Prognostic factors and outcomes in primary urethral cancer: results from the international collaboration on primary urethral carcinoma.

PURPOSE To evaluate risk factors for survival in a large international cohort of patients with primary urethral cancer (PUC). METHODS A series of 154 patients (109 men, 45 women) were diagnosed with PUC in ten referral centers between 1993 and 2012. Kaplan-Meier analysis with log-rank test was used to investigate various potential prognostic factors for recurrence-free (RFS) and overall survival (OS). Multivariate models were constructed to evaluate independent risk factors for recurrence and death. RESULTS Median age at definitive treatment was 66 years (IQR 58-76). Histology was urothelial carcinoma in 72 (47 %), squamous cell carcinoma in 46 (30 %), adenocarcinoma in 17 (11 %), and mixed and other histology in 11 (7 %) and nine (6 %), respectively. A high degree of concordance between clinical and pathologic nodal staging (cN+/cN0 vs. pN+/pN0; p < 0.001) was noted. For clinical nodal staging, the corresponding sensitivity, specificity, and overall accuracy for predicting pathologic nodal stage were 92.8, 92.3, and 92.4 %, respectively. In multivariable Cox-regression analysis for patients staged cM0 at initial diagnosis, RFS was significantly associated with clinical nodal stage (p < 0.001), tumor location (p < 0.001), and age (p = 0.001), whereas clinical nodal stage was the only independent predictor for OS (p = 0.026). CONCLUSIONS These data suggest that clinical nodal stage is a critical parameter for outcomes in PUC.

Age- and Gender-related Disparities in Primary Percutaneous Coronary Interventions for Acute ST-segment elevation Myocardial Infarction.

BACKGROUND Previous analyses reported age- and gender-related differences in the provision of cardiac care. The objective of the study was to compare circadian disparities in the delivery of primary percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI) according to the patient's age and gender. METHODS We investigated patients included into the Acute Myocardial Infarction in Switzerland (AMIS) registry presenting to one of 11 centers in Switzerland providing primary PCI around the clock, and stratified patients according to gender and age. FINDINGS A total of 4723 patients presented with AMI between 2005 and 2010; 1319 (28%) were women and 2172 (54%) were ≥65 years of age. More than 90% of patients <65 years of age underwent primary PCI without differences between gender. Elderly patients and particularly women were at increased risk of being withheld primary PCI (males adj. HR 4.91, 95% CI 3.93-6.13; females adj. HR 9.31, 95% CI 7.37-11.75) as compared to males <65 years of age. An increased risk of a delay in door-to-balloon time >90 minutes was found in elderly males (adj HR 1.66 (95% CI 1.40-1.95), p<0.001) and females (adj HR 1.57 (95% CI 1.27-1.93), p<0.001), as well as in females <65 years (adj HR 1.47 (95% CI 1.13-1.91), p = 0.004) as compared to males <65 years of age, with significant differences in circadian patterns during on- and off-duty hours. CONCLUSIONS In a cohort of patients with AMI in Switzerland, we observed discrimination of elderly patients and females in the circadian provision of primary PCI.

Glucose-Induced Temporary Visual Recovery in Primary Open-Angle Glaucoma: A Double-Blind, Randomized Study

Purpose To investigate the effect of topical glucose on visual parameters in individuals with primary open-angle glaucoma (POAG). Design Double-blind, randomized, crossover study. Participants Nondiabetic pseudophakic patients with definite POAG were recruited; 29 eyes of 16 individuals participated in study 1. A follow-up study (study 2) included 14 eyes of 7 individuals. Intervention Eyes were randomly allocated to receive 50% glucose or saline eye drops every 5 minutes for 60 minutes. Main Outcome Measures The contrast sensitivity and best-corrected logarithm of the minimum angle of resolution (logMAR). Results The 50% glucose reached the vitreous in pseudophakic but not phakic individuals. Glucose significantly improved the mean contrast sensitivity at 12 cycles/degree compared with 0.9% saline by 0.26 log units (95% confidence interval [CI], 0.13–0.38; P < 0.001) and 0.40 log units (95% CI, 0.17–0.60; P < 0.001) in the follow-up study. The intraocular pressure, refraction, and central corneal thickness were not affected by glucose; age was not a significant predictor of the response. Conclusions Topical glucose temporarily improves psychophysical visual parameters in some individuals with POAG, suggesting that neuronal energy substrate delivery to the vitreous reservoir may recover function of “sick” retinal neurons.

Implications of intraglandular lymph node metastases in primary carcinomas of the parotid gland

OBJECTIVES/HYPOTHESIS Assess the diagnostic and prognostic relevance of intraglandular lymph node (IGLN) metastases in primary parotid gland carcinomas (PGCs). STUDY DESIGN Retrospective study at a tertiary referral university hospital. METHODS We reviewed the records of 95 patients with primary PGCs, treated at least surgically, between 1997 and 2010. We assessed the clinicopathological associations of IGLN metastases, their prognostic significance, and predictive value in the diagnosis of occult neck lymph node metastases RESULTS Twenty-four (25.26%) patients had IGLN metastases. This feature was significantly more prevalent in patients with advanced pT status (P = .01), pN status (P < .01), and overall stage (P < .001); high-risk carcinomas (P = .01); as well as in patients with treatment failures (P < .01). IGLN involvement was significantly associated with decreased univariate disease-free survival (P < .001). Positive and negative predictive values and accuracy for IGLN involvement in the detection of occult neck lymph node metastases were 63.64%, 90.48%, and 84.91%, respectively. The diagnostic values were generally higher in patients with low-risk subtype of PGCs. CONCLUSIONS IGLN involvement provides prognostic information and is associated with advanced tumoral stage and higher risk of recurrence. This feature could be used as a potential readout to determine whether a neck dissection in clinically negative neck lymph nodes is needed or not. LEVEL OF EVIDENCE 4.

Consensus and differences in primary radiotherapy for localized and locally advanced prostate cancer in Switzerland: A survey on patterns of practice

INTRODUCTION External beam radiotherapy (EBRT), with or without androgen deprivation therapy (ADT), is an established treatment option for nonmetastatic prostate cancer. Despite high-level evidence from several randomized trials, risk group stratification and treatment recommendations vary due to contradictory or inconclusive data, particularly with regard to EBRT dose prescription and ADT duration. Our aim was to investigate current patterns of practice in primary EBRT for prostate cancer in Switzerland. MATERIALS AND METHODS Treatment recommendations on EBRT and ADT for localized and locally advanced prostate cancer were collected from 23 Swiss radiation oncology centers. Written recommendations were converted into center-specific decision trees, and analyzed for consensus and differences using a dedicated software tool. Additionally, specific radiotherapy planning and delivery techniques from the participating centers were assessed. RESULTS The most commonly prescribed radiation dose was 78 Gy (range 70-80 Gy) across all risk groups. ADT was recommended for intermediate-risk patients for 6 months in over 80 % of the centers, and for high-risk patients for 2 or 3 years in over 90 % of centers. For recommendations on combined EBRT and ADT treatment, consensus levels did not exceed 39 % in any clinical scenario. Arc-based intensity-modulated radiotherapy (IMRT) is implemented for routine prostate cancer radiotherapy by 96 % of the centers. CONCLUSION Among Swiss radiation oncology centers, considerable ranges of radiotherapy dose and ADT duration are routinely offered for localized and locally advanced prostate cancer. In the vast majority of cases, doses and durations are within the range of those described in current evidence-based guidelines.

Prognostic Implication of Lymphovascular Invasion Detected by Double Immunostaining for D2-40 and MITF1 in Primary Cutaneous Melanoma.

BACKGROUND Lymphovascular invasion (LVI) is associated with adverse outcomes in primary cutaneous melanoma (PCM). Detection of LVI by hematoxylin and eosin staining alone is 0%-6%, but targeting lymphovascular structures increases the detection rate. OBJECTIVE To examine the prognostic significance of LVI detected by immunostaining for D2-40 and microphthalmia-associated transcription factor 1 (MITF1) in PCM. METHODS The authors retrospectively analyzed 120 PCM samples. We compared the LVI detection rates of immunostaining for D2-40 only (22%), double staining for D2-40 and MITF1 (38%), and hematoxylin and eosin, and examined the association of LVI with clinicopathologic variables and clinical outcomes. RESULTS Immunolabeling with both methods significantly increased the LVI detection rate. Double staining for D2-40 and MITF1 as well as D2-40-detected LVI was significantly associated with increased Breslow thickness, number of mitoses, and sentinel lymph node (SLN) metastasis. D2-40-detected LVI was also associated with ulceration. Although the difference was not significant, double staining for D2-40 and MITF1 allowed for easier detection of LVI than D2-40 alone. LIMITATIONS This study was conducted in a tertiary referral institution; therefore, a referral bias cannot be excluded. CONCLUSIONS Immunolabeling increased detection of LVI in PCM. Because LVI is a positive predictive marker for SLN metastasis, the authors propose using anti-D2-40 and anti-MITF1 in the evaluation of LVI in patients with PCM with a certain risk of SLN metastasis.

Promoting palliative care in the community: production of the primary palliative care toolkit by the European Association of Palliative Care Taskforce in primary palliative care

BACKGROUND A multidisciplinary European Association of Palliative Care Taskforce was established to scope the extent of and learn what facilitates and hinders the development of palliative care in the community across Europe. AIM To document the barriers and facilitators for palliative care in the community and to produce a resource toolkit that palliative care specialists, primary care health professionals or policymakers, service developers, educationalists and national groups more generally could use to facilitate the development of palliative care in their own country. DESIGN (1) A survey instrument was sent to general practitioners with knowledge of palliative care services in the community in a diverse sample of European countries. We also conducted an international systematic review of tools used to identify people for palliative care in the community. (2) A draft toolkit was then constructed suggesting how individual countries might best address these issues, and an online survey was then set up for general practitioners and specialists to make comments. Iterations of the toolkit were then presented at international palliative care and primary care conferences. RESULTS Being unable to identify appropriate patients for palliative care in the community was a major barrier internationally. The systematic review identified tools that might be used to help address this. Various facilitators such as national strategies were identified. A primary palliative care toolkit has been produced and refined, together with associated guidance. CONCLUSION Many barriers and facilitators were identified. The primary palliative care toolkit can help community-based palliative care services to be established nationally.

High intratumoral levels of FoxP3+ lymphocytes are associated with better prognosis in primary resected esophageal adenocarcinomas.

Background: Tumor infiltrating T-lymphocytes (TILs) have been shown to play an important prognostic role in many carcinomas. The identification of prognostic relevant morphological or molecular factors is a major area of interest in the diagnostic process and for the treatment of highly aggressive esophageal adenocarcinoma. Studies about the impact of TILs in this tumor have not shown completely congruent results yet. We present a comprehensive study about the clinical and pathological impact of TIL in esophageal adenocarcinomas. Methods: A next generation tissue microarray (TMA) of 117 primary resected esophageal adenocarcinomas was analyzed for CD3+, CD8+ and FoxP3+ TIL using immunohistochemistry. The TMA contained three cores of the tumor center and the tumor periphery per each case. Slides were scanned with a high-resolution scanner (ScanScope CS; Aperio) and an image analysis software (Aperio Image Scope) was used to determine the TIL counts. The results were correlated with clinicopathological parameters. Results: CD3+, CD8+ and FoxP3+ TIL counts showed a significant correlation among each other (p<0.001 each, range: 0.27-0.77). TIL counts were categorized as high and low levels, according to the median. Tumors with high FoxP3+ intratumoral lymphocyte counts were more frequently of lower pT category (p<0.001) and without lymph node metastasis (p=0.04). High levels of FoxP3+ lymphocytes in the tumor center and the periphery were also associated with better prognosis (p<0.001 and p=0.041, respectively) in univariate analysis. A similar prognostic impact was seen for high levels of CD3+ and CD8+ TIL in the tumor center, but not in the periphery (p=0.047 and p=0.011, respectively). In multivariate analysis high central FoxP3+TIL levels were an independent prognostic factor (HR=0.4; p=0.023) which was similar to a combination score of CD3+/CD8+/FoxP3+ TIL (HR=0.54; p=0.027) or CD8+/Foxp3+ TIL (HR=0.052; p=0.020) and superior to pT- and pN category (p>0.05 each). Conclusion: This study demonstrates a significant beneficial prognostic impact of high TIL counts in the tumor center of esophageal adenocarcinomas, in particular with regards to the subpopulation of FoxP3+ and CD8+ T-regulatory cells. The determination of intratumoral lymphocytic counts and application of TIL scores can improve prognostic accuracy of pathologic reports of these tumors and may be helpful for better risk stratification of esophageal adenocarcinoma patients.

Multigrade teaching in primary education as a promising pedagogy for teacher education in Austria and Finland

This chapter focuses on teaching practices used in multigrade classes and the importance of them being incorporated in teacher education as promising pedagogies for future use. Multigrade classes - defined as classes in which two or more grades are taught together - are common worldwide. Hence, there is a need for teacher candidates to become familiar with how to teach in split grade classrooms. However, research on multigrade teaching as well as its development in teacher education studies has been neglected, even though multigrade teachers need special skills to organize instruction in their heterogeneous classrooms. We argue that in successful multigrade teaching practices, the heterogeneity of students is taken into account and cultivated. Based on content analysis of teacher interviews conducted in Austrian and Finnish primary schools, we recommend teaching practices such as spiral curricula, working plans, and peer learning as promising teacher education pedagogies for future multigrade class teaching. We also suggest that the professional skills required in high-quality teaching practices in multigrade teaching should be further studied by researchers and educators.

Cognitively engaging chronic physical activity, but not aerobic exercise, affects executive functions in primary school children: A group-randomized controlled trial

Although the positive effects of different kinds of physical activity (PA) on cognitive functioning have already been demonstrated in a variety of studies, the role of cognitive engagement in promoting children’s executive functions is still unclear. The aim of the present study was therefore to investigate the effects of two qualitatively different chronic PA interventions on executive functions in primary school children. 181 children aged between 10 and 12 years were assigned to either a 6-week physical education program with a high level of physical exertion and high cognitive engagement (team games), a physical education program with high physical exertion but low cognitive engagement (aerobic exercise), or to a physical education program with both low physical exertion and low cognitive engagement (control condition). Executive functions (updating, inhibition, shifting) and aerobic fitness (multistage 20-meter shuttle run test) were measured before and after the respective condition. Results revealed that both interventions (team games and aerobic exercise) have a positive impact on children’s aerobic fitness (4-5 % increase in estimated VO2max). Importantly, an improvement in shifting performance was found only in the team games and not in the aerobic exercise or control condition. Thus, the inclusion of cognitive engagement in PA seems to be the most promising type of chronic intervention to enhance executive functions in children, providing further evidence for the importance of the qualitative aspects of PA.

Effects of a Transdiagnostic Internet Intervention («velibra») for Anxiety Disorders in Primary Care: Results of a Randomized Controlled Trial

Internet-based cognitive behavioral self-help treatment (ICBT) for anxiety disorders has shown promising results in several trials, but there is yet a lack of studies of ICBT in „real world” primary care settings. In this randomized controlled trial we recruited participants through general practitioners. The aim of the study was to examine whether treatment-as-usual (TAU) in primary care settings plus ICBT is superior to TAU alone in reducing anxiety symptoms and other outcome measures among individuals meeting diagnostic criteria of a least one of three anxiety disorders (social anxiety disorder, panic disorder with or without agoraphobia, generalized anxiety disorder). 150 adults fulfilling diagnostic criteria for a least one of the anxiety disorders according to a diagnostic interview are randomly assigned to one of the two conditions: TAU plus ICBT versus TAU. Randomization is stratified by primary disorder, medication (yes/no) and concurrent psychotherapy. ICBT consists of a transdiagnostic and tailored Internet-based self-help program for several anxiety disorders which also includes cognitive bias modification for interpretation (CBM-I). Primary outcomes are symptoms of disorder-specific anxiety measures and diagnostic status after the intervention (9 weeks). Secondary outcomes include primary outcomes at 3-month follow-up and secondary measures such as general symptomatology, depression, quality of life, adherence to ICBT and satisfaction with ICBT. The study is currently being completed. Primary results along with results for specific subgroups (e.g. primary diagnosis, concurrent medication and/or psychotherapy) will be presented and discussed.

Accuracy of diagnostic testing in primary ciliary dyskinesia.

Diagnosis of primary ciliary dyskinesia (PCD) lacks a "gold standard" test and is therefore based on combinations of tests including nasal nitric oxide (nNO), high-speed video microscopy analysis (HSVMA), genotyping and transmission electron microscopy (TEM). There are few published data on the accuracy of this approach.Using prospectively collected data from 654 consecutive patients referred for PCD diagnostics we calculated sensitivity and specificity for individual and combination testing strategies. Not all patients underwent all tests.HSVMA had excellent sensitivity and specificity (100% and 93%, respectively). TEM was 100% specific, but 21% of PCD patients had normal ultrastructure. nNO (30 nL·min(-1) cut-off) had good sensitivity and specificity (91% and 96%, respectively). Simultaneous testing using HSVMA and TEM was 100% sensitive and 92% specific.In conclusion, combination testing was found to be a highly accurate approach for diagnosing PCD. HSVMA alone has excellent accuracy, but requires significant expertise, and repeated sampling or cell culture is often needed. TEM alone is specific but misses 21% of cases. nNO (≤30 nL·min(-1)) contributes well to the diagnostic process. In isolation nNO screening at this cut-off would miss ∼10% of cases, but in combination with HSVMA could reduce unnecessary further testing. Standardisation of testing between centres is a future priority.