Pilot study of bevacizumab in combination with docetaxel and cyclophosphamide as adjuvant treatment for patients with early stage HER-2 negative breast cancer, including analysis of candidate circulating markers of cardiac toxicity: ICORG 08-10 trial.

BACKGROUND: Combining bevacizumab and chemotherapy produced superior response rates compared with chemotherapy alone in metastatic breast cancer. As bevacizumab may cause hypertension (HTN) and increase the risk of cardiac failure, we performed a pilot study to evaluate the feasibility and toxicity of a non-anthracycline-containing combination of docetaxel with cyclophosphamide and bevacizumab in early stage breast cancer patients. METHODS: Treatment consisted of four 3-weekly cycles of docetaxel and cyclophosphamide (75/600 mg/m2). Bevacizumab was administered 15 mg/kg intravenously on day 1, and then every 3 weeks to a total of 18 cycles of treatment. Serum biomarker concentrations of vascular endothelial growth factor (VEGF), cardiac troponin-I (cTnI), myeloperoxidase (MPO), and placental growth factor (PlGF) were quantified using enzyme-linked immunosorbent assay (ELISA) in 62 patients at baseline and whilst on treatment to determine their utility as biomarkers of cardiotoxicity, indicated by left ventricular ejection fraction (LVEF). RESULTS: A total of 106 patients were accrued in nine sites. Median follow up was 65 months (1-72 months). Seventeen protocol-defined relapse events were observed, accounting for an overall disease-free survival (DFS) rate of 84%. The DFS rates for hormone receptor positive (HR+) and triple-negative (TN) patients were 95% versus 43%, respectively. The median time to relapse was 25 (12-54) months in TN patients versus 38 (22-71) months in HR+ patients. There have been 13 deaths related to breast cancer . The overall survival (OS) rate was 88%. The 5-year OS rate in HR+ versus TN was 95% versus 57%. None of the measured biomarkers predicted the development of cardiotoxicity. CONCLUSIONS: We observed a low relapse rate in node-positive, HR+ patients; however, results in TN breast cancer were less encouraging. Given the negative results of three large phase III trials, it is unlikely that this approach will be investigated further. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00911716.

Adolescent Smoking Prevention: Feasibility and Effect of Participatory Video Production.

PURPOSE: This study tested whether a youth participatory video production program for smoking prevention is feasible and effective. DESIGN AND METHODS: A participatory video production program was implemented in eight twice-weekly sessions at a youth summer camp in a community center in a low-income neighborhood. Twenty-three youths participated. Descriptive statistics and a qualitative analysis were conducted to test the feasibility of the program by assessing attendance rates, the time and resources required, reasons for participation, and program satisfaction using checklists and interviews. Smoking intention was measured via pre- and post-intervention surveys and a quantitative analysis utilizing a Wilcoxon Signed Rank test to detect differences in intention for non-smoking. RESULTS: Participants worked in groups to produce four video clips containing anti-smoking messages. Three main themes (active engagement, participation for community health, and personal growth and healthy development) emerged from the qualitative interview data. >75% of the participants considered the program excellent and stated that it met their expectations. Significant positive changes were also found from baseline to post-intervention in intention not to smoke. CONCLUSIONS: This study demonstrated the effect of a participatory digital media production approach and confirmed its feasibility for youth health promotion and health education. Participants' active involvement in producing anti-smoking videos for a community health-promotion campaign decreased their intention to smoke and empowered them as advocates for a non-smoking community. PRACTICE IMPLICATIONS: These findings confirm the feasibility and utility of digital media use and interactive technology for actively engaging young people in health promotion.

Effects of multimedia vocabulary instruction on adolescents with learning disabilities.

The purpose of this experimental study is to investigate the effects of using content acquisition podcasts (CAPs), an example of instructional technology, to provide vocabulary instruction to adolescents with and without learning disabilities (LD). A total of 279 urban high school students, including 30 with LD in an area related to reading, were randomly assigned to one of four experimental conditions with instruction occurring at individual computer terminals over a 3-week period. Each of the four conditions contained different configurations of multimedia-based instruction and evidence-based vocabulary instruction. Dependent measures of vocabulary knowledge indicated that students with LD who received vocabulary instruction using CAPs through an explicit instructional methodology and the keyword mnemonic strategy significantly outperformed other students with LD who were taught using the same content, but with multimedia instruction that did not adhere to a specific theoretical design framework. Results for general education students mirrored those for students with LD. Students also completed a satisfaction measure following instruction with multimedia and expressed overall agreement that CAPs are useful for learning vocabulary terms.

Clinical correlation and molecular evaluation confirm that the MLH1 p.Arg182Gly (c.544A>G) mutation is pathogenic and causes Lynch syndrome.

Approximately 25 % of mismatch repair (MMR) variants are exonic nucleotide substitutions. Some result in the substitution of one amino acid for another in the protein sequence, so-called missense variants, while others are silent. The interpretation of the effect of missense and silent variants as deleterious or neutral is challenging. Pre-symptomatic testing for clinical use is not recommended for relatives of individuals with variants classified as 'of uncertain significance'. These relatives, including non-carriers, are considered at high-risk as long as the contribution of the variant to disease causation cannot be determined. This results in continuing anxiety, and the application of potentially unnecessary screening and prophylactic interventions. We encountered a large Irish Lynch syndrome kindred that carries the c.544A>G (p.Arg182Gly) alteration in the MLH1 gene and we undertook to study the variant. The clinical significance of the variant remains unresolved in the literature. Data are presented on cancer incidence within five kindreds with the same germline missense variant in the MLH1 MMR gene. Extensive testing of relevant family members in one kindred, a review of the literature, review of online MMR mutation databases and use of in silico phenotype prediction tools were undertaken to study the significance of this variant. Clinical, histological, immunohistochemical and molecular evidence from these families and other independent clinical and scientific evidence indicates that the MLH1 p.Arg182Gly (c.544A>G) change causes Lynch syndrome and supports reclassification of the variant as pathogenic.

Metatarsophalangeal joint pathology in crossover second toe deformity: a cadaveric study.

BACKGROUND: Ligamentous and capsular insufficiency of the second metatarsophalangeal joint has been surgically treated for over two decades, mainly with indirect surgical repairs, which stabilize adjacent soft tissue and shorten or decompress the osseous structures. While ligamentous insufficiency has been described and recognized, degeneration of the plantar plate and tears of the capsule have rarely been documented. The purpose of this study was to document and describe the presence and pattern of plantar plate tears in specimens with crossover second toe deformities, and based on this, to develop an anatomical grading system to assist in the assessment and treatment of this condition. METHODS: Sixteen below-knee cadaveric specimens with a clinical diagnosis of a second crossover toe deformity were examined, and dissected by removing the metatarsal head. The pathologic findings of plantar plate and capsular pathology, as well as ligamentous disruption, were observed and recorded. Demographics of the specimens were recorded, and simulated weightbearing radiographs were obtained prior to dissection so that pertinent angular measurements could be obtained. RESULTS: Demographics demonstrated a high percentage of female specimens, and a typically older population that has been reported for this condition. Radiographic findings documented a high percentage of hallux valgus and hallux rigidus deformities. The MTP-2 and MTP-3 angles were divergent consistent with a crossover toe deformity. We consistently found transverse tears in the plantar plate region immediately proximal to the capsular insertion on the base of the proximal phalanx. With increasing deformity, wider distal transverse tears extending from lateral to medial were found. Midsubstance tears, collateral ligament tears, and complete disruption of the plantar plate were found in more severe deformities. CONCLUSION: In this largest series of cadaveric dissections of crossover second toe deformities, we describe the types and extent of plantar plate tears associated with increasing deformity of the second ray. We present, based on these findings, an anatomic grading system to describe the progressive anatomic changes in the plantar plate.

Hallux valgus and first ray mobility: a cadaveric study.

BACKGROUND: Several studies have demonstrated that patients with hallux valgus (HV) deformities have increased first ray sagittal mobility. However, the change in mobility that occurs after surgical correction of HV deformities has not been extensively evaluated. This study was done to determine if surgical realignment of the first ray in cadaver specimens with a proximal crescentic osteotomy and distal soft tissue reconstruction (DSTR) would reduce the first ray sagittal motion as measured with an external-type micrometer (the Klaue device). METHODS: Twelve fresh-frozen below-knee cadaver specimens with an HV deformity (HV angle > 15 degrees, 1-2 IM angle > 9 degrees) were used for the study. Standardized simulated weightbearing radiographs were obtained before and after the surgical correction of the deformity. The first ray sagittal motion was measured with an external micrometer (Klaue device) before correction of the HV deformity and after the procedure. All specimens had correction of the hallux valgus deformity with a DSTR and proximal crescentic osteotomy. Internal fixation was applied to secure the osteotomy site. RESULTS: The HV angle was corrected from a mean of 28.6 degrees to a mean of 11.0 degrees. The 1-2 IM angle was corrected from a mean of 12.9 degrees to a mean of 6.8 degrees. The average preoperative first ray sagittal motion was 11.0 mm (range, 8.5 mm to 13.5 mm). After the surgical repair, the mean sagittal first ray motion was significantly decreased (p <.0005) to a mean of 5.2 mm (range, 3.5 mm to 7.5 mm). CONCLUSION: After correction of HV deformities with a DSTR and a proximal crescentic osteotomy, first ray mobility in cadaver specimens was significantly reduced. The stabilization of first ray mobility that occurred immediately after surgical correction despite leaving the capsule of the first metatarsocuneiform (MC) joint undisturbed suggests that extrinsic anatomic features may play a role in first ray mobility. Additionally, stability of the first ray may be restored with a bunion procedure that does not sacrifice the first MC joint.