Surgery for low-grade glioma infiltrating the central cerebral region: location as a predictive factor for neurological deficit, epileptological outcome, and quality of life

OBJECT A main concern with regard to surgery for low-grade glioma (LGG, WHO Grade II) is maintenance of the patient's functional integrity. This concern is particularly relevant for gliomas in the central region, where damage can have grave repercussions. The authors evaluated postsurgical outcomes with regard to neurological deficits, seizures, and quality of life. METHODS Outcomes were compared for 33 patients with central LGG (central cohort) and a control cohort of 31 patients with frontal LGG (frontal cohort), all of whom had had medically intractable seizures before undergoing surgery with mapping while awake. All surgeries were performed in the period from February 2007 through April 2010 at the same institution. RESULTS For the central cohort, the median extent of resection was 92% (range 80%-97%), and for the frontal cohort, the median extent of resection was 93% (range 83%-98%; p = 1.0). Although the rate of mild neurological deficits was similar for both groups, seizure freedom (Engel Class I) was achieved for only 4 (12.1%) of 33 patients in the central cohort compared with 26 (83.9%) of 31 patients in the frontal cohort (p < 0.0001). The rate of return to work was lower for patients in the central cohort (4 [12.1%] of 33) than for the patients in the frontal cohort (28 [90.3%] of 31; p < 0.0001). CONCLUSIONS Resection of central LGG is feasible and safe when appropriate intraoperative mapping is used. However, seizure control for these patients remains poor, a finding that contrasts markedly with seizure control for patients in the frontal cohort and with that reported in the literature. For patients with central LGG, poor seizure control ultimately determines quality of life because most will not be able to return to work.

Tumor regression grade of urothelial bladder cancer after neoadjuvant chemotherapy: a novel and successful strategy to predict survival.

Histopathologic tumor regression grades (TRGs) after neoadjuvant chemotherapy predict survival in different cancers. In bladder cancer, corresponding studies have not been conducted. Fifty-six patients with advanced invasive urothelial bladder cancer received neoadjuvant chemotherapy before cystectomy and lymphadenectomy. TRGs were defined as follows: TRG1: complete tumor regression; TRG2: >50% tumor regression; TRG3: 50% or less tumor regression. Separate TRGs were assigned for primary tumors and corresponding lymph nodes. The prognostic impact of these 2 TRGs, the highest (dominant) TRG per patient, and competing tumor features reflecting tumor regression (ypT/ypN stage, maximum diameter of the residual tumor) were determined. Tumor characteristics in initial transurethral resection of the bladder specimens were tested for response prediction. The frequency of TRGs 1, 2, and 3 in the primary tumors were n=16, n=19, and n=21; corresponding data from the lymph nodes were n=31, n=9, and n=16. Interobserver agreement in determination of the TRG was strong (κ=0.8). Univariately, all evaluated parameters were significantly (P≤0.001) related to overall survival; however, the segregation of the Kaplan-Meier curves was best for the dominant TRG. In multivariate analysis, only dominant TRG predicted overall survival independently (P=0.035). In transurethral resection specimens of the chemotherapy-naive bladder cancer, the only tumor feature with significant (P<0.03) predictive value for therapy response was a high proliferation rate. In conclusion, among all parameters reflecting tumor regression, the dominant TRG was the only independent risk factor. A favorable chemotherapy response is associated with a high proliferation rate in the initial chemotherapy-naive bladder cancer. This feature might help personalize neoadjuvant chemotherapy.

Inducible caspase 9 suicide gene to improve the safety of allodepleted T cells after haploidentical stem cell transplantation.

Addback of donor T cells following T cell-depleted stem cell transplantation (SCT) can accelerate immune reconstitution and be effective against relapsed malignancy. After haploidentical SCT, a high risk of graft-versus-host disease (GVHD) essentially precludes this option, unless the T cells are first depleted of alloreactive precursor cells. Even then, the risks of severe GVHD remain significant. To increase the safety of the approach and thereby permit administration of larger T cell doses, we used a suicide gene, inducible caspase 9 (iCasp9), to transduce allodepleted T cells, permitting their destruction should administration have adverse effects. We made a retroviral vector encoding iCasp9 and a selectable marker (truncated CD19). Even after allodepletion (using anti-CD25 immunotoxin), donor T cells could be efficiently transduced, expanded, and subsequently enriched by CD19 immunomagnetic selection to >90% purity. These engineered cells retained antiviral specificity and functionality, and contained a subset with regulatory phenotype and function. Activating iCasp9 with a small-molecule dimerizer rapidly produced >90% apoptosis. Although transgene expression was downregulated in quiescent T cells, iCasp9 remained an efficient suicide gene, as expression was rapidly upregulated in activated (alloreactive) T cells. We have demonstrated the clinical feasibility of this approach after haploidentical transplantation by scaling up production using clinical grade materials.

Dominance of chemokine ligand 2 and matrix metalloproteinase-2 and -9 and suppression of pro-inflammatory cytokines in the epidural compartment after intervertebral disc extrusion in a canine model

BACKGROUND CONTEXT In canine intervertebral disc (IVD) disease, a useful animal model, only little is known about the inflammatory response in the epidural space. PURPOSE To determine messenger RNA (mRNA) expressions of selected cytokines, chemokines, and matrix metalloproteinases (MMPs) qualitatively and semiquantitatively over the course of the disease and to correlate results to neurologic status and outcome. STUDY DESIGN/SETTING Prospective study using extruded IVD material of dogs with thoracolumbar IVD extrusion. PATIENT SAMPLE Seventy affected and 13 control (24 samples) dogs. OUTCOME MEASURES Duration of neurologic signs, pretreatment, neurologic grade, severity of pain, and outcome were recorded. After diagnostic imaging, decompressive surgery was performed. METHODS Messenger RNA expressions of interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor (TNF), interferon (IFN)γ, MMP-2, MMP-9, chemokine ligand (CCL)2, CCL3, and three housekeeping genes was determined in the collected epidural material by Panomics 2.0 QuantiGene Plex technology. Relative mRNA expression and fold changes were calculated. Relative mRNA expression was correlated statistically to clinical parameters. RESULTS Fold changes of TNF, IL-1β, IL-2, IL-4, IL-6, IL-10, IFNγ, and CCL3 were clearly downregulated in all stages of the disease. MMP-9 was downregulated in the acute stage and upregulated in the subacute and chronic phase. Interleukin-8 was upregulated in acute cases. MMP-2 showed mild and CCL2 strong upregulation over the whole course of the disease. In dogs with severe pain, CCL3 and IFNγ were significantly higher compared with dogs without pain (p=.017/.020). Dogs pretreated with nonsteroidal anti-inflammatory drugs revealed significantly lower mRNA expression of IL-8 (p=.017). CONCLUSIONS The high CCL2 levels and upregulated MMPs combined with downregulated T-cell cytokines and suppressed pro-inflammatory genes in extruded canine disc material indicate that the epidural reaction is dominated by infiltrating monocytes differentiating into macrophages with tissue remodeling functions. These results will help to understand the pathogenic processes representing the basis for novel therapeutic approaches. The canine IVD disease model will be rewarding in this process.

Cerebral High-grade Oligodendroglioma with Sarcomatous Transdifferentiation ("Oligosarcoma") in a Boxer Dog.

A 9-year-old Boxer dog was referred to the Veterinary Teaching Hospital of the University of Bern for a history of chronic neck pain and gait problems, which rapidly progressed to a non-ambulatory status. Magnetic resonance imaging (MRI) examination of the head revealed a large intra-axial space-occupying lesion that was divided in two portions interconnected by a thin isthmus at the level of the cerebellar tentorium. Histopathology revealed a biphasic malignant neoplasm composed of neuroepithelial and mesenchymal elements. The former displayed characteristics of conventional anaplastic oligodendroglioma involving brisk mitotic activity and glomeruloid microvascular proliferation on a background of a fibrillary round cells with "honeycomb-like" perinuclear vacuolation. Conversely, the sarcomatous moiety exhibited haphazard fascicles of spindle cells amidst an intricate mesh of pericellular basal lamina and broad bands of collagen. Both tumor cell populations immunoreacted for Olig-2 and – to a lesser extent – GFAP. In addition, the sarcomatous areas focally expressed vimentin, muscular actin, and smooth muscle actin. "Oligosarcoma" - an exquisitely uncommon pattern of oligodendroglial malignancy in humans - has not previously been reported to affect dogs, although oligodendroglioma is a common CNS tumor in this species. Whether canine oligosarcoma shares with its human counterpart not only morphological aspects, but also molecular signatures, clinical behavior and responsiveness to therapy merits further investigation. In humans, oligodendroglial differentiation tends to confer significant clinical advantage with respect to prognosis and adjuvant treatment options. The awareness of such hallmarks and the investigation of their impact on prognosis are crucial for improved therapeutical strategies in dogs.

Clinical herniation – how to improve differentiation between WFNS grade IV and V

Objective: Current data show a favorable outcome after poor grade subarachnoid hemorrhage (SAH) in up to 50% of patients. This limits the use of the WFNS scale for drawing treatment decisions. We therefore analyzed how clinical signs of herniation might improve the existing WFNS grading. Therefore we compared the current WFNS grading and a modified WFNS grading with respect to outcome. Method: We performed a retrospective study including 182 poor grade SAH patients. Patients were graded according to the original WFNS scale and additionally into a modified classification the “WFNS herniation” (WFNSh grade IV: no herniation; grade V clinical signs of herniation). Outcome was compared between these two grading systems with respect to the dichotomized modified Rankin scale after 6 months. Results: The WFNS and WFNSh showed a positive predictive value (PPV) for poor outcome of 74.3% (OR 3.79, 95% confidence interval [CI]=1.94, 7.54) and 85.7% (OR 8.27, 95% CI=3.78, 19.47), respectively. With respect to mortality the PPV was 68.3% (OR 3.9, 95% CI=2.01, 7.69) for the WFNS grade V and 77.9% (OR 6.22, 95% CI=3.07, 13.14) for the WFNSh grade V. Conclusions: Using positive clinical signs of herniation instead of “no response to pain stimuli” (motor Glasgow Coma Scale Score) can improve WFNS V grading. Using this modification, prediction of poor outcome or death improves.

P-T-t estimation of syn-kinematic strain in low-grade quartz-feldspar bearing rocks using thermodynamic modeling and 40Ar/39Ar dating techniques: example of the Plan-de-Phasy shear zone unit (Briançonnais Zone, Western Alps)

Pressure–Temperature–time (P–T–t) estimates of the syn-kinematic strain at the peak-pressure conditions reached during shallow underthrusting of the Briançonnais Zone in the Alpine subduction zone was made by thermodynamic modelling and 40Ar/39Ar dating in the Plan-de-Phasy unit (SE of the Pelvoux Massif, Western Alps). The dated phengite minerals crystallized syn-kinematically in a shear zone indicating top-to-the-N motion. By combining X-ray mapping with multi-equilibrium calculations, we estimate the phengite crystallization conditions at 270 ± 50 °C and 8.1 ± 2 kbar at an age of 45.9 ± 1.1 Ma. Combining this P–T–t estimate with data from the literature allows us to constrain the timing and geometry of Alpine continental subduction. We propose that the Briançonnais units were scalped on top of the slab during ongoing continental subduction and exhumed continuously until collision.

Small-diameter titanium grade IV and titanium-zirconium implants in edentulous mandibles: five-year results from a double-blind, randomized controlled trial.

BACKGROUND The aim of this study was to compare the 5-year survival and success rates of 3.3 mm dental implants either made from titanium-zirconium (TiZr) alloy or from Grade IV titanium (Ti Grade IV) in mandibular implant-based removable overdentures. METHODS The core study had a follow-up period of 36 months and was designed as a randomized, controlled, double-blind, split-mouth multicenter clinical trial. Patients with edentulous mandibles received two Straumann Bone Level implants (diameter 3.3 mm, SLActive®), one of TiZr (test) and one of Ti Grade IV (control), in the interforaminal region. This follow-up study recruited patients from the core study and evaluated the plaque and sulcus bleeding indices, radiographic crestal bone level, as well as implant survival and success 60 months after implant placement. RESULTS Of the 91 patients who initially received implants, 75 completed the 36 month follow-up and 49 were available for the 60 month examination. Two patients were excluded so that a total of 47 patients with an average age of 72 ± 8 years were analysed. The characteristics and 36-month performance of the present study cohort did not differ from the non-included initial participants (p > 0.05). In the period since the 36-month follow-up examination, no implant was lost. The cumulative implant survival rate was 98.9 % for the TiZr group and 97.8 % for the Ti Grade IV group. Crestal bone level changes at 60 months were not different in the test and control group (TiZr -0.60 ± 0.69 mm and Ti Grade IV -0.61 ± 0.83 mm; p = 0.96). The cumulative implant success rate after 60 months was 95.8 and 92.6 % for TiZr and Ti Grade IV, respectively. CONCLUSIONS After 60 months, the positive outcomes of the 36 month results for TiZr and Ti Grade IV implants were confirmed, with no significant differences with regard to crestal bone level change, clinical parameters and survival or success rates. TiZr implants performed equally well compared to conventional Ti Grade IV 3.3 mm diameter-reduced implants for mandibular removable overdentures. TRIAL REGISTRATION Registered on www.clinicaltrials.gov: NCT01878331.

Small-diameter titanium Grade IV and titanium-zirconium implants in edentulous mandibles: three-year results from a double-blind, randomized controlled trial

OBJECTIVE The aim of this study was to compare crestal bone-level changes, soft tissue parameters and implant success and survival between small-diameter implants made of titanium/zirconium (TiZr) alloy or of Grade IV titanium (Ti) in edentulous mandibles restored with removable overdentures. MATERIALS AND METHODS This was a randomized, controlled, double-blind, split-mouth multicenter clinical trial. Patients with edentulous mandibles received two Straumann bone-level implants (diameter 3.3 mm), one of Ti Grade IV (control) and one of TiZr (test), in the interforaminal region. Implants were loaded after 6-8 weeks and removable Locator-retained overdentures were placed within 2 weeks of loading. Modified plaque and sulcus bleeding indices, radiographic bone level, and implant survival and success were evaluated up to 36 months. RESULTS Of 91 treated patients, 75 completed the three-year follow-up. Three implants were lost (two control and one test implant). The survival rates were 98.7% and 97.3%, and the mean marginal bone level change was -0.78 ± 0.75 and -0.60 ± 0.71 mm for TiZr and Ti Grade IV implants. Most patients had a plaque score of 0 or 1 (54% for test and 51.7% for control), and a sulcus bleeding score of 0 (46.1% for test and 44.9% for control). No significant differences were found between the two implant types for bone-level change, soft tissue parameters, survival and success. CONCLUSIONS After 36 months, similar outcomes were found between Ti Grade IV and TiZr implants. The results confirm that the results seen at 12 months continue over time.

Does parental monitoring influence the use of alcohol and drugs among inner city 7th grade students?

Objective. To examine associations between parental monitoring and adolescent alcohol/drug use. ^ Methods. 981 7th grade students from 10 inner-city middle schools were surveyed at the 3 month follow-up of an HIV, STD, and pregnancy prevention program. Data from 549 control subjects were used for analyses. Multinomial logistic regression was used to examine associations between five parental monitoring variables and substance use, coded as: low risk [never drank alcohol or used drugs (0)], moderate risk [drank alcohol, no drug use (1)], and high risk [both drank alcohol and used drugs or just used drugs (2)]. ^ Results. Participants were 58.3% female, 39.6% African American, 43.8% Hispanic, mean age 13.3 years. Lifetime alcohol use was 47.9%. Lifetime drug use was 14.9%. Adjusted for gender, age, race, and family structure, each individual parental monitoring variable (perceived parental monitoring, less permissive parental monitoring, greater supervision (public places), greater supervision (teen clubs), and less time spent with older teens) was significant and protective for the moderate and high risk groups. When all 5 variables were entered into a single model, only perceived parental monitoring was significantly associated (OR=0.40, 95% CI 0.29-0.55) for the moderate risk group. For the high risk group, 3 variables were significantly protective (perceived parental monitoring OR=0.28, CI 0.18-0.42, less time spent with older teens OR=0.75, CI 0.60-0.93, and greater supervision (public places) OR=0.79, CI 0.64-0.99). ^ Conclusion. The association between parental monitoring and substance abuse is complex and varied for different risk levels. Implications for intervention development are addressed. ^

An investigation into the relationship between screen time, consumption of advertised foods, and physical activity among Texas 4th grade elementary school children

Background. The high prevalence of obesity among children has spurred creation of a list of possible causative factors, including the advertising of foods of minimal nutritional value, a decrease in physical activity, and increased media use. Few studies show prevalence rates of these factors among large cohorts of children. ^ Methods. Using data from the 2004-2005 School Physical Activity and Nutrition project (SPAN), a secondary analysis of 7907 4th-grade children (mean age 9.74 years) was conducted. In addition, a comic-book–based intervention that addressed advertised food consumption, physical activity, and media use was developed and evaluated using a pre-post test design among 4th-grade children in an urban school district. ^ Results. Among a cohort of 4th-grade children across the state of Texas, children who had more than 2 hours of video game or computer time the previous day were more than twice as likely to drink soda and eat candy or pastries. In addition, children who watched more than 2 hours of TV the previous day were more than three times as likely to consume chips, punch, soda, candy, frozen desserts, or pastries (AOR 3.41, 95% CI: 1.58, 7.37). A comic-book based intervention held great promise and acceptance among 4th-grade children. Outcome evaluation showed that while results moved in a positive direction, they were not statistically significant. ^ Conclusion. Statistically significant associations were found between screen time and eating various types of advertised food. The comic book intervention was widely accepted by the children exposed to it, and pre-post surveys indicated they moved constructs in a positive direction. Further research is needed to look at more specific ways in which children are exposed to TV, and the relationship of the TV viewing time with their consumption of advertised foods. In addition, researchers should look at comic book interventions more closely and attempt to utilize them in more in studies with a longer follow-up time. ^

Development and evaluation of a nutrition education program designed to increase fruit and vegetable consumption in girls, ages 9--12

The purpose of this study is to evaluate the theory-based Eat 5 nutrition badge. It is designed to increase fruit and vegetable (F&V) intake in 4th-6th grade junior Girl Scouts. Twenty-two troops were recruited and randomized by grade level (4th, 5th, 6th, or mixed) into either the intervention or control conditions. The leaders in the intervention condition received a brief training and the materials and conducted the program with their troops during four meetings. The Girl Scouts in the intervention condition completed 1-day Food Frequency Questionnaires and Nutrition Questionnaires both before and after completing the Eat 5 badge, and a third measurement of F&V intake three months after the posttest. Girl Scouts in the control condition were only evaluated at the three time periods.^ The primary hypotheses were that the Girl Scouts in the intervention condition would increase their daily intake of fruits and vegetables at both the posttest and three months later, compared to the Girl Scouts in the control condition. Other study questions investigated the impact of the Eat 5 program on intervening variables such as knowledge, self-efficacy, barriers, norms, F&V preference, and F&V selection and preparation skills.^ A nested ANOVA, with troop as the unit of analysis nested within condition, was used to assess the effects of the program. Pretest F&V intake and grade level were used as covariates. Pretest mean F&V intake for the total sample of 210 girls was 2.50 servings per day; 3.0 for the intervention group (n = 101). Significant increases in F&V intake (to 3.4 servings per day), knowledge, and fruit and vegetable preference were found for the intervention condition troops compared to the troops in the control condition. Three months later, the mean F&V intake had returned to pretest levels.^ This study indicates that social groups such as Girl Scouts can provide a channel for nutrition education. Long term effects were not sustained by the intervention; a possible cause was the lack of change in self-efficacy. Therefore, additional interventions are recommended such as booster lessons to maintain increased F&V intake by Girl Scouts. ^

The heart challenge: The effect of regular aerobic exercise on body fat distribution in third and fourth grade school children: A randomized clinical trial

The pattern of body fat distribution known as "centralized", and characterized by a predominance of subcutaneous fat on the trunk and a "pot belly", has been associated with an increased risk of chronic disease. These patterns of fat distribution, as well as the lifestyle habit variables associated with adult fatness and chronic morbidity clearly begin to develop during childhood, indicating the need for intervention and primary prevention of obesity, particularly the centralized form, during childhood or adolescence. The purpose of this study was to determine whether regular aerobic exercise could beneficially alter the distribution of body fat in 8 and 9 year old children. One hundred and eighty-eight participants were randomized into either a regular aerobic exercise treatment group or a standard physical education program control group. A variety of aerobic activities was used for intervention 5 days per week during physical education class for a period of 12 weeks. Fat distribution was measured by a number of the most commonly used indices, including ratios of body circumferences and skinfolds and indices derived from a principal components analysis. Change over time in average pulse rate was used to determine if intervention actually occurred. Approximately 10% of the students were remeasured, allowing the calculation of intra- and interexaminer measurement reliability estimates for all indices.^ This study group was comparable to the U.S. population, though the study children were slightly larger for certain measures. No effect of the exercise intervention was found. The most likely explanation for this was inadequacy of the intervention, as indicated by the lack of any change in average pulse rate with treatment. The results of the measurement reliability analysis are reported and indicate that body circumference ratios are more precise than skinfold ratios, particularly when multiple observers are used. Reliability estimates for the principal component indices were also high.^ It remains unclear whether the distribution of body fat can be altered with exercise. It is likely that this issue will remain undecided until one highly reliable, valid, and sensitive measure of fat distribution can be found. ^

SHRIMP U-Pb dating of high-grade migmatites and related magmatites from Northwestern Oates Land, East Antarctica

High- to very-high-grade migmatitic basement rocks of the Wilson Hills area in northwestern Oates Land (Antarctica) form part of a low-pressure high-temperature belt located at the western inboard side of the Ross-orogenic Wilson Terrane. Zircon, and in part monazite, from four very-high grade migmatites (migmatitic gneisses to diatexites) and zircon from two undeformed granitic dykes from a central granulite-facies zone of the basement complex were dated by the SHRIMP U-Pb method in order to constrain the timing of metamorphic and related igneous processes and to identify possible age inheritance. Monazite from two migmatites yielded within error identical ages of 499 +/- 10 Ma and 493 +/- 9 Ma. Coexisting zircon gave ages of 500 +/- 4 Ma and 484 +/- 5 Ma for a metatexite (two age populations) and 475 +/- 4 Ma for a diatexite. Zircon populations from a migmatitic gneiss and a posttectonic granitic dyke yielded well-defined ages of 488 +/- 6 Ma and 482 +/- 4 Ma, respectively. There is only minor evidence of age inheritance in zircons of these four samples. Zircon from two other samples (metatexite, posttectonic granitic dyke) gave scattered 206Pb-238U ages. While there is a component similar in age and in low Th/U ratio to those of the other samples, inherited components with ages up to c. 3 Ga predominate. In the metatexite, a major detrital contribution from 545 - 680 Ma old source rocks can be identified. The new age data support the model that granulite- to high-amphibolite-facies metamorphism and related igneous processes in basement rocks of northwestern Oates Land were confined to a relatively short period of time of Late Cambrian to early Ordovican age. An age of approximately 500 Ma is estimated for the Ross-orogenic granulite-facies metamorphism from consistent ages of monazite from two migmatites and of the older zircon age population in one metatexite. The variably younger zircon ages are interpreted to reflect mineral formation in the course of the post-granulite-facies metamorphic evolution, which led to a widespread high-amphibolite-facies retrogression and in part late-stage formation of ms+bi assemblages in the basement rocks and which lasted until about 465 Ma. The presence of inherited zircon components of latest Neoproterozoic to Cambrian age indicates that the high- to very-grade migmatitic basement in northwestern Oates Land originated from clastic series of Cambrian age and, therefore, may well represent the deeper-crustal equivalent of lower-grade metasedimentary series of the Wilson Terrane.