Quantification of cerebrospinal fluid tumor DNA in lung cancer patients with suspected leptomeningeal carcinomatosis.

Cerebrospinal fluid tumor-derived DNA (CSF-tDNA) analysis is a promising approach for monitoring the neoplastic processes of the central nervous system. We applied a lung cancer-specific sequencing panel (CAPP-Seq) to 81 CSF, blood, and tissue samples from 24 lung cancer patients who underwent lumbar puncture (LP) for suspected leptomeningeal disease (LMD). A subset of the cohort (N = 12) participated in a prospective trial of osimertinib for refractory LMD in which serial LPs were performed before and during treatment. CSF-tDNA variant allele fractions (VAFs) were significantly higher than plasma circulating tumor DNA (ctDNA) VAFs (median CSF-tDNA, 32.7%; median plasma ctDNA, 1.8%; P < 0.0001). Concentrations of tumor DNA in CSF and plasma were positively correlated (Spearman's ρ, 0.45; P = 0.03). For LMD diagnosis, cytology was 81.8% sensitive and CSF-tDNA was 91.7% sensitive. CSF-tDNA was also strongly prognostic for overall survival (HR = 7.1; P = 0.02). Among patients with progression on targeted therapy, resistance mutations, such as EGFR T790M and MET amplification, were common in peripheral blood but were rare in time-matched CSF, indicating differences in resistance mechanisms based on the anatomic compartment. In the osimertinib cohort, patients with CNS progression had increased CSF-tDNA VAFs at follow-up LP. Post-osimertinib CSF-tDNA VAF was strongly prognostic for CNS progression (HR = 6.2, P = 0.009). Detection of CSF-tDNA in lung cancer patients with suspected LMD is feasible and may have clinical utility. CSF-tDNA improves the sensitivity of LMD diagnosis, enables improved prognostication, and drives therapeutic strategies that account for spatial heterogeneity in resistance mechanisms.

Unraveling molecular advancements in chordoma tumorigenesis and treatment response: a review of scientific discoveries and clinical implications.

Chordomas are tumors thought to originate from notochordal remnants that occur in midline structures from the cloves of the skull base to the sacrum. In adults, the most common location is the sacrum, followed by the clivus and then mobile spine, while in children a clival origin is most common. Most chordomas are slow growing. Clinical presentation of chordomas tend to occur late, with local invasion and large size often complicating surgical intervention. Radiation therapy with protons has been proven to be an effective adjuvant therapy. Unfortunately, few adjuvant systemic treatments have demonstrated significant effectiveness, and chordomas tend to recur despite intensive multimodal care. However, insight into the molecular underpinnings of chordomas may guide novel therapeutic approaches including selection for immune and molecular therapies, individualized prognostication of outcomes, and real-time noninvasive assessment of disease burden and evolution. At the genomic level, elevated levels of brachyury stemming from duplications and mutations resulting in altered transcriptional regulation may introduce druggable targets for new surgical adjuncts. Transcriptome and epigenome profiling have revealed promoter- and enhancer-dependent mechanisms of protein regulation, which may influence therapeutic response and long-term disease history. Continued scientific and clinical advancements may offer further opportunities for treatment of chordomas. Single-cell transcriptome profiling has further provided insight into the heterogeneous molecular pathways contributing to chordoma propagation. New technologies such as spatial transcriptomics and emerging biochemical analytes such as cell-free DNA have further augmented the surgeon-clinician's armamentarium by facilitating detailed characterization of intra- and intertumoral biology while also demonstrating promise for point-of-care tumor quantitation and assessment. Recent and ongoing clinical trials highlight accelerating interest to translate laboratory breakthroughs in chordoma biology and immunology into clinical care. In this review, the authors dissect the landmark studies exploring the molecular pathogenesis of chordoma. Incorporating this into an outline of ongoing clinical trials and discussion of emerging technologies, the authors aimed to summarize recent advancements in understanding chordoma pathogenesis and how neurosurgical care of chordomas may be augmented by improvements in adjunctive treatments.

Distinct Hodgkin lymphoma subtypes defined by noninvasive genomic profiling.

The scarcity of malignant Hodgkin and Reed-Sternberg cells hampers tissue-based comprehensive genomic profiling of classic Hodgkin lymphoma (cHL). By contrast, liquid biopsies show promise for molecular profiling of cHL due to relatively high circulating tumour DNA (ctDNA) levels1-4. Here we show that the plasma representation of mutations exceeds the bulk tumour representation in most cases, making cHL particularly amenable to noninvasive profiling. Leveraging single-cell transcriptional profiles of cHL tumours, we demonstrate Hodgkin and Reed-Sternberg ctDNA shedding to be shaped by DNASE1L3, whose increased tumour microenvironment-derived expression drives high ctDNA concentrations. Using this insight, we comprehensively profile 366 patients, revealing two distinct cHL genomic subtypes with characteristic clinical and prognostic correlates, as well as distinct transcriptional and immunological profiles. Furthermore, we identify a novel class of truncating IL4R mutations that are dependent on IL-13 signalling and therapeutically targetable with IL-4Rα-blocking antibodies. Finally, using PhasED-seq5, we demonstrate the clinical value of pretreatment and on-treatment ctDNA levels for longitudinally refining cHL risk prediction and for detection of radiographically occult minimal residual disease. Collectively, these results support the utility of noninvasive strategies for genotyping and dynamic monitoring of cHL, as well as capturing molecularly distinct subtypes with diagnostic, prognostic and therapeutic potential.

Treatment Course and Outcomes of Intracranial Teratomas in Pediatric Patients: A Retrospective 15-Year Case Series Study.

INTRODUCTION: There is no standard treatment paradigm for intracranial teratomas, a rare subset of primary intracranial non-germinomatous germ cell tumors (NGGCT), which comprise less than 1% of pediatric brain tumors. This case series retrospectively analyzes treatment and outcomes of pediatric intracranial teratomas from a single institution. METHODS: Authors reviewed a comprehensive pathology database at Stanford's Lucile Packard Children's Hospital for intracranial teratomas in pediatric patients treated from 2006 to 2021; their demographics, treatment, and clinical course were analyzed. RESULTS: Among 14 patients, median follow-up time was 4.6 years and mean age at diagnosis was 10.5 years. Ten had elevated tumor markers and underwent chemotherapy as initial treatment for NGGCT. Ultimately, these patients all required surgery for progressive or residual disease. Two patients did not undergo radiation. After biopsy or resection, 8 patients had pure mature teratoma, five had mixed germ cell tumor with teratoma component, and one had immature teratoma. The patient with immature teratoma died during chemotherapy from septic shock. No patients experienced recurrence. Common sequelae were endocrine (42.8%) and eye movement (50.0%) abnormalities. DISCUSSION/CONCLUSION: We highlight the variable treatment course and outcome for pediatric patients with intracranial teratomas. Elevated tumor markers at presentation, along with imaging findings, favor chemotherapy initiation for presumed NGGCT. Resection of residual tumor is recommended even if tumor markers return to normal. Prognosis remains excellent; no patients had recurrence with a median follow-up of 4.6 years.

Tracing Founder Mutations in Circulating and Tissue-Resident Follicular Lymphoma Precursors.

Follicular lymphomas (FL) are characterized by BCL2 translocations, often detectable in blood years before FL diagnosis, but also observed in aging healthy individuals, suggesting additional lesions are required for lymphomagenesis. We directly characterized early cooperating mutations by ultradeep sequencing of prediagnostic blood and tissue specimens from 48 subjects who ultimately developed FL. Strikingly, CREBBP lysine acetyltransferase (KAT) domain mutations were the most commonly observed precursor lesions, and largely distinguished patients developing FL (14/48, 29%) from healthy adults with or without detected BCL2 rearrangements (0/13, P = 0.03 and 0/20, P = 0.007, respectively). CREBBP variants were detectable a median of 5.8 years before FL diagnosis, were clonally selected in FL tumors, and appeared restricted to the committed B-cell lineage. These results suggest that mutations affecting the CREBBP KAT domain are common lesions in FL cancer precursor cells (CPC), with the potential for discriminating subjects at risk of developing FL or monitoring residual disease. SIGNIFICANCE: Our study provides direct evidence for recurrent genetic aberrations preceding FL diagnosis, revealing the combination of BCL2 translocation with CREBBP KAT domain mutations as characteristic committed lesions of FL CPCs. Such prediagnostic mutations are detectable years before clinical diagnosis and may help discriminate individuals at risk for lymphoma development. This article is highlighted in the In This Issue feature, p. 1275.

Opioid Usage in Lumbar Disc Herniation Patients with Nonsurgical, Early Surgical, and Late Surgical Treatments.

OBJECTIVE: To assess opioid usage in surgical and nonsurgical patients with lumbar disc herniation receiving different treatments and timing of treatments. METHODS: Individuals with newly diagnosed lumbar intervertebral disc herniation without myelopathy were queried from a health claims database. Patients were categorized into 3 cohorts: nonsurgical, early surgery, and late surgery. Early surgery cohort patients underwent surgery within 30 days postdiagnosis; late surgery cohort patients had surgery after 30 days but before 1 year postdiagnosis. The index date was defined as the diagnosis date for nonsurgical patients and the initial surgery date for surgical patients. The primary outcome was the average daily opioid morphine milligram equivalents (MME) prescribed. Additional outcomes included percentage of opioid-using patients and cumulative opioid burden. RESULTS: Inclusion criteria were met by 573,082 patients: 533,226 patients received nonsurgical treatments, 22,312 patients received early surgery, and 17,544 patients received late surgery. Both surgical cohorts experienced a postsurgical increase in opioid usage, which then sharply declined and gradually plateaued, with daily opioid MME consistently lower in the early versus late surgery cohort. The early surgery cohort also consistently had a lower prevalence of opioid-using patients than the late surgery cohort. Patients receiving nonsurgical treatment demonstrated the highest 1-year post index cumulative opioid burden, and the early surgery cohort consistently had lower cumulative opioid MME than the late surgery cohort. CONCLUSIONS: Early surgery in patients with lumbar disc herniation is associated with lower long-term average daily MME, incidence of opioid use, and 1-year cumulative MME burden compared with nonsurgical and late surgery treatment approaches.

Use of Polysomnography and CPAP in Children Who Received Adenotonsillectomy, US 2004 to 2018.

OBJECTIVES: 1) To determine the prevalence polysomnogram (PSG) and continuous positive airway pressure (CPAP) therapy use in children who received adenotonsillectomy (AT) for sleep symptoms. 2) To identify health care disparities in these regards. STUDY DESIGN: Retrospective database analysis. METHODS: This study used data from Optum (Health Services Innovation Company) to identify 92,490 children who received AT for sleep symptoms between 2004 and 2018. Prevalence of preoperative PSG and postoperative PSG and CPAP were described. Clinical and demographic characteristics were compared between children who had preoperative PSG and those who did not. Characteristics of children with trisomy 21 (T21) were compared to assess PSG and CPAP use in a high-risk cohort. Predictive modeling was used to identify patient characteristics associated with postoperative PSG and CPAP use. RESULTS: Preoperative PSG was obtained in 5.5% of children overall and 33.2% of children with T21. Male sex, obesity, other medical comorbidities, non-White race/ethnicity, and higher parent education were associated with preoperative PSG. Fewer than 3% of children received postoperative PSGs and approximately 3% went on to receive CPAP therapy postoperatively. Multiple logistic regression showed that age at surgery, male sex, obesity, other medical comorbidities, non-White race/ethnicity, and higher parent education were associated with postoperative PSG and CPAP use. CONCLUSIONS AND RELEVANCE: This study described the prevalence pre-AT PSG use and post-AT PSG and CPAP use for persistent symptoms and identified sleep health care disparities in these regards. These results show that increased, equitable access to PSG is needed in children, particularly in the workup and treatment persistent symptoms after AT. LEVEL OF EVIDENCE: 4 Laryngoscope, 133:184-188, 2023.

Circulating Tumor DNA Profiling for Detection, Risk Stratification, and Classification of Brain Lymphomas.

PURPOSE: Clinical outcomes of patients with CNS lymphomas (CNSLs) are remarkably heterogeneous, yet identification of patients at high risk for treatment failure is challenging. Furthermore, CNSL diagnosis often remains unconfirmed because of contraindications for invasive stereotactic biopsies. Therefore, improved biomarkers are needed to better stratify patients into risk groups, predict treatment response, and noninvasively identify CNSL. PATIENTS AND METHODS: We explored the value of circulating tumor DNA (ctDNA) for early outcome prediction, measurable residual disease monitoring, and surgery-free CNSL identification by applying ultrasensitive targeted next-generation sequencing to a total of 306 tumor, plasma, and CSF specimens from 136 patients with brain cancers, including 92 patients with CNSL. RESULTS: Before therapy, ctDNA was detectable in 78% of plasma and 100% of CSF samples. Patients with positive ctDNA in pretreatment plasma had significantly shorter progression-free survival (PFS, P < .0001, log-rank test) and overall survival (OS, P = .0001, log-rank test). In multivariate analyses including established clinical and radiographic risk factors, pretreatment plasma ctDNA concentrations were independently prognostic of clinical outcomes (PFS HR, 1.4; 95% CI, 1.0 to 1.9; P = .03; OS HR, 1.6; 95% CI, 1.1 to 2.2; P = .006). Moreover, measurable residual disease detection by plasma ctDNA monitoring during treatment identified patients with particularly poor prognosis following curative-intent immunochemotherapy (PFS, P = .0002; OS, P = .004, log-rank test). Finally, we developed a proof-of-principle machine learning approach for biopsy-free CNSL identification from ctDNA, showing sensitivities of 59% (CSF) and 25% (plasma) with high positive predictive value. CONCLUSION: We demonstrate robust and ultrasensitive detection of ctDNA at various disease milestones in CNSL. Our findings highlight the role of ctDNA as a noninvasive biomarker and its potential value for personalized risk stratification and treatment guidance in patients with CNSL.[Media: see text].

Determinants of resistance to engineered T cell therapies targeting CD19 in large B cell lymphomas.

Most relapsed/refractory large B cell lymphoma (r/rLBCL) patients receiving anti-CD19 chimeric antigen receptor (CAR19) T cells relapse. To characterize determinants of resistance, we profiled over 700 longitudinal specimens from two independent cohorts (n = 65 and n = 73) of r/rLBCL patients treated with axicabtagene ciloleucel. A method for simultaneous profiling of circulating tumor DNA (ctDNA), cell-free CAR19 (cfCAR19) retroviral fragments, and cell-free T cell receptor rearrangements (cfTCR) enabled integration of tumor and both engineered and non-engineered T cell effector-mediated factors for assessing treatment failure and predicting outcomes. Alterations in multiple classes of genes are associated with resistance, including B cell identity (PAX5 and IRF8), immune checkpoints (CD274), and those affecting the microenvironment (TMEM30A). Somatic tumor alterations affect CAR19 therapy at multiple levels, including CAR19 T cell expansion, persistence, and tumor microenvironment. Further, CAR19 T cells play a reciprocal role in shaping tumor genotype and phenotype. We envision these findings will facilitate improved chimeric antigen receptor (CAR) T cells and personalized therapeutic approaches.

Rapid intraoperative diagnosis of pediatric brain tumors using Raman spectroscopy: A machine learning approach.

Background: Surgical resection is a mainstay in the treatment of pediatric brain tumors to achieve tissue diagnosis and tumor debulking. While maximal safe resection of tumors is desired, it can be challenging to differentiate normal brain from neoplastic tissue using only microscopic visualization, intraoperative navigation, and tactile feedback. Here, we investigate the potential for Raman spectroscopy (RS) to accurately diagnose pediatric brain tumors intraoperatively. Methods: Using a rapid acquisition RS device, we intraoperatively imaged fresh ex vivo brain tissue samples from 29 pediatric patients at the Lucile Packard Children's Hospital between October 2018 and March 2020 in a prospective fashion. Small tissue samples measuring 2-4 mm per dimension were obtained with each individual tissue sample undergoing multiple unique Raman spectra acquisitions. All tissue samples from which Raman spectra were acquired underwent individual histopathology review. A labeled dataset of 678 unique Raman spectra gathered from 160 samples was then used to develop a machine learning model capable of (1) differentiating normal brain from tumor tissue and (2) normal brain from low-grade glioma (LGG) tissue. Results: Trained logistic regression model classifiers were developed using our labeled dataset. Model performance was evaluated using leave-one-patient-out cross-validation. The area under the curve (AUC) of the receiver-operating characteristic (ROC) curve for our tumor vs normal brain model was 0.94. The AUC of the ROC curve for LGG vs normal brain was 0.91. Conclusions: Our work suggests that RS can be used to develop a machine learning-based classifier to differentiate tumor vs non-tumor tissue during resection of pediatric brain tumors.

Health Care Resource Utilization in Management of Opioid-Naive Patients With Newly Diagnosed Neck Pain.

Importance: Research has uncovered heterogeneity and inefficiencies in the management of idiopathic low back pain, but few studies have examined longitudinal care patterns following newly diagnosed neck pain. Objective: To understand health care utilization in patients with new-onset idiopathic neck pain. Design, Setting, and Participants: This cross-sectional study used nationally sourced longitudinal data from the IBM Watson Health MarketScan claims database (2007-2016). Participants included adult patients with newly diagnosed neck pain, no recent opioid use, and at least 1 year of continuous postdiagnosis follow-up. Exclusion criteria included prior or concomitant diagnosis of traumatic cervical disc dislocation, vertebral fractures, myelopathy, and/or cancer. Only patients with at least 1 year of prediagnosis lookback were included. Data analysis was performed from January 2021 to January 2022. Main Outcomes and Measures: The primary outcome of interest was 1-year postdiagnosis health care expenditures, including costs, opioid use, and health care service utilization. Early services were those received within 30 days of diagnosis. Multivariable regression models and regression-adjusted statistics were used. Results: In total, 679 030 patients (310 665 men [45.6%]) met the inclusion criteria, of whom 7858 (1.2%) underwent surgery within 1 year of diagnosis. The mean (SD) age was 44.62 (14.87) years among nonsurgical patients and 49.69 (9.53) years among surgical patients. Adjusting for demographics and comorbidities, 1-year regression-adjusted health care costs were $24 267.55 per surgical patient and $515.69 per nonsurgical patient. Across all health care services, $95 379 949 was accounted for by nonsurgical patients undergoing early imaging who did not receive any additional conservative therapy or epidural steroid injections, for a mean (SD) of $477.53 ($1375.60) per patient and median (IQR) of $120.60 ($20.70-$452.37) per patient. On average, patients not undergoing surgery, physical therapy, chiropractic manipulative therapy, or epidural steroid injection, who underwent either early advanced imaging (magnetic resonance imaging or computed tomography) or both early advanced and radiographic imaging, accumulated significantly elevated health care costs ($850.69 and $1181.67, respectively). Early conservative therapy was independently associated with 24.8% (95% CI, 23.5%-26.2%) lower health care costs. Conclusions and Relevance: In this cross-sectional study, early imaging without subsequent intervention was associated with significantly increased health care spending among patients with newly diagnosed idiopathic neck pain. Early conservative therapy was associated with lower costs, even with increased frequency of therapeutic services, and may have reduced long-term care inefficiency.

An integrated risk model stratifying seizure risk following brain tumor resection among seizure-naive patients without antiepileptic prophylaxis.

OBJECTIVE: The natural history of seizure risk after brain tumor resection is not well understood. Identifying seizure-naive patients at highest risk for postoperative seizure events remains a clinical need. In this study, the authors sought to develop a predictive modeling strategy for anticipating postcraniotomy seizures after brain tumor resection. METHODS: The IBM Watson Health MarketScan Claims Database was canvassed for antiepileptic drug (AED)- and seizure-naive patients who underwent brain tumor resection (2007-2016). The primary event of interest was short-term seizure risk (within 90 days postdischarge). The secondary event of interest was long-term seizure risk during the follow-up period. To model early-onset and long-term postdischarge seizure risk, a penalized logistic regression classifier and multivariable Cox regression model, respectively, were built, which integrated patient-, tumor-, and hospitalization-specific features. To compare empirical seizure rates, equally sized cohort tertiles were created and labeled as low risk, medium risk, and high risk. RESULTS: Of 5470 patients, 983 (18.0%) had a postdischarge-coded seizure event. The integrated binary classification approach for predicting early-onset seizures outperformed models using feature subsets (area under the curve [AUC] = 0.751, hospitalization features only AUC = 0.667, patient features only AUC = 0.603, and tumor features only AUC = 0.694). Held-out validation patient cases that were predicted by the integrated model to have elevated short-term risk more frequently developed seizures within 90 days of discharge (24.1% high risk vs 3.8% low risk, p < 0.001). Compared with those in the low-risk tertile by the long-term seizure risk model, patients in the medium-risk and high-risk tertiles had 2.13 (95% CI 1.45-3.11) and 6.24 (95% CI 4.40-8.84) times higher long-term risk for postdischarge seizures. Only patients predicted as high risk developed status epilepticus within 90 days of discharge (1.7% high risk vs 0% low risk, p = 0.003). CONCLUSIONS: The authors have presented a risk-stratified model that accurately predicted short- and long-term seizure risk in patients who underwent brain tumor resection, which may be used to stratify future study of postoperative AED prophylaxis in highest-risk patient subpopulations.

Prediction of Discharge Status and Readmissions after Resection of Intradural Spinal Tumors.

OBJECTIVE: Intradural spinal tumors are uncommon and while associations between clinical characteristics and surgical outcomes have been explored, there remains a paucity of literature unifying diverse predictors into an integrated risk model. To predict postresection outcomes for patients with spinal tumors. METHODS: IBM MarketScan Claims Database was queried for adult patients receiving surgery for intradural tumors between 2007 and 2016. Primary outcomes-of-interest were nonhome discharge and 90-day postdischarge readmissions. Secondary outcomes included hospitalization duration and postoperative complications. Risk modeling was developed using a regularized logistic regression framework (LASSO, least absolute shrinkage and selection operator) and validated in a withheld subset. RESULTS: A total of 5,060 adult patients were included. Most surgeries utilized a posterior approach (n = 5,023, 99.3%) and tumors were most commonly found in the thoracic region (n = 1,941, 38.4%), followed by the lumbar (n = 1,781, 35.2%) and cervical (n = 1,294, 25.6%) regions. Compared to models using only tumor-specific or patient-specific features, our integrated models demonstrated better discrimination (area under the curve [AUC] [nonhome discharge] = 0.786; AUC [90-day readmissions] = 0.693) and accuracy (Brier score [nonhome discharge] = 0.155; Brier score [90-day readmissions] = 0.093). Compared to those predicted to be lowest risk, patients predicted to be highest-risk for nonhome discharge required continued care 16.3 times more frequently (64.5% vs. 3.9%). Similarly, patients predicted to be at highest risk for postdischarge readmissions were readmitted 7.3 times as often as those predicted to be at lowest risk (32.6% vs. 4.4%). CONCLUSION: Using a diverse set of clinical characteristics spanning tumor-, patient-, and hospitalization-derived data, we developed and validated risk models integrating diverse clinical data for predicting nonhome discharge and postdischarge readmissions.

Racial Disparities in Surgical Treatment of Obstructive Sleep Apnea.

Objective: Determine risk factors for failure to receive surgical treatment among patients with obstructive sleep apnea. Study Design: Population-based observational longitudinal cohort study. Setting: Population-based database. Methods: Multivariate analysis of 500,792 individuals with obstructive sleep apnea from Optum's deidentified Clinformatics Data Mart database (2004-2018). Results: Black race, increased age, diabetes, atrial fibrillation, obesity, and congestive heart failure were independently associated with a decreased rate of surgery for obstructive sleep apnea. Asian race, hypertension, arrhythmias other than atrial fibrillation, pulmonary disease, and liver disease were independently associated with an increased rate of surgery for obstructive sleep apnea. Conclusion: Racial disparities in health outcomes related to health care access and in economic resources have an enormous impact on public health and social equity. We found differences in rates of surgery for obstructive sleep apnea based on race. These data are consistent with others demonstrating disparities in medical treatment of sleep apnea with positive pressure and underline a need for a change in awareness and treatment in these populations.

Circulating tumor DNA in head and neck cancer: Early successes and future promise.

LAY SUMMARY: The genetic components (DNA) of human papillomavirus-related throat cancer (in the oropharynx) might be measured after surgery to help to predict whether treatment has been successful.

Risk of Second Primary Malignancies After External Beam Radiotherapy for Thyroid Cancer.

AIM: To investigate the association between external beam radiotherapy (EBRT) and the incidence of second primary tumors in patients with thyroid cancer. MATERIALS AND METHODS: Data were extracted from the Surveillance, Epidemiology, and End Results 9 database. The study cohort included patients diagnosed with thyroid cancer between 1973 and 2017. Risk factors for second primary malignancies were identified with Cox proportional hazards models. Propensity score-matched analyses were used to assess the association between EBRT and second primary malignancies. RESULTS: Out of 72,392 patients with thyroid cancer, 7,684 (10.6%) developed a subsequent primary malignancy. Propensity score-matched analysis demonstrated patients receiving EBRT were more likely to develop second primary malignancies [30-year cumulative incidence=35.3% (95% confidence interval (CI)=30.4-39.8% vs. 28.1% (95% CI=27.0-29.2%); hazard ratio=1.17 (95% CI=1.03-1.33)]. CONCLUSION: In patients with thyroid cancer, EBRT is associated with an increased incidence of second primary malignancies.

Incorporating patient-centered quality-of-life measures for outcome assessment after Chiari malformation type I decompression in a pediatric population: a pilot study.

OBJECTIVE: Optimal management of pediatric Chiari malformation type I (CM-I) is much debated, chiefly due to the lack of validated tools for outcome assessment, with very few tools incorporating patient-centered measures of health-related quality of life (HRQOL). Although posterior fossa decompression (PFD) benefits a subset of patients, prediction of its impact across patients is challenging. The primary aim of this study was to investigate the role of patient-centered HRQOL measures in the assessment and prediction of outcomes after PFD. METHODS: The authors collected HRQOL data from a cohort of 20 pediatric CM-I patients before and after PFD. The surveys included assessments of selected Patient-Reported Outcomes Measurement Information System (PROMIS) health domains and were used to generate the PROMIS preference (PROPr) score, which is a measure of HRQOL. PROMIS is a reliable standardized measure of HRQOL domains such as pain, fatigue, depression, and physical function, which are all relevant to CM-I. The authors then compared the PROPr scores with Chicago Chiari Outcome Scale (CCOS) scores derived from time-matched clinical documentation. Finally, the authors used the PROPr scores as an outcome measure to predict postsurgical HRQOL improvement at 1 year on the basis of patient demographic characteristics, comorbidities, and radiological and physical findings. The Wilcoxon signed-rank test, Mann-Whitney U-test, and Kendall's correlation were used for statistical analysis. RESULTS: Aggregate analysis revealed improvement of pain severity after PFD (p = 0.007) in anatomical patterns characteristic of CM-I. Most PROMIS domain scores trended toward improvement after surgery, with anxiety and pain interference reaching statistical significance (p < 0.002 and p < 0.03, respectively). PROPr scores also significantly improved after PFD (p < 0.008). Of the baseline patient characteristics, preexisting scoliosis was the most accurate negative predictor of HRQOL improvement after PFD (median -0.095 vs 0.106, p < 0.001). A correlation with modest magnitude (Kendall's tau range 0.19-0.47) was detected between the patient-centered measures and CCOS score. CONCLUSIONS: The authors observed moderate improvement of HRQOL, when measured using a modified panel of PROMIS question banks, in this pilot cohort of pediatric CM-I patients after PFD. Further investigations are necessary to validate this tool for children with CM-I and to determine whether these scores correlate with clinical and radiographic findings.

Enhanced detection of minimal residual disease by targeted sequencing of phased variants in circulating tumor DNA.

Circulating tumor-derived DNA (ctDNA) is an emerging biomarker for many cancers, but the limited sensitivity of current detection methods reduces its utility for diagnosing minimal residual disease. Here we describe phased variant enrichment and detection sequencing (PhasED-seq), a method that uses multiple somatic mutations in individual DNA fragments to improve the sensitivity of ctDNA detection. Leveraging whole-genome sequences from 2,538 tumors, we identify phased variants and their associations with mutational signatures. We show that even without molecular barcodes, the limits of detection of PhasED-seq outperform prior methods, including duplex barcoding, allowing ctDNA detection in the ppm range in participant samples. We profiled 678 specimens from 213 participants with B cell lymphomas, including serial cell-free DNA samples before and during therapy for diffuse large B cell lymphoma. In participants with undetectable ctDNA after two cycles of therapy using a next-generation sequencing-based approach termed cancer personalized profiling by deep sequencing, an additional 25% have ctDNA detectable by PhasED-seq and have worse outcomes. Finally, we demonstrate the application of PhasED-seq to solid tumors.

Risk of secondary neoplasms after external-beam radiation therapy treatment of pediatric low-grade gliomas: a SEER analysis, 1973-2015.

OBJECTIVE: Although past studies have associated external-beam radiation therapy (EBRT) with higher incidences of secondary neoplasms (SNs), its effect on SN development from pediatric low-grade gliomas (LGGs), defined as WHO grade I and II gliomas of astrocytic or oligodendrocytic origin, is not well understood. Utilizing a national cancer registry, the authors sought to characterize the risk of SN development after EBRT treatment of pediatric LGG. METHODS: A total of 1245 pediatric patient (aged 0-17 years) records from 1973 to 2015 were assembled from the Surveillance, Epidemiology, and End Results (SEER) database. Univariable and multivariable subdistribution hazard regression models were used to evaluate the prognostic impact of demographic, tumor, and treatment-related covariates. Propensity score matching was used to balance baseline characteristics. Cumulative incidence analyses measured the time to, and rate of, SN development, stratified by receipt of EBRT and controlled for competing mortality risk. The Fine and Gray semiparametric model was used to estimate future SN risk in EBRT- and non-EBRT-treated pediatric patients. RESULTS: In this study, 366 patients received EBRT and 879 did not. Forty-six patients developed SNs after an LGG diagnosis, and 27 of these patients received EBRT (OR 3.61, 95% CI 1.90-6.95; p < 0.001). For patients alive 30 years from the initial LGG diagnosis, the absolute risk of SN development in the EBRT-treated cohort was 12.61% (95% CI 8.31-13.00) compared with 4.99% (95% CI 4.38-12.23) in the non-EBRT-treated cohort (p = 0.013). Cumulative incidence curves that were adjusted for competing events still demonstrated higher rates of SN development in the EBRT-treated patients with LGGs. After matching across available covariates and again adjusting for the competing risk of mortality, a clear association between EBRT and SN development remained (subhazard ratio 2.26, 95% CI 1.21-4.20; p = 0.010). CONCLUSIONS: Radiation therapy was associated with an increased risk of future SNs for pediatric patients surviving LGGs. These data suggest that the long-term implications of EBRT should be considered when making treatment decisions for this patient population.

Defining and describing treatment heterogeneity in new-onset idiopathic lower back and extremity pain through reconstruction of longitudinal care sequences.

BACKGROUND CONTEXT: Despite established guidelines, long-term management of surgically-treated low back pain (LBP) and lower extremity pain (LEP) remains heterogeneous. Understanding care heterogeneity could inform future approaches for standardization of practices. PURPOSE: To describe treatment heterogeneity in surgically-managed LBP and LEP. STUDY DESIGN/SETTING: Retrospective study of a nationwide commercial database spanning inpatient and outpatient encounters for enrollees of eligible employer-supplied healthcare plans (2007-2016). PATIENT SAMPLE: A population-based sample of opioid-naïve adult patients with newly-diagnosed LBP or LEP were identified. Inclusion required at least 12-months of pre-diagnosis and post-diagnosis continuous follow-up. EXPOSURE: Included treatments/evaluations include conservative management (chiropractic manipulative therapy, physical therapy, epidural steroid injections), imaging (x-ray, MRI, CT), pharmaceuticals (opioids, benzodiazepines), and spine surgery (decompression, fusion). OUTCOME MEASURES: Primary outcomes-of-interest were 12-month net healthcare expenditures (inpatient and outpatient) and 12-month opioid usage. METHODS: Analyses include interrogation of care sequence heterogeneity and temporal trends in sequence-initiating services. Comparisons were conducted in the framework of sequence-specific treatment sequences, which reflect the personalized order of healthcare services pursued by each patient. Outlier sequences characterized by high opioid use and costs were identified from frequently observed surgical treatment sequences using Mahalanobis distance. RESULTS: A total of 2,496,908 opioid-naïve adult patients with newly-diagnosed LBP or LEP were included (29,519 surgical). In the matched setting, increased care sequence heterogeneity was observed in surgical patients (0.51 vs. 0.12 previously-unused interventions/studies pursued per month). Early opioid and MRI use has decreased between 2008 and 2015 but is matched by increases in early benzodiazepine and x-ray use. Outlier sequences, characterized by increased opioid use and costs, were found in 5.8% of surgical patients. Use of imaging prior to conservative management was common in patients pursuing outlier sequences compared to non-outlier sequences (96.5% vs. 63.8%, p<.001). Non-outlier sequences were more frequently characterized by early conservative interventions (31.9% vs. 7.4%, p<.001). CONCLUSIONS: Surgically-managed LBP and LEP care sequences demonstrate high heterogeneity despite established practice guidelines. Outlier sequences associated with high opioid usage and costs can be identified and are characterized by increased early imaging and decreased early conservative management. Elements that may portend suboptimal longitudinal management could provide opportunities for standardization of patient care.