Interleukin 7 signaling in dendritic cells regulates the homeostatic proliferation and niche size of CD4+ T cells.

Interleukin 7 (IL-7) and T cell antigen receptor signals have been proposed to be the main drivers of homeostatic T cell proliferation. However, it is not known why CD4(+) T cells undergo less-efficient homeostatic proliferation than CD8(+) T cells do. Here we show that systemic IL-7 concentrations increased during lymphopenia because of diminished use of IL-7 but that IL-7 signaling on IL-7 receptor-alpha-positive (IL-7Ralpha(+)) dendritic cells (DCs) in lymphopenic settings paradoxically diminished the homeostatic proliferation of CD4(+) T cells. This effect was mediated at least in part by IL-7-mediated downregulation of the expression of major histocompatibility complex class II on IL-7Ralpha(+) DCs. Our results indicate that IL-7Ralpha(+) DCs are regulators of the peripheral CD4(+) T cell niche and that IL-7 signals in DCs prevent uncontrolled CD4(+) T cell population expansion in vivo.

A pilot study of consolidative immunotherapy in patients with high-risk pediatric sarcomas.

PURPOSE: Patients with metastatic or recurrent Ewing's sarcoma family of tumors and alveolar rhabdomyosarcoma have <25% 5-year survival in most studies. This study administered a novel immunotherapy regimen aimed at consolidating remission in these patients. EXPERIMENTAL DESIGN: Fifty-two patients with translocation positive, recurrent, or metastatic Ewing's sarcoma family of tumors or alveolar rhabdomyosarcoma underwent prechemotherapy cell harvest via apheresis for potential receipt of immunotherapy. Following completion of standard multimodal therapy, 30 patients ultimately initiated immunotherapy and were sequentially assigned to three cohorts. All cohorts received autologous T cells, influenza vaccinations, and dendritic cells pulsed with peptides derived from tumor-specific translocation breakpoints and E7, a peptide known to bind HLA-A2. Cohort 1 received moderate-dose recombinant human interleukin-2 (rhIL-2), cohort 2 received low-dose rhIL-2, and cohort 3 did not receive rhIL-2. RESULTS: All immunotherapy recipients generated influenza-specific immune responses, whereas immune responses to the translocation breakpoint peptides occurred in 39%, and only 25% of HLA-A2(+) patients developed E7-specific responses. Toxicity was minimal. Intention-to-treat analysis revealed a 31% 5-year overall survival for all patients apheresed (median potential follow-up 7.3 years) with a 43% 5-year overall survival for patients initiating immunotherapy. CONCLUSIONS: Consolidative immunotherapy is a scientifically based and clinically practical approach for integrating immunotherapy into a multimodal regimen for chemoresponsive cancer. Patients receiving immunotherapy experienced minimal toxicity and favorable survival. The robust influenza immune responses observed suggest that postchemotherapy immune incompetence will not fundamentally limit this approach. Future studies will seek to increase efficacy by using more immunogenic antigens and more potent dendritic cells.

A pain in the neck: lateral thyrohyoid ligament syndrome.

A lateralized pain in the neck is a common symptom encountered by the otolaryngologist. This complaint, frequently caused by lateral thyrohyoid ligament syndrome, is often misdiagnosed. The pathophysiology of this syndrome may relate to overuse and inflammation. [change made here after initial online publication]. Typically, patients present with chronic unilateral neck pain often associated with odynophagia. The point of maximum tenderness localizes over the axis of the lateral thyrohyoid ligament. We present a series of 15 patients, in whom treatment with depot steroid and local anesthetic injection (n = 14) improved symptoms in 12 (86%), with complete resolution in nine (64%) patients.

Etiology and Time to Presentation of Unilateral Vocal Fold Paralysis.

OBJECTIVE: To determine the etiology, laterality, and time to presentation of unilateral vocal fold paralysis (UVFP) at a tertiary care institution over 10 years. STUDY DESIGN: Case series with chart review. SETTING: Academic medical center. SUBJECTS AND METHODS: All patients seen between 2002 and 2012 by the Department of Otolaryngology at the Washington University School of Medicine (WUSM), with a diagnosis of unilateral vocal fold paralysis, were included. Medical records were reviewed for symptom onset date, presentation date(s), and etiology of UVFP. RESULTS: Of the patients, 938 met inclusion criteria and were included. In total, 522 patients (55.6%) had UVFP due to surgery; 158 (16.8%) were associated with thyroid/parathyroid surgery, while 364 (38.8%) were due to nonthyroid surgery. Of the patients, 416 (44.4%) had nonsurgical etiologies, 124 (13.2%) had idiopathic UVFP, and 621 (66.2%) had left-sided UVFP. The diagnosis was more common on the left side in cases of intrathoracic surgeries and malignancies, as expected, but also in idiopathic, carotid endarterectomy, intubation, and skull base tumors. In total, 9.8% of patients presented first to an outside otolaryngologist at a median time of 2.1 months after onset, but these patients presented to WUSM at a median time of 9.5 months. Overall, 70.6% of patients presented to a WUSM otolaryngologist within 3 months of onset. CONCLUSION: Iatrogenic injury remains the most common cause of UVFP. Thyroidectomy remains the leading cause of surgery-related UVFP. Patients are typically seen within 3-4 months of onset; however, a significant delay exists for those referred to WUSM.

Systemic effects of subcutaneous heparin use in otolaryngology patients.

OBJECTIVES: To describe a population of otolaryngology patients who developed systemic anticoagulation from pharmacologic deep vein thrombosis prophylaxis using subcutaneous low-dose unfractionated heparin and describe associated adverse events and identify risk factors for this occurrence. STUDY DESIGN: Retrospective case series with chart review. SETTING: Single-institution, academic tertiary care center. SUBJECTS AND METHODS: Patients who developed prolonged partial thromboplastin times from routine administration of subcutaneous low-dose unfractionated heparin postoperatively were retrospectively identified during a 16-month period. Data regarding demographics, disease characteristics, laboratory values, associated complications, and risk factors were collected and analyzed. RESULTS: Five patients, all with head and neck cancer, postoperatively developed prolonged partial thromboplastin time levels with prophylactic subcutaneous low-dose unfractionated heparin. All had body mass index ≤ 20 kg/m(2) and received 5000 units of subcutaneous low-dose unfractionated heparin 3 times daily. Four had impaired renal function. Adverse events included 5 postoperative wound hematomas, an emergent reintubation, and a case of persistent mucosal bleeding. These bleeding complications accounted for 25% of all bleeding complications in otolaryngology patients during the same period. CONCLUSION: Unanticipated systemic effects of subcutaneous low-dose unfractionated heparin can cause significant morbidity in surgically treated patients with head and neck cancer. From this case series, risk factors appear to include subcutaneous low-dose unfractionated heparin 3 times daily dose frequency, low body mass index, and renal dysfunction. For this at-risk patient population, a protocol is needed to minimize both deep vein thromboses and complications of prophylactic therapy.

Impact of Otitis Media Severity on Children's Quality of Life.

OBJECTIVE: Children with otitis media (OM) suffer sleep disturbances, loss of appetite, earache, and behavioral problems. Our objective was to quantitate the average burden of OM and to compare the associated impact of tympanostomy tubes on infant health related quality of life (HR-QoL). STUDY DESIGN: Multi-institutional prospective cross-sectional study. SETTING: Otolaryngology, family practice, and pediatric clinics. SUBJECTS AND METHODS: Children ages 6 to 24 months of age with or without recurrent OM. Patient history, the PedsQL Infant QoL survey, and the 6-item child with OM survey (Otitis Media 6 [OM-6]) were collected from providers and parents. RESULTS: Data from 1208 patients were analyzed. Mean age was 14.7 months, and 54% were male. The mean OM-6 score of children with recurrent OM was 3.3, whereas similarly aged well-children had a mean OM-6 score of 2.5. The mean PedsQL Infant scores of recurrent OM patients were significantly worse than those of children from well-child visits. Worse OM-6 scores were correlated with poorer PedsQL Infant scores, Pearson r = -0.581 (1-12 months) and -0.558 (13-24 months), P < .001. Otolaryngology patients who were recommended to undergo ear tube placement had significantly poorer OM-6 scores and worse PedsQL Infant scores, whereas patients with prior tube placement had significantly better OM-6 and PedsQL Infant scores. CONCLUSION: Children with recurrent OM had significantly worse HR-QoL than similarly aged healthy children. Increased burden of OM strongly affected HR-QoL, and recommendation for tube placement was associated with increased disease burden and poorer HR-QoL. The presence of tympanostomy tubes was associated with better OM-6 and PedsQL Infant scores.

Caregiver Quality of Life Is Related to Severity of Otitis Media in Children.

OBJECTIVE: Otitis media (OM) in children is the most frequent reason for physician visits in developed countries and burdens caregivers, society, and the child. Our objective was to describe the impact of OM severity on parent/caregiver quality of life (QoL). STUDY DESIGN: Multi-institutional prospective cross-sectional study. SETTING: Otolaryngology, family, and pediatric practices. SUBJECTS AND METHODS: Children 6 to 24 months old with and without a primary diagnosis of recurrent OM and their caregivers. Physicians provided patient history, and parents/caregivers completed a Family Information Form, the PedsQL Family Impact survey, the Patient Reported Outcomes Measurement Information System (PROMIS) survey, and the OM 6-item severity survey (OM-6). RESULTS: A total of 2413 subjects were enrolled and data from 1208 patients and physician were analyzed. The average child age was 16 months, and 54% were male. The mean OM-6 score was 3.2. The mean PedsQL Family Impact score for parents was 66.9 from otolaryngology sites and 78.8 from pediatrics/family practice sites (P < .001). Higher (worse) OM-6 scores correlated significantly with worse PedsQL Family Impact scores (Pearson r = -0.512, P < .01). Similarly, increasing OM-6 scores strongly correlated with increased parental anxiety, depression, and fatigue, as well as decreased satisfaction (all P < .01). CONCLUSIONS: Worse PedsQL Family Impact and PROMIS scores were highly correlated with elevated OM-6 scores, suggesting that severity of childhood OM significantly affects parent/caregiver QoL. Understanding the impact of a child's illness on parent/caregiver QoL can help physicians counsel patients and families and provide better family-centered, compassionate care.

Practical guide to understanding clinical research compliance.

Noncompliance with federal regulations, as monitored through institutional review boards for the ethical conduct of clinical research, can occur, even to seasoned investigators. The cause of this noncompliance can be that an investigator is overloaded, does not know the regulations, or does not take the time to pay attention to the details. Sometimes it happens just because of inevitable human error that can befall us all at any time. The authors begin by citing the inherent differences between clinical practice and clinical research. This is followed by an illustration of common noncompliance errors, with examples, followed by general and specific concepts and methods to minimize noncompliance events. The objective of this article is to condense the myriad details involved in conducting clinical research into a set of manageable recommendations that can be recalled easily before and during the research. The material supporting these recommendations comes from years of institutional review board work at several institutions and consultation with experienced principal investigators and their research coordinators.

Practical guide to understanding the need for clinical practice guidelines.

With recent changes in the landscape of health care, clinical practice guidelines (CPGs) have proliferated. Attitudes about guidelines differ considerably, forming 2 competing viewpoints with considerable tension between them. Some feel CPGs are unneeded or are efforts to create automated "cookie cutter" medical practice; at best, they are perceived as suggestions that may be altered by experience. Others feel they are mandates that must be followed to the letter. This article attempts to explain how and why we have arrived at this point and to explain the origins of the differing viewpoints. We begin by describing the 2 viewpoints and proceed to define the origin of medicine as a profession and to chronicle the evolution of health insurance, medical education, and scientific methods for evaluating evidence.

Practical guide to understanding Comparative Effectiveness Research (CER).

"Comparative effectiveness research" (CER) is not a new concept; however, recently it has been popularized as a method to develop scientifically sound actionable data by which patients, physicians, payers, and policymakers may make informed health care decisions. Fundamental to CER is that the comparative data are derived from large diverse populations of patients assembled from point-of-care general primary care practices and that measured outcomes include patient value judgments. The challenge is to obtain scientifically valid data to be acted upon by decision-making stakeholders with potentially quite diversely different agenda. The process requires very thoughtful research designs modulated by complex statistical and analytic methods. This article is composed of a guiding narrative with an extensive set of tables outlining many of the details required in performing and understanding CER. It ends with short discussions of three example papers, limitations of the method, and how a practicing physician may view such reports.

Practical guide to understanding multivariable analyses: Part A.

Multivariable analyses are complex statistical methods to evaluate the impact of multiple variables on outcomes of interest. Books have been written on each of these methods detailing the mathematical and statistical objectives and processes. However, we have found very little in the way of brief reports that help the nonstatistically trained physician obtain a basic understanding of multivariable analyses in order to have some understanding of the increasing literature using these methods. This work is organized in 2 parts. This article, Part A, addresses the "big 4" algebraic methods of multivariable analysis. The primary focus of Part A is to present a brief "primer" to help the reader understand the methods and uses; it expressly avoids the many details of statistical assumptions, calculations, and myriad branching alternatives. Part B will concentrate on conjunctive consolidation and will focus on enough information to allow the interested reader to actually perform the analysis. For the statistical scholar, we have included references to several voluminous serious works.

Practical guide to understanding multivariable analyses, Part B: conjunctive consolidation.

Conjunctive consolidation, one method of multivariable analysis by arranging data into clusters, is intuitive and transparent. An unexpected consequence in writing this article was the discovery of just how useful it is in critically analyzing articles and in designing new projects. It has stimulated a fresh understanding as to the value of multivariable thinking in all clinical research. This article is organized into the sequential steps for performing conjunctive consolidation for critically analyzing an article of interest and for completing the process, pending all required data are available. Investigators, particularly those who perform clinical research, should consider conjunctive consolidation as a valuable method of multivariable analysis with which to report data.

The role of Stenotrophomonas maltophilia in refractory chronic rhinosinusitis.

BACKGROUND: Stenotrophomonas maltophilia is a multidrug-resistant Gram-negative bacillus that has been implicated in serious nosocomial infections. This microbe has also been isolated from sinus cultures in refractory chronic rhinosinusitis (CRS). The goal of this study was to elucidate the implications of S. maltophilia-positive cultures in the setting of CRS. The objectives of the study were (1) to define clinical and microbiological characteristics and (2) to assess management strategy and overall outcomes of S. maltophilia-positive sinus cultures in CRS patients. METHODS: A retrospective review was performed of 101 patients over a 5-year period. RESULTS: The mean age was 56.9 years with a female/male ratio of 1.1:1. Previous sinus surgery had been performed in 90.1% of patients. Greater than 97% of patients had been given antibiotics in the previous 6 months. The most common presenting symptom was discolored nasal drainage (76.2%) with endoscopic evidence of pus or crusting in 83.2% of cases. Monotherapy with trimethoprim sulfamethoxazole (TMX) or fluoroquinolones was used in 41 and 26%, respectively. This intervention resulted in overall symptom and endoscopic improvement in 70% of cases. CONCLUSION: The presence of S. maltophilia isolates on culture are associated with clinically relevant symptoms and endoscopic findings in patients with refractory CRS. Despite its multidrug-resistant nature, monotherapy with TMX or fluoroquinolones appears to be effective in providing patients with bacterial infection with symptom relief in a majority of cases.

Endoscopic management of sphenoclival neoplasms: anatomical correlates and patient outcomes.

OBJECTIVE: To characterize the endoscopic anatomy of the sphenoid sinus and the adjacent clivus and cavernous sinus, and to review patient outcomes for neoplasms in this region. STUDY DESIGN: Cadaver dissection and chart review. SETTING: Cadaver laboratory and tertiary care center. SUBJECTS AND METHODS: Fresh-frozen cadaver heads were dissected to study the endoscopic anatomy of the sphenoclival region. Retrospective chart review of patients undergoing endoscopic resection of sphenoclival neoplasms between 2000 and 2008 was performed. RESULTS: Transnasal endoscopic access to the sphenoid sinus was obtained in 10 cadaver heads. A clival window with mean dimensions of 1.4 cm x 1.7 cm was created. Through the clival window, identification and dissection of the basilar and vertebral arteries, mamillary bodies, third ventricle, cranial nerves III through VI, and cervical rootlets were possible. Nineteen patients with mean age of 56.2 years were treated. The most common pathologies were inverted papilloma (5), chordoma (4), squamous cell carcinoma (2), and adenoid cystic carcinoma (2). None of the patients required adjunct craniotomies. Nine patients received adjuvant therapies. Thirteen (68.4%) patients had no evidence of disease, five (26.3%) patients were alive with disease, and one (5.3%) patient died of disease at mean follow-up of 32.6 months. CONCLUSION: The sphenoclival region poses a significant surgical challenge given its central location at the skull base and proximity to critical structures. This study demonstrates that transnasal endoscopic access to the sphenoclival region is technically feasible and allows successful surgical extirpation of tumors with a low complication rate and acceptable patient outcomes.

Computed tomography findings in sinonasal Wegener's granulomatosis.

BACKGROUND: Wegener's granulomatosis (WG), an autoimmune disease, is intimately associated with the sinonasal tract, with involvement reported in 85% of patients during the course of the disease process. The objective of this study was (1) to describe Lund-Mackay (L-M) scores, (2) to delineate patterns of neo-osteogenesis and bony erosion, and (3) to analyze the impact of surgery on the computed tomography (CT) findings of WG patients. METHODS: A retrospective review was performed on 74 patients with WG presenting to a tertiary care referral center. CT analysis was performed and graded by two independent reviewers. RESULTS: The mean age was 53 years with a male/female ratio of 0.6:1. The average L-M score was 10.0. Neo-osteogenesis was evident in 78% of the patients with overall average neo-osteogenesis score of 4.2 (range, 0-16). Bony erosion was noted on imaging in 62% of patients with overall average score for bony erosion of 2.0 (range, 0-8). Patients having undergone previous sinus surgery compared with no previous surgery had statistically significant elevation of overall L-M, bony erosion, and neo-osteogenesis scores (p=0.024, 0.0009, and 0.0015, respectively). CONCLUSION: CT imaging in WG patients shows elevated L-M scores and evidence of bony erosion and neo-osteogenesis. Furthermore, surgical manipulation in WG patients is associated with increased bony abnormalities and greater elevations of L-M scores, possibly because of worsening vasculitis and/or inflammation. The presence of concurrent neo-osteogenesis and bony destruction of the paranasal sinuses should raise clinical suspicion of WG in patients presenting with symptoms of chronic rhinosinusitis.