A Comparative Evaluation of Mediastinal Nodal SUVmax and Derived Ratios from 18F-FDG PET/CT Imaging to Predict Nodal Metastases in Non-Small Cell Lung Cancer.

18F-FDG positron emission tomography with computed tomography (PET/CT) is a standard imaging modality for the nodal staging of non-small cell lung cancer (NSCLC). To improve the accuracy of pre-operative staging, we compare the staging accuracy of mediastinal lymph node (LN) standard uptake values (SUV) with four derived SUV ratios based on the SUV values of primary tumours (TR), the mediastinal blood pool (MR), liver (LR), and nodal size (SR). In 2015-2017, 53 patients (29 women and 24 men, mean age 67.4 years, range 53-87) receiving surgical resection have pre-operative evidence of mediastinal nodal involvement (cN2). Among these, 114 mediastinal nodes are resected and available for correlative PET/CT analysis. cN2 status accuracy is low, with only 32.5% of the cN2 cases confirmed pathologically. Using receiver operating characteristic (ROC) curve analyses, a SUVmax of N2 LN performs well in predicting the presence of N2 disease (AUC, 0.822). Based on the respective selected thresholds for each ROC curve, normalisation of LN SUVmax to that for mediastinum, liver and tumour improved sensitivities of LN SUVmax from 68% to 81.1-89.2% while maintaining acceptable specificity (68-70.1%). In conclusion, normalised SUV ratios (particularly LR) improve current pre-operative staging performance in detecting mediastinal nodal involvement.

Oncological Safety of Oncoplastic Level II Mammoplasties After Neoadjuvant Chemotherapy for Large Breast Cancers: A Matched-Cohort Analysis.

BACKGROUND: Oncoplastic surgery (OPS) has extended the indications for breast-conserving surgery (BCS). Its role in patients with large breast cancers treated with neoadjuvant chemotherapy (NAC) is unclear. This study evaluated the oncological safety of OPS for tumors with partial response after NAC. METHODS: A consecutive series of 65 patients who underwent OPS (study group) after NAC for large breast cancer from January 2004 to July 2018 was compared with 130 matched patients treated by NAC, followed by standard BCS in 65 cases and mastectomy in 65 cases (two case-controlled groups). RESULTS: The mean initial radiological tumor size was 46 mm. Residual pathological tumor size was 22 mm in the OPS cohort, 19 mm in the standard BCS cohort, and 31 mm in the mastectomy cohort (p > 0.05). The mean follow-up was 59 months in the study cohort. Five-year local recurrence rates were 0%, 0%, and 10.5% (0-22%) for the OPS, BCS, and mastectomy cohorts, respectively, while 5-year regional recurrence rates were 4.1% (0-11.1%), 0, and 19.4% (0-35.2%, p > 0.05), respectively. Five-year overall survival was 85.3% for the OPS cohort, 94.1% for the standard BCS cohort (p = 0.194), and 79.9% for the mastectomy cohort (p = 0.165). CONCLUSIONS: OPS is safe after NAC for large breast cancers, and provides excellent local control, identical to that of tumors with a better response, treated by standard BCS. After NAC, OPS can be a valuable treatment option for tumors that did not shrink optimally and would not be suitable for standard BCS.

Seasonality of deaths with respect to age and cause in Chitral District Pakistan.

BACKGROUND: Seasonal variability in mortality has been studied in various regions globally. Proper evaluation of seasonally fluctuating mortality is important to establish effective public health measures. We investigated the overall, age-specific, and cause-specific seasonality of deaths in Chitral District in Pakistan. METHOD: Data on 2577 deaths were provided by the Agha Khan Health Support Program. Seasonal mortality patterns concerning age and causes were examined using the X-12 ARIMA pseudo-additive decomposition method. RESULTS: Of the total deceased, 59.6% were males. The proportion of deceased males was significantly higher than the female (40.4%, p< 0.001). The average age at death was 57.7 years (SD = 28.7). On average, approximately 43 deaths occurred each month. More than 10% of the deaths occurred in children less than 5-years-of-age. Among all the causes of death, the most frequent was cardiovascular disease (n = 666, 25.8%) followed by respiratory disease (n = 482, 18.7%). Significant seasonality in the overall deaths was evident, with a peak in winter. Deaths in people ≥ 55-years-of-age were significantly seasonal and peaked in winter. Deaths due to cardiovascular, respiratory, and kidney related diseases were also significantly seasonal with winter peaks. Further, deaths due to external causes were significantly seasonal with summer peak. CONCLUSION: In the winter season, all-cause, except external, and age-specific mortality peaks in Chitral District, Pakistan. Deaths due to external causes and cardiovascular, respiratory, and kidney related diseases were significant seasonal effects.

High-Resolution Copy Number Patterns From Clinically Relevant FFPE Material.

Systematic tumour profiling is essential for biomarker research and clinically for assessing response to therapy. Solving the challenge of delivering informative copy number (CN) profiles from formalin-fixed paraffin embedded (FFPE) material, the only likely readily available biospecimen for most cancers, involves successful processing of small quantities of degraded DNA. To investigate the potential for analysis of such lesions, whole-genome CNVseq was applied to 300 FFPE primary tumour samples, obtained from a large-scale epidemiological study of melanoma. The quality and the discriminatory power of CNVseq was assessed. Libraries were successfully generated for 93% of blocks, with input DNA quantity being the only predictor of success (success rate dropped to 65% if <20 ng available); 3% of libraries were dropped because of low sequence alignment rates. Technical replicates showed high reproducibility. Comparison with targeted CN assessment showed consistency with the Next Generation Sequencing (NGS) analysis. We were able to detect and distinguish CN changes with a resolution of ≤10 kb. To demonstrate performance, we report the spectrum of genomic CN alterations (CNAs) detected at 9p21, the major site of CN change in melanoma. This successful analysis of CN in FFPE material using NGS provides proof of principle for intensive examination of population-based samples.

Minimising the use of physical restraint in acute mental health services: The outcome of a restraint reduction programme ('REsTRAIN YOURSELF').

BACKGROUND: Physical restraint is a coercive intervention used to prevent individuals from harming themselves or others. However, serious adverse effects have been reported. Minimising the use of restraint requires a multimodal approach to target both organisational and individual factors. The 'Six Core Strategies' developed in America, underpinned by prevention and trauma informed principles, is one such approach. OBJECTIVE: An adapted version of the Six Core Strategies was developed and its impact upon physical restraint usage in mental health Trusts in the United Kingdom evaluated. This became known as 'REsTRAIN YOURSELF. The hypothesis was that restraint would be reduced by 40% on the implementation wards over a six-month period. DESIGN: A non-randomised controlled trial design was employed. SETTING: Fourteen, adult, mental health wards from seven mental health hospitals in the North West of England took part in the study. Two acute care wards were targeted from all eligible acute wards within each site in negotiation with each Trust. The intervention wards (total n = 144 beds, mean = 20.1 beds per ward) and control wards (total n = 147 beds, mean = 21.0 beds per ward) were primarily mixed gender but included single sex wards also (2 female-only and 1 male-only in each group). All wards offered pharmacological and psychosocial interventions over short admission durations (circa 15 days) for patients with a mixture of enduring mental health problems. METHOD: As part of a pre and post-test method, physical restraint figures were collected using prospective, routine hospital records before and 6 months after the intervention. Restraint rates on seven wards receiving the REsTRAIN YOURSELF intervention were compared with those on seven control wards over three study phases (baseline, implementation and adoption). RESULTS: In total, 1680 restraint incidents were logged over the study period. The restraint rate was significantly lower on the intervention wards in the adoption phase (6.62 events/1000 bed-days, 95% CI 5.53-7.72) compared to the baseline phase (9.38, 95% CI 8.19-10.55). Across all implementation wards there was an average reduction of restraint by 22%, with some wards showing a reduction of 60% and others less so (8%). The association between ward type and study phase was statistically significant. CONCLUSION: In conclusion, it is possible that reductions in the use of physical restraint are achievable using a model such as the Six Core Strategies. This approach can be adapted for global settings and changes can be sustained over time with continued support.

Identification and validation of DOCK4 as a potential biomarker for risk of bone metastasis development in patients with early breast cancer.

Skeletal metastasis occurs in around 75% of advanced breast cancers, with the disease incurable once cancer cells disseminate to bone, but there remains an unmet need for biomarkers to identify patients at high risk of bone recurrence. This study aimed to identify such a biomarker and to assess its utility in predicting response to adjuvant zoledronic acid (zoledronate). We used quantitative proteomics (stable isotope labelling by amino acids in cell culture-mass spectrometry; SILAC-MS) to compare protein expression in a bone-homing variant (BM1) of the human breast cancer cell line MDA-MB-231 with parental non-bone-homing cells to identify novel biomarkers for risk of subsequent bone metastasis in early breast cancer. SILAC-MS showed that dedicator of cytokinesis protein 4 (DOCK4) was upregulated in bone-homing BM1 cells, confirmed by western blotting. BM1 cells also had enhanced invasive ability compared with parental cells, which could be reduced by DOCK4-shRNA. In a training tissue microarray (TMA) comprising 345 patients with early breast cancer, immunohistochemistry followed by Cox regression revealed that high DOCK4 expression correlated with histological grade (p = 0.004) but not oestrogen receptor status (p = 0.19) or lymph node involvement (p = 0.15). A clinical validation TMA used tissue samples and the clinical database from the large AZURE adjuvant study (n = 689). Adjusted Cox regression analyses showed that high DOCK4 expression in the control arm (no zoledronate) was significantly prognostic for first recurrence in bone (HR 2.13, 95%CI 1.06-4.30, p = 0.034). No corresponding association was found in patients who received zoledronate (HR 0.812, 95%CI 0.176-3.76, p = 0.790), suggesting that treatment with zoledronate may counteract the higher risk for bone relapse from high DOCK4-expressing tumours. High DOCK4 expression was not associated with metastasis to non-skeletal sites when these were assessed collectively. In conclusion, high DOCK4 in early breast cancer is significantly associated with aggressive disease and with future bone metastasis and is a potentially useful biomarker for subsequent bone metastasis risk. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

The Prognostic Value of Immune Factors in the Tumor Microenvironment of Penile Squamous Cell Carcinoma.

The host's immune system plays a pivotal role in many tumor types, including squamous cell carcinomas (SCCs). We aim to identify immunological prognosticators for lymph node metastases (LNM) and disease-specific survival (DSS) in penile SCC. For this retrospective observational cohort study, penile SCC patients (n = 213) treated in the Netherlands Cancer Institute, were selected if sufficient formalin-fixed, paraffin-embedded tumor material was available. Analysis included previously described high-risk human papilloma virus (hrHPV) status, immunohistochemical scores for classical and non-classical human leukocyte antigen (HLA) class I, programmed death ligand-1 (PD-L1) expression, and novel data on tumor-infiltrating macrophages and cytotoxic an regulatory T-cells. Clinicopathological characteristics and extended follow-up were also included. Regression analyses investigated relationships of the immune parameters with LNM and DSS. In the total cohort, diffuse PD-L1 tumor-cell expression, CD163+ macrophage infiltration, non-classical HLA class I upregulation, and low stromal CD8+ T-cell infiltration were all associated with LNM. In the multivariable model, only tumor PD-L1 expression remained a significant predictor for LNM (odds ratio (OR) 2.8, p = 0.05). hrHPV negativity and diffuse PD-L1 tumor-cell expression were significantly associated with poor DSS and remained so upon correction for clinical parameters [hazard ratio (HR) 9.7, p < 0.01 and HR 2.8, p = 0.03]. The only immune factor with different expression in HPV+ and HPV- tumors was PD-L1, with higher PD-L1 expression in the latter (p = 0.03). In the HPV- cohort (n = 158), LNM were associated with diffuse PD-L1 tumor-cell expression, high intratumoral CD163+ macrophage infiltration, and low number of stromal CD8+ T-cells. The first two parameters were also linked to DSS. In the multivariable regression model, diffuse PD-L1 expression remained significantly unfavorable for DSS (HR 5.0, p < 0.01). These results emphasize the complexity of the tumor microenvironment in penile cancer and point toward several possible immunotherapy targets. Here described immune factors can aid risk-stratification and should be evaluated in clinical immunotherapy studies to ultimately lead to patient tailored treatment.

Is magnetic resonance imaging helpful in detecting significant prostate cancer in patients with haematospermia, normal prostate specific antigen level and digital rectal examination. A single institution, observational, and retrospective study in a United Kingdom hospital.

INTRODUCTION: Haematospermia is an uncommon clinical condition that may be associated with prostate cancer. The optimal investigation of haematospermia is unknown. The aim of this study was to investigate haematospermia as a presenting symptom of significant pathology and to assess the diagnostic value of magnetic resonance imaging (MRI). MATERIAL AND METHODS: Patient and treatment parameters were collected from a practice cohort of men referred to a urology center presenting with haematospermia. We used a multivariate logistic regression model to test the independent significance of MRI in detecting prostate cancer (PCa) after adjusting for other known predictors of PCa detection. RESULTS: A total of 125 men (median age 58 years) were evaluated between 2012-2015. In the univariate and multivariate logistic regression model MRI was a significant predictor of PCa diagnosis after adjusting for age, prostate specific antigen (PSA) and digital rectal examination (DRE) results (Odds Ratio (OR) 14.15, p = 0.001). Of 107 patients who underwent MRI prostate imaging, 31 (28.9%) had reports suspicious of PCa. In 26 patients, other benign conditions were detected on MRI. PCa was detected in 12 (25.5%) of the 47 men (median age 61 years; range 43 to 85) who underwent prostate biopsies. Eight (17%) of these patients had Gleason ≥7 grade cancer. The persistence of haematospermia was not an independent predictor of cancer diagnosis (OR 0.20, p = 0.15). CONCLUSIONS: PCa is not commonly associated with haematospermia. MRI seems to be improving detection rate of a significant PCa, particularly in patients presenting with haematospermia and normal PSA levels and DRE examination. Duration of haematospermia does not predict the presence of PCa.

Long-term Results After Oncoplastic Surgery for Breast Cancer: A 10-year Follow-up.

OBJECTIVE: The aim of this study was to evaluate the long-term oncologic outcome after oncoplastic surgery (OPS). BACKGROUND: OPS combines wide tumor excision with reduction mammoplasty techniques thus extending breast conserving surgery to large tumors that might else be proposed a mastectomy. Little data are available about the oncologic results for breast conserving surgery of these larger tumors. METHODS: From January 2004 until March 2016, a total of 350 oncoplastic breast reductions were prospectively entered into a database. Patients were included if their breast reshaping included a reduction mammoplasty with skin excision (Level 2 oncoplastic techniques). RESULTS: Histologic subtypes were: invasive ductal carcinoma in 219 cases (62.6%), ductal carcinoma in situ (DCIS) in 88 cases (25.1%), and invasive lobular carcinoma in 43 (12.3%) cases. Seventy-three of the invasive cancers (27.9%) received neoadjuvant chemotherapy. The mean resection weight was 177 grams. The mean pathological tumor size was 26 mm (range 0-180 mm) and varied from 23 mm (4-180 mm) for invasive cancers to 32 mm (0-100 mm) for DCIS. Specimen margins were involved in 12.6% of the cases; 10.5% of invasive ductal, 14.7% of DCIS, and 20.9% of invasive lobular. The overall breast conservation rate was 92% and varied from 87.4% for DCIS to 93.5% for the invasive cancers. Thirty-one patients (8.9%) developed one or more postoperative complications, inducing a delay in postoperative treatments in 4.6% of patients. The median follow up was 55 months. The cumulative 5-year incidences for local, regional, and distant recurrences were 2.2%, 1.1%, and 12.4%, respectively. CONCLUSIONS: Oncoplastic breast reductions allow wide resections with free margins and can be used for large cancers as an alternative to mastectomy.

Aquatic biodiversity in sedimentation ponds receiving road runoff - What are the key drivers?

Recently, increased attention has been paid to biodiversity conservation provided by blue-green solutions such as engineered ponds that are primarily established for water treatment and flood control. However, little research has been done to analyse the factors that affect biodiversity in such ponds. The purpose of this study was to evaluate the influence of environmental factors on aquatic biodiversity, mainly macroinvertebrate communities, in road sedimentation ponds in order to provide a foundation for recommendations on aquatic biodiversity conservation. Multivariate statistical methods, including unconstrained and constrained analysis, were applied to examine the relationships between organisms and the water quality as well as physical factors (including plant cover). Stepwise multiple regressions indicated that the most important variables governing the variation in the biological community composition were pond size, average annual daily traffic, metals, chloride, distance to the closest pond from study pond, dissolved oxygen, hydrocarbons, and phosphorus. The presence of most taxa was positively correlated with pond size and negatively correlated with metals. Small ponds with high pollutant loadings were associated with a low diversity and dominated by a few pollution tolerant taxa such as oligochaetes. A comprehensive understanding of impacts of various environmental factors on aquatic biodiversity is important to effectively promote and conserve aquatic biodiversity in such sedimentation ponds. Our results indicate that road sedimentation ponds should be designed large enough, because large ponds are likely to provide a more heterogeneous habitat and thus contain a species rich fauna. In addition, larger ponds seem to be less contaminated due to dilution compared to smaller ponds, thereby maintaining a higher biodiversity. Finally, creating some additional ponds in the vicinity of the sedimentation ponds in areas with few water bodies would increase the connectivity that facilitates the movement of invertebrates between ponds.

Genomic Subtypes of Non-invasive Bladder Cancer with Distinct Metabolic Profile and Female Gender Bias in KDM6A Mutation Frequency.

Bladder cancer incurs a higher lifetime treatment cost than other cancers due to frequent recurrence of non-invasive disease. Improved prognostic biomarkers and localized therapy are needed for this large patient group. We defined two major genomic subtypes of primary stage Ta tumors. One of these was characterized by loss of 9q including TSC1, increased KI67 labeling index, upregulated glycolysis, DNA repair, mTORC1 signaling, features of the unfolded protein response, and altered cholesterol homeostasis. Comparison with muscle-invasive bladder cancer mutation profiles revealed lower overall mutation rates and more frequent mutations in RHOB and chromatin modifier genes. More mutations in the histone lysine demethylase KDM6A were present in non-invasive tumors from females than males.

Patient understanding of liver cirrhosis and improvement using multimedia education.

OBJECTIVE: For patients to engage with the long-term management of liver cirrhosis, sufficient understanding of their condition is essential. The aim of this study was to assess baseline patient knowledge and to test whether a condition-specific multimedia screencast could improve this. DESIGN: Service quality improvement study. SETTING: A UK tertiary liver centre. Patients were recruited during 12 general hepatology outpatient clinics. PATIENTS: Fifty-two patients with liver cirrhosis were included. Sixty-two per cent were male; their median age was 56 years and their median clinic attendance period was 3 years. INTERVENTIONS: Participants completed a baseline questionnaire assessing their knowledge of the management and complications of cirrhosis. They then watched a tailored screencast discussing this condition, which had been developed by expert hepatologists in collaboration with patient representatives. Knowledge was reassessed using a new copy of the original questionnaire after an interval of at least one month. MAIN OUTCOME MEASURES: Patient scores on knowledge questionnaires at baseline and follow-up. RESULTS: Fifty-two patients achieved a median score of 25.0% before viewing the screencast. Thirty-five patients then completed a follow-up questionnaire after an interval period. The median questionnaire score in this group improved from 25.0% to 66.7%; an increase of 41.7% compared with baseline (p<0.001). CONCLUSIONS: Despite regular review at a specialist clinic, participants had poor baseline knowledge of liver cirrhosis. Delivering information by screencast led to a significant improvement. We therefore present an effective way to empower patients with accurate, up-to-date and retainable information that can easily be translated to many other conditions.

A Case-Matched Gender Comparison Transcriptomic Screen Identifies eIF4E and eIF5 as Potential Prognostic Markers in Male Breast Cancer.

Purpose: Breast cancer affects both genders, but is understudied in men. Although still rare, male breast cancer (MBC) is being diagnosed more frequently. Treatments are wholly informed by clinical studies conducted in women, based on assumptions that underlying biology is similar.Experimental Design: A transcriptomic investigation of male and female breast cancer was performed, confirming transcriptomic data in silico Biomarkers were immunohistochemically assessed in 697 MBCs (n = 477, training; n = 220, validation set) and quantified in pre- and posttreatment samples from an MBC patient receiving everolimus and PI3K/mTOR inhibitor.Results: Gender-specific gene expression patterns were identified. eIF transcripts were upregulated in MBC. eIF4E and eIF5 were negatively prognostic for overall survival alone (log-rank P = 0.013; HR = 1.77, 1.12-2.8 and P = 0.035; HR = 1.68, 1.03-2.74, respectively), or when coexpressed (P = 0.01; HR = 2.66, 1.26-5.63), confirmed in the validation set. This remained upon multivariate Cox regression analysis [eIF4E P = 0.016; HR = 2.38 (1.18-4.8), eIF5 P = 0.022; HR = 2.55 (1.14-5.7); coexpression P = 0.001; HR = 7.04 (2.22-22.26)]. Marked reduction in eIF4E and eIF5 expression was seen post BEZ235/everolimus, with extended survival.Conclusions: Translational initiation pathway inhibition could be of clinical utility in MBC patients overexpressing eIF4E and eIF5. With mTOR inhibitors that target this pathway now in the clinic, these biomarkers may represent new targets for therapeutic intervention, although further independent validation is required. Clin Cancer Res; 23(10); 2575-83. ©2016 AACR.

Expression of Programmed Death Ligand 1 in Penile Cancer is of Prognostic Value and Associated with HPV Status.

PURPOSE: PD-L1 (programmed death ligand 1) inhibits T-cell function and prevents tumor eradication. This is facilitated by PD-L1 positive tumor cells and PD-L1 positive immune cells, and can be prevented by anti-PD-1 (programmed death 1)/PD-L1 immunotherapy. In advanced penile cancer there is a need for new therapeutic strategies. We investigated PD-L1 expression in penile cancers and compared PD-L1 expression with disease specific survival, lymph node metastases at diagnosis and high risk HPV status in a large patient cohort. MATERIALS AND METHODS: A total of 213 primary tumors were immunohistochemically stained for PD-L1 and scored for tumor (percentage), stroma (binary) and PD-L1 positive tumor infiltrating macrophages. Additionally, PD-L1 positive tumors were scored for expression pattern, that is diffuse or predominantly present at the tumor-stroma margin. RESULTS: Staining was successful in 200 tumors, of which 75% were high risk HPV negative. Median followup was 62 months. Of 200 tumors 96 (48%) were PD-L1 positive (scored 1% or greater), of which 59 (62%) had a marginal expression pattern and 79 (82%) were high risk HPV negative (p = 0.03). Compared to PD-L1 negative tumors, the PD-L1 expression patterns had different prognostic values in the whole cohort as well as in the high risk HPV negative subgroup. On multivariable analyses a marginal expression pattern was associated with absent lymph node metastases (OR 0.4) while diffuse expression was associated with poor survival (HR 2.58). These results were more prominent in the high risk HPV negative subgroup (OR 0.25, HR 3.92). CONCLUSIONS: PD-L1 was expressed in 48% of penile carcinomas and mainly in high risk HPV negative tumors. The pattern of expression was a prognostic factor as marginal expression was associated with absent lymph node metastases and diffuse expression was associated with poor survival.

Variability in physical contamination assessment of source segregated biodegradable municipal waste derived composts.

Physical contaminants (glass, metal, plastic and 'other') and stones were isolated and categorised from three finished commercial composts derived from source segregated biodegradable municipal waste (BMW). A subset of the identified physical contaminant fragments were subsequently reintroduced into the cleaned compost samples and sent to three commercial laboratories for testing in an inter-laboratory trial using the current PAS100:2011 method (AfOR MT PC&S). The trial showed that the 'other' category caused difficulty for all three laboratories with under reporting, particularly of the most common 'other' contaminants (paper and cardboard) and, over-reporting of non-man-made fragments. One laboratory underreported metal contaminant fragments (spiked as silver foil) in three samples. Glass, plastic and stones were variably underreported due to miss-classification or over reported due to contamination with compost (organic) fragments. The results are discussed in the context of global physical contaminant test methods and compost quality assurance schemes.

A validated microRNA profile with predictive potential in glioblastoma patients treated with bevacizumab.

PURPOSE: We investigated whether microRNA expression data from glioblastoma could be used to produce a profile that defines a bevacizumab responsive group of patients. PATIENTS AND METHODS: TCGA microRNA expression data from tumors resected at first diagnosis of glioblastoma in patients treated with bevacizumab at any time during the course of their disease were randomly separated into training (n = 50) and test (n = 37) groups for model generation. MicroRNA-seq data for 51 patients whose treatment included bevacizumab in the BELOB trial were used as an independent validation cohort. RESULTS: Using penalized regression we identified 8 microRNAs as potential predictors of overall survival in the training set. We dichotomized the response score based on the most prognostic minimum of a density plot of the response scores (log-rank HR = 0.16, p = 1.2e(-5)) and validated the profile in the test cohort (one-sided log-rank HR = 0.34, p = 0.026). Analysis of the profile using all samples in the TCGA glioblastoma dataset, regardless of treatment received, (n = 473) showed that the prediction of patient benefit was not significant (HR = 0.84, p = 0.083) suggesting the profile is specific to bevacizumab. Further independent validation of our microRNA profile in RNA-seq data from patients treated with bevacizumab (alone or in combination with CCNU) at glioblastoma recurrence in the BELOB trial confirmed that our microRNA profile predicted patient benefit from bevacizumab (HR = 0.59, p = 0.043). CONCLUSION: We have identified and validated an 8-microRNA profile that predicts overall survival in patients with glioblastoma treated with bevacizumab. This may be useful for identifying patients who are likely to benefit from this agent.

Hydrocortisone as an Intervention for Dexamethasone-Induced Adverse Effects in Pediatric Patients With Acute Lymphoblastic Leukemia: Results of a Double-Blind, Randomized Controlled Trial.

PURPOSE: Dexamethasone is a key component in the treatment of pediatric acute lymphoblastic leukemia (ALL), but can induce serious adverse effects. Recent studies have led to the hypothesis that neuropsychological adverse effects may be a result of cortisol depletion of the cerebral mineralocorticoid receptors. We examined whether including a physiologic dose of hydrocortisone in dexamethasone treatment can reduce neuropsychologic and metabolic adverse effects in children with ALL. PATIENTS AND METHODS: We performed a multicenter, double-blind, randomized controlled trial with a crossover design. Of 116 potentially eligible patients (age 3 to 16 years), 50 were enrolled and were treated with two consecutive courses of dexamethasone in accordance with Dutch Childhood Oncology Group ALL protocols. Patients were randomly assigned to receive either hydrocortisone or placebo in a circadian rhythm (10 mg/m(2)/d) during both dexamethasone courses. Primary outcome measure was parent-reported Strength and Difficulties Questionnaire in Dutch, which assesses psychosocial problems. Other end points included questionnaires, neuropsychological tests, and metabolic parameters. RESULTS: Of 48 patients who completed both courses, hydrocortisone had no significant effect on outcome; however, a more detailed analysis revealed that in 16 patients who developed clinically relevant psychosocial adverse effects, addition of hydrocortisone substantially reduced their Strength and Difficulties Questionnaire in Dutch scores in the following domains: total difficulties, emotional symptoms, conduct problems, and impact of difficulties. Moreover, in nine patients who developed clinically relevant, sleep-related difficulties, addition of hydrocortisone reduced total sleeping problems and disorders of initiating and maintaining sleep. In contrast, hydrocortisone had no effect on metabolic parameters. CONCLUSION: Our results suggest that adding a physiologic dose of hydrocortisone to dexamethasone treatment can reduce the occurrence of serious neuropsychological adverse effects and sleep-related difficulties in pediatric patients with ALL.

The prognostic significance of tumour-stroma ratio in endometrial carcinoma.

BACKGROUND: High tumour stromal content has been found to predict adverse clinical outcome in a range of epithelial tumours. The aim of this study was to assess the prognostic significance of tumour-stroma ratio (TSR) in endometrial adenocarcinomas and investigate its relationship with other clinicopathological parameters. METHODS: Clinicopathological and 5-year follow-up data were obtained for a retrospective series of endometrial adenocarcinoma patients (n=400). TSR was measured using a morphometric approach (point counting) on digitised histologic hysterectomy specimens. Inter-observer agreement was determined using Cohen's Kappa statistic. TSR cut-offs were optimised using log-rank functions and prognostic significance of TSR on overall survival (OS) and disease-free survival (DFS) were determined using Cox Proportional Hazards regression analysis and Kaplan-Meier curves generated. Associations of TSR with other clinicopathological parameters were determined using non-parametric tests followed by Holm-Bonferroni correction for multiple comparisons. RESULTS: TSR as a continuous variable associated with worse OS (P=0.034) in univariable Cox-regression analysis. Using the optimal cut-off TSR value of 1.3, TSR-high (i.e. low stroma) was associated with worse OS (HR=2.51; 95% CI=1.22-5.12; P=0.021) and DFS (HR=2.19; 95% CI=1.15-4.17; P=0.017) in univariable analysis. However, TSR did not have independent prognostic significance in multivariable analysis, when adjusted for known prognostic variables. A highly significant association was found between TSR and tumour grade (P<0.001) and lymphovascular space invasion (P<0.001), both of which had independent prognostic significance in this study population. CONCLUSIONS: Low tumour stromal content associates with both poor outcome and with other adverse prognostic indicators in endometrial cancer, although it is not independently prognostic. These findings contrast with studies on many--although not all--cancers and suggest that the biology of tumour-stroma interactions may differ amongst cancer types.

A Rac/Cdc42 exchange factor complex promotes formation of lateral filopodia and blood vessel lumen morphogenesis.

During angiogenesis, Rho-GTPases influence endothelial cell migration and cell-cell adhesion; however it is not known whether they control formation of vessel lumens, which are essential for blood flow. Here, using an organotypic system that recapitulates distinct stages of VEGF-dependent angiogenesis, we show that lumen formation requires early cytoskeletal remodelling and lateral cell-cell contacts, mediated through the RAC1 guanine nucleotide exchange factor (GEF) DOCK4 (dedicator of cytokinesis 4). DOCK4 signalling is necessary for lateral filopodial protrusions and tubule remodelling prior to lumen formation, whereas proximal, tip filopodia persist in the absence of DOCK4. VEGF-dependent Rac activation via DOCK4 is necessary for CDC42 activation to signal filopodia formation and depends on the activation of RHOG through the RHOG GEF, SGEF. VEGF promotes interaction of DOCK4 with the CDC42 GEF DOCK9. These studies identify a novel Rho-family GTPase activation cascade for the formation of endothelial cell filopodial protrusions necessary for tubule remodelling, thereby influencing subsequent stages of lumen morphogenesis.