to those without these conditions. Overall we found a significant improvement in headache symptoms after endoscopic sinus surgery, but subgroup analysis of patients with or without asthma, nasal polyposis and purulent rhinosinusitis showed no differences between the groups.

The learning curve in stapes surgery and its implication to training.

OBJECTIVE: To identify the stapedotomy learning curve of two U.K. otolaryngologists. STUDY DESIGN: A retrospective review of the outcome of first 100 stapedotomy operations by each surgeon. Included in the study was a postal survey of the incidence of stapes surgery by U.K. otolaryngologists. SETTING: Two tertiary referral centers. PATIENTS: All ears in which primary stapedotomy was performed for otosclerosis. Nonotosclerotic cases and malleus stapedotomy cases were excluded. INTERVENTION: One surgeon used the technique of small fenestra stapedotomy with either a Teflon-wire or titanium piston but without vein graft interposition, whereas the second used the technique of stapedotomy with vein graft interposition and a Teflon piston. MAIN OUTCOME MEASURES: A moving average with a window of 15 dB was used to plot learning curves for the postoperative air-bone gaps. Using a postoperative air-bone gap of 20 dB or better as a definition of 'success,' the success rates with the increase in surgical experience of both surgeons were plotted on graphs, the learning curves. The end point of the learning curve was defined as the point where the curve reached its peak, and the results were sustainable. RESULTS: There was no clear-cut end point in both learning curves, although it appears that there is a landmark point at 60 to 80 cases for both surgeons. Both surgeons also had one "dead ear" in their first 15 cases. The postal survey showed that some trainers only performed small numbers of stapes surgery, whereas some otolaryngologists who performed stapedotomies regularly were not trainers. CONCLUSIONS: The study supports a learning curve in stapes surgery. To maximize the training opportunity of trainee surgeons, it may be advisable for learning centers to form network to provide target training for the trainee who has demonstrated the necessary dexterity and temperament of an otologist.

Integration of copy number and transcriptomics provides risk stratification in prostate cancer: A discovery and validation cohort study.

BACKGROUND: Understanding the heterogeneous genotypes and phenotypes of prostate cancer is fundamental to improving the way we treat this disease. As yet, there are no validated descriptions of prostate cancer subgroups derived from integrated genomics linked with clinical outcome. METHODS: In a study of 482 tumour, benign and germline samples from 259 men with primary prostate cancer, we used integrative analysis of copy number alterations (CNA) and array transcriptomics to identify genomic loci that affect expression levels of mRNA in an expression quantitative trait loci (eQTL) approach, to stratify patients into subgroups that we then associated with future clinical behaviour, and compared with either CNA or transcriptomics alone. FINDINGS: We identified five separate patient subgroups with distinct genomic alterations and expression profiles based on 100 discriminating genes in our separate discovery and validation sets of 125 and 103 men. These subgroups were able to consistently predict biochemical relapse (p = 0.0017 and p = 0.016 respectively) and were further validated in a third cohort with long-term follow-up (p = 0.027). We show the relative contributions of gene expression and copy number data on phenotype, and demonstrate the improved power gained from integrative analyses. We confirm alterations in six genes previously associated with prostate cancer (MAP3K7, MELK, RCBTB2, ELAC2, TPD52, ZBTB4), and also identify 94 genes not previously linked to prostate cancer progression that would not have been detected using either transcript or copy number data alone. We confirm a number of previously published molecular changes associated with high risk disease, including MYC amplification, and NKX3-1, RB1 and PTEN deletions, as well as over-expression of PCA3 and AMACR, and loss of MSMB in tumour tissue. A subset of the 100 genes outperforms established clinical predictors of poor prognosis (PSA, Gleason score), as well as previously published gene signatures (p = 0.0001). We further show how our molecular profiles can be used for the early detection of aggressive cases in a clinical setting, and inform treatment decisions. INTERPRETATION: For the first time in prostate cancer this study demonstrates the importance of integrated genomic analyses incorporating both benign and tumour tissue data in identifying molecular alterations leading to the generation of robust gene sets that are predictive of clinical outcome in independent patient cohorts.

Is physical function a more appropriate measure than volume excess in the assessment of breast cancer-related lymphoedema (BCRL)?

The aim of this study was to objectively measure impairment of arm function in women with breast cancer-related lymphoedema (BCRL), and investigate possible associations between this, arm volume excess, and psychological morbidity as measured by the Medical Outcomes Study 36-item short form (SF-36) questionnaire. A total of 48 patients were recruited. Manual dexterity was significantly impaired in the affected arm, independent of dominant or non-dominant arm involvement, but was not associated with arm volume excess. Psychological morbidity was significantly impaired in the domains of 'physical function' and 'bodily pain' when compared with population controls. Degree of impairment in the 'physical function' domain correlated with the absolute level of objectively tested manual dexterity. Impairment of manual dexterity appears to have a greater impact than arm volume excess on the overall psychological morbidity associated with BCRL, suggesting that greater emphasis should be placed upon arm function in the assessment, treatment targeting, and monitoring of patients with this condition.

Training improves medical student performance in image interpretation.

The aim of this study was to objectively quantify the effects of radiological teaching on student performance in interpreting radiological images, and to establish whether training location affects performance. 114 clinical students were asked to anonymously interpret radiological cases before and after 26 weeks clinical training. Improvements were assessed by comparing performance on the median question in each assessment using the Kruskal-Wallis analysis. Variations according to different placements were assessed by the Mann-Whitney U-test. There was a highly significant (p<0.001) improvement in the performance of the group with training. The proportion of correct answers to the median question improved from 8% to 43%. Differences between training placements were non-significant. Our study suggests that radiology teaching significantly improves student performance. Future work should look to define the contribution of "clinical exposure" towards this improvement, as well as the various teaching methods employed.

Elevated levels of FOXA1 facilitate androgen receptor chromatin binding resulting in a CRPC-like phenotype.

Castration-resistant prostate cancer (CRPC) continues to pose a significant clinical challenge with new generation second-line hormonal therapies affording limited improvement in disease outcome. As the androgen receptor (AR) remains a critical driver in CRPC, understanding the determinants of its transcriptional activity is important for developing new AR-targeted therapies. FOXA1 is a key component of the AR transcriptional complex yet its role in prostate cancer progression and the relationship between AR and FOXA1 are not completely resolved. It is well established that FOXA1 levels are elevated in advanced prostate cancer and metastases. We mimicked these conditions by overexpressing FOXA1 in the androgen-responsive LNCaP prostate cancer cell line and observed a significant increase in AR genomic binding at novel regions that possess increased chromatin accessibility. High levels of FOXA1 resulted in increased proliferation at both sub-optimal and high 5α-dihydrotestosterone (DHT) concentrations. Immunohistochemical staining for FOXA1 in a clinical prostate cancer cohort revealed that high FOXA1 expression is associated with shorter time to biochemical recurrence after radical prostatectomy (hazard ratio (HR) 5.0, 95% confidence interval (CI) 1.2-21.1, P=0.028), positive surgical margins and higher stage disease at diagnosis. The gene expression program that results from FOXA1 overexpression is enriched for PTEN, Wnt and other pathways typically represented in CRPC gene signatures. Together, these results suggest that in an androgen-depleted state, elevated levels of FOXA1 enhance AR binding at genomic regions not normally occupied by AR, which in turn facilitates prostate cancer cell growth.

N-acetyl-L-aspartyl-L-glutamate peptidase-like 2 is overexpressed in cancer and promotes a pro-migratory and pro-metastatic phenotype.

N-acetyl-L-aspartyl-L-glutamate peptidase-like 2 (NAALADL2) is a member of the glutamate carboxypeptidase II family, best characterized by prostate-specific membrane antigen (PSMA/NAALAD1). Using immunohistochemistry (IHC), we have shown overexpression of NAALADL2 in colon and prostate tumours when compared with benign tissue. In prostate cancer, NAALADL2 expression was associated with stage and Grade, as well as circulating mRNA levels of the NAALADL2 gene. Overexpression of NAALADL2 was shown to predict poor survival following radical prostatectomy. In contrast to PSMA/NAALAD1, NAALADL2 was localized at the basal cell surface where it promotes adhesion to extracellular matrix proteins. Using stable knockdown and overexpression cell lines, we have demonstrated NAALADL2-dependent changes in cell migration, invasion and colony-forming potential. Expression arrays of the knockdown and overexpression cell lines have identified nine genes that co-expressed with NAALADL2, which included membrane proteins and genes known to be androgen regulated, including the prostate cancer biomarkers AGR2 and SPON2. Androgen regulation was confirmed in a number of these genes, although NAALADL2 itself was not found to be androgen regulated. NAALADL2 was also found to regulate levels of Ser133 phosphorylated C-AMP-binding protein (CREB), a master regulator of a number of cellular processes involved in cancer development and progression. In combination, these data suggest that changes in expression of NAALADL2 can impact upon a number of pro-oncogenic pathways and processes, making it a useful biomarker for both diagnosis and prognosis.

Show the data, don't conceal them.

Data presentation and statistical analysis in scientific writing are agreed to be in need of improvement, despite the profusion of advice and instruction. Recent evidence supports the need for better planning and analysis of animal experiments. This series of short articles aims to provide advice in small easily digested pieces, on a variety of topics, both basic and more specialized, that are relevant to readers of the journal. The present article encourages authors to present data clearly, preferably as a dot plot, so that the distribution of the values can be recognized. The use of different measures of distribution of a population, and different measures of precision of an estimate is contrasted.

Comparing the accuracy of initial head CT reporting by radiologists, radiology trainees, neuroradiographers and emergency doctors.

OBJECTIVES: Demand for out-of-hours cranial CT imaging is increasing and some departments have considered addressing this shortfall by allowing non-radiologists to provisionally report imaging studies. The aim of this work was to assess whether it is appropriate for non-radiologists to report head CTs by comparing the misreporting rates of those who regularly report head CTs with two groups of non-radiologists who do not usually report them: neuroradiographers and emergency doctors. METHODS: 62 candidates were asked to report 30 head CTs, two-thirds of which were abnormal, and the results were compared by non-parametric statistical analysis. RESULTS: There was no evidence of a difference in the score between neuroradiographers, neuroradiologists and general consultant radiologists. Neuroradiographers scored significantly higher than senior radiology trainees, and the emergency doctors scored least well. CONCLUSION: The results of this preliminary study show that appropriately trained neuroradiographers are competent at reporting the range of abnormalities assessed with this test and that their misreporting rates are similar to those who already independently report these studies.