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Purpose The primary goal of this study was to evaluate the feasibility and effectiveness of a structured, multidisciplinary intervention targeted to maintain the overall quality of life (QOL), which is more comprehensive than psychosocial distress, of patients undergoing radiation therapy for advanced-stage cancer. Patients and Methods Radiation therapy patients with advanced cancer and an estimated 5-year survival rate of 0% to 50% were randomly assigned to either an eight-session structured multidisciplinary intervention arm or a standard care arm. The eight 90-minute sessions addressed the five domains of QOL including cognitive, physical, emotional, spiritual, and social functioning. The primary end point of maintaining overall QOL was assessed by a single-item linear analog scale (Linear Analog Scale of Assessment or modified Spitzer Uniscale). QOL was assessed at baseline, week 4 (end of multidisciplinary intervention), week 8, and week 27. Results Of the 103 participants, overall QOL at week 4 was maintained by the patients in the intervention (n = 49), whereas QOL at week 4 significantly decreased for patients in the control group (n = 54). This change reflected a 3-point increase from baseline in the intervention group and a 9-point decrease from baseline in the control group (P = .009). Intervention participants maintained their QOL, and controls gradually returned to baseline by the end of the 6-month follow-up period. Conclusion Although intervention participants maintained and actually improved their QOL during radiation therapy, control participants experienced a significant decrease in their QOL. Thus, a structured multidisciplinary intervention can help maintain or even improve QOL in patients with advanced cancer who are undergoing cancer treatment.

OBJECTIVESTo develop and validate a questionnaire for supraesophageal manifestations of reflux (SER) that will facilitate its study in clinical and research settings.STUDY DESIGNThe Supraesophageal Reflux Questionnaire (SERQ) and previously validated Reflux Symptom Index (RSI) were subjected to multiple types of validity testing, including content validity, concurrent validity, reproducibility, and predictive validity.RESULTSThe concurrent validity and reproducibility of both instruments was good to excellent for most items tested. The predictive validity of the SERQ was superior to the RSI when it included the covariates of history of sinusitis, use of over‐the‐counter antacid medications, age, gender, and body mass index.CONCLUSIONSThe SERQ will serve as both a useful clinical and research tool by offering not only SER symptom information, like the RSI, but also information about the patient's medical history and medication usage that will facilitate use of the SERQ in research protocols.EBM rating: B‐2b

Frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) is caused by mutations in the gene encoding the microtubule-associated protein, tau. Some FTDP-17 mutations affect exon 10 splicing. To correct aberrant exon 10 splicing while retaining endogenous transcriptional control, we evaluated the feasibility of using spliceosome-mediated RNA trans-splicing (SMaRT) to reprogram tau mRNA. We designed a pre-trans-splicing molecule containing human tau exons 10 to 13 and a binding domain complementary to the 3′ end of tau intron 9. A minigene comprising tau exons 9, 10, and 11 and minimal flanking intronic sequences was used as a target. RT-PCR analysis of SH-SY5Y cells or COS cells cotransfected with a minigene and a pre-trans-splicing molecule using primers to opposite sides of the predicted splice junction generated products containing exons 9 to 13. Sequencing of the chimeric products showed that an exact exon 9–exon 10 junction had been created, thus demonstrating that tau RNA can be reprogrammed by trans-splicing. Furthermore, by using the same paradigm with a minigene containing full-length intronic sequences, we show that cis-splicing exclusion of exon 10 can be by-passed by trans-splicing and that conversion of exon 10 – tau RNA into exon 10 + tau RNA could be achieved with ≈34% efficiency. Our results demonstrate that an alternatively spliced exon can be replaced by trans-splicing and open the way to novel therapeutic applications of SMaRT for tauopathies and other disorders linked to aberrant alternative splicing.

Background and Purpose— With the changes in management of atrial fibrillation (AF) over time, it is possible that the time trends of post-AF stroke incidence and mortality have changed. We sought to determine whether the incidence and survival of ischemic stroke after AF diagnosis have improved. Methods— We identified the Olmsted County, Minn, residents who developed first AF from 1980 to 2000 and followed them in medical records to 2004. The outcomes were first ischemic stroke and death. Results— Of the 4117 subjects diagnosed with first AF and without previous stroke, 446 (11%) sustained a first ischemic stroke during a mean follow-up time of 5.5±5.0 years. The age- and sex-adjusted incidence of stroke decreased, on average, by 3.4% per year ( P =0.0001), concurrent with an increase in warfarin and aspirin use (both P <0.0001) and reduction of systolic blood pressure ( P <0.001). The age-adjusted ischemic stroke incidence was higher in women ( P =0.039), but not after adjusting for systolic blood pressure ( P =0.41). Compared with the general Minnesota white population, the relative mortality hazard ratio was 1.88 for men and 1.84 for women without stroke and 3.03 for men and 3.80 for women ( P <0.05) with stroke. The relative mortality hazard did not vary by age or calendar year of AF diagnosis. Conclusions— Post-AF ischemic stroke incidence decreased significantly from 1980 to 2000, during which time a substantial increase in the use of antithrombotic therapy and reduction of systolic blood pressure was evident. The relative mortality risk of stroke, however, had not improved over time.

Abstract We evaluated somatic genetic alterations in the kinase domain of the EGFR gene in the tumors of 219 non–small cell lung cancer patients of primarily Caucasian and African American origins. We identified 26 patients (12%) whose tumors had a mutation in the EGFR gene, and 11 (5%) patients carried novel genomic variations consistent with germ-line polymorphisms. All but one mutation were identified in Caucasian patients affected with adenocarcinoma. EGFR mutations were more frequent in women and in nonsmokers, but a significant portion of the affected patients were men (12 of 26) and current or past smokers accounted for half of the patients affected (13 of 26). Screening subjects with EGFR mutations may identify patients whose tumors could respond to targeted therapy using tyrosine kinase inhibitors.

ABSTRACTOBJECTIVE:To describe the quality of life (QOL) over time for adults with newly diagnosed high-grade gliomas and to examine the relationship between QOL and outcome data collected in three prospective cooperative group clinical trials.METHODS:The QOL study was a companion protocol for three Phase II high-grade glioma protocols. Five self-administered forms were completed by patients to assess QOL at study entry, 2 months, and 4 months after enrollment.RESULTS:QOL data were available for baseline, first, and second subsequent follow-up evaluations for 89%, 71%, and 69% of patients, respectively. A significant proportion of patients (47.1%) experienced impaired QOL (QOL ≤ 50) in at least one measure at subsequent evaluations, whereas most patients (88%) with impaired QOL at baseline continued to have impaired QOL at subsequent evaluations. On multivariable analyses, baseline QOL measures were predictive of QOL at the time of follow-up. In addition, patients who underwent a gross total resection were much less likely to have impaired QOL (P = 0.006), were less likely to experience worsening depression (P = 0.0008), and were more likely to have improved QOL (P = 0.003) at their first follow-up evaluation. Changes in QOL measures over time were not found to be associated with survival in multivariable analyses that adjusted for known prognostic variables; variables that were independently associated with improved survival were better performance status (P &lt; 0.001), younger age (P &lt; 0.001), and greater extent of resection (P &lt; 0.001).CONCLUSION:Baseline QOL was predictive of QOL over time. Gross total resection was associated with longer survival and improved QOL over time for patients with high-grade gliomas.

AbstractMUC1 (CD227) is a large transmembrane epithelial mucin glycoprotein, which is aberrantly overexpressed in most adenocarcinomas and is a target for immune therapy for epithelial tumors. Recently, MUC1 has beendetected in a variety of hematopoietic cell malignancies including T and B cell lymphomas and myelomas; however, its function in these cells is not clearly defined. Using the Jurkat T cell lymphoma cell line and normal human T cells, we demonstrate that MUC1 is not only expressed in these cells but is also phosphorylated upon T cell receptor (TCR) ligation and associates with the Src-related T cell tyrosine kinase, p56lck. Upon TCR-mediated activation of Jurkat cells, MUC1 is found in the low-density membrane fractions, where linker of T cell activation is contained. Abrogation of MUC1 expression in Jurkat cells by MUC1-specific small interfering RNA resulted in defects in TCR-mediated downstream signaling events associated with T cell activation. These include reduction in Ca2+ influx and extracellular signal-regulated kinase 1/2 phosphorylation, leading to a decrease in CD69 expression, proliferation, and interleukin-2 production. These results suggest a regulatory role of MUC1 in modulating proximal signal transduction events through its interaction with proteins of the activation complex.