Osteosarcoma PDX-Derived Cell Line Models for Preclinical Drug Evaluation Demonstrate Metastasis Inhibition by Dinaciclib through a Genome-Targeted Approach.

PURPOSE: Models to study metastatic disease in rare cancers are needed to advance preclinical therapeutics and to gain insight into disease biology. Osteosarcoma is a rare cancer with a complex genomic landscape in which outcomes for patients with metastatic disease are poor. As osteosarcoma genomes are highly heterogeneous, multiple models are needed to fully elucidate key aspects of disease biology and to recapitulate clinically relevant phenotypes. EXPERIMENTAL DESIGN: Matched patient samples, patient-derived xenografts (PDX), and PDX-derived cell lines were comprehensively evaluated using whole-genome sequencing and RNA sequencing. The in vivo metastatic phenotype of the PDX-derived cell lines was characterized in both an intravenous and an orthotopic murine model. As a proof-of-concept study, we tested the preclinical effectiveness of a cyclin-dependent kinase inhibitor on the growth of metastatic tumors in an orthotopic amputation model. RESULTS: PDXs and PDX-derived cell lines largely maintained the expression profiles of the patient from which they were derived despite the emergence of whole-genome duplication in a subset of cell lines. The cell lines were heterogeneous in their metastatic capacity, and heterogeneous tissue tropism was observed in both intravenous and orthotopic models. Single-agent dinaciclib was effective at dramatically reducing the metastatic burden. CONCLUSIONS: The variation in metastasis predilection sites between osteosarcoma PDX-derived cell lines demonstrates their ability to recapitulate the spectrum of the disease observed in patients. We describe here a panel of new osteosarcoma PDX-derived cell lines that we believe will be of wide use to the osteosarcoma research community.

Development and characterization of new patient-derived xenograft (PDX) models of osteosarcoma with distinct metastatic capacities.

Models to study metastatic disease in rare cancers are needed to advance preclinical therapeutics and to gain insight into disease biology, especially for highly aggressive cancers with a propensity for metastatic spread. Osteosarcoma is a rare cancer with a complex genomic landscape in which outcomes for patients with metastatic disease are poor. As osteosarcoma genomes are highly heterogeneous, a large panel of models is needed to fully elucidate key aspects of disease biology and to recapitulate clinically-relevant phenotypes. We describe the development and characterization of osteosarcoma patient-derived xenografts (PDXs) and a panel of PDX-derived cell lines. Matched patient samples, PDXs, and PDX-derived cell lines were comprehensively evaluated using whole genome sequencing and RNA sequencing. PDXs and PDX-derived cell lines largely maintained the expression profiles of the patient from which they were derived despite the emergence of whole-genome duplication (WGD) in a subset of cell lines. These cell line models were heterogeneous in their metastatic capacity and their tissue tropism as observed in both intravenous and orthotopic models. As proof-of-concept study, we used one of these models to test the preclinical effectiveness of a CDK inhibitor on the growth of metastatic tumors in an orthotopic amputation model. Single-agent dinaciclib was effective at dramatically reducing the metastatic burden in this model.

Cost-effectiveness of routine type and screens in select urological surgeries.

PURPOSE: To evaluate the cost-effectiveness of obtaining a preoperative type and screen (T/S) for common urologic procedures. METHODS: A decision tree model was constructed to track surgical patients undergoing two preoperative blood ordering strategies as follows: obtaining a preoperative T/S versus not doing so. The model was applied to the National (Nationwide) Inpatient Sample (NIS) data, from January 1, 2006 to September 30, 2015. Cost estimates for the model were created from combined patient-level data with published costs of a T/S, type and crossmatch (T/C), a unit of pRBC, and one unit of emergency-release transfusion (ERT). The primary outcome was the incremental cost per ERT prevented, expressed as an incremental cost-effectiveness ratio (ICER) between the two preoperative blood ordering strategies. A cost-effectiveness analysis determined the ICER of obtaining preoperative T/S to prevent an emergency-release transfusion (ERT), with a willingness-to-pay threshold of $1,500.00. RESULTS: A total of 4,113,144 surgical admissions from 2006 to 2015 were reviewed. The overall transfusion rate was 10.54% (95% CI, 10.17-10.91) for all procedures. The ICER of preoperative T/S was $1500.00 per ERT prevented. One-way sensitivity analysis demonstrated that the risk of transfusion should exceed 4.12% to justify preoperative T/S. CONCLUSION: Routine preoperative T/S for radical prostatectomy (rate = 3.88%) and penile implants (rate = .91%) does not represent a cost-effective practice for these surgeries. It is important for urologists to review their institution T/S policy to reduce inefficiencies within the preoperative setting.

Cost-Effectiveness of Routine Type and Screens in Select Endonasal Skull Base Surgeries.

Objective The study aimed to evaluate the cost-effectiveness of obtaining preoperative type and screens (T/S) for common endonasal skull base procedures, and determine patient and hospital factors associated with receiving blood transfusions. Study Design Retrospective database analysis of the 2006 to 2015 National (nationwide) Inpatient Sample and cost-effectiveness analysis. Main Outcome Measures Multivariate regression analysis was used to identify factors associated with transfusions. A cost-effectiveness analysis was then performed to determine the incremental cost-effectiveness ratio (ICER) of obtaining preoperative T/S to prevent an emergency-release transfusion (ERT), with a willingness-to-pay threshold of $1,500. Results A total of 93,105 cases were identified with an overall transfusion rate of 1.89%. On multivariate modeling, statistically significant factors associated with transfusion included nonelective admission (odds ratio [OR]: 2.32; 95% confidence interval [CI]: 1.78-3.02), anemia (OR: 4.42; 95% CI: 3.35-5.83), coagulopathy (OR: 4.72; 95% CI: 2.94-7.57), diabetes (OR: 1.45; 95% CI: 1.14-1.84), liver disease (OR: 2.37; 95% CI: 1.27-4.43), pulmonary circulation disorders (OR: 3.28; 95% CI: 1.71-6.29), and metastatic cancer (OR: 5.85; 95% CI: 2.63-13.0; p < 0.01 for all). The ICER of preoperative T/S was $3,576 per ERT prevented. One-way sensitivity analysis demonstrated that the risk of transfusion should exceed 4.12% to justify preoperative T/S. Conclusion Routine preoperative T/S does not represent a cost-effective practice for these surgeries using nationally representative data. A selective T/S policy for high-risk patients may reduce costs.

Cost-Effectiveness of Open vs. Endoscopic Repair of Zenker's Diverticulum.

OBJECTIVE: To evaluate the cost-effectiveness of open versus endoscopic surgical repair of Zenker's diverticulum. METHODS: In this study, an economic decision tree was utilized to compare the cost-effectiveness of open surgery compared to endoscopic surgery. The primary outcome in this analysis was the incremental cost-effectiveness ratio (ICER) that was calculated based on the economic decision tree. The probability of post-operative esophageal perforation complications, revision rates, and effectiveness of each procedure along with associated costs were extracted to construct the decision tree. Univariate sensitivity analysis was then utilized to determine how changes in esophageal perforation rate affect the cost-effectiveness of each surgical approach. RESULTS: The ICER of open surgery for Zenker's diverticulum was $67 877, above most acceptable willingness to pay (WTP) thresholds. Additionally, if the probability of esophageal perforation with endoscopic surgery is above 5%, then open surgery becomes a more cost-effective option. Probabilistic sensitivity analysis using Monte Carlo simulations also showed that at the WTP thresholds of $30 000 and $50 000, endoscopic surgery is the most cost-effective method with 83.9% and 67.6% certainty, respectively. CONCLUSION: Open surgery and endoscopic surgery are 2 treatment strategies for Zenker's diverticulum that each have their own advantages and disadvantages that can complicate the decision-making process. With no previous cost-effectiveness analysis of open versus endoscopic surgery for Zenker's diverticulum, our results support the endoscopic approach at most common WTP thresholds. Particularly with the current focus on rising healthcare costs, our results can serve as an important adjunct to medical decision-making for patients undergoing treatment for Zenker's diverticulum.

A Comprehensive Circulating Tumor DNA Assay for Detection of Translocation and Copy-Number Changes in Pediatric Sarcomas.

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 (CNA). We analyzed 64 prospectively collected plasma samples from 17 patients with pediatric sarcoma. Translocations were detected in the pretreatment 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 pretreatment 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 CNAs in the plasma of patients with pediatric sarcoma. While we describe our experience in pediatric sarcomas, this approach can be applied to other tumors that are driven by structural variants.

Presentation and outcomes of chronic rhinosinusitis following liver and kidney transplant.

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.

Odontogenic sinusitis publication trends from 1990 to 2019: a systematic review.

PURPOSE: Odontogenic sinusitis (ODS) is underrepresented in the literature compared to other forms of rhinosinusitis, specifically in sinusitis guidelines and position statements. ODS publication characteristics could help explain why ODS has received less attention in sinusitis guidelines and position statements. The purpose of this study was to explore trends in the quantity and quality of ODS studies over 3 decades from 1990 to 2019. METHODS: A systematic review was performed to identify all ODS studies from 1990 to 2019. The following variables from all ODS studies were compared between and across the 3 decades: authors' specialties, journal specialties, authors' geographic origins (continents), study topics, study designs, and evidence levels. RESULTS: From 1990 to 2019, there were 254 ODS studies that met inclusion criteria. Numbers of publications increased each decade, with 161 being published from 2010 to 2019. Otolaryngologists and dental authors published over 75% of ODS studies each decade, with 60-75% of ODS articles being published in otolaryngology or dental journals. European and Asian authors published the most ODS studies each decade. Overall, 92-100% of ODS publications per decade were level 4 and 5 evidence, with no significant changes between or across decades. CONCLUSION: While numbers of ODS publications increased each decade from 1990 to 2019, evidence levels remained low without significant changes over time. Otolaryngologists and dental authors published the majority of ODS studies each decade, with a minority of these studies being multidisciplinary. More ODS studies are needed across all aspects of the condition, and future projects would benefit from improved study designs and multidisciplinary collaboration.

Acute epiglottitis: Analysis of U.S. mortality trends from 1979 to 2017.

PURPOSE: Evaluate trends in mortality due to acute epiglottitis before and after adoption of Haemophilus influenza Type b vaccination (Hib) in pediatric and adult populations. MATERIALS AND METHODS: Patients who died from acute epiglottis from 1979 to 2017 identified using National Vital Statistics System. Mortality rates calculated using age-adjusted US census data expressed in rate per 100,000 individuals. Trends analyzed using the National Cancer Institute Joinpoint Regression Program (version 4.7.0; Bethesda, Maryland). RESULTS: 1187 epiglottitis-related deaths were identified over thirty-nine years. Total deaths decreased from 65 in 1979 to 15 in 2017. Adult deaths accounted for 63.5% and decreased from 0.015 per 100,000 individuals (24 deaths) in 1979 to 0.006 per 100,000 individuals (14 deaths) in 2017. Best fitting log-liner regression model showed APC of -3.5% (95% CI, -4.2 to -2.7%) from 1979 to 2017. Pediatric and adolescent deaths accounted for 443 (37.3%) deaths, decreasing from 0.064 per 100,000 individuals (41 deaths) in 1979 to 0.001 per 100,000 individuals (1 death) in 2017. APC was -11.1% (95% CI, -13.8% to -8.3%) in 1979 to 1990; 46.5% (95% CI, -16.6% to 157.3%) in 1990 to 1993; -61.6% (95% CI, -88% to 23%) in 1993 to 1996; and 1.1% (95% CI, -2.4% to 4.7%) in 1996 to 2017. CONCLUSIONS: Mortality from acute epiglottitis decreased after widespread adoption of Hib vaccination in the US. Adults are now more likely than children to die of acute epiglottitis. Further research including multi-institutional cohort studies must be done to elucidate causative factors contributing to remaining cases of mortality.

Tracheal Resection in the Management of Thyroid Cancer: An Evidence-Based Approach.

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; I2 = 1.85%) airway complications, 2.8% (CI 1.6-3.9; P < .001; I2 = 13.34%) bilateral recurrent laryngeal nerve paralysis, 2.2% (CI 1.2-3.1; P < .001; I2 = 6.72%) anastomotic dehiscence. Circumferential resection pooled estimates major complications, locoregional recurrence, distal recurrence, overall survival: 14.1% (CI 8.3-19.9; P < .001; I2 = 35.26%), 15% (CI 9.6-20.3; P < .001; I2 = 38.2%), 19.7% (CI 13.7-25.8; P < .001; I2 = 28.83%), 74.5% (CI 64.4-84.6; P < .001; I2 = 85.07%). Window resection estimates: 19.8% (CI 6.9-32.8; P < .001; I2 = 18.83%) major complications, 25.6% (CI 5.1-46.1; P < .014; I2 = 84.68%) locoregional recurrence, 15.6% (CI 9.7-21.5; P < .001; I2 = 0%) distal recurrence, 77.1% (CI 58-96.2; P < .001; I2 = 78.77%) overall survival. CONCLUSION: Management of invasive thyroid carcinoma may require tracheal resection to achieve locoregional control. Nevertheless, postoperative complications are not insignificant, and therefore this risk cannot be overlooked when counseling patients perioperatively. Laryngoscope, 131:932-946, 2021.

An internally validated diagnostic tool for acute invasive fungal sinusitis.

BACKGROUND: Acute 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. METHODS: Retrospective 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. RESULTS: A 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). CONCLUSION: We 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.

Comparative Tumor RNA Sequencing Analysis for Difficult-to-Treat Pediatric and Young Adult Patients With Cancer.

Importance: Pediatric cancers are epigenetic diseases; therefore, considering tumor gene expression information is necessary for a complete understanding of the tumorigenic processes. Objective: To evaluate 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. Design, Setting, and Participants: This cohort study was conducted as a consortium between the University of California, Santa Cruz (UCSC) Treehouse Childhood Cancer Initiative and clinical genomic trials. RNA sequencing (RNA-Seq) data were obtained from the following 4 clinical sites and analyzed at UCSC: British Columbia Children's Hospital (n = 31), Lucile Packard Children's Hospital at Stanford University (n = 80), CHOC Children's Hospital and Hyundai Cancer Institute (n = 46), and the Pacific Pediatric Neuro-Oncology Consortium (n = 24). The study dates were January 1, 2016, to March 22, 2017. Exposures: Participants underwent tumor RNA-Seq profiling as part of 4 separate clinical trials at partner hospitals. The UCSC either downloaded RNA-Seq data from a partner institution for analysis in the cloud or provided a Docker pipeline that performed the same analysis at a partner institution. The UCSC then compared each participant's tumor RNA-Seq profile with more than 11 000 uniformly analyzed tumor profiles from pediatric and young adult patients with cancer, downloaded from public data repositories. These comparisons were used to identify genes and pathways that are significantly overexpressed in each patient's tumor. Results of the UCSC analysis were presented to clinical partners. Main Outcomes and Measures: Feasibility of a third-party institution (UCSC Treehouse Childhood Cancer Initiative) to obtain tumor RNA-Seq data from patients, conduct comparative analysis, and present analysis results to clinicians; and proportion of patients for whom comparative tumor gene expression analysis provided useful clinical and biological information. Results: Among 144 samples from children and young adults (median age at diagnosis, 9 years; range, 0-26 years; 72 of 118 [61.0%] male [26 patients sex unknown]) with a relapsed, refractory, or rare cancer treated on precision medicine protocols, RNA-Seq-derived gene expression was potentially useful for 99 of 144 samples (68.8%) compared with DNA mutation information that was potentially useful for only 34 of 74 samples (45.9%). Conclusions and Relevance: This study's findings suggest that tumor RNA-Seq comparisons may be feasible and highlight the potential clinical utility of incorporating such comparisons into the clinical genomic interpretation framework for difficult-to-treat pediatric and young adult patients with cancer. The study also highlights for the first time to date the potential clinical utility of harmonized publicly available genomic data sets.

Genome-Informed Targeted Therapy for Osteosarcoma.

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 identified, 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-specific candidate drivers, we used a simple heuristic based on degree and rank order of copy-number amplification (identified by whole-genome sequencing) and changes in gene expression as identified by RNA sequencing. Using patient-derived tumor xenografts, we demonstrate that targeting of patient-specific SCNAs leads to significant 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-specific dependencies could be identified 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 article is highlighted in the In This Issue feature, p. 1.