Cilia dysfunction underlies a class of human diseases with variable penetrance in different organ systems. Across eukaryotes, intraflagellar transport (IFT) facilitates cilia biogenesis and cargo trafficking, but our understanding of mammalian IFT is insufficient. Here we perform live analysis of cilia ultrastructure, composition and cargo transport in native mammalian tissue using olfactory sensory neurons. Proximal and distal axonemes of these neurons show no bias towards IFT kinesin-2 choice, and Kif17 homodimer is dispensable for distal segment IFT. We identify Bardet–Biedl syndrome proteins (BBSome) as bona fide constituents of IFT in olfactory sensory neurons, and show that they exist in 1:1 stoichiometry with IFT particles. Conversely, subpopulations of peripheral membrane proteins, as well as transmembrane olfactory signalling pathway components, are capable of IFT but with significantly less frequency and/or duration. Our results yield a model for IFT and cargo trafficking in native mammalian cilia and may explain the penetrance of specific ciliopathy phenotypes in olfactory neurons.

National Institutes of Health and the St. Baldrick's Foundation.

The AHOD0831 study for paediatric patients with high risk Hodgkin lymphoma tested a response-based approach designed to limit cumulative alkylator exposure and reduce radiation volumes. Patients (Stage IIIB/IVB) received two cycles of ABVE-PC (doxorubicin, bleomycin, vincristine, etoposide, prednisone, cyclophosphamide). Rapid early responders [RER, no positron emission tomography (PET) activity above mediastinal blood pool] were consolidated with 2 cycles of ABVE-PC. Slow early responders (SER) received 2 cycles of ifosfamide/vinorelbine and 2 cycles of ABVE-PC. Radiotherapy was administered to sites of initial bulk and/or SER. By intent-to-treat analysis, 4-year second event-free survival (EFS; freedom from second relapse or malignancy) was 91Á9% [95% confidence interval (CI): 86Á1-95Á3%], below the projected baseline of 95% (P = 0Á038). Fiveyear first EFS and overall survival (OS) rates are 79Á1% (95% CI: 71Á5-84Á8%) and 95% (95% CI: 88Á8-97Á8%). Eight of 11 SER patients with persistent PET positive lesions at the end of chemotherapy had clinical evidence of active disease (3 biopsy-proven, 5 with progressive disease or later relapses). Although this response-directed approach did not reach the ambitiously high pre-specified target for second EFS, EFS and OS rates are comparable with results of recent trials despite the reduction in radiotherapy volumes from historical involved fields. Persistent PET at end of chemotherapy identifies a cohort at an especially high risk for relapse/early progression.

Background

This limited chemotherapy response-based approach was successful in patients who had a negative PET1 result, had MC histology, or had a low red blood cell sedimentation rate. In this treatment paradigm, evaluation of increased chemotherapy intensity or the integration of active new agents is indicated for patients who have nodular sclerosis histology with a high ESR or who have a positive PET1 result. Cancer 2018. © 2018 American Cancer Society.

PURPOSE Population-based studies of children and adolescents with Hodgkin lymphoma (HL) report a survival disadvantage in nonwhite—non-Hispanic black (NHB) and Hispanic—patients. Whether disparities persist after adjustment for clinical and treatment-related variables is unknown. We examined survival by race/ethnicity in children receiving risk-based, response-adapted, combined-modality therapy for HL in contemporary Children’s Oncology Group trials. PATIENTS AND METHODS This pooled analysis used individual-level data from 1,605 patients (younger than age 1 to 21 years) enrolled in phase III trials for low-risk (AHOD0431), intermediate-risk (AHOD0031), and high-risk (AHOD0831) HL from 2002 to 2012. Event-free survival (EFS) and overall survival (OS) were compared between non-Hispanic white (NHW) and nonwhite patients. Cox proportional hazards for survival were estimated for both de novo and relapsed HL, adjusting for demographics, disease characteristics, and therapy. RESULTS At median follow up of 6.9 years, cumulative incidence of relapse was 17%. Unadjusted 5-year EFS and OS were 83% (SE, 1.2%) and 97% (SE, < 1%), respectively. Neither differed by race/ethnicity. In multivariable analyses for OS, nonwhite patients had a 1.88× higher hazard of death (95% CI, 1.1 to 3.3). Five-year postrelapse survival probabilities by race were as follows: NHW, 90%; NHB, 66%; and Hispanic, 80% ( P < .01). Compared with NHW, Hispanic and NHB children had 2.7-fold (95% CI, 1.2 to 6.2) and 3.5-fold (95% CI, 1.5 to 8.2) higher hazard of postrelapse mortality, respectively. CONCLUSION In patients who were treated for de novo HL in contemporary Children’s Oncology Group trials, EFS did not differ by race/ethnicity; however, adjusted OS was significantly worse in nonwhite patients, a finding driven by increased postrelapse mortality in this population. Additional studies examining treatment and survival disparities after relapse are warranted.

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Physical therapists are gaining recognition as first-line health care providers in the treatment of musculoskeletal pain. This increased autonomy necessitates greater responsibility in determining appropriateness of T T STUDY DESIGN: Literature review and crosssectional study. T T BACKGROUND:Direct access to physical therapy necessitates greater responsibility to determine appropriateness of care by recognizing the potential for concomitant disease or systemic involvement. Recent research has identified excessive variability in the reporting of red flag symptoms. An initial step to improve the identification of red flag symptoms is the development of a standardized screening tool. T T OBJECTIVE:To describe the development of a review-of-systems screening tool appropriate for use by orthopaedic physical therapists. T T METHODS:First, a red flag symptom item bank was compiled from a systematic literature review to allow for further psychometric testing and development of a screening tool. Second, physical therapists in 11 outpatient clinics recruited patients presenting with primary complaints of neck, shoulder, low back, or knee pain. Patients completed the red flag symptom item bank and standard questionnaires for comorbidities, negative mood, quality of life, pain, and function. The development of the screening tool involved identifying and combining different 3-item sets that characterized the highest number of patients reporting at least 1 positive symptom response (operationally defined as "red flag symptom responder"). T T RESULTS:The literature search yielded 103 studies that met the inclusion criteria, and the final item bank consisted of 97 items representing 8 body systems. Four hundred thirty-one patients with primary complaints of neck (n = 93), shoulder (n = 108), low back (n = 119), or knee (n = 111) disorders contributed to the cross-sectional study. The number of red flag symptom responders was 393 of 431 (91.2%). These patients were older, more likely to be female, had lower income, and were more likely to report neck or back pain (all, P<.05). A 10-item review-of-systems screening tool correctly identified 372 of 393 (94.7%) responders, and a 23-item version identified all 393 (100%) responders. The review-of-systems screening tools and the complete 97-item bank had similar correlations with concurrent clinical measures, except for depressive symptoms. T T CONCLUSION:Concise red flag symptom identification appears to be feasible in outpatient orthopaedic physical therapy settings. Future research will determine how this reviewof-systems screening tool needs refinement for different patient populations and whether it predicts clinical outcomes or the need for referral to other providers.