Treatment of advanced soft-tissue sarcomas using a combined strategy of high-dose ifosfamide, high-dose doxorubicin and salvage therapies

Having determined in a phase I study the maximum tolerated dose of high-dose ifosfamide combined with high-dose doxorubicin, we now report the long-term results of a phase II trial in advanced soft-tissue sarcomas. Forty-six patients with locally advanced or metastatic soft-tissue sarcomas were included, with age <60 years and all except one in good performance status (0 or 1). The chemotherapy treatment consisted of ifosfamide 10 g m(-2) (continuous infusion for 5 days), doxorubicin 30 mg m(-2) day(-1) x 3 (total dose 90 mg m(-2)), mesna and granulocyte-colony stimulating factor. Cycles were repeated every 21 days. A median of 4 (1-6) cycles per patient was administered. Twenty-two patients responded to therapy, including three complete responders and 19 partial responders for an overall response rate of 48% (95% CI: 33-63%). The response rate was not different between localised and metastatic diseases or between histological types, but was higher in grade 3 tumours. Median overall survival was 19 months. Salvage therapies (surgery and/or radiotherapy) were performed in 43% of patients and found to be the most significant predictor for favourable survival (exploratory multivariate analysis). Haematological toxicity was severe, including grade > or =3 neutropenia in 59%, thrombopenia in 39% and anaemia in 27% of cycles. Three patients experienced grade 3 neurotoxicity and one patient died of septic shock. This high-dose regimen is toxic but nonetheless feasible in multicentre settings in non elderly patients with good performance status. A high response rate was obtained. Prolonged survival was mainly a function of salvage therapies.

Combined alpha-methylacyl coenzyme A racemase/p53 analysis to identify dysplasia in inflammatory bowel disease

Identification of dysplasia in inflammatory bowel disease represents a major challenge for both clinicians and pathologists. Clear diagnosis of dysplasia in inflammatory bowel disease is sometimes not possible with biopsies remaining "indefinite for dysplasia." Recent studies have identified molecular alterations in colitis-associated cancers, including increased protein levels of alpha-methylacyl coenzyme A racemase, p53, p16 and bcl-2. In order to analyze the potential diagnostic use of these parameters in biopsies from inflammatory bowel disease, a tissue microarray was manufactured from colons of 54 patients with inflammatory bowel disease composed of 622 samples with normal mucosa, 78 samples with inflammatory activity, 6 samples with low-grade dysplasia, 12 samples with high-grade dysplasia, and 66 samples with carcinoma. In addition, 69 colonoscopic biopsies from 36 patients with inflammatory bowel disease (28 low-grade dysplasia, 8 high-grade dysplasia, and 33 indefinite for dysplasia) were included in this study. Immunohistochemistry for alpha-methylacyl coenzyme A racemase, p53, p16 and bcl-2 was performed on both tissue microarray and biopsies. p53 and alpha-methylacyl coenzyme A racemase showed the most discriminating results, being positive in most cancers (77.3% and 80.3%) and dysplasias (94.4% and 94.4%) but only rarely in nonneoplastic epithelium (1.6% and 9.4%; P < .001). Through combining the best discriminators, p53 and alpha-methylacyl coenzyme A racemase, a stronger distinction between neoplastic tissues was possible. Of all neoplastic lesions, 75.8% showed a coexpression of alpha-methylacyl coenzyme A racemase and p53, whereas this was found in only 4 of 700 nonneoplastic samples (0.6%). alpha-methylacyl coenzyme A racemase/p53 coexpression was also found in 10 of 33 indefinite for dysplasia biopsies (30.3 %), suggesting a possible neoplastic transformation in these cases. Progression to dysplasia or carcinoma was observed in 3 of 10 p53/alpha-methylacyl coenzyme A racemase-positive, indefinite-for-dysplasia cases, including 1 of 7 cases without and 2 of 3 cases with p53 mutation. It is concluded that combined alpha-methylacyl coenzyme A racemase/p53 analysis may represent a helpful tool to confirm dysplasia in inflammatory bowel disease.

Association of urethral toxicity with dose exposure in combined high-dose-rate brachytherapy and intensity-modulated radiation therapy in intermediate- and high-risk prostate cancer

INTRODUCTION: To report acute and late toxicities in patients with intermediate- and high-risk prostate cancer treated with combined high-dose-rate brachytherapy (HDR-B) and intensity-modulated radiation therapy (IMRT). MATERIALS AND METHODS: From March 2003 to September 2005, 64 men were treated with a single implant HDR-B with 21 Gy given in three fractions, followed by 50 Gy IMRT along with organ tracking. Median age was 66.1 years, and risk of recurrence was intermediate in 47% of the patients or high in 53% of the patients. Androgen deprivation therapy was received by 69% of the patients. Toxicity was scored according to the CTCAE version 3.0. Median follow-up was 3.1 years. RESULTS: Acute grade 3 genitourinary (GU) toxicity was observed in 7.8% of the patients, and late grades 3 and 4 GU toxicity was observed in 10.9% and 1.6% of the patients. Acute grade 3 gastrointestinal (GI) toxicity was experienced by 1.6% of the patients, and late grade 3 GI toxicity was absent. The urethral V(120) (urethral volume receiving > or =120% of the prescribed HDR-B dose) was associated with acute (P=.047) and late > or = grade 2 GU toxicities (P=.049). CONCLUSIONS: Late grades 3 and 4GU toxicity occurred in 10.9% and 1.6% of the patients after HDR-B followed by IMRT in association with the irradiated urethral volume. The impact of V(120) on GU toxicity should be validated in further studies.

IDH/MGMT-driven molecular classification of low-grade glioma is a strong predictor for long-term survival

BACKGROUND Low-grade gliomas (LGGs) are rare brain neoplasms, with survival spanning up to a few decades. Thus, accurate evaluations on how biomarkers impact survival among patients with LGG require long-term studies on samples prospectively collected over a long period. METHODS The 210 adult LGGs collected in our databank were screened for IDH1 and IDH2 mutations (IDHmut), MGMT gene promoter methylation (MGMTmet), 1p/19q loss of heterozygosity (1p19qloh), and nuclear TP53 immunopositivity (TP53pos). Multivariate survival analyses with multiple imputation of missing data were performed using either histopathology or molecular markers. Both models were compared using Akaike's information criterion (AIC). The molecular model was reduced by stepwise model selection to filter out the most critical predictors. A third model was generated to assess for various marker combinations. RESULTS Molecular parameters were better survival predictors than histology (ΔAIC = 12.5, P< .001). Forty-five percent of studied patients died. MGMTmet was positively associated with IDHmut (P< .001). In the molecular model with marker combinations, IDHmut/MGMTmet combined status had a favorable impact on overall survival, compared with IDHwt (hazard ratio [HR] = 0.33, P< .01), and even more so the triple combination, IDHmut/MGMTmet/1p19qloh (HR = 0.18, P< .001). Furthermore, IDHmut/MGMTmet/TP53pos triple combination was a significant risk factor for malignant transformation (HR = 2.75, P< .05). CONCLUSION By integrating networks of activated molecular glioma pathways, the model based on genotype better predicts prognosis than histology and, therefore, provides a more reliable tool for standardizing future treatment strategies.

Facial esthetics in children with unilateral cleft lip and palate 3 years after alveolar bonegrafting combined with rhinoplasty between 2 and 4 years of age

OBJECTIVES To evaluate facial esthetics in patients with unilateral cleft lip and palate (UCLP) after alveolar bone grafting combined with rhinoplasty between 2 and 4 years of age. DESIGN Retrospective case-control study. SETTING The Department of Pediatric Surgery, Institute of Mother and Child, Warsaw, Poland. MATERIAL AND METHODS Photographs of full faces and cropped images of five nasolabial components: nasal deviation, nasal form, nasal profile, vermillion border, and inferior view were assessed by 5 professional and 14 layraters in 29 children (23 boys and 6 girls; mean age = 5.3 years, SD 0.5; Early-grafted group) and 30 children (20 boys and 10 girls; mean age = 5.5 years, SD 1.0; Non-grafted group) with complete unilateral cleft lip and palate repaired with a one-stage closure. The groups differed regarding the timing of alveolar bone grafting: in the Early-grafted group, alveolar bone grafting in combination with rhinoplasty (ABG-R) was performed between 2 and 4 years of age (mean age = 2.3 years; SD 0.6); in the Non-grafted group, the alveolar defect was grafted after 9 years of age. No primary nose correction was carried out in any group. To rate esthetics, a modified five-grade esthetic index of Asher-McDade was used, where grade 1 means the most esthetic and grade 5 - the least esthetic outcome. RESULTS Esthetics of full faces and of all nasolabial elements in the Early-grafted group was significantly better than in Non-grafted group. The scores in the Early-grafted group ranged from 2.30 to 2.66 points, whereas in the Non-grafted group ranged from 2.66 to 3.17 points. All intergroup differences were statistically significant (p < 0.05). CONCLUSIONS Three years post-operatively, early alveolar bone grafting combined with rhinoplasty is favorable for facial esthetics in children with UCLP, but a longer follow-up is needed to assess whether the improvement was permanent.

The association between classroom characteristics and student physical activity in physical education classrooms

Background. With the rapid rise in childhood obesity, physical activity participation among young children has become the subject of much recent attention. Physical education classes have been specifically targeted as a method of providing opportunities for all children to be active. Unfortunately, student participation in moderate-to-vigorous physical activity during these classes still falls far below the current recommendations. While some research to date has reported the levels of activity among elementary-aged children, research is limited on the relationship between these activity levels and the environmental characteristics that exist within the PE classroom. ^ Purpose. The purpose of this study is to examine the association between specific classroom characteristics and contextual characteristics (lesson context, class size, class location, teacher gender, and teacher encouragement for PA) with elementary aged children's moderate-to-vigorous activity during PE class. ^ Methods. A secondary analysis of 211 3rd, 4th and 5th grade physical education classes amongst 39 elementary schools in Harris County, TX and 35 elementary schools in Travis County, TX was conducted using cross-sectional data from the evaluation of a school-based health program. Lesson context and student activity levels were measured using a direct observation measurement tool. Additionally, these variables were further analyzed against a number of classroom characteristics to determine any significant associations. ^ Results. Overall, elementary PE classes are still participating in low levels of moderate-to-vigorous physical activity averaging only 38% of class time. Additionally, close to 25% of class time is spent in classroom management. Male directed classes spent significantly more time in game activities and female directed classes spent more time in fitness, knowledge, and skill activities. Classes that took place outdoors were more active and spent more time in games than those that took place indoors. Significant correlations were demonstrated between class size and time spent in management context. Time spent in management context was also correlated with time spent sitting and standing. Additionally, positive correlations were demonstrated between time very active and teachers that praised students and encouraged physical activity among their classes.^

Assigning dates to thin gneissic veins in high-grade metamorphic terranes: A cautionary tale from Akilia, southwest Greenland

A granodiorite from Akilia, southwest Greenland, previously suggested to date putative life-bearing rocks to greater than or equal to3.84 Ga, is re-investigated using whole-rock major and trace-element geochemistry, and detailed cathodoluminescence image-guided secondary ion mass spectrometer analyses of zircon U-Th-Pb and rare earth elements. Complex zircon internal structure reveals three episodes of zircon growth and/or recrystallization dated to c. 3.84 Ga, 3.62 Ga and 2.71 Ga. Rare earth element abundances imply a significant role for garnet in zircon generation at 3.62 Ga and 2.71 Ga. The 3.62 Ga event is interpreted as partial melting of a c. 3.84 Ga grey gneiss precursor at granulite facies with residual garnet. Migration of this 3.62 Ga magma (or melt-crystal mush) away from the melt source places a maximum age limit on any intrusive relationship. These early Archaean relationships have been complicated further by isotopic reworking in the 2.71 Ga event, which could have included a further episode of partial melting. This study highlights a general problem associated with dating thin gneissic veins in polyphase metamorphic terranes, where field relationships may be ambiguous and zircon inheritance can be expected.

Responding to interpersonal and physically provoking situations in classrooms: emotional intensity in children with attention deficit hyperactivity disorder

The present research investigated the emotional functioning of children with and without Attention Deficit Hyperactivity Disorder (ADHD), in order to examine the relationships between emotional intensity and classroom-based responses to physically and interpersonally provoking situations. Seventy children (35 with ADHD and 35 without ADHD) in Years 3–8 participated and were matched on age, gender, grade, and school class. Each child was observed individually in the classroom over two 20-min periods. The Responses to Interpersonal and Physically Provoking Situations Observation Schedule was used to record the frequency and severity of responses and the triggers for these during the observational periods. Children later rated their emotional intensity in response to hypothetical scenarios on the Emotional Intensity Scale for Children. Results revealed children with ADHD displayed significantly more frequent and severe challenging and solitary off-task behaviours, and significantly more frequent vocalisations and severe interactional off-task behaviours. For triggers, environmental and teacher-initiated distractions were significantly more frequently observed in children with ADHD. There were no differences in ratings of emotional intensity between children with and without ADHD, although a number of significant and meaningful correlations were observed between positive emotional intensity scores and responses and triggers.

The effect of basketball sport aerobics on basketball skill development for fifth-grade students

The purpose of this study was to investigate the effectiveness of an experimental teaching method, Sport Aerobics, on the basketball skill acquisition of fifth grade students. This study investigated the differences in the shooting, dribbling, and passing scores of students taught with Sport Aerobics instruction compared to those taught with a traditional method, Practice Style. Sport Aerobics is an instructional method based on a theoretical framework developed by the researcher to enhance skill acquisition. This framework leads to teaching strategies such as using immediate feedback and specific cueing; arranging for students to engage in object free movement; arranging lessons, according to the framework's concept of movement progression, into lessons staged according to skill and sub-skill complexity; and instructing based on whole group organization. Sport Aerobic instructional strategies were designed to facilitate process learning that is recognized as important in today's development learning approach for age related curriculums. In contrast, the traditional Practice Style uses product-oriented strategies. ^ Four classrooms, consisting of seventy-nine fifth grade students from two physical education programs, at different locations, were randomly assigned to two treatments; Sport Aerobics and Practice Style for instruction over a 15 period curriculum. Using the American Alliance Physical Education Recreation & Dance tests, both groups were pretested and posttested for skill achievement of shooting, dribbling, and passing. Pretest and posttest skill score samples were collected and evaluated. ANCOVAs were performed on the posttests adjusted for the pretests to determine whether or not there would be greater achievement of skills with the Sport Aerobics method. Results failed to establish significant scoring differences between the two methods. Based on the literature and study findings a recommendation is made that longer lesson units will assist in the investigation of the effectiveness of both the instructional model and the individual elements that facilitate skill acquisition. ^

The impact of looping of fourth grade students on their reading achievement

This study examines the effects of looping (staying with the same teacher for two grade levels) on the reading achievement of fourth graders within a large, urban, multicultural school. Looping was expected to have a positive effect on reading achievement and reading qualities. Additional benefits, such as its effect on anxiety levels and self-concept were also assumed to accrue from looping. ^ A causal-comparative design was employed. Four existing classrooms consisting of eighty-one fourth grade students comprised the treatment and comparison groups. The two “looping” treatment groups consisted of students who had the same teacher for their third and fourth grade school years. The remaining two classes comprised the comparison groups. Pre- and post-tests for reading achievement total scores and subscores for main idea and comparisons were obtained using the Florida Comprehensive Assessment Test (FCAT). Assessments were also obtained from the State-Trait Anxiety Inventory for Children, modified to reflect reading, and the Self-Perception Profile for Children. The difference in pre- and post-test FCAT scores were analyzed via a four group simple ANOVA to examine the effects of the looping model on reading achievement and reading qualities. Similar simple ANOVAs were performed to investigate the relationship of looping to anxiety and self-concept. ^ The findings led to the conclusion that looping was significantly related to improvement in reading achievement and reading qualities. In addition, the hypothesized relationship of lower anxiety in the looping group compared to the comparison group was supported. There were no significant effects on self-concept for any of the comparisons. ^ The study clearly demonstrated the positive effects of looping, on total reading achievement scores, on reading qualities of fourth grade students who participated in looping classes and on differences in students' anxiety. Looping did not have an effect on general self-concept. ^ The results demonstrate the effects of looping on teaching methods. In looping practice teachers have the advantage of knowing their students and the students' readiness and can make adaptations of teaching methods accordingly. From the students' perspective, the looped students do not have to adapt to a new teacher and thus, experience lower anxiety. ^

The Mismatch of the Language of Textbooks and Language of ESL Students in Content Classrooms

Debate concerning bilingual education effectiveness may focus around the definition of academic language. Two aspects of such-vocabulary and grammar-were examined in 4th and 8th grade textbooks. Results showed substantial increases in the number of abstract words and complex sentences, suggesting more daunting language demands for older non-English-speaking students.

Relationships between gifted selection criteria and performance in sixth -grade gifted science

This study examined the relationships between gifted selection criteria used in the Dade County Public Schools of Miami, Florida and performance in sixth grade gifted science classes.^ The goal of the study was to identify significant predictors of performance in sixth grade gifted science classes. Group comparisons of performance were also made. Performance in sixth grade gifted science was defined as the numeric average of nine weeks' grades earned in sixth grade gifted science classes.^ The sample consisted of 100 subjects who were formerly enrolled in sixth grade gifted science classes over two years at a large, multiethnic public middle school in Dade County.^ The predictors analyzed were I.Q. score (all scales combined), full scale I.Q. score, verbal scale I.Q. score, performance scale I.Q. score, combined Stanford Achievement Test (SAT) score (Reading Comprehension plus Math Applications), SAT Reading Comprehension score, and SAT Math Applications score. Combined SAT score and SAT Math Applications score were significantly positively correlated to performance in sixth grade gifted science. Performance scale I.Q. score was significantly negatively correlated to performance in sixth grade gifted science. The other predictors examined were not significantly correlated to performance.^ Group comparison results showed the mean average of nine weeks grades for the full scale I.Q. group was greater than the verbal and performance scale I.Q. groups. Females outperformed males to a highly significant level. Mean g.p.a. for ethnic groups was greatest for Asian students, followed by white non-Hispanic, Hispanic, and black. Students not receiving a lunch subsidy outperformed those receiving subsidies.^ Comparisons of performance based on gifted qualification plan showed the mean g.p.a. for traditional plan and Plan B groups were not different. Mean g.p.a. for students who qualified for gifted using automatic Math Applications criteria was highest, followed by automatic Reading Comprehension criteria and Plan B Matrix score. Both automatic qualification groups outperformed the traditional group. The traditional group outperformed the Plan B Matrix group. No significant differences in mean g.p.a. between the Plan B subgroups and the traditional plan group were found. ^

A qualitative study of selected fourth -grade teachers' perceptions of the Sunshine State Standards

Despite a history of grappling with educational standards, never before has the federal government attempted to establish explicit national standards for what American children should learn in school. Recently, U.S. educators have developed voluntary national content standards, or explicit expectations of what students should know and be able to do. Not surprisingly, this major curriculum reform has provoked considerable debate. Today, teachers face difficult challenges working towards the implementation of standards. The objective of this study was to describe and explain the perceptions of a selected team of fourth-grade teachers regarding the language arts component of their state's Sunshine State Standards (SSS). The exploratory questions that guided this qualitative study were: (a) How are the SSS perceived by these fourth-grade teachers? (b) In what ways do the SSS affect teachers' self-perceptions? and, (c) To what extent and how do the SSS affect the participants' professional classroom behavior? ^ Direct observations, interviews, analysis of relevant documents and the researcher's critical reflective journal served as the methods of inquiry employed in this qualitative study. Bandura's Teacher Self-Efficacy Scale was used as a tool to help categorize the data specifically related to self-perception. ^ Analysis of the data suggests that participants perceived the SSS as a useful guideline as they taught. The SSS were a decisive factor in teachers' planning. They were the actual guide lines used by teachers to plan their lessons. However, participants did not believe the SSS were attainable by all students or were fair to students with special needs. They also believed there was not sufficient time allocated for the effective implementation of the SSS. This lack of time created pressure among some of the participants and others even felt disempowered regarding the curriculum and the instructional focus implemented during the test preparation time. The SSS negatively affected the participants when they felt constraints during this time, which led to their inability to carry out important activities in their classrooms. Thus, the SSS directly affected the participants' behavior in their classrooms. ^

The impact of looping of fourth grade students on their reading achievement

This study examines the effects of looping (staying with the same teacher for two grade levels) on the reading achievement of fourth graders within a large, urban, multicultural school. Looping was expected to have a positive effect on reading achievement and reading qualities. Additional benefits, such as its effect on anxiety levels and self-concept were also assumed to accrue from looping. A causal-comparative design was employed. Four existing classrooms consisting of eighty-one fourth grade students comprised the treatment and comparison groups. The two "looping" treatment groups consisted of students who had the same teacher for their third and fourth grade school years. The remaining two classes comprised the comparison groups. Pre- and post-tests for reading achievement total scores and subscores for main idea and comparisons were obtained using the Florida Comprehensive Assessment Test (FCAT). Assessments were also obtained from the State-Trait Anxiety Inventory for Children, modified to reflect reading, and the Self- Perception Profile for Children. The difference in pre- and post-test FCAT scores were analyzed via a four group simple ANOVA to examine the effects of the looping model on reading achievement and reading qualities. Similar simple ANOVAs were performed to investigate the relationship of looping to anxiety and self-concept. The findings led to the conclusion that looping was significantly related to improvement in reading achievement and reading qualities. In addition, the hypothesized relationship of lower anxiety in the looping group compared to the comparison group was supported. There were no significant effects on self-concept for any of the comparisons. The study clearly demonstrated the positive effects of looping, on total reading achievement scores, on reading qualities of fourth grade students who participated in looping classes and on differences in students' anxiety. Looping did not have an effect on general self-concept. The results demonstrate the effects of looping on teaching methods. In looping practice teachers have the advantage of knowing their students and the students' readiness and can make adaptations of teaching methods accordingly. From the students' perspective, the looped students do not have to adapt to a new teacher and thus, experience lower anxiety.

ROLE OF STAT1 AND CXCL10 IN THE TUMOUR IMMUNE MICROENVIRONMENT OF HIGH-GRADE SEROUS OVARIAN CANCER

High-grade serous ovarian cancer (HGSC) is the most prevalent epithelial ovarian cancer characterized by late detection, metastasis and resistance to chemotherapy. Previous studies on the tumour immune microenvironment in HGSC identified STAT1 and CXCL10 as the most differentially expressed genes between treatment naïve chemotherapy resistant and sensitive tumours. Interferon-induced STAT1 is a transcription factor, which induces many genes including tumour suppressor genes and those involved in recruitment of immune cells to the tumour immune microenvironment (TME), including CXCL10. CXCL10 is a chemokine that recruits tumour infiltrating lymphocytes (TILs) and exhibits angiostatic function. The current study was performed to determine the effects of differential STAT1 and CXCL10 expression on HGSC disease progression and TME. STAT1 expression and intratumoural CD8+ T cells were evaluated as prognostic and predictive biomarkers via immunohistochemistry on 734 HGSC tumours accrued from the Terry Fox Research Institute-Canadian Ovarian Experimental Unified Resource. The combined effect of STAT1 expression and CD8+ TIL density was confirmed as prognostic and predictive companion biomarkers in the second independent biomarker validation study. Significant positive correlation between STAT1 expression and intratumoral CD8+ TIL density was observed. The effects of enforced CXCL10 expression on HGSC tumour growth, vasculature and immune tumour microenvironment were studied in the ID8 mouse ovarian cancer cell engraftment in immunocompetent C57BL/6 mice. Significant decrease in tumour progression in mice injected with ID8 CXCL10 overexpressing cells compared to mice injected with ID8 vector control cells was observed. Multiplexed cytokine analysis of ascites showed differential expression of IL-6, VEGF and CXCL9 between the two groups. Endothelial cell marker staining showed differences in tumour vasculature between the two groups. Immune transcriptomic profiling identified distinct expression profiles in genes associated with cytokines, chemokines, interferons, T cell function and apoptosis between the two groups. These findings provide evidence that STAT1 is an independent biomarker and in combination with CD8+ TIL density could be applied as novel immune-based biomarkers in HGSC. These results provide the basis for future studies aimed at understanding mechanisms underlying differential tumour STAT1 and CXCL10 expression and its role in pre-existing tumour immunologic diversity, thus potentially contributing to biomarker guided immune modulatory therapies.