A yeast functional screen predicts new candidate ALS disease genes.

Amyotrophic lateral sclerosis (ALS) is a devastating and universally fatal neurodegenerative disease. Mutations in two related RNA-binding proteins, TDP-43 and FUS, that harbor prion-like domains, cause some forms of ALS. There are at least 213 human proteins harboring RNA recognition motifs, including FUS and TDP-43, raising the possibility that additional RNA-binding proteins might contribute to ALS pathogenesis. We performed a systematic survey of these proteins to find additional candidates similar to TDP-43 and FUS, followed by bioinformatics to predict prion-like domains in a subset of them. We sequenced one of these genes, TAF15, in patients with ALS and identified missense variants, which were absent in a large number of healthy controls. These disease-associated variants of TAF15 caused formation of cytoplasmic foci when expressed in primary cultures of spinal cord neurons. Very similar to TDP-43 and FUS, TAF15 aggregated in vitro and conferred neurodegeneration in Drosophila, with the ALS-linked variants having a more severe effect than wild type. Immunohistochemistry of postmortem spinal cord tissue revealed mislocalization of TAF15 in motor neurons of patients with ALS. We propose that aggregation-prone RNA-binding proteins might contribute very broadly to ALS pathogenesis and the genes identified in our yeast functional screen, coupled with prion-like domain prediction analysis, now provide a powerful resource to facilitate ALS disease gene discovery.

An examination of educational gaps in the diagnosis and treatment of myelodysplastic syndromes.

BACKGROUND: Myelodysplastic syndromes (MDS) comprise a heterogeneous group of hematologic malignancies, with an incidence rate of 3.4 cases per 100,000 in the United States. MDS affects patients predominantly over 60 years of age. As these syndromes are not well understood by many medical practitioner, patients with MDS may be underrecognized or underdiagnosed. The availability of new MDS treatment options further establishes the need to more closely assess gaps in clinical practice and underscores the necessity to develop educational activities to address those gaps. METHODS: A multidisciplinary panel was convened to examine current educational needs and gaps. A group consensus approach incorporating a modified nominal group technique was utilized to prioritize and review needs identified in the pre-meeting survey and to evaluate data provided by panelists prior to the meeting. RESULTS: The panel identified and prioritized seven educational areas of need: (1) MDS disease awareness, (2) diagnosis, (3) classification and risk stratification, (4) treatment issues, (5) referral to stem cell transplantation or new treatment protocols, (6) clinical monitoring and toxicity management, and (7) translation of new data into patient care. CONCLUSIONS: In-depth knowledge is critical to the timely diagnosis and optimal care of MDS patients. A number of key educational needs exist. Educational programs should be practical in orientation to integrate data into practice, and they should be tailored for the intended audience. In addition, an effective educational program must be easily applied by participants.

How do U.S. medical oncologists learn and apply new clinical trials information from press releases in nonmedical media? A case study based on ECOG 4599.

BACKGROUND: Practicing oncologists are expected to easily assimilate large amounts of rapidly evolving clinical data. We hypothesized that U.S. oncologists rapidly familiarize themselves with new, practice-relevant, phase III clinical trial data. We tested this hypothesis in relation to the release of phase III data from the Eastern Cooperative Oncology Group 4599 trial on the role of bevacizumab in advanced non-small cell lung cancer (NSCLC). METHODS: We queried approximately 310 medical oncologists concerning their awareness of the bevacizumab data within 1 and 3 weeks after the data release or immediately after the 2005 Annual Meeting of the American Society of Clinical Oncology (ASCO). RESULTS: Prior to the ASCO meeting, 57% and 56% of the oncologists in the two research meetings, respectively, indicated "awareness" of the data release. Less than 25% selected an accurate descriptor of the released information from a short list of plausible options. After the ASCO meeting, the figures were 88% and 34%. Over 50% said they plan to use bevacizumab in NSCLC treatment as soon as reimbursement is secure. Eighty-two percent said they plan to use it in second- or third-line treatment; 56% said they plan to use it during second-line chemotherapy despite progression during first-line use. A large majority intend to use bevacizumab in dosages, tumor types, drug combinations, and/or patients not specifically supported by phase III data. CONCLUSION: Release of clinically relevant phase III data through electronic and print media is a poor vehicle for informing U.S. medical oncologists. For a commercially available agent, this can have important implications for potential use in untested and potentially unsafe clinical settings. Effective educational strategies for dealing with the new paradigm of "instant" release of clinical data need to be developed.

Adjuvant Therapy Choices in Patients With Resected Non-Small-Cell Lung Cancer: Correlation of Doctors' Treatment Plans and Relevant Phase III Trial Data.

PURPOSE: To evaluate case-based choices selected from among preselected options for adjuvant therapy management in patients with completely resected non-small-cell lung cancer (NSCLC). METHODS: In a series of meetings in which US oncologists participated in case-based discussions, market research data were acquired using audience response keypad technology. Participant's anonymous responses to specific case-based questions were recorded electronically and tabulated. RESULTS: Core behaviors among the majority of physician participants are driven by emerging level 1 evidence. However, a "more aggressive than literature-supported treatment posture" is frequently selected. For the scenario involving a patient with completely resected pT1N0 disease, approximately 60% recommended observation but one third of respondents indicated they would propose three to four cycles of platinum-based adjuvant chemotherapy. Twenty-three percent would recommend adjuvant radiation following adjuvant chemotherapy for a patient with completely resected pT2N1 (stage IIB) disease. In the stage IIB setting, when cisplatin or carboplatin chemotherapy choices were specified, carboplatin-based combinations were selected by 43.6% compared with 30% for cisplatin regimens. Eight respondents (3.5%) favored observation for the stage IIB setting. This is consistent with the preponderance of level 1 evidence for adjuvant management. Carboplatin combinations are also recommended despite the availability of only abstract data and a meeting report for a single phase III trial showing a survival benefit for carboplatin based management in stage IB disease. The use of radiation as an element in adjuvant therapy in the settings assessed in this research is not supported by prospective data. CONCLUSIONS: Treatment plans that include adjuvant platinum-based chemotherapy have been widely adopted by US oncologists for a large fraction of patients with completely resected NSCLC. Recommendations for adjuvant chemotherapy for the patient described here with stage IA disease, or for adjuvant radiation alone or after adjuvant chemotherapy, for the stage IIB disease patient presented are overly aggressive, not evidence based, and carry potential harm. In settings in which level 1 evidence for a survival benefit from adjuvant chemotherapy does exist, some of the specific adjuvant chemotherapy regimens selected, while widely used in NSCLC patients with more advanced disease, have not yet been demonstrated to provide improved disease-free or overall survival as adjuvant treatment. Individualized adjuvant treatment recommendations not specifically grounded in level 1 evidence appear to be widely recommended by US medical oncologists for patients with completely resected NSCLC.