US FDA best practices for initiating early feasibility studies for neurological devices in the United States.

This article describes the efforts of the US Food and Drug Administration (FDA) Office of Neurological and Physical Medicine Devices to facilitate early clinical testing of potentially beneficial neurological devices in the US. Over the past 5 years, the FDA has made significant advances to this aim by developing early feasibility study best practices and encouraging developers and innovators to initiate their clinical studies in the US. The FDA uses several regulatory approaches to help start neurological device clinical studies, such as early engagement with sponsors and developers, in-depth interaction during the FDA review phase of a regulatory submission, and provision of an FDA toolkit that reviewers can apply to the most challenging submissions.

Technical development and initial animal experience with a novel, uncovered, self-expanding, highly flexible aortic stent with improved side branch access.

PURPOSE: To present a novel, uncovered, self-expanding aortic stent for use as a thoracoabdominal stent-graft extension to improve distal flow in aortic dissections complicated by malperfusion syndrome and to enhance the remodeling process in the abdominal aorta after thoracic endovascular aortic repair. METHODS: This aortic prosthesis is a laser cut, self-expanding nitinol stent that is designed to provide an optimal balance between radial support and flexibility to negotiate tortuous arterial anatomy. Undulating circumferential rings provide radial force, while flexibility is achieved through the shape and configuration of the longitudinal connectors that extend from the valley of one ring to the offset peak of the next ring. Delivery and deployment characteristics, in vivo flexibility of the stent, and side branch accessibility through the bare stent struts were evaluated in 4 anesthetized domestic swine weighing 68 to 73 kg. RESULTS: All 11 attempted stent implantations were successful in the 4 pigs using a retrograde transiliac access. The stents were positioned and deployed exactly at the intended target locations and conformed well to the aortic anatomy, even in the tortuous aortic arch, with no evidence of stent kinking or collapse. Overall, 21 major aortic side branches were intentionally covered with the bare stent struts; perfusion was not impaired in any branch vessel. Superselective catheterization of the side branches with coronary guiding catheters through the stent struts was possible for all vessels, as was side branch stenting in 3/3 attempts. CONCLUSION: This initial feasibility study demonstrates the ability to deploy this novel self-expanding aortic stent in pigs. The high flexibility of the stent allowed conformability with tortuous aortic anatomy. Access to side branches overstented with bare stent struts was excellent. Clinical evaluation of the device is planned for the near future.

[Fitness Check for elder drivers]. / Fitness-Check für ältere Kraftfahrerinnen und Kraftfahrer.

There is no compulsory and regular medical/psychological checkup for elderly drivers in Germany. In the near future, a growing danger to traffic safety is expected because of the increasing percentage of elderly people and increasing prevalence of geriatric diseases. To close this safety gap, TUV SUD Life Service GmbH has put into practice a voluntary consulting concept for elderly drivers (Fitness Check). The consultation is based on medical anamnesis and examination, psychological exploration of driving behaviour and achievement testing. If necessary, driving ability is tested during a car ride. Conditions, the course of and results of 51 checkups from 2006 to 2008 in Munich are described and conclusions discussed.

Comparative effects of paclitaxel and rapamycin on smooth muscle migration and survival: role of AKT-dependent signaling.

OBJECTIVE: Advances in stent technology have enabled the delivery of drugs to improve outcomes after stent deployment. However, the optimal payloads for stents are not clear, and the appropriate stent-based therapies for high-risk patients, such as diabetics, have not been clearly established. METHODS AND RESULTS: We used smooth muscle cell culture models to compare the activities of rapamycin and paclitaxel. Smooth muscle cells were grown in normal or high glucose to induce insulin resistance. Both paclitaxel and rapamycin activate mitogen-activated protein kinase pathways similarly. However, rapamycin potently activates AKT-dependent signaling, an effect that overrides the downregulation of this pathway by insulin resistance and that causes phosphorylation of the AKT-dependent transcription factor FOXO1. This effect is associated with attenuation of the anti-migratory effects of rapamycin under high glucose conditions that are not observed with paclitaxel, as well as with increased protection against ceramide-induced cytotoxicity, both of which are dependent on FOXO1 phosphorylation. CONCLUSIONS: Differences between the ability of rapamycin and paclitaxel to activate AKT may account for their differential cell survival and antichemotactic activities. These observations may provide a basis for understanding clinical differences between rapamycin- and paclitaxel-coated stents. The approaches used in these studies can be expanded to other candidate stent payloads as a method for triage in preclinical studies.

FDA Regulation of Neurological and Physical Medicine Devices: Access to Safe and Effective Neurotechnologies for All Americans.

The United States Food and Drug Administration (FDA) ensures that patients in the U.S. have access to safe and effective medical devices. The Division of Neurological and Physical Medicine Devices reviews medical technologies that interface with the nervous system. This article addresses how to navigate the FDA's regulatory landscape to successfully bring medical devices to patients.

Shape is not associated with the origin of pericolonic tumor deposits.

Pericolonic tumor deposits (PTDs) are associated with an adverse outcome in colorectal cancer. According to the International Union Against Cancer they are classified as N1 or V1/V2 depending on their shape. This recommendation, however, is not well supported by the literature. To elucidate the origin of PTDs, we performed a histomorphologic study of 69 PTDs, which were found in 7 of 21 colorectal specimens using the whole-mount step-section technique. Depending on the origin, the nodules were classified as venous invasions, lymphatic invasions, nerve sheath infiltrations, free PTDs, and continuous growth in 18 (26%), 3 (4%), 6 (9%), 34 (49%), and 8 (12%) of 69 PTDs, respectively. Polycyclic and oval-round shapes were identified in all categories. Continuous growth was found only within the inner third of the adhering fat, whereas the other morphologic features were found in all regions. The data of this study do not support PTD classification on the basis of their shape.

Shift from cytoplasmic to nuclear maspin expression correlates with shorter overall survival in node-negative colorectal cancer.

Maspin has been characterized as a potent tumor suppressor in many in vitro and in vivo studies. In contrast, in stage III colon cancer, an association with shorter overall survival as well as sensitivity to chemotherapy was found for cases with nuclear maspin expression. Because 20% of node-negative colorectal cancer cases show a fatal clinical course, we hypothesized that immunohistochemical maspin expression could be of help to identify higher-risk cases. Therefore, we analyzed survival in a study employing 156 cases of stage I/II colorectal cases. Immunohistochemical cytoplasmic and/or nuclear maspin expression was found in 72% and 48% of the cases, respectively. Significant correlations between cytoplasmic expression and high tumor grade (P < .01) and between nuclear expression and tumor budding (P < .001) were shown. No differences concerning overall survival and immunohistochemical maspin expression were found when the complete collective was analyzed. However, evaluation of the pT3 cases revealed a highly significant worse mean overall survival of cases with a combination of nuclear expression and cytoplasmic loss of maspin compared to cases with the opposite expression pattern nuclear loss and cytoplasmic expression (mean overall survival 40 versus 63 months, respectively; P < .001). The other possible combinations (complete positive and complete negative) showed intermediate mean overall survival times with 54 and 49 months, respectively. Our findings suggest a compartment-dependent function of maspin in colorectal cancer, which can be useful in identifying stage II cases with a higher risk for fatal outcome with a possible benefit from adjuvant chemotherapy.

Cytostatic activity of paclitaxel in coronary artery smooth muscle cells is mediated through transient mitotic arrest followed by permanent post-mitotic arrest: comparison with cancer cells.

The anti-cancer agent paclitaxel (PTX) is an effective anti-restenosis agent on drug eluting stents, primarily due to growth inhibition of coronary artery smooth muscle cells (CASMC) across a wide dose range. In this study, we compared the effects of PTX on CASMC to apoptotic-prone HL60 leukemia cells and apoptotic-reluctant A549 lung cancer cells to assess cell survival mechanisms. In comparison to HL60 and A549 cells, CASMC had a shorter mitotic arrest and a lower mitotic index. While CASMC and A549 cells did not become apoptotic and displayed a multi-nucleated phenotype, HL60 cells showed prolonged mitotic arrest followed by apoptosis. CASMC exiting mitosis were arrested in G1 as MN tetraploid cells, with decreased levels of cyclin B1 and PCNA. CASMC remained metabolically active, becoming permanently arrested as evidenced by increased levels of beta-galactosidase activity. These cells did not demonstrate elevated levels of inflammatory markers. Our findings suggest that a weak mitotic checkpoint or inhibited apoptotic cascade, or a combination of both, determine cell survival following PTX treatment. These in vitro findings suggest a mechanism for the cytostatic activity of PTX in CASMC for the inhibition of restenosis.

Paclitaxel induces primary and postmitotic G1 arrest in human arterial smooth muscle cells.

Paclitaxel (PTX), a microtubule-active drug, causes mitotic arrest leading to apoptosis in certain tumor cell lines. Here we investigated the effects of PTX on human arterial smooth muscle cell (SMC) cells. In SMC, PTX caused both (a) primary arrest in G(1) and (b) post-mitotic arrest in G(1). Post-mitotic cells were multinucleated (MN) with either 2C (near-diploid) or 4C (tetraploid) DNA content. At PTX concentrations above 12 ng/ml, MN cells had 4C DNA content consistent with the lack of cytokinesis during abortive mitosis. Treatment with 6-12 ng/ml PTX yielded MN cells with 2C DNA content. Finally, 1-6 ng/ml of PTX, the lowest concentrations that affected cell proliferation, caused G(1) arrest without multinucleation. It is important that PTX did not cause apoptosis in SMC. The absence of apoptosis could be explained by mitotic exit and G(1) arrest as well as by low constitutive levels of caspase expression and by p53 and p21 induction. Thus, following transient mitotic arrest, SMC exit mitosis to form MN cells. These post-mitotic cells were subsequently arrested in G(1) but maintained normal elongated morphology and were viable for at least 21 days. We conclude that in SMC PTX causes post-mitotic cell cycle arrest rather than cell death.