Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group.

Currently, the most widely used criteria for assessing response to therapy in high-grade gliomas are based on two-dimensional tumor measurements on computed tomography (CT) or magnetic resonance imaging (MRI), in conjunction with clinical assessment and corticosteroid dose (the Macdonald Criteria). It is increasingly apparent that there are significant limitations to these criteria, which only address the contrast-enhancing component of the tumor. For example, chemoradiotherapy for newly diagnosed glioblastomas results in transient increase in tumor enhancement (pseudoprogression) in 20% to 30% of patients, which is difficult to differentiate from true tumor progression. Antiangiogenic agents produce high radiographic response rates, as defined by a rapid decrease in contrast enhancement on CT/MRI that occurs within days of initiation of treatment and that is partly a result of reduced vascular permeability to contrast agents rather than a true antitumor effect. In addition, a subset of patients treated with antiangiogenic agents develop tumor recurrence characterized by an increase in the nonenhancing component depicted on T2-weighted/fluid-attenuated inversion recovery sequences. The recognition that contrast enhancement is nonspecific and may not always be a true surrogate of tumor response and the need to account for the nonenhancing component of the tumor mandate that new criteria be developed and validated to permit accurate assessment of the efficacy of novel therapies. The Response Assessment in Neuro-Oncology Working Group is an international effort to develop new standardized response criteria for clinical trials in brain tumors. In this proposal, we present the recommendations for updated response criteria for high-grade gliomas.

Molecular and functional characterization of a novel cardiac-specific human tropomyosin isoform.

BACKGROUND: Tropomyosin (TM), an essential actin-binding protein, is central to the control of calcium-regulated striated muscle contraction. Although TPM1alpha (also called alpha-TM) is the predominant TM isoform in human hearts, the precise TM isoform composition remains unclear. METHODS AND RESULTS: In this study, we quantified for the first time the levels of striated muscle TM isoforms in human heart, including a novel isoform called TPM1kappa. By developing a TPM1kappa-specific antibody, we found that the TPM1kappa protein is expressed and incorporated into organized myofibrils in hearts and that its level is increased in human dilated cardiomyopathy and heart failure. To investigate the role of TPM1kappa in sarcomeric function, we generated transgenic mice overexpressing cardiac-specific TPM1kappa. Incorporation of increased levels of TPM1kappa protein in myofilaments leads to dilated cardiomyopathy. Physiological alterations include decreased fractional shortening, systolic and diastolic dysfunction, and decreased myofilament calcium sensitivity with no change in maximum developed tension. Additional biophysical studies demonstrate less structural stability and weaker actin-binding affinity of TPM1kappa compared with TPM1alpha. CONCLUSIONS: This functional analysis of TPM1kappa provides a possible mechanism for the consequences of the TM isoform switch observed in dilated cardiomyopathy and heart failure patients.

From breaking the rule to making the rules : the adoption, entrenchment and diffusion of gender quotas in France

Once a country allergic to any type of preferential treatment or quota measure for women, France has become a country that applies gender quotas to regulate women's presence and representation in politics, the business sector, public bodies, public administration, and even some civil society organizations. While research has concentrated on the adoption of electoral gender quotas in many countries and their international diffusion, few studies focus on explaining the successful diffusion of gender quotas from politics to other domains in the same country. This paper proposes to fill this gap by studying the particularly puzzling case of a country that at one point strongly opposed the adoption of gender quotas in politics, but, in less than a decade, transformed into one of the few countries applying gender quotas across several policy domains. This paper argues that the legal entrenchment of the parity principle, the institutionalization of parity in several successive women's policy agencies, and key players in these newly created agencies are mainly responsible for this unexpected development. The diffusion of gender quotas in France thus offers an illuminating example of under which conditions women's policy agencies can act autonomously to diffuse and impose a new tool for gender equality

Adolescent Drug Abuse Diagnosis (ADAD) vs. Health of Nation Outcome Scale for Children and Adolescents (HoNOSCA) in clinical outcome measurement.

BACKGROUND: The Adolescent Drug Abuse Diagnosis (ADAD) and Health of Nation Outcome Scales for Children and Adolescents (HoNOSCA) are both measures of outcome for adolescent mental health services. AIMS: To compare the ADAD with HoNOSCA; to examine their clinical usefulness. METHODS: Comparison of the ADAD and HoNOSCA outcome measures of 20 adolescents attending a psychiatric day care unit. RESULTS: ADAD change was positively correlated with HoNOSCA change. HoNOSCA assesses the clinic's day-care programme more positively than the ADAD. The ADAD detects a group for which the mean score remains unchanged whereas HoNOSCA does not. CONCLUSIONS: A good convergent validity emerges between the two assessment tools. The ADAD allows an evidence-based assessment and generally enables a better subject discrimination than HoNOSCA. HoNOSCA gives a less refined evaluation but is more economic in time and possibly more sensitive to change. Both assessment tools give useful information and enabled the Day-care Unit for Adolescents to rethink the process of care and of outcome, which benefited both the institution and the patients.

How family caregivers' medical and moral assumptions influence decision making for patients in the vegetative state: a qualitative interview study.

Background Decisions on limiting life-sustaining treatment for patients in the vegetative state (VS) are emotionally and morally challenging. In Germany, doctors have to discuss, together with the legal surrogate (often a family member), whether the proposed treatment is in accordance with the patient's will. However, it is unknown whether family members of the patient in the VS actually base their decisions on the patient's wishes. Objective To examine the role of advance directives, orally expressed wishes, or the presumed will of patients in a VS for family caregivers' decisions on life-sustaining treatment. Methods and sample A qualitative interview study with 14 next of kin of patients in a VS in a long-term care setting was conducted; 13 participants were the patient's legal surrogates. Interviews were analysed according to qualitative content analysis. Results The majority of family caregivers said that they were aware of aforementioned wishes of the patient that could be applied to the VS condition, but did not base their decisions primarily on these wishes. They gave three reasons for this: (a) the expectation of clinical improvement, (b) the caregivers' definition of life-sustaining treatments and (c) the moral obligation not to harm the patient. If the patient's wishes were not known or not revealed, the caregivers interpreted a will to live into the patient's survival and non-verbal behaviour. Conclusions Whether or not prior treatment wishes of patients in a VS are respected depends on their applicability, and also on the medical assumptions and moral attitudes of the surrogates. We recommend repeated communication, support for the caregivers and advance care planning.

Role of disease activity for decision making ability in early multiple sclerosis

Background and purpose: Decision making (DM) has been defined as the process through which a person forms preferences, selects and executes actions, and evaluates the outcome related to a selected choice. This ability represents an important factor for adequate behaviour in everyday life. DM impairment in multiple sclerosis (MS) has been previously reported. The purpose of the present study was to assess DM in patients with MS at the earliest clinically detectable time point of the disease. Methods: Patients with definite (n=109) or possible (clinically isolated syndrome, CIS; n=56) MS, a short disease duration (mean 2.3 years) and a minor neurological disability (mean EDSS 1.8) were compared to 50 healthy controls aged 18 to 60 years (mean age 32.2) using the Iowa Gambling Task (IGT). Subjects had to select a card from any of 4 decks (A/B [disadvantageous]; C/D [advantageous]). The game consisted of 100 trials then grouped in blocks of 20 cards for data analysis. Skill in DM was assessed by means of a learning index (LI) defined as the difference between the averaged last three block indexes and first two block indexes (LI=[(BI-3+BI-4+BI-5)/3-(BI-1+B2)/2]). Non parametric tests were used for statistical analysis. Results: LI was higher in the control group (0.24, SD 0.44) than in the MS group (0.21, SD 0.38), however without reaching statistical significance (p=0.7). Interesting differences were detected when MS patients were grouped according to phenotype. A trend to a difference between MS subgroups and controls was observed for LI (p=0.06), which became significant between MS subgroups (p=0.03). CIS patients who confirmed MS diagnosis by presenting a second relapse after study entry showed a dysfunction in the IGT in comparison to the other CIS (p=0.01) and definite MS (p=0.04) patients. In the opposite, CIS patients characterised by not entirely fulfilled McDonald criteria at inclusion and absence of relapse during the study showed an normal learning pattern on the IGT. Finally, comparing MS patients who developed relapses after study entry, those who remained clinically stable and controls, we observed impaired performances only in relapsing patients in comparison to stable patients (p=0.008) and controls (p=0.03). Discussion: These results raise the assumption of a sustained role for both MS relapsing activity and disease heterogeneity (i.e. infra-clinical severity or activity of MS) in the impaired process of decision making.

'Doctor, what would you do in my position?' Health professionals and the decision-making process in pregnancy monitoring.

OBJECTIVE: Routine prenatal screening for Down syndrome challenges professional non-directiveness and patient autonomy in daily clinical practices. This paper aims to describe how professionals negotiate their role when a pregnant woman asks them to become involved in the decision-making process implied by screening. METHODS: Forty-one semi-structured interviews were conducted with gynaecologists-obstetricians (n=26) and midwives (n=15) in a large Swiss city. RESULTS: Three professional profiles were constructed along a continuum that defines the relative distance or proximity towards patients' demands for professional involvement in the decision-making process. The first profile insists on enforcing patient responsibility, wherein the healthcare provider avoids any form of professional participation. A second profile defends the idea of a shared decision making between patients and professionals. The third highlights the intervening factors that justify professionals' involvement in decisions. CONCLUSIONS: These results illustrate various applications of the principle of autonomy and highlight the complexity of the doctor-patient relationship amidst medical decisions today.

Decision making and management of gliomas: practical considerations.

Over the last decade, diagnostic options and introduction of novel treatments have expanded the armamentarium in the management of malignant glioma. Combined chemoradiotherapy has become the standard of care in glioblastoma up to the age of 70 years, while treatment in elderly patients or with lower grade glioma is less well defined. Molecular markers define different disease subtypes and allow for adapted treatment selection. This review focuses on simple questions arising in the daily management of patients.

Making land-use fit to planning goals. Weaknesses and opportunities within the Swiss land management regime

In Switzerland, the issue of land consumption has made it to the front of the political agenda in recent years. Studies conducted on a national level have concluded that there is an excess of land zoned for construction (ARE, 2008), which is seen as contributing to urban sprawl. This situation is looked upon as a failure of the Federal Law on Spatial Planning (LAT, 1979) and there is a political push to change it in order to reinforce zoning regulations. In this article, we look on the issue from a different angle. While there may be large quantities of land zoned for construction, in many urban areas land actually available for development is scarce. Building on the idea that planning's efficiency is linked to its capacity of influencing actual land-use, we focus on how this situation can be dealt with within the current Swiss institutional context.

The trail making test as a screening instrument for driving performance in older drivers; a translational research.

BACKGROUND: In many countries, primary care physicians determine whether or not older drivers are fit to drive. Little, however, is known regarding the effects of cognitive decline on driving performance and the means to detect it. This study explores to what extent the trail making test (TMT) can provide indications to clinicians about their older patients' on-road driving performance in the context of cognitive decline. METHODS: This translational study was nested within a cohort study and an exploratory psychophysics study. The target population of interest was constituted of older drivers in the absence of important cognitive or physical disorders. We therefore recruited and tested 404 home-dwelling drivers, aged 70 years or more and in possession of valid drivers' licenses, who volunteered to participate in a driving refresher course. Forty-five drivers also agreed to undergo further testing at our lab. On-road driving performance was evaluated by instructors during a 45 minute validated open-road circuit. Drivers were classified as either being excellent, good, moderate, or poor depending on their score on a standardized evaluation of on-road driving performance. RESULTS: The area under the receiver operator curve for detecting poorly performing drivers was 0.668 (CI95% 0.558 to 0.778) for the TMT-A, and 0.662 (CI95% 0.542 to 0.783) for the TMT-B. TMT was related to contrast sensitivity, motion direction, orientation discrimination, working memory, verbal fluency, and literacy. Older patients with a TMT-A ≥ 54 seconds or a TMT-B ≥ 150 seconds have a threefold (CI95% 1.3 to 7.0) increased risk of performing poorly during the on-road evaluation. TMT had a sensitivity of 63.6%, a specificity of 64.9%, a positive predictive value of 9.5%, and a negative predictive value of 96.9%. CONCLUSION: In screening settings, the TMT would have clinicians uselessly consider driving cessation in nine drivers out of ten. Given the important negative impact this could have on older drivers, this study confirms the TMT not to be specific enough for clinicians to justify driving cessation without complementary investigations on driving behaviors.

Influence of the morphology of the dural sac on surgical decision making in lumbar spinal stenosis

Introduction: Surgical decision making in lumbar spinal stenosis (LSS) takes into account primarily clinical symptoms as well as concordant radiological findings. We hypothesized that a wide variation of operative threshold would be found in particular as far as judgment of severity of radiological stenosis is concerned. Patients and methods: The number of surgeons who would proceed to decompression was studied relative to the perceived severity of radiological stenosis based either on measurements of dural sac cross sectional area (DSCA) or on the recently described morphological grading as seen on axial T2 MRI images. A link to an electronic survey page with a set of ten axial T2 MRI images taken from ten patients with either low back pain or LSS were sent to members of three national or international spine societies. Those 10 images were randomly presented initially and re-shuffled on a second page including this time DSCA measurements in mm2, ranging from 14 to 226 mm2, giving a total of 20 images to appraise. Morphological grades were ranging from grade A to D. Surgeons were asked if they would consider decompression given the radiological appearance of stenosis and that symptoms of neurological claudication were severe in patients who were otherwise fit for surgery. Fisher's exact test was performed following dichotomization of data when appropriate. Results: A total of 142 spine surgeons (113 orthopedic spine surgeons, 29 neurosurgeons) responded from 25 countries. A substantial agreement was observed in operating patients with severe (grade C) or extreme (grade D) stenosis as defined by the morphological grade compared to lesser stenosis (A&B) grades (p<0.0001). Decision to operate was not dependent on number of years in practice, medical density in practicing country or specialty although more neurosurgeons would operate on grade C stenosis (p<0.005). Disclosing the DSCA measurement did not alter the decision to operate. Although 20 surgeons only had prior knowledge of the description of the morphological grading, their responses showed no statistically significant difference with those of the remaining 122 physicians. Conclusions: This study showed that surgeons across borders are less influenced by DSCA in their decision making than by the morphological appearance of the dural sac. Classifying LSS according to morphology rather than surface measurements appears to be consistent with current clinical practice.

Shared decision making development in Switzerland: room for improvement!

In Switzerland there is a strong movement at a national policy level towards strengthening patient rights and patient involvement in health care decisions. Yet, there is no national programme promoting shared decision making. First decision support tools (prenatal diagnosis and screening) for the counselling process have been developed and implemented. Although Swiss doctors acknowledge that shared decision making is important, hierarchical structures and asymmetric physician-patient relationships are still prevailing. The last years have seen some promising activities regarding the training of medical students and the development of patient support programmes. Swiss direct democracy and the habit of consensual decision making and citizen involvement in general may provide a fertile ground for SDM development in the primary care setting.

Nation-wide survey on radiation doses in diagnostic and interventional radiology in Switzerland in 1998.

A nation-wide survey on radiation doses in diagnostic and interventional radiology was conducted in Switzerland in 1998 aiming at establishing their collective radiological impact on the Swiss population. The study consisted on the one hand of surveying the frequency of more than 250 types of examinations, covering conventional radiology, mammography, fluoroscopy, angiography, interventional radiology, CT, bone densitometry, conventional tomography and dental radiology. On the other hand, for each type of examination the associated patient dose was established by modeling. The results of this study show that about 9.5 million diagnostic and interventional examinations are performed annually in Switzerland (1.34 per caput) and that the associated annual collective dose is of the order of 7100 person.Sv (1.0 mSv per caput). Switzerland is similar to other European countries in terms of the frequency of examinations and the collective dose.

The making of frozen-hydrated, vitreous lamellas from cells for cryo-electron microscopy.

There has been a long standing desire to produce thick (up to 500 nm) cryo-sections of fully hydrated cells and tissue for high-resolution analysis in their natural state by cryo-transmission electron microscopy. Here, we present a method that can successfully produce sections (lamellas in FIB-SEM terminology) of fully hydrated, unstained cells from high-pressure frozen samples by focused ion beam (FIB) milling. The samples are therefore placed in thin copper tubes and vitrified by high-pressure freezing. For transfer, handling and subsequent milling, the tubes are placed in a novel connective device (ferrule) that protects the sample from devitrification and contamination and passes through all operation steps. A piezo driven sample positioning stage (cryo-nano-bench, CNB) with three degrees of freedom was additionally developed to enable accurate milling of frozen-hydrated lamellas. With the CNB, high-pressure frozen samples can be milled to produce either thin lamellas (<100 nm), for direct imaging by high-resolution cryo-TEM or thicker lamellas (300-500 nm) for cryo-electron tomography. The sample remains vitreous throughout the process by using the presented tools and methods. The results are an important step towards investigating larger cells and even tissue in there natural state which in the end will enable us to gain better insights into cellular processes.

The frequency and prognostic impact of dic(9;20)(p13.2;q11.2) in childhood B-cell precursor acute lymphoblastic leukemia: results from the NOPHO ALL-2000 trial.

The dic(9;20)(p13.2;q11.2) is reported to be present in ∼2% of childhood B-cell precursor acute lymphoblastic leukemia (BCP ALL). However, it easily escapes detection by G-banding analysis and its true prevalence is hence unknown. We performed interphase fluorescence in situ hybridization analyses-in a three-step manner-using probes for: (i) CDKN2A at 9p21, (ii) 20p and 20q subtelomeres and (iii) cen9 and cen20. Out of 1033 BCP ALLs diagnosed from 2001 to 2006, 533 were analyzed; 16% (84/533) displayed 9p21 deletions, of which 30% (25/84) had dic(9;20). Thus, dic(9;20)-positivity was found in 4.7% (25/533), making it the third most common genetic subgroup after high hyperdiploidy and t(12;21)(p13;q22). The dic(9;20) was associated with a female predominance and an age peak at 3 years; 18/25 (72%) were allocated to non-standard risk treatment at diagnosis. Including cases detected by G-banding alone, 29 dic(9;20)-positive cases were treated according to the NOPHO ALL 2000 protocol. Relapses occurred in 24% (7/29) resulting in a 5-year event-free survival of 0.69, which was significantly worse than for t(12;21) (0.87; P=0.002) and high hyperdiploidy (0.82; P=0.04). We conclude that dic(9;20) is twice as common as previously surmised, with many cases going undetected by G-banding analysis, and that dic(9;20) should be considered a non-standard risk abnormality.