Osteosarcoma is a highly aggressive cancer for which treatment has remained essentially unchanged for more than 30 years. Osteosarcoma is characterized by widespread and recurrent somatic copy-number alterations (SCNA) and structural rearrangements. In contrast, few recurrent point mutations in protein-coding genes have been identifi ed, suggesting that genes within SCNAs are key oncogenic drivers in this disease. SCNAs and structural rearrangements are highly heterogeneous across osteosarcoma cases, suggesting the need for a genome-informed approach to targeted therapy. To identify patient-specifi c candidate drivers, we used a simple heuristic based on degree and rank order of copy-number amplifi cation (identifi ed by whole-genome sequencing) and changes in gene expression as identifi ed by RNA sequencing. Using patient-derived tumor xenografts, we demonstrate that targeting of patient-specifi c SCNAs leads to signifi cant decrease in tumor burden, providing a road map for genome-informed treatment of osteosarcoma. SIGNIFICANCE: Osteosarcoma is treated with a chemotherapy regimen established 30 years ago. Although osteosarcoma is genomically complex, we hypothesized that tumor-specifi c dependencies could be identifi ed within SCNAs. Using patient-derived tumor xenografts, we found a high degree of response for "genome-matched" therapies, demonstrating the utility of a targeted genome-informed approach.

This cohort study evaluates the feasibility and utility of incorporating comparative gene expression information into the precision medicine framework for difficult-to-treat pediatric and young adult patients with cancer.

Most circulating tumor DNA (ctDNA) assays are designed to detect recurrent mutations.Pediatric sarcomas share few recurrent mutations but rather are characterized by translocations and copy number changes. We applied CAncer Personalized Profiling by deep Sequencing (CAPP-Seq) for detection of translocations found in the most common pediatric sarcomas. We also applied ichorCNA to the combined off-target reads from our hybrid capture to simultaneously detect copy number alterations. We analyzed 64 prospectively collected plasma samples from 17 pediatric sarcoma patients.Translocations were detected in the pre-treatment plasma of 13 patients and were confirmed by tumor sequencing in 12 patients. Two of these patients had evidence of complex chromosomal rearrangements in their ctDNA. We also detected copy number changes in the pre-treatment plasma of 7 patients. We found that ctDNA levels correlated with metastatic status and clinical response. Furthermore, we detected rising ctDNA levels before relapse was clinically apparent, demonstrating the high sensitivity of our assay. This assay can be utilized for simultaneous detection of translocations and copy number alterations in the plasma of pediatric sarcoma patients. While we describe our experience in pediatric sarcomas, this approach can be applied to other tumors that are driven by structural variants.

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BackgroundAcute invasive fungal sinusitis (AIFS) is a potentially life‐threatening diagnosis in immunocompromised patients. Identifying patients who could benefit from evaluation and intervention can be challenging for referring providers and otolaryngologists alike. We aimed to develop and validate an accessible diagnostic tool to estimate the probability of AIFS.MethodsRetrospective chart review from 1999 to 2017 identified all patients evaluated for possible AIFS at a tertiary care center. AIFS was diagnosed by pathologic confirmation of fungal tissue angioinvasion. Stepwise selection and univariate logistic regression were used to screen risk factors for a multivariable predictive model. Model performance was assessed using Tukey's goodness‐of‐fit test and the area under the receiver operator characteristic curve (AUC). Model coefficients were internally validated using bootstrapping with 1000 iterations.ResultsA total of 283 patients (244 negative controls, 39 with AIFS) were included. Risk factors in our final diagnostic model included: fever ≥38°C (log‐odds ratio [LOR] 1.72; 95% CI, 0.53 to 2.90), unilateral facial swelling, pain, or erythema (LOR 2.84; 95% CI, 1.46 to 4.23), involvement of the orbit or pterygopalatine fossa on imaging (LOR 3.02; 95% CI, 1.78 to 4.26), and mucosal necrosis seen on endoscopy (LOR 5.52; 95% CI, 3.81 to 7.24), with p < 0.01 for all factors. The model had adequate goodness of fit (p > 0.05) and discrimination (AUC = 0.96).ConclusionWe present an internally validated diagnostic tool to stratify the risk for AIFS. The estimated risk may help determine which patients can be observed with serial nasal endoscopy, which ones could be biopsied, and which ones would benefit from immediate surgical intervention.

Objective This study aims to describe presenting characteristics of patients diagnosed with non-invasive chronic rhinosinusitis (CRS) following liver or kidney transplant and determine factors associated with disease-related complications, selection of endoscopic sinus surgery (ESS), and disease resolution in this population. Study design Retrospective chart review. Setting An academic tertiary care center (Mayo Clinic, Rochester, Minnesota). Subjects and methods Liver and kidney transplant recipients evaluated by Mayo Clinic otolaryngologists for CRS between 1998 and 2018 were identified. Univariate and multivariate logistic regression analyses were used to determine patient factors and treatment modalities associated with developing complications, selection of ESS, and disease resolution. Results Fifty-seven patients met inclusion criteria. No patients developed intraorbital or intracranial complications of their CRS. Multivariate modeling demonstrated that the presence of polyps ( P = 0.036) was associated with undergoing ESS within one year of presentation. A higher Lund–Mackay (LM) computed tomography score ( P = 0.023) and older age ( P = 0.018) were significantly associated with decreased disease resolution. No other factors were significantly associated with the use of endoscopic sinus surgery within one year of otolaryngology presentation or resolution of CRS in this cohort. Conclusion The risk of developing CRS-related intraorbital or intracranial complications in this immunecompromised patient cohort may be lower than originally thought. For liver- and kidney-recipients stable on immunosuppressive medication for many years, prognostic factors for CRS may mirror those for immunocompetent patients.

How to Cite this Article Spillinger A Park K Shenouda K Folbe AJ Endoscopic management of postradiation skull base osteoradionecrosis Int Forum Allergy Rhinol-Osteoradionecrosis (ORN) of the skull base is a rare but potentially life-threatening complication after radiotherapy in the treatment of nasopharyngeal carcinoma (NPC). It portends a poor prognosis, mainly due to risk of exsanguination from internal carotid artery (ICA) rupture. 1 Limited data exist regarding the use of conservative therapies, such as hyperbaric oxygen, tocopherol, and pentoxifylline, and surgery remains the mainstay treatment. 2,3 Despite the major role of surgery in managing skull base ORN, there exists a paucity of literature regarding experiences with endoscopic endonasal approaches. The objective of this study was to perform a systematic review and metaanalysis to synthesize experiences with endoscopic skull base surgery (ESBS) and determine resolution and complication rates.

Objective: Determine the effect of patient demographics and surgical approach on patient outcomes after tracheal resection in the management of thyroid cancer. Study Design: Systematic review and meta-analysis. Methods: Systematic review of literature was performed using PubMed, Embase, and Cochrane Library to identify patients with thyroid carcinoma who underwent tracheal resection. Pooled estimates for patient demographics, presenting findings, complications, and outcomes are determined using random-effects meta-analyses. Results: Ninety-six relevant studies encompassing 1,179 patients met inclusion criteria. Meta-analysis pooled rates of complications: 1.7% (confidence interval [CI] 0.8-2.5; P < .001; I 2 = 1.85%) airway complications, 2.8% (CI 1.6-3.9; P < .001; I 2 = 13.34%) bilateral recurrent laryngeal nerve paralysis, 2.2% (CI 1.2-3.1; P < .001; I 2 = 6.72%) anastomotic dehiscence. Circumferential resection pooled estimates major complications,