Publications by authors named "R Lor Randall"

709 Publications

Is osseous reattachment of the greater trochanter necessary compared to soft-tissue-only abductor repair in proximal femoral megaprosthesis reconstruction?

J Surg Oncol 2021 Mar 25. Epub 2021 Mar 25.

Department of Orthopedic Surgery, UC Davis Medical Center, University of California, Sacramento, California, USA.

Background: One of the challenges to surgical reconstruction following oncologic proximal femur resection is reliable re-establishment of the abductor mechanism. Surgical and functional outcomes following re-approximation of the abductor mechanism to a metallic endoprosthetic after tumor resection of the proximal femur have not been well established in the literature.

Methods: A retrospective review was performed, inclusive of patients who received a proximal femur replacement with a metallic endoprosthesis following tumor resection. Patients were divided into two groups: (1) those that received an abductor repair involving a trochanteric osteotomy and osseous fixation of the greater trochanter/abductor mechanism to the endoprosthesis, and (2) those that did not have a trochanteric osteotomy and therefore had an abductor repair consisting of only soft tissue reattachment to the endoprosthesis. The two groups were assessed for demographic characteristics, diagnosis, surgical outcomes including rates of complication and failure, radiographic evidence of trochanteric failure, and functional outcomes. Descriptive statistics, comparative statistics, and logistic regression analyses were performed to discern differences between the two study groups.

Results: Fifty-three patients were included in the analysis, 29 had abductor reconstructions involving reattachment of the greater trochanter to the metallic endoprosthesis and 24 had soft tissue reconstruction of the abductor mechanism without bony fixation. There were no differences between the two groups for demographic data, cancer diagnosis, follow up, or survivorship. Radiographic evidence of trochanteric dissociation from the endoprosthesis was observed in 45% of osteotomy cases. Only 10% of patients in the trochanter osteotomy group and 38% of the soft tissue only group were able to resume a normal, non-Trendelenburg gait at final postoperative visit (p = .024). Need for an assistive ambulatory device was seen in 83% and 67% of the osteotomy and soft-tissue-only patients, respectively (p = .21).

Conclusion: Re-establishing the abductor mechanism following proximal femur oncologic resection remains a challenge to orthopedic oncologists. Even when possible, salvage of the greater trochanter for reattachment to the endoprosthesis did not lead to improved function in this series, when compared to a similar cohort that received a soft-tissue-only abductor repair. Abductor mechanism reconstruction with a greater trochanteric osteotomy and subsequent fixation to the proximal femur endoprosthesis had a high rate of radiographic failure. Additionally, reattachment of the greater trochanter to the proximal femur endoprosthesis demonstrated no improvement in Trendelenburg gait or reliance on an assistive ambulatory device when compared to a soft-tissue-only abductor repair.
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http://dx.doi.org/10.1002/jso.26477DOI Listing
March 2021

Ischial osteoid osteoma: A cause of persistent hip pain in an adolescent patient with bilateral femoroacetabular impingement.

Radiol Case Rep 2021 May 24;16(5):1037-1041. Epub 2021 Feb 24.

Department of Orthopedic Surgery, University of Utah Health, 590 Wakara Way, Salt Lake City, UT 84108, USA.

A 15-year-old boy presented with left-sided hip pain and imaging consistent with the diagnosis of femoroacetabular impingement. Following hip arthroscopy, which included an osteochondroplasty, labral repair, and capsular repair, the patient's anterior hip pain improved. However, his deep aching hip pain persisted until an ischial osteoid osteoma was identified and treated with radiofrequency ablation. At 3 years follow-up, the patient reports high satisfaction and minimal pain. We present this case to illustrate the importance of considering all potential causes of persistent hip pain following hip arthroscopy, including benign bone tumors which may be difficult to visualize on plain radiographs.
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http://dx.doi.org/10.1016/j.radcr.2021.02.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917454PMC
May 2021

Willingness of patients with sarcoma to participate in cancer surveillance research: a cross-sectional patient survey.

BMJ Open 2021 Feb 26;11(2):e042742. Epub 2021 Feb 26.

Department of Surgery, McMaster University, Hamilton, Ontario, Canada

Objectives: To determine the proportion of patients with extremity sarcoma who would be willing to participate in a clinical trial in which they would be randomised to one of four different postoperative sarcoma surveillance regimens. Additionally, we assessed patients' perspectives on the burden of cancer care, factors that influence comfort with randomisation and the importance of cancer research.

Design: Prospective, cross-sectional patient survey.

Setting: Outpatient sarcoma clinics in Canada, the USA and Spain between May 2017 and April 2020. Survey data were entered into a study-specific database.

Participants: Patients with extremity sarcoma who had completed definitive treatment from seven clinics across Canada, the USA and Spain.

Main Outcome Measures: The proportion of patients with extremity sarcoma who would be willing to participate in a randomised controlled trial (RCT) that evaluates varying postoperative cancer surveillance regimens.

Results: One hundred thirty complete surveys were obtained. Respondents reported a wide range of burdens related to clinical care and surveillance. The majority of patients (85.5%) responded that they would agree to participate in a cancer surveillance RCT if eligible. The most common reason to participate was that they wanted to help future patients. Those that would decline to participate most commonly reported that participating in research would be too much of a burden for them at a time when they are already feeling overwhelmed. However, most patients agreed that cancer research will help doctors better understand and treat cancer.

Conclusions: These results demonstrate that most participants would be willing to participate in an RCT that evaluates varying postoperative cancer surveillance regimens. Participants' motivation for trial participation included altruistic reasons to help future patients and deterrents to trial participation included the overwhelming burden of a cancer diagnosis. These results will help inform the development of patient-centred RCT protocols in sarcoma surveillance research.

Level Of Evidence: V.
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http://dx.doi.org/10.1136/bmjopen-2020-042742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919570PMC
February 2021

Local Control For High-Grade Nonrhabdomyosarcoma Soft Tissue Sarcoma Assigned to Radiation Therapy on ARST0332: A Report From the Childrens Oncology Group.

Int J Radiat Oncol Biol Phys 2021 Feb 3. Epub 2021 Feb 3.

Department of Orthopedics, University of California Davis, Sacramento, California.

Purpose: The ARST0332 trial for pediatric and young adults with nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) used risk-based treatment including primary resection with lower-than-standard radiation doses to optimize local control (LC) while minimizing long-term toxicity in those requiring radiation therapy (RT). RT for high-grade NRSTS was based on extent of resection (R0: negative margins, R1: microscopic margins, R2/U: gross disease/unresectable); those with >5 cm tumors received chemotherapy (CT; ifosfamide/doxorubicin). This analysis evaluates LC for patients assigned to RT and prognostic factors associated with local recurrence (LR).

Methods And Materials: Patients aged <30 years with high-grade NRSTS received RT (55.8 Gy) for R1 ≤5 cm tumor (arm B); RT (55.8 Gy)/CT for R0/R1 >5 cm tumor (arm C); or neoadjuvant RT (45 Gy)/CT plus delayed surgery, CT, and postoperative boost to 10.8 Gy R0 <5 mm margins/R1 or 19.8 Gy for R2/unresected tumors (arm D).

Results: One hundred ninety-three eligible patients had 24 LRs (arm B 1/15 [6.7%], arm C 7/65 [10.8%], arm D 16/113 [14.2%]) at median time to LR of 1.1 years (range, 0.11-5.27). Of 95 eligible for delayed surgery after neoadjuvant therapy, 89 (93.7%) achieved R0/R1 margins. Overall LC after RT were as follows: R0, 106 of 109 (97%); R1, 51 of 60 (85%); and R2/unresectable, 2 of 6 (33%). LR predictors include extent of delayed resection (P <.001), imaging response before delayed surgery (P < .001), histologic subtype (P <.001), and no RT (P = .046). The 5-year event-free survival was significantly lower (P = .0003) for patients unable to undergo R0/R1 resection.

Conclusions: Risk-based treatment for young patients with high-grade NRSTS treated on ARST0332 produced very high LC, particularly after R0 resection (97%), despite lower-than-standard RT doses. Neoadjuvant CT/RT enabled delayed R0/R1 resection in most patients and is preferred over adjuvant therapy due to the lower RT dose delivered.
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http://dx.doi.org/10.1016/j.ijrobp.2021.01.051DOI Listing
February 2021

The plant AlcR-pAlcA ethanol-inducible system displays gross growth artefacts independently of downstream pAlcA-regulated inducible constructs.

Sci Rep 2021 Jan 25;11(1):2142. Epub 2021 Jan 25.

Department of Plant Developmental Genetics, IPMB, The University of Zürich, Zürich, Switzerland.

The AlcR fungal protein responds to ethanol and binds to the fungal pAlcA promoter in its presence. This system was transferred to plants over twenty years ago and was claimed to function in the same manner in plants. However, never has the control experiment with plants containing the AlcR gene alone, with no downstream inducible construct, been made. In this paper, I conduct several experiments with this control, growing p35:AlcR plants in the presence or absence of ethanol. I found that when these plants were grown in the presence of ethanol, growth in several tissues and several stages of growth was retarded. This demonstrates that this system is not suitable for use in the plant sciences, and casts doubt on the conclusions of papers that have published phenotypes using this system.
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http://dx.doi.org/10.1038/s41598-020-80903-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835360PMC
January 2021

Mutations in SKI in Shprintzen-Goldberg syndrome lead to attenuated TGF-β responses through SKI stabilization.

Elife 2021 Jan 8;10. Epub 2021 Jan 8.

Developmental Signalling Laboratory, The Francis Crick Institute, London, United Kingdom.

Shprintzen-Goldberg syndrome (SGS) is a multisystemic connective tissue disorder, with considerable clinical overlap with Marfan and Loeys-Dietz syndromes. These syndromes have commonly been associated with enhanced TGF-β signaling. In SGS patients, heterozygous point mutations have been mapped to the transcriptional co-repressor SKI, which is a negative regulator of TGF-β signaling that is rapidly degraded upon ligand stimulation. The molecular consequences of these mutations, however, are not understood. Here we use a combination of structural biology, genome editing, and biochemistry to show that SGS mutations in SKI abolish its binding to phosphorylated SMAD2 and SMAD3. This results in stabilization of SKI and consequently attenuation of TGF-β responses, both in knockin cells expressing an SGS mutation and in fibroblasts from SGS patients. Thus, we reveal that SGS is associated with an attenuation of TGF-β-induced transcriptional responses, and not enhancement, which has important implications for other Marfan-related syndromes.
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http://dx.doi.org/10.7554/eLife.63545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834018PMC
January 2021

Tissue engineered platforms for studying primary and metastatic neoplasm behavior in bone.

J Biomech 2021 Jan 30;115:110189. Epub 2020 Dec 30.

Department of Biomedical Engineering, University of California, Davis, Davis, CA 95616, United States; Department of Orthopaedic Surgery, UC Davis Health, Sacramento, CA 95817, United States. Electronic address:

Cancer is the second leading cause of death in the United States, claiming more than 560,000 lives each year. Osteosarcoma (OS) is the most common primary malignant tumor of bone in children and young adults, while bone is a common site of metastasis for tumors initiating from other tissues. The heterogeneity, continual evolution, and complexity of this disease at different stages of tumor progression drives a critical need for physiologically relevant models that capture the dynamic cancer microenvironment and advance chemotherapy techniques. Monolayer cultures have been favored for cell-based research for decades due to their simplicity and scalability. However, the nature of these models makes it impossible to fully describe the biomechanical and biochemical cues present in 3-dimensional (3D) microenvironments, such as ECM stiffness, degradability, surface topography, and adhesivity. Biomaterials have emerged as valuable tools to model the behavior of various cancers by creating highly tunable 3D systems for studying neoplasm behavior, screening chemotherapeutic drugs, and developing novel treatment delivery techniques. This review highlights the recent application of biomaterials toward the development of tumor models, details methods for their tunability, and discusses the clinical and therapeutic applications of these systems.
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http://dx.doi.org/10.1016/j.jbiomech.2020.110189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855491PMC
January 2021

Seeking international consensus on approaches to primary tumour treatment in Ewing sarcoma.

Clin Sarcoma Res 2020 Nov 17;10(1):21. Epub 2020 Nov 17.

University College Hospital, 250 Euston Road, London, NW1 2PG, UK.

Background: The local treatment of Ewing sarcoma of bone involves surgery, radiotherapy or both. The selection of treatment depends on the anatomical extent of the tumour, the effectiveness of the proposed treatment, its morbidity, and the expectation of cure. However, not only are there variations in the approach to local treatment between individual patients, but also between treatment centres and countries. Our aim was to explore variation in practice and develop consensus statements about local treatment.

Methods: A three stage modified Delphi technique was used with international collaborators. This involved an expert panel to identify areas of controversy, an online survey of international collaborators and a consensus meeting in London, UK in June 2017. In the consensus meeting, teams of clinicians discussed the local management of selected cases and their responses were collected with electronic voting.

Results: Areas of greater or less consensus were identified. The lack of evidence underpinning different approaches was noted and areas for collaborative research became apparent.

Conclusion: This has demonstrated that there is an international consensus around many aspects of the local treatment of Ewing sarcoma of bone, including the use of specialist MultiDisciplinary Team (MDT) meetings with access to all appropriate treatments. However, considerable variation remains including the use of different staging investigations, decision making, definitions of response, and radiotherapy doses and timing. Further collaborative work should be undertaken to determine the impact of these variations in order to define best practice.
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http://dx.doi.org/10.1186/s13569-020-00144-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672819PMC
November 2020

Long-term survival of participants in the CENTAUR trial of sodium phenylbutyrate-taurursodiol in amyotrophic lateral sclerosis.

Muscle Nerve 2021 01 30;63(1):31-39. Epub 2020 Oct 30.

Sean M. Healey & AMG Center for ALS & the Neurological Clinical Research Institute, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

An orally administered, fixed-dose coformulation of sodium phenylbutyrate-taurursodiol (PB-TURSO) significantly slowed functional decline in a randomized, placebo-controlled, phase 2 trial in ALS (CENTAUR). Herein we report results of a long-term survival analysis of participants in CENTAUR. In CENTAUR, adults with ALS were randomized 2:1 to PB-TURSO or placebo. Participants completing the 6-month (24-week) randomized phase were eligible to receive PB-TURSO in the open-label extension. An all-cause mortality analysis (35-month maximum follow-up post-randomization) incorporated all randomized participants. Participants and site investigators were blinded to treatment assignments through the duration of follow-up of this analysis. Vital status was obtained for 135 of 137 participants originally randomized in CENTAUR. Median overall survival was 25.0 months among participants originally randomized to PB-TURSO and 18.5 months among those originally randomized to placebo (hazard ratio, 0.56; 95% confidence interval, 0.34-0.92; P = .023). Initiation of PB-TURSO treatment at baseline resulted in a 6.5-month longer median survival as compared with placebo. Combined with results from CENTAUR, these results suggest that PB-TURSO has both functional and survival benefits in ALS.
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http://dx.doi.org/10.1002/mus.27091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820979PMC
January 2021

Genetic Lesions of Type I Interferon Signalling in Human Antiviral Immunity.

Trends Genet 2021 01 22;37(1):46-58. Epub 2020 Sep 22.

Translational and Clinical Research Institute, Immunity and Inflammation Theme, Newcastle University, Newcastle upon Tyne NE2 4HH, UK; Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 4LP, UK.

The concept that type I interferons (IFN-I) are essential to antiviral immunity derives from studies on animal models and cell lines. Virtually all pathogenic viruses have evolved countermeasures to IFN-I restriction, and genetic loss of viral IFN-I antagonists leads to virus attenuation. But just how important is IFN-I to antiviral defence in humans? The recent discovery of genetic defects of IFN-I signalling illuminates this and other questions of IFN biology, including the role of the mucosa-restricted type III IFNs (IFN-III), informing our understanding of the place of the IFN system within the concerted antiviral response. Here we review monogenic lesions of IFN-I signalling pathways and summarise the organising principles which emerge.
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http://dx.doi.org/10.1016/j.tig.2020.08.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508017PMC
January 2021

Pilot Study: Evaluating the Impact of Pharmacist Patient-Specific Medication Recommendations for Diabetes Mellitus Therapy to Family Medicine Residents.

Pharmacy (Basel) 2020 Aug 31;8(3). Epub 2020 Aug 31.

Daniel K Inouye College of Pharmacy, University of Hawaii at Hilo, Hilo, HI 96720, USA.

Pharmacists have demonstrated effectiveness in managing diabetes mellitus (DM) and lowering hemoglobin A1C (A1C) through direct patient management. Often patients with diabetes and elevated A1C may not be able to come into the clinic for separate appointments with a pharmacist or for diabetes education classes. A novel way that pharmacists can assist in improving the control of patients' diabetes and improve prescriber understanding and the use of medications for diabetes is by providing medication recommendations to medical residents prior to the patient's appointment with the medical resident. The results of this pilot study indicate that the recommendations provided to family medicine residents and implemented at the patient's office visit helped to lower A1C levels, although the population size was too small to show statistical significance. This pilot study's results support performing a larger study to determine if the pharmacist's recommendation not only improves patient care by lowering A1C levels but if it also helps improve medical resident's understanding and use of medications for diabetes.
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http://dx.doi.org/10.3390/pharmacy8030158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7559418PMC
August 2020

Trial of Sodium Phenylbutyrate-Taurursodiol for Amyotrophic Lateral Sclerosis.

N Engl J Med 2020 09;383(10):919-930

From the Sean M. Healey and AMG Center for ALS and the Neurological Clinical Research Institute, Massachusetts General Hospital, Harvard Medical School (S.P., J.D.B., S.B., M.C., D.D., M.M., J.O., L.P., A.V.S., E.T., P.V., J. Walker, H.Y., R.E.T., M.E.C.), the Biostatistics Center, Massachusetts General Hospital, Harvard Medical School (E.A.M., J. Chan, D.S.), and Spaulding Rehabilitation Hospital, Harvard Medical School (S.P.), Boston, the University of Massachusetts Memorial Medical Center, Worcester (M.A.O.), and Amylyx Pharmaceuticals (J. Cohen, J. Klee, K.L., P.D.Y.) and Harvard University (W.G.), Cambridge - all in Massachusetts; Pentara, Millcreek, UT (S.H., S.P.D., N.E., K.H.); Swedish Neuroscience Institute, Seattle (M.A.E.); Hennepin Healthcare, Minneapolis (S.M.); the Department of Neurology, Oregon Health and Science University, Portland (C.K.); the Department of Neurology, Wake Forest School of Medicine, Winston-Salem, NC (J.B.C.); the Department of Neurology, Ohio State University College of Medicine, Columbus (A.Q.); the Department of Neurology, University of Florida College of Medicine, Gainesville (J. Wymer); the Department of Neurology, University of Michigan, Ann Arbor (S.A.G.); Texas Neurology, Dallas (D.H.); the Department of Neurology, Lewis Katz School of Medicine, Temple University (T.H.-P.), and the Department of Neurology, University of Pennsylvania Perelman School of Medicine (C.Q.) - both in Philadelphia; Glenn Biggs Institute for Alzheimer's and Neurodegenerative Disease, University of Texas Health Science Center at San Antonio, San Antonio (C.E.J.); the Brain Science Institute and Department of Neurology, Johns Hopkins University, Baltimore (J.D.R.); the Department of Neurology, University of Kentucky College of Medicine, Lexington (E.J.K.); California Pacific Medical Center and Forbes Norris MDA-ALS Research and Treatment Center, San Francisco (J. Katz, L.J.); Barrow Neurological Institute, Phoenix, AZ (S.L., M.H., G.K., R.R., J.M.S.); the Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis (T.M.M.); the Department of Neurology, Mount Sinai Beth Israel, Icahn School of Medicine at Mount Sinai, New York (S.N.S.); the Department of Neurology, University of South Florida Morsani College of Medicine, Tampa (T.H.V.); the Departments of Neurology and Pathology, Emory University School of Medicine, Atlanta (C.N.F., J.D.G.); Ochsner Health System, New Orleans (K.M.J.); the Department of Neurology, University of Iowa Carver College of Medicine, Iowa City (A.S.); the Department of Neurology, University of California, Irvine, School of Medicine, Irvine (N.A.G.); Neurology Associates, Lincoln, NB (G.L.P.); independent consultant, Nobleboro, ME (P.L.A.); and Statistics Collaborative, Washington, DC (J. Wittes).

Background: Sodium phenylbutyrate and taurursodiol have been found to reduce neuronal death in experimental models. The efficacy and safety of a combination of the two compounds in persons with amyotrophic lateral sclerosis (ALS) are not known.

Methods: In this multicenter, randomized, double-blind trial, we enrolled participants with definite ALS who had had an onset of symptoms within the previous 18 months. Participants were randomly assigned in a 2:1 ratio to receive sodium phenylbutyrate-taurursodiol (3 g of sodium phenylbutyrate and 1 g of taurursodiol, administered once a day for 3 weeks and then twice a day) or placebo. The primary outcome was the rate of decline in the total score on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) through 24 weeks. Secondary outcomes were the rates of decline in isometric muscle strength, plasma phosphorylated axonal neurofilament H subunit levels, and the slow vital capacity; the time to death, tracheostomy, or permanent ventilation; and the time to death, tracheostomy, permanent ventilation, or hospitalization.

Results: A total of 177 persons with ALS were screened for eligibility, and 137 were randomly assigned to receive sodium phenylbutyrate-taurursodiol (89 participants) or placebo (48 participants). In a modified intention-to-treat analysis, the mean rate of change in the ALSFRS-R score was -1.24 points per month with the active drug and -1.66 points per month with placebo (difference, 0.42 points per month; 95% confidence interval, 0.03 to 0.81; P = 0.03). Secondary outcomes did not differ significantly between the two groups. Adverse events with the active drug were mainly gastrointestinal.

Conclusions: Sodium phenylbutyrate-taurursodiol resulted in slower functional decline than placebo as measured by the ALSFRS-R score over a period of 24 weeks. Secondary outcomes were not significantly different between the two groups. Longer and larger trials are necessary to evaluate the efficacy and safety of sodium phenylbutyrate-taurursodiol in persons with ALS. (Funded by Amylyx Pharmaceuticals and others; CENTAUR ClinicalTrials.gov number, NCT03127514.).
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http://dx.doi.org/10.1056/NEJMoa1916945DOI Listing
September 2020

National Comprehensive Cancer Network guidelines compliance of a sarcoma service: A retrospective review.

World J Clin Oncol 2020 Jun;11(6):389-396

Department of Orthopedic Surgery, University of California-Davis Medical Center, Sacramento, CA 95817, United States.

Background: Clinical workup and treatment guidelines have been published by the National Comprehensive Cancer Network (NCCN) to ensure patients are treated uniformly and appropriately. This study sought to retrospectively review patients with a new diagnosis of sarcoma who were treated in a National Cancer Institute (NCI) designated center and determine compliance rates with guidelines for sarcoma.

Aim: To evaluate our compliance of NCCN sarcoma guidelines at a major NCI designated center and to report instances of deviation that could be used for future studies to improve patient care.

Methods: Data was collected retrospectively as an internal review and quality assessment of 35 newly diagnosed and treated patients. Demographic data were recorded and information concerning whether patients had appropriate imaging, biopsy and management. Variables of interest were expressed as raw numbers and percentages.

Results: Primary site imaging was obtained in 100% of cases. Chest and full-body imaging were obtained in 97% and 100% of indicated cases, respectively. Tissue was obtained preoperatively in 97% of cases. Imaging was reviewed at multidisciplinary Treatment Planning Conference (TPC) in 97% of cases. Pathology was reviewed in 94% of cases in TPC. Both tumor, node, metastasis staging and plan of care were reviewed in 100% of cases in TPC. Treatment guidelines were followed in 94% of cases reviewed.

Conclusion: This study evaluated the workup and treatment provided by a single NCI designated sarcoma service to a series of patients with pathologies defined with the NCCN sarcoma treatment guidelines. Although adherence to NCCN was reported to be very high future prospective studies are required to investigate whether NCCN guidelines impact patient outcomes.
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http://dx.doi.org/10.5306/wjco.v11.i6.389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450813PMC
June 2020

Philosophy Problems Become Real During the COVID-19 Pandemic.

J Bone Joint Surg Am 2020 08;102(15):e88

The Ohio State University, Columbus, Ohio.

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http://dx.doi.org/10.2106/JBJS.20.00512DOI Listing
August 2020

Pathological response in children and adults with large unresected intermediate-grade or high-grade soft tissue sarcoma receiving preoperative chemoradiotherapy with or without pazopanib (ARST1321): a multicentre, randomised, open-label, phase 2 trial.

Lancet Oncol 2020 08 20;21(8):1110-1122. Epub 2020 Jul 20.

Department of Radiation Oncology, Rush University Medical Center, Chicago, IL, USA.

Background: Outcomes for children and adults with advanced soft tissue sarcoma are poor with traditional therapy. We investigated whether the addition of pazopanib to preoperative chemoradiotherapy would improve pathological near complete response rate compared with chemoradiotherapy alone.

Methods: In this joint Children's Oncology Group and NRG Oncology multicentre, randomised, open-label, phase 2 trial, we enrolled eligible adults (aged ≥18 years) and children (aged between 2 and <18 years) from 57 hospitals in the USA and Canada with unresected, newly diagnosed trunk or extremity chemotherapy-sensitive soft tissue sarcoma, which were larger than 5 cm in diameter and of intermediate or high grade. Eligible patients had Lansky (if aged ≤16 years) or Karnofsky (if aged >16 years) performance status score of at least 70. Patients received ifosfamide (2·5 g/m per dose intravenously on days 1-3 with mesna) and doxorubicin (37·5 mg/m per dose intravenously on days 1-2) with 45 Gy preoperative radiotherapy, followed by surgical resection at week 13. Patients were randomly assigned (1:1) using a web-based system, in an unmasked manner, to receive oral pazopanib (if patients <18 years 350 mg/m once daily; if patients ≥18 years 600 mg once daily) or not (control group), with pazopanib not given immediately before or after surgery at week 13. The study projected 100 randomly assigned patients were needed to show an improvement in the number of participants with a 90% or higher pathological response at week 13 from 40% to 60%. Analysis was done per protocol. This study has completed accrual and is registered with ClinicalTrials.gov, NCT02180867.

Findings: Between July 7, 2014, and Oct 1, 2018, 81 eligible patients were enrolled and randomly assigned to the pazopanib group (n=42) or the control group (n=39). At the planned second interim analysis with 42 evaluable patients and a median follow-up of 0·8 years (IQR 0·3-1·6) in the pazopanib group and 1 year (0·3-1·6) in the control group, the number of patients with a 90% pathological response or higher was 14 (58%) of 24 patients in the pazopanib group and four (22%) of 18 patients in the control group, with a between-group difference in the number of 90% or higher pathological response of 36·1% (83·8% CI 16·5-55·8). On the basis of an interim analysis significance level of 0·081 (overall one-sided significance level of 0·20, power of 0·80, and O'Brien-Fleming-type cumulative error spending function), the 83·8% CI for response difference was between 16·5% and 55·8% and thus excluded 0. The improvement in pathological response rate with the addition of pazopanib crossed the predetermined boundary and enrolment was stopped. The most common grade 3-4 adverse events were leukopenia (16 [43%] of 37 patients), neutropenia (15 [41%]), and febrile neutropenia (15 [41%]) in the pazopanib group, and neutropenia (three [9%] of 35 patients) and febrile neutropenia (three [9%]) in the control group. 22 (59%) of 37 patients in the pazopanib group had a pazopanib-related serious adverse event. Paediatric and adult patients had a similar number of grade 3 and 4 toxicity. There were seven deaths (three in the pazopanib group and four in the control group), none of which were treatment related.

Interpretation: In this presumed first prospective trial of soft tissue sarcoma spanning nearly the entire age spectrum, adding pazopanib to neoadjuvant chemoradiotherapy improved the rate of pathological near complete response, suggesting that this is a highly active and feasible combination in children and adults with advanced soft tissue sarcoma. The comparison of survival outcomes requires longer follow-up.

Funding: National Institutes of Health, St Baldrick's Foundation, Seattle Children's Foundation.
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http://dx.doi.org/10.1016/S1470-2045(20)30325-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745646PMC
August 2020

Manipulation of low-level features modulates grouping strength of auditory objects.

Psychol Res 2020 Jul 20. Epub 2020 Jul 20.

Department of Biomedical Engineering, Medical College of Wisconsin & Marquette University, Milwaukee, USA.

A central challenge of auditory processing involves the segregation, analysis, and integration of acoustic information into auditory perceptual objects for processing by higher order cognitive operations. This study explores the influence of low-level features on auditory object perception. Participants provided perceived musicality ratings in response to randomly generated pure tone sequences. Previous work has shown that music perception relies on the integration of discrete sounds into a holistic structure. Hence, high (versus low) ratings were viewed as indicative of strong (versus weak) object formation. Additionally, participants rated sequences in which random subsets of tones were manipulated along one of three low-level dimensions (timbre, amplitude, or fade-in) at one of three strengths (low, medium, or high). Our primary findings demonstrate how low-level acoustic features modulate the perception of auditory objects, as measured by changes in musicality ratings for manipulated sequences. Secondarily, we used principal component analysis to categorize participants into subgroups based on differential sensitivities to low-level auditory dimensions, thereby highlighting the importance of individual differences in auditory perception. Finally, we report asymmetries regarding the effects of low-level dimensions; specifically, the perceptual significance of timbre. Together, these data contribute to our understanding of how low-level auditory features modulate auditory object perception.
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http://dx.doi.org/10.1007/s00426-020-01391-4DOI Listing
July 2020

Role of (Neo)adjuvant Denosumab for Giant Cell Tumor of Bone.

Curr Treat Options Oncol 2020 07 4;21(8):68. Epub 2020 Jul 4.

Orthopaedic Surgery, UC Davis, Sacramento, USA.

Opinion Statement: Denosumab is a RANK ligand inhibitor approved for the treatment of giant cell tumor of bone. While the role of denosumab in the setting of advanced and unresectable disease is well established, its role in surgically resectable disease is currently under discussion. Several prospective and retrospective series on neoadjuvant therapy in potentially resectable tumor with high morbidity surgery reported a relapse rate of 10-20% after resection and 30-40% after curettage. At the same time, less morbid surgery has obvious clinical advantages for the patient, and several studies have shown the efficacy of denosumab in downgrading of the surgical procedure. Currently, the role of neoadjuvant denosumab in operable GCTB is limited to selected cases in which a diffuse reactive bone formation and peripheral ossification can make an easier surgical procedure, for example, in tumors with a large soft tissue component. A planned resection may become less morbid when preoperative denosumab is administered. Whenever a segmental resection is thought to be indicated at diagnosis, denosumab may be considered in the neoadjuvant setting. A preoperative course of 6 months is considered safe and effective. Two case scenarios are presented and critically discussed. Because of the high recurrence rates after denosumab treatment followed by curettage, we discourage the use of denosumab when curettage is considered feasible. In this setting, a short course of preoperative denosumab (2-6 months) may be considered for highly selected cases, for example in pathological fractures. The role of adjuvant denosumab needs further investigation. Long-term disease control has been reported in case of non-surgical lesions, even after treatment interruption, but there is no consensus on ideal treatment duration and dosage for these scenarios. In all cases, multidisciplinary discussion with oncology, pathologist, radiologist, and surgeons is mandatory. Patient's comorbidities, dental conditions, and preferences, including family planning, should always be taken into account.
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http://dx.doi.org/10.1007/s11864-020-00766-4DOI Listing
July 2020

Opportunistic muscle measurements on staging chest CT for extremity and truncal soft tissue sarcoma are associated with survival.

J Surg Oncol 2020 Oct 1;122(5):869-876. Epub 2020 Jul 1.

Department of Radiology, Stanford University, Stanford, California.

Background And Objectives: Computed tomography (CT) measurements of sarcopenia have been proposed as biomarkers associated with outcomes in various cancers and have typically been evaluated at the L3 vertebral level. However, staging imaging for patients with extremity and truncal soft tissue sarcoma (STS) often only includes chest CT imaging which precludes evaluation at L3. Therefore, we sought to evaluate muscle metrics at T12 on standard staging chest CT scans and evaluate for correlation with overall and event-free survival in patients with STS.

Methods: CT chest imaging for 89 patients with intermediate and high-grade STS (53 male, 36 female; 58.5 ± 19.0 years old, follow-up 37.4 ± 27.1 months) was reviewed on PACS at T12 for skeletal muscle density (SMD) and skeletal muscle index (SMI).

Results: Overall survival increased with increased SMD on univariate (hazard ratio [HR] = 0.61 [0.43, 0.86]) and age-adjusted analysis (HR = 0.65 [0.42, 0.89]. Event-free survival also increased with increased SMD in univariate analyses (HR = 0.68 [0.49, 0.95]) but did not maintain significance after adjusting for age (HR = 0.68 [0.43, 1.07]). SMI was not a predictor of overall or event-free survival.

Conclusions: Higher SMD measured on routinely obtained staging chest CTs in STS patients is associated with improved survival.
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http://dx.doi.org/10.1002/jso.26077DOI Listing
October 2020

What's Important: Being Yourself, Even Under Stress.

J Bone Joint Surg Am 2020 12;102(23):2106-2108

Orthopaedic Institute for Children, University of California Los Angeles, Los Angeles, California.

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http://dx.doi.org/10.2106/JBJS.20.00250DOI Listing
December 2020

Direct Antiviral Activity of IFN-Stimulated Genes Is Responsible for Resistance to Paramyxoviruses in ISG15-Deficient Cells.

J Immunol 2020 07 18;205(1):261-271. Epub 2020 May 18.

Biomedical Sciences Research Complex, School of Biology, University of St Andrews, St Andrews KY16 9ST, United Kingdom; and

IFNs, produced during viral infections, induce the expression of hundreds of IFN-stimulated genes (ISGs). Some ISGs have specific antiviral activity, whereas others regulate the cellular response. Besides functioning as an antiviral effector, ISG15 is a negative regulator of IFN signaling, and inherited ISG15 deficiency leads to autoinflammatory IFNopathies, in which individuals exhibit elevated ISG expression in the absence of pathogenic infection. We have recapitulated these effects in cultured human A549-ISG15 cells and (using A549-UBA7 cells) confirmed that posttranslational modification by ISG15 (ISGylation) is not required for regulation of the type I IFN response. ISG15-deficient cells pretreated with IFN-α were resistant to paramyxovirus infection. We also showed that IFN-α treatment of ISG15-deficient cells led to significant inhibition of global protein synthesis, leading us to ask whether resistance was due to the direct antiviral activity of ISGs or whether cells were nonpermissive because of translation defects. We took advantage of the knowledge that IFN-induced protein with tetratricopeptide repeats 1 (IFIT1) is the principal antiviral ISG for parainfluenza virus 5. Knockdown of IFIT1 restored parainfluenza virus 5 infection in IFN-α-pretreated, ISG15-deficient cells, confirming that resistance was due to the direct antiviral activity of the IFN response. However, resistance could be induced if cells were pretreated with IFN-α for longer times, presumably because of inhibition of protein synthesis. These data show that the cause of virus resistance is 2-fold; ISG15 deficiency leads to the early overexpression of specific antiviral ISGs, but the later response is dominated by an unanticipated, ISG15-dependent loss of translational control.
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http://dx.doi.org/10.4049/jimmunol.1901472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311202PMC
July 2020

Innate Intracellular Antiviral Responses Restrict the Amplification of Defective Virus Genomes of Parainfluenza Virus 5.

J Virol 2020 06 16;94(13). Epub 2020 Jun 16.

School of Biology, Centre for Biomolecular Sciences, University of St. Andrews, St. Andrews, United Kingdom

During the replication of parainfluenza virus 5 (PIV5), copyback defective virus genomes (DVGs) are erroneously produced and are packaged into "infectious" virus particles. Copyback DVGs are the primary inducers of innate intracellular responses, including the interferon (IFN) response. While DVGs can interfere with the replication of nondefective (ND) virus genomes and activate the IFN-induction cascade before ND PIV5 can block the production of IFN, we demonstrate that the converse is also true, i.e., high levels of ND virus can block the ability of DVGs to activate the IFN-induction cascade. By following the replication and amplification of DVGs in A549 cells that are deficient in a variety of innate intracellular antiviral responses, we show that DVGs induce an uncharacterized IFN-independent innate response(s) that limits their replication. High-throughput sequencing was used to characterize the molecular structure of copyback DVGs. While there appears to be no sequence-specific break or rejoining points for the generation of copyback DVGs, our findings suggest there are region, size, and/or structural preferences selected for during for their amplification. Copyback defective virus genomes (DVGs) are powerful inducers of innate immune responses both and They impact the outcome of natural infections, may help drive virus-host coevolution, and promote virus persistence. Due to their potent interfering and immunostimulatory properties, DVGs may also be used therapeutically as antivirals and vaccine adjuvants. However, little is known of the host cell restrictions which limit their amplification. We show here that the generation of copyback DVGs readily occurs during parainfluenza virus 5 (PIV5) replication, but that their subsequent amplification is restricted by the induction of innate intracellular responses. Molecular characterization of PIV5 copyback DVGs suggests that while there are no genome sequence-specific breaks or rejoin points for the generation of copyback DVGs, genome region, size, and structural preferences are selected for during their evolution and amplification.
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http://dx.doi.org/10.1128/JVI.00246-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7307174PMC
June 2020

What factors influence patient experience in orthopedic oncology office visits?

World J Clin Oncol 2020 Mar;11(3):136-142

Department of Orthopaedic Surgery, University of California-Davis Medical Center, Sacramento, CA 95817, United States.

Background: Patient satisfaction and reported outcomes are becoming increasingly important in determining the efficacy of clinical care. To date no study has evaluated the patient experience in the orthopedic oncology outpatient setting to determine which factors of the encounter are priorities to the patient.

Aim: To evaluate what factors impact patient experience and report satisfaction in an outpatient orthopedic oncology clinic.

Methods: Press Ganey patient surveys from a single outpatient orthopedic oncology clinic at a tertiary care setting were prospectively collected per routine medical care. All orthopedic oncology patients who were seen in clinic and received electronic survey were included. All survey responses were submitted within one month of clinic appointment. IRB approval was obtained to retrospectively collect survey responses from 2015 to 2016. Basic demographic data along with survey category responses were collected and statistically analyzed.

Results: One hundred sixty-two patient surveys were collected. Average patient age was 54.4 years (SD = 16.2 years) and were comprised of 51.2% female and 48.4% male. 64.2% of patients were from in-state. Out of state residents were more likely to recommend both the practice and attending physician. The likelihood to recommend attending physician was positively associated with MD friendliness/courtesy (OR = 14.4, 95%CI: 2.5-84.3), MD confidence (OR = 48.2, 95%CI: 6.2-376.5), MD instructions follow-up care (OR = 2.5, 95%CI: 0.4-17.4), and sensitivity to needs (OR = 16.1, 95%CI: 1-262.5). Clinic operations performed well in the categories of courtesy of staff (76%) and cleanliness (75%) and less well in ease of getting on the phone (49%), information about delays (36%), and wait time (37%).

Conclusion: Orthopedic specialties can utilize information from this study to improve care from the patient perspective. Future studies may be directed at how to improve these areas of care which are most valued by the patient.
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http://dx.doi.org/10.5306/wjco.v11.i3.136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7103527PMC
March 2020

Chronic urticaria in the real-life clinical practice setting in the UK: results from the noninterventional multicentre AWARE study.

Clin Exp Dermatol 2020 Dec 26;45(8):1003-1010. Epub 2020 Aug 26.

Centre for Dermatology, Salford Royal Hospital, Salford, UK.

Background: Chronic urticaria (CU) is a skin condition characterized by repeated occurrence of itchy weals and/or angio-oedema for > 6 weeks.

Aim: To provide data demonstrating the real-life burden of CU in the UK.

Methods: This UK subset of the worldwide, prospective, noninterventional AWARE study included patients aged 18-75 years diagnosed with H1-antihistamine (H1-AH)-refractory chronic spontaneous urticaria (CSU) for > 2 months. Baseline characteristics, disease activity, treatments, comorbidities and healthcare resource use were documented. Quality of life (QoL), work productivity and activity impairment were assessed.

Results: Baseline analysis included 252 UK patients. Mean age and body mass index were 45.0 years and 29.0 kg/m , respectively. Most patients were female (77.8%) and had moderate/severe disease activity (mean Urticaria Activity Score over 7 days was 18.4) and a 'spontaneous' component to their CU (73.4% CSU; 24.6% CSU and chronic inducible urticaria). Common comorbidities included depression/anxiety (24.6%), asthma (23.8%) and allergic rhinitis (12.7%). A previous treatment was recorded for 57.9% of patients. Mean Dermatology Life Quality Index score was 9.5, and patients reported impairments in work productivity and activity. Healthcare resource use was high. Severity of CSU was associated with female sex, obesity, anxiety and diagnosis. Only 28.5% of patients completed all nine study visits, limiting analysis of long-term treatment patterns and disease impact.

Conclusions: Adult H1-AH-refractory patients with CU in the UK reported high rates of healthcare resource use and impairment in QoL, work productivity and activity at baseline. The differing structures of UK healthcare may explain the high study discontinuation rates versus other countries.
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http://dx.doi.org/10.1111/ced.14230DOI Listing
December 2020

Polyostotic osteoid osteoma: A case report.

Radiol Case Rep 2020 Apr 8;15(4):411-415. Epub 2020 Feb 8.

Department of Radiology, University of California Davis Medical Center, 4860 Y Street, Suite 3100, Sacramento, CA 95817, USA.

Osteoid osteomas are common, benign osteoblastic tumors that can occur in any bone in the body. They are almost always solitary, with only rare reports of multiple tumors in the same patient. When multiple, they typically are found within the same bone. We present a unique case of a young female athlete who presented initially at 16 years old with a right tibial osteoid osteoma and later at 18 years old with a right acetabular osteoid osteoma. Our case demonstrates the rare entity of polyostotic osteoid osteoma, the potential limitations of MRI in the diagnosis of osteoid osteoma, and the utility of radiofrequency ablation in the treatment of osteoid osteoma.
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http://dx.doi.org/10.1016/j.radcr.2020.01.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7015827PMC
April 2020

Bone Tumors and Reconstructive Options in Pediatric and Young Adult Patients.

Instr Course Lect 2019 ;68:613-626

Sarcomas represent less than 1% of adult cancers but account for approximately 21% of pediatric malignancies and pose great risks for mortality and morbidity in children and young adults. Both benign bone and soft-tissue tumors may not be life-threatening but can be limb-threatening. Missed diagnosis, misdiagnosis, and mismanagement of either benign or malignant tumors may lead to increased mortality and morbidity. A good understanding of the clinical presentation, radiographic findings, and treatment options is needed to make the proper diagnosis and successfully treat these patients. Children and young adults present unique challenges in the management these tumors. Often, there is no right or wrong answer. Surgeons must work with patients and their families to make the right reconstructive decision.
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February 2020

Patient and public involvement facilitators: Could they be the key to the NHS quality improvement agenda?

Health Expect 2020 04 5;23(2):461-472. Epub 2020 Feb 5.

Centre for Professional Work & Society, School of Business & Economics, Loughborough University, Loughborough, UK.

Objective: Research into patient and public involvement (PPI) has not examined in detail patient and public involvement facilitators' (PPIFs) roles and activities. This study analysed PPIFs' roles using qualitative data gathered from three different UK health-care organizations.

Design: Thematic analysis was used to examine cross-sectional data collected using a mixed-methods approach from three organizations: a mental health trust, a community health social enterprise and an acute hospital trust. The data set comprised of 27 interviews and 48 observations.

Findings: Patient and public involvement facilitators roles included the leadership and management of PPI interventions, developing health-care practices and influencing quality improvements (QI). They usually occupied middle-management grades but their PPIF role involved working in isolation or in small teams. They reported facilitating the development and maintenance of relationships between patients and the public, and health-care professionals and service managers. These roles sometimes required them to use conflict resolution skills and involved considerable emotional labour. Integrating information from PPI into service improvement processes was reported to be a challenge for these individuals.

Conclusions: Patient and public involvement facilitators capture and hold information that can be used in service improvement. However, they work with limited resources and support. Health-care organizations need to offer more practical support to PPIFs in their efforts to improve care quality, particularly by making their role integral to developing QI strategies.
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http://dx.doi.org/10.1111/hex.13023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104637PMC
April 2020

Perceptions of Stress: Patient and Caregiver Experiences With Stressors During Hospitalization.

Clin J Oncol Nurs 2020 02;24(1):51-57

Sanford Health.

Background: Hospitalization for a cancer diagnosis and treatment may trigger stressful experiences for patients and family caregivers.

Objectives: The purpose of this study was to identify patients' and caregivers' perceptions of stressors during hospitalization and evaluate their education needs.

Methods: A descriptive correlational research design was used to determine whether there is any correlation between the stress perceptions of patients and family caregivers and their need for additional education on health-related issues.

Findings: Patients reported experiencing mild to extreme stress for sleep deprivation, pain, tube and line restrictions, and financial issues. In addition to these stressors, family caregivers also perceived that waiting for test results was a main reason for stress in patients. A positive significant correlation was found between the total sample mean stress scores of patients and their need for additional education on health-related issues.
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http://dx.doi.org/10.1188/20.CJON.51-57DOI Listing
February 2020

Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in .

Sci Immunol 2019 12;4(42)

Division of Evolution and Genomic Sciences, School of Biological Sciences, University of Manchester, Manchester, UK.

Excessive type I interferon (IFNα/β) activity is implicated in a spectrum of human disease, yet its direct role remains to be conclusively proven. We investigated two siblings with severe early-onset autoinflammatory disease and an elevated IFN signature. Whole-exome sequencing revealed a shared homozygous missense Arg148Trp variant in , a transcription factor that functions exclusively downstream of innate IFNs. Cells bearing STAT2 in homozygosity (but not heterozygosity) were hypersensitive to IFNα/β, which manifest as prolonged Janus kinase-signal transducers and activators of transcription (STAT) signaling and transcriptional activation. We show that this gain of IFN activity results from the failure of mutant STAT2 to interact with ubiquitin-specific protease 18, a key STAT2-dependent negative regulator of IFNα/β signaling. These observations reveal an essential in vivo function of STAT2 in the regulation of human IFNα/β signaling, providing concrete evidence of the serious pathological consequences of unrestrained IFNα/β activity and supporting efforts to target this pathway therapeutically in IFN-associated disease.
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http://dx.doi.org/10.1126/sciimmunol.aav7501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115903PMC
December 2019

A risk-based treatment strategy for non-rhabdomyosarcoma soft-tissue sarcomas in patients younger than 30 years (ARST0332): a Children's Oncology Group prospective study.

Lancet Oncol 2020 01 27;21(1):145-161. Epub 2019 Nov 27.

Seattle Children's Hospital, Seattle, WA, USA.

Background: Tumour grade, tumour size, resection potential, and extent of disease affect outcome in paediatric non-rhabdomyosarcoma soft-tissue sarcoma (NRSTS), but no risk stratification systems exist and the standard of care is poorly defined. We developed a risk stratification system from known prognostic factors and assessed it in the context of risk-adapted therapy for young patients with NRSTS.

Methods: In this prospective study, eligible patients enrolled in 159 hospitals in three countries were younger than 30 years, had a Lansky (patients ≤16 years) or Karnofsky (patients >16 years) performance status score of at least 50, and a new diagnosis of a WHO (2002 criteria) intermediate (rarely metastasising) or malignant soft-tissue tumour (apart from tumour types eligible for other Children's Oncology Group studies and tumours for which the therapy in this trial was deemed inappropriate), malignant peripheral nerve sheath tumour, non-metastatic and grossly resected dermatofibrosarcoma protuberans, undifferentiated embryonal sarcoma of the liver, or unclassified malignant soft-tissue sarcoma. Each patient was assigned to one of three risk groups and one of four treatment groups. Risk groups were: low (non-metastatic R0 or R1 low-grade, or ≤5 cm R1 high-grade tumour); intermediate (non-metastatic R0 or R1 >5 cm high-grade, or unresected tumour of any size or grade); or high (metastatic tumour). The treatment groups were surgery alone, radiotherapy (55·8 Gy), chemoradiotherapy (chemotherapy and 55·8 Gy radiotherapy), and neoadjuvant chemoradiotherapy (chemotherapy and 45 Gy radiotherapy, then surgery and radiotherapy boost based on margins with continued chemotherapy). Chemotherapy included six cycles of ifosfamide 3 g/m per dose intravenously on days 1-3 and five cycles of doxorubicin 37·5 mg/m per dose intravenously on days 1-2 every 3 weeks with sequence adjusted on the basis of timing of surgery or radiotherapy. The primary outcomes were event-free survival, overall survival, and the pattern of treatment failure. Analysis was done per protocol. This study has been completed and is registered with ClinicalTrials.gov, NCT00346164.

Findings: Between Feb 5, 2007, and Feb 10, 2012, 550 eligible patients were enrolled, of whom 21 were treated in the incorrect group and excluded from this analysis. 529 evaluable patients were included in the analysis: low-risk (n=222), intermediate-risk (n=227), high-risk (n=80); surgery alone (n=205), radiotherapy (n=17), chemoradiotherapy (n=111), and neoadjuvant chemoradiotherapy (n=196). At a median follow-up of 6·5 years (IQR 4·9-7·9), 5-year event-free survival and overall survival were: 88·9% (95% CI 84·0-93·8) and 96·2% (93·2-99·2) in the low-risk group; 65·0% (58·2-71·8) and 79·2% (73·4-85·0) in the intermediate-risk group; and 21·2% (11·4-31·1) and 35·5% (23·6-47·4) in the high-risk group, respectively. Risk group predicted event-free survival and overall survival (p<0·0001). No deaths from toxic events during treatment were reported. Nine patients had unexpected grade 4 adverse events (chemoradiotherapy group, n=2; neoadjuvant chemoradiotherapy group, n=7), including three wound complications that required surgery (all in the neoadjuvant chemoradiotherapy group).

Interpretation: Pre-treatment clinical features can be used to effectively define treatment failure risk and to stratify young patients with NRSTS for risk-adapted therapy. Most low-risk patients can be cured without adjuvant therapy, thereby avoiding known long-term treatment complications. Survival remains suboptimal for intermediate-risk and high-risk patients and novel therapies are needed.

Funding: National Institutes of Health, St Baldrick's Foundation, Seattle Children's Foundation, American Lebanese Syrian Associated Charities.
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http://dx.doi.org/10.1016/S1470-2045(19)30672-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946838PMC
January 2020

A Novel Method to Prevent Terminal Appositional Overgrowth Following Pediatric Below Knee Amputations A Case Series and Review of the Literature.

Bull Hosp Jt Dis (2013) 2019 Dec;77(4):269-274

The terminal overgrowth of the tibia following pediatric transtibial amputation is a common problem leading to pain, disability, and repeat surgical procedures. We present three patients who underwent transtibial amputation due to sarcoma of the lower extremity followed by compress osseointegration prosthesis fixation. The minimum follow-up was 1 year. The average age of patients was 10.8 years. There were no complications that required surgical revision. To date, there has been no evidence of terminal appositional overgrowth in this series. The application of an end-cap implant utilizing compressive osseointegration fixation can prevent terminal bone overgrowth in pediatric transtibial amputations.
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December 2019