CARE program: NCI and FDA interagency collaborations to support oncology small business entrepreneurs.

The National Cancer Institute's Small Business Innovation Research Development Center (NCI SBIR) supports the commercialization of novel cancer-related technologies by providing resources to 300-400 small businesses each year. Whereas Federal funding is crucial for the translation of technologies to the clinic, the majority of these technologies will need to undergo regulatory review to reach clinical testing. Many small businesses find navigating their regulatory pathway challenging, largely due to lack of regulatory expertise on small startup teams with limited revenue. In collaboration with the US Food and Drug Administration (FDA), NCI SBIR launched a new regulatory assistance program called Connecting Awardees with Regulatory Experts (CARE). The goal of the CARE program is to connect NCI-funded small businesses with the FDA to receive feedback on their regulatory questions during early-stage product development. The program has a multipronged support approach and also educates companies about the FDA process and existing resources. To date, 141 companies have participated in the interagency program. Follow-up surveys indicate that the program guided the companies in planning the next regulatory steps for their technology development (89%) and provided critical information that changed their future NCI small business grant project aims (81%). Overall, companies reported they would recommend the program to other companies (90%). This paper will discuss the CARE program outcomes as well as other NCI and FDA collaborations that support early-stage small businesses, including the joint development of funding opportunities and online resources that focus on the oncology startup community.

Correlation of Population Factors, Compliance with Masking and Social Distance, Vaccination, and COVID-19 Infection in Central Appalachia.

OBJECTIVES: Compliance with coronavirus disease 2019 (COVID-19) guidelines, including the use of masks and social distancing and vaccinations, has been poor. Our study examined what factors may identify those who will be more or less compliant, especially in regard to those with identified higher risk. METHODS: A telephone survey of 200 adult patients from two practices, one general internal medicine and the other rheumatology, was performed in May and June 2021. Questions included age, sex, perception of immunocompetence, smoking history, mask and social distancing compliance, COVID-19 symptoms and/or test-proven infection, and immunization status for COVID-19. Those agreeing to participate also underwent chart review for body mass index, physician-assessed immunocompetence, and diabetes mellitus. RESULTS: No clinical factors approached statistical significance for the prediction of compliance or noncompliance. Compliance with mask and social distancing highly correlated with vaccination and avoidance of infection, however. CONCLUSIONS: Attempts to improve compliance cannot be focused on any of the particular groups examined in this study.

An international, phase III randomized trial in patients with mucinous epithelial ovarian cancer (mEOC/GOG 0241) with long-term follow-up: and experience of conducting a clinical trial in a rare gynecological tumor.

OBJECTIVES: We evaluated four different treatment regimens for advanced-stage mucinous epithelial ovarian cancer. METHODS: We conducted a multicenter randomized factorial trial (UK and US). Patients were diagnosed with primary mEOC: FIGO stage II-IV or recurrence after stage I disease. Treatment arms were paclitaxel-carboplatin, oxaliplatin-capecitabine, paclitaxel-carboplatin-bevacizumab, or oxaliplatin-capecitabine-bevacizumab. Chemotherapy was given 3-weekly for 6 cycles, and bevacizumab (3-weekly) was continued as maintenance (for 12 cycles). Endpoints included overall-survival (OS), progression-free survival (PFS), toxicity and quality of life (QoL). RESULTS: The trial stopped after 50 patients were recruited due to slow accrual. Median follow-up was 59 months. OS hazard ratios (HR) for the two main comparisons were: 0.78 (p = 0.48) for Oxal-Cape vs. Pac-Carbo (each with/without bevacizumab), and 1.04 (p = 0.92) for bevacizumab vs. no bevacizumab. Corresponding PFS HRs were: 0.84 and 0.80. Retrospective central pathology review revealed only 45% (18/40) cases with available material had confirmed primary mEOC. Among these, OS HR for Oxal-Cape vs. Pac-Carbo was 0.36 (p = 0.14); PFS HR = 0.62 (p = 0.40). Grade 3-4 toxicity was seen in 61% Pac-Carbo, 61% Oxal-Cape, 54% Pac-Carbo-Bev, and 85% Oxal-Cape-Bev. QoL was similar between the four arms. CONCLUSION: mEOC/GOG0241 represents an example of a randomized rare tumor trial. Logistical challenges led to early termination, including difficulties in local histopathological diagnosis and accessing drugs outside their labelled indication. There was misalignment between central funders who support clinical trials in rare cancers and the deprioritisation of such work by those managing and funding research at a local level. Rare cancer trials should include centralised pathology review before treatment. Clinical trial registry number: ISRCTN83438782.

Nearly Missed: Painless Aortic Dissection Masquerading as Infective Endocarditis.

Aortic dissection is a life-threatening emergency associated with significant mortality rate. Early diagnosis is essential to improve the survival. Although the most common presentation is severe chest pain, it can be variable leading to delay in the diagnosis especially if it is painless. Painless aortic dissection is a rare entity with sparse data available based on case reports. We present a case of a young male with an atypical presentation where the presumptive diagnosis of infective endocarditis was made based on initial presentation but was eventually diagnosed as painless aortic dissection.

Age is no barrier: predictors of academic success in older learners.

Although predictors of academic success have been identified in young adults, such predictors are unlikely to translate directly to an older student population, where such information is scarce. The current study aimed to examine cognitive, psychosocial, lifetime, and genetic predictors of university-level academic performance in older adults (50-79 years old). Participants were mostly female (71%) and had a greater than high school education level (M = 14.06 years, SD = 2.76), on average. Two multiple linear regression analyses were conducted. The first examined all potential predictors of grade point average (GPA) in the subset of participants who had volunteered samples for genetic analysis (N = 181). Significant predictors of GPA were then re-examined in a second multiple linear regression using the full sample (N = 329). Our data show that the cognitive domains of episodic memory and language processing, in conjunction with midlife engagement in cognitively stimulating activities, have a role in predicting academic performance as measured by GPA in the first year of study. In contrast, it was determined that age, IQ, gender, working memory, psychosocial factors, and common brain gene polymorphisms linked to brain function, plasticity and degeneration (APOE, BDNF, COMT, KIBRA, SERT) did not influence academic performance. These findings demonstrate that ageing does not impede academic achievement, and that discrete cognitive skills as well as lifetime engagement in cognitively stimulating activities can promote academic success in older adults.

Safeguards to prevent neurologic complications after epidural steroid injections: consensus opinions from a multidisciplinary working group and national organizations.

BACKGROUND: Epidural corticosteroid injections are a common treatment for radicular pain caused by intervertebral disc herniations, spinal stenosis, and other disorders. Although rare, catastrophic neurologic injuries, including stroke and spinal cord injury, have occurred with these injections. METHODS: A collaboration was undertaken between the U.S. Food and Drug Administration Safe Use Initiative, an expert multidisciplinary working group, and 13 specialty stakeholder societies. The goal of this collaboration was to review the existing evidence regarding neurologic complications associated with epidural corticosteroid injections and produce consensus procedural clinical considerations aimed at enhancing the safety of these injections. U.S. Food and Drug Administration Safe Use Initiative representatives helped convene and facilitate meetings without actively participating in the deliberations or decision-making process. RESULTS: Seventeen clinical considerations aimed at improving safety were produced by the stakeholder societies. Specific clinical considerations for performing transforaminal and interlaminar injections, including the use of nonparticulate steroid, anatomic considerations, and use of radiographic guidance are given along with the existing scientific evidence for each clinical consideration. CONCLUSION: Adherence to specific recommended practices when performing epidural corticosteroid injections should lead to a reduction in the incidence of neurologic injuries.

An evidence-based clinical guideline for the diagnosis and treatment of lumbar disc herniation with radiculopathy.

BACKGROUND CONTEXT: The objective of the North American Spine Society's (NASS) Evidence-Based Clinical Guideline for the Diagnosis and Treatment of Lumbar Disc Herniation with Radiculopathy is to provide evidence-based recommendations to address key clinical questions surrounding the diagnosis and treatment of lumbar disc herniation with radiculopathy. The guideline is intended to reflect contemporary treatment concepts for symptomatic lumbar disc herniation with radiculopathy as reflected in the highest quality clinical literature available on this subject as of July 2011. The goals of the guideline recommendations are to assist in delivering optimum efficacious treatment and functional recovery from this spinal disorder. PURPOSE: To provide an evidence-based educational tool to assist spine specialists in the diagnosis and treatment of lumbar disc herniation with radiculopathy. STUDY DESIGN: Systematic review and evidence-based clinical guideline. METHODS: This guideline is a product of the Lumbar Disc Herniation with Radiculopathy Work Group of NASS' Evidence-Based Guideline Development Committee. The work group consisted of multidisciplinary spine care specialists trained in the principles of evidence-based analysis. A literature search addressing each question and using a specific search protocol was performed on English-language references found in Medline, Embase (Drugs and Pharmacology), and four additional evidence-based databases to identify articles. The relevant literature was then independently rated using the NASS-adopted standardized levels of evidence. An evidentiary table was created for each of the questions. Final recommendations to answer each clinical question were developed via work group discussion, and grades were assigned to the recommendations using standardized grades of recommendation. In the absence of Level I to IV evidence, work group consensus statements have been developed using a modified nominal group technique, and these statements are clearly identified as such in the guideline. RESULTS: Twenty-nine clinical questions were formulated and addressed, and the answers are summarized in this article. The respective recommendations were graded by strength of the supporting literature, which was stratified by levels of evidence. CONCLUSIONS: The clinical guideline has been created using the techniques of evidence-based medicine and best available evidence to aid practitioners in the care of patients with symptomatic lumbar disc herniation with radiculopathy. The entire guideline document, including the evidentiary tables, suggestions for future research, and all the references, is available electronically on the NASS Web site at http://www.spine.org/Pages/PracticePolicy/ClinicalCare/ClinicalGuidlines/Default.aspx and will remain updated on a timely schedule.

An evidence-based clinical guideline for the diagnosis and treatment of degenerative lumbar spinal stenosis (update).

BACKGROUND CONTEXT: The evidence-based clinical guideline on the diagnosis and treatment of degenerative lumbar spinal stenosis by the North American Spine Society (NASS) provides evidence-based recommendations to address key clinical questions surrounding the diagnosis and treatment of degenerative lumbar spinal stenosis. The guideline is intended to reflect contemporary treatment concepts for symptomatic degenerative lumbar spinal stenosis as reflected in the highest quality clinical literature available on this subject as of July 2010. The goals of the guideline recommendations are to assist in delivering optimum efficacious treatment and functional recovery from this spinal disorder. PURPOSE: Provide an evidence-based educational tool to assist spine care providers in improving quality and efficiency of care delivered to patients with degenerative lumbar spinal stenosis. STUDY DESIGN: Systematic review and evidence-based clinical guideline. METHODS: This report is from the Degenerative Lumbar Spinal Stenosis Work Group of the NASS's Evidence-Based Clinical Guideline Development Committee. The work group consisted of multidisciplinary spine care specialists trained in the principles of evidence-based analysis. The original guideline, published in 2006, was carefully reviewed. A literature search addressing each question and using a specific search protocol was performed on English language references found in MEDLINE, EMBASE (Drugs and Pharmacology), and four additional, evidence-based, databases to identify articles published since the search performed for the original guideline. The relevant literature was then independently rated by a minimum of three physician reviewers using the NASS-adopted standardized levels of evidence. An evidentiary table was created for each of the questions. Final recommendations to answer each clinical question were arrived at via work group discussion, and grades were assigned to the recommendations using standardized grades of recommendation. In the absence of Levels I to IV evidence, work group consensus statements have been developed using a modified nominal group technique, and these statements are clearly identified as such in the guideline. RESULTS: Sixteen key clinical questions were assessed, addressing issues of natural history, diagnosis, and treatment of degenerative lumbar spinal stenosis. The answers are summarized in this document. The respective recommendations were graded by the strength of the supporting literature that was stratified by levels of evidence. CONCLUSIONS: A clinical guideline for degenerative lumbar spinal stenosis has been updated using the techniques of evidence-based medicine and using the best available clinical evidence to aid both practitioners and patients involved with the care of this condition. The entire guideline document, including the evidentiary tables, suggestions for future research, and all references, will be available electronically at the NASS Web site (www.spine.org) and will remain updated on a timely schedule.

An evidence-based clinical guideline for the diagnosis and treatment of cervical radiculopathy from degenerative disorders.

BACKGROUND CONTEXT: The North American Spine Society (NASS) Evidence-Based Clinical Guideline on the Diagnosis and Treatment of Cervical Radiculopathy from Degenerative Disorders provides evidence-based recommendations on key clinical questions concerning the diagnosis and treatment of cervical radiculopathy from degenerative disorders. The guideline addresses these questions based on the highest quality clinical literature available on this subject as of May 2009. The guideline's recommendations assist the practitioner in delivering optimum efficacious treatment of and functional recovery from this common disorder. PURPOSE: Provide an evidence-based educational tool to assist spine care providers in improving quality and efficiency of care delivered to patients with cervical radiculopathy from degenerative disorders. STUDY DESIGN: Systematic review and evidence-based clinical guideline. METHODS: This report is from the Cervical Radiculopathy from Degenerative Disorders Work Group of the NASS' Evidence-Based Clinical Guideline Development Committee. The work group consisted of multidisciplinary spine care specialists trained in the principles of evidence-based analysis. Each member of the group formatted a series of clinical questions to be addressed by the group. The final questions agreed on by the group are the subjects of this report. A literature search addressing each question using a specific search protocol was performed on English language references found in MEDLINE, EMBASE (Drugs and Pharmacology), and four additional evidence-based databases. The relevant literature was then independently rated by a minimum of three reviewers using the NASS-adopted standardized levels of evidence. An evidentiary table was created for each of the questions. Final recommendations to answer each clinical question were arrived at via work group discussion, and grades were assigned to the recommendations using standardized grades of recommendation. In the absence of Levels I to IV evidence, work group consensus statements have been developed using a modified nominal group technique, and these statements are clearly identified as such in the guideline. RESULTS: Eighteen clinical questions were formulated, addressing issues of natural history, diagnosis, and treatment of cervical radiculopathy from degenerative disorders. The answers are summarized in this article. The respective recommendations were graded by the strength of the supporting literature, which was stratified by levels of evidence. CONCLUSIONS: A clinical guideline for cervical radiculopathy from degenerative disorders has been created using the techniques of evidence-based medicine and best available evidence to aid both practitioners and patients involved with the care of this condition. The entire guideline document, including the evidentiary tables, suggestions for future research, and all references, is available electronically at the NASS Web site (www.spine.org) and will remain updated on a timely schedule.

An evidence-based clinical guideline for the diagnosis and treatment of degenerative lumbar spondylolisthesis.

BACKGROUND CONTEXT: The objective of the North American Spine Society (NASS) evidence-based clinical guideline on the diagnosis and treatment of degenerative lumbar spondylolisthesis is to provide evidence-based recommendations on key clinical questions concerning the diagnosis and treatment of degenerative lumbar spondylolisthesis. The guideline is intended to address these questions based on the highest quality clinical literature available on this subject as of January 2007. The goal of the guideline recommendations is to assist the practitioner in delivering optimum, efficacious treatment of and functional recovery from this common disorder. PURPOSE: To provide an evidence-based, educational tool to assist spine care providers in improving the quality and efficiency of care delivered to patients with degenerative lumbar spondylolisthesis. STUDY DESIGN: Systematic review and evidence-based clinical guideline. METHODS: This report is from the Degenerative Lumbar Spondylolisthesis Work Group of the NASS Evidence-Based Clinical Guideline Development Committee. The work group was comprised of multidisciplinary spine care specialists, all of whom were trained in the principles of evidence-based analysis. Each member participated in the development of a series of clinical questions to be addressed by the group. The final questions agreed on by the group are the subject of this report. A literature search addressing each question and using a specific search protocol was performed on English language references found in MEDLINE, EMBASE (Drugs and Pharmacology) and four additional, evidence-based, databases. The relevant literature was then independently rated by at least three reviewers using the NASS-adopted standardized levels of evidence. An evidentiary table was created for each of the questions. Final grades of recommendation for the answer to each clinical question were arrived at via face-to-face meetings among members of the work group using standardized grades of recommendation. When Level I-IV evidence was insufficient to support a recommendation to answer a specific clinical question, expert consensus was arrived at by the work group through the modified nominal group technique and is clearly identified as such in the guideline. RESULTS: Nineteen clinical questions were formulated, addressing issues of prognosis, diagnosis, and treatment of degenerative lumbar spondylolisthesis. The answers to these 19 clinical questions are summarized in this document. The respective recommendations were graded by the strength of the supporting literature that was stratified by levels of evidence. CONCLUSIONS: A clinical guideline for degenerative lumbar spondylolisthesis has been created using the techniques of evidence-based medicine and using the best available evidence as a tool to aid practitioners involved with the care of this condition. The entire guideline document, including the evidentiary tables, suggestions for future research, and all references, is available electronically at the NASS Web site (www.spine.org) and will remain updated on a timely schedule.

Age-related differences in inhibitory processes during interlimb coordination.

The study examined the neurophysiological correlates of age-related changes in the coordination of hand and foot movements. Young and older adults (N=30) performed cyclical isodirectional and non-isodirectional hand-foot movements with contralateral and ipsilateral limb combinations. Motor evoked potentials (MEPs) and silent period durations following transcranial magnetic stimulation (TMS) were measured from the right extensor carpi radialis (ECR) muscle during the interlimb coordination tasks. Older adults demonstrated lower coordination stability than younger adults, particularly when performing non-isodirectional movements with ipsilateral limbs. For all coordination tasks, MEP amplitude was lower in older compared with young participants. Young adults showed significantly longer silent period durations when the coordination pattern involved ipsilateral limbs than during contralateral limb coordination. In contrast, silent period durations did not differ between contralateral and ipsilateral limb coordination in older adults. These results suggest that deterioration in motor performance with advancing age may be associated with a decreased ability to modulate inhibitory function.

Precues enable multiple response preprogramming: evidence from startle.

When one or more response dimensions in a choice reaction time (RT) task are provided beforehand (or precued), RT decreases, indicating that the precued part of a response was prepared in advance. In this study, a startling acoustic stimulus was used to investigate the amount of preprogramming that occurs when part of the response is precued because a startling stimulus has been shown to directly trigger preprogrammed responses. Participants performed wrist flexion/extension movements in a precued one to four choice RT paradigm. A control auditory stimulus (82 dB) or a startling acoustic stimulus (124 dB) accompanied the visual "go" signal on each trial. Although RT latencies were significantly reduced by the startle, many more errors were observed in the startled conditions. Importantly, the errors seen at short RT latencies largely reflected multiple movements to the cued response alternatives, suggesting that multiple responses were preprogrammed.

FDA drug approval summary: alemtuzumab as single-agent treatment for B-cell chronic lymphocytic leukemia.

On September 19, 2007, the U.S. Food and Drug Administration granted regular approval and expanded labeling for alemtuzumab (Campath); Genzyme Corporation, Cambridge, MA) as single-agent treatment for B-cell chronic lymphocytic leukemia (B-CLL). Alemtuzumab was initially approved in 2001 under accelerated approval regulations. Conversion to regular approval was based on a single study submitted to verify clinical benefit. Efficacy and safety were demonstrated in an open-label, international, multicenter, randomized trial of 297 patients with previously untreated, Rai stage I-IV B-CLL experiencing progression of their disease. Patients were randomized to either alemtuzumab, 30 mg i.v. over 2 hours three times per week on alternate days for a maximum of 12 weeks, or chlorambucil, 40 mg/m(2) orally every 28 days for a maximum of 12 months. The progression-free survival time, the primary study endpoint, was significantly longer in the alemtuzumab arm than in the chlorambucil arm. Both the overall and complete response rates were also significantly higher in the alemtuzumab arm. No differences in survival were observed. There were no new safety signals identified in patients receiving alemtuzumab. The most serious, and sometimes fatal, toxicities of alemtuzumab are cytopenias, infusion reactions, and infections.

Degenerative lumbar spinal stenosis: an evidence-based clinical guideline for the diagnosis and treatment of degenerative lumbar spinal stenosis.

BACKGROUND CONTEXT: The objective of the North American Spine Society (NASS) evidence-based clinical guideline for the diagnosis and treatment of degenerative lumbar spinal stenosis (DLSS) is to provide evidence-based recommendations to address key clinical questions surrounding the diagnosis and treatment of DLSS. The guideline is intended to reflect contemporary treatment concepts for symptomatic DLSS as reflected in the highest quality clinical literature available on this subject as of April 2006. The goals of the guideline recommendations are to assist in delivering optimum, efficacious treatment, and functional recovery from this spinal disorder. PURPOSE: To provide an evidence-based tool that assists practitioners in improving the quality and efficiency of care delivered to patients with DLSS. STUDY DESIGN/SETTING: Evidence-based clinical guideline. METHODS: This report is from the Spinal Stenosis Work Group of the NASS Clinical Guidelines Committee. The work group comprised medical, diagnostic, interventional, and surgical spinal care specialists, all of whom were trained in the principles of evidence-based analysis. In the development of this guideline, the work group arrived at a consensus definition of a working diagnosis of lumbar spinal stenosis by use of a modification of the nominal group technique. Each member of the group formatted a series of clinical questions to be addressed by the group and the final list of questions agreed on by the group is the subject of this report. A literature search addressing each question and using a specific literature search protocol was performed on English language references found in MEDLINE, EMBASE (Drugs and Pharmacology), and four additional, evidence-based, databases. The relevant literature to answer each clinical question was then independently rated by at least two reviewers using the NASS-adopted standardized levels of evidence. An evidentiary table was created for each of the questions. Any discrepancies in evidence levels among the initial raters were resolved by at least two additional members' review of the reference and independent rating. Final grades of recommendation for the answer to each clinical question were arrived at in face-to-face meetings among members of the work group using the NASS-adopted standardized grades of recommendation. When Levels I to IV evidence was insufficient to support a recommendation to answer a specific clinical question, expert consensus was arrived at by the work group through the modified nominal group technique and is clearly identified as such in the guideline. RESULTS: Eighteen clinical questions were asked, addressing issues of prognosis, diagnosis, and treatment of DLSS. The answers to these 18 clinical questions are summarized in this document along with their respective levels of evidence and grades of recommendation in support of these answers. CONCLUSIONS: A clinical guideline for DLSS has been created using the techniques of evidence-based medicine and using the best available evidence as a tool to aid both practitioners and patients involved with the care of this disease. The entire guideline document including the evidentiary tables, suggestions for future research, and all references is available electronically at the NASS Web site (www.spine.org) and will remain updated on a timely schedule.

Pneumomediastinum, pneumopericardium, and epidural pneumatosis in DKA.

Pneumomediastinum (PM) is an uncommon condition characterized by the presence of air in the mediastinum. It is associated with alveolar rupture that allows air to traverse along the bronchovascular bundle into the mediastinum. A review of the world medical literature identified 50 additional cases of PM and pneumopericardium (PC) associated with diabetic ketoacidosis (DKA). We report the occurrence of PM, PC, as well as epidural pneumatosis occurring simultaneously in a patient with DKA. Epidural pneumatosis in association with this metabolic derangement has not been previously described.

Tumor expression of 4-1BB ligand sustains tumor lytic T cells.

Inadequate costimulation by solid tumors is generally believed to induce immune tolerance during primary tumor growth. We looked for tumor-specific immunity vs. tolerance in patients with Ewing's sarcoma. Circulating T cells from patients with progressively growing Ewing's tumors displayed MHC restricted tumor-induced proliferation and robust tumor lysis. Tumor-reactive T cells reside within the memory CD3+CD8+ subset and are CD28-/4-1BB+. Autologous Ewing's tumors expressed 4-1BBL, and tumor-induced T cell proliferation and activation required costimulation by 4-1BBL. Stimulation of PBL with anti-CD3/4-1BBL, but not anti-CD3/anti-CD28 induced tumor lytic effectors. Similarly, in a xenograft model, anti-CD3/4-1BBL expanded T cells controlled primary growth and prevented metastasis of autologous tumors while nonactivated and anti-CD3/anti-CD28 activated CD8+ cells did not. These results question prevailing models of tumor induced tolerance accompanying progressive tumor growth; rather, we show coexistence of progressive tumor growth and anti-tumor immunity, with costimulation provided by the tumor itself. They further demonstrate a potential new therapeutic role for 4-1BBL mediated costimulation in expanding tumor reactive CTLs for use in the adoptive immunotherapy of cancer.