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.

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.

Getting what you pay for: impact of copayments on physical therapy and opioid initiation, timing, and continuation for newly diagnosed low back pain.

BACKGROUND CONTEXT: Physical therapy (PT) is an important component of low back pain (LBP) management. Despite established guidelines, heterogeneity in medical management remains common. PURPOSE: We sought to understand how copayments impact timing and utilization of PT in newly diagnosed LBP. STUDY DESIGN/SETTING: The IBM Watson Health MarketScan claims database was used in a longitudinal setting. PATIENT SAMPLE: Adult patients with LBP. OUTCOME MEASURES: The primary outcomes-of-interest were timing and overall utilization of PT services. Additional outcomes-of-interest included timing of opioid prescribing. METHODS: Actual and inferred copayments based on nonnonprimary care provider visit claims were used to evaluate the relationship between PT copayment and incidence of PT initiation. Multivariable regression models were used to evaluate factors influencing PT usage. RESULTS: Overall, 2,467,389 patients were included. PT initiation, among those with at ≥1 PT service during the year after LBP diagnosis (30.6%), occurred at a median of 8 days postdiagnosis (IQR 1-55). Among those with at least one PT encounter, incidence of subsequent PT visits was significantly lower for those with high initial PT copayments. High initial PT copayments, while inversely correlated with PT utilization, were directly correlated with subsequent opioid use (0.77 prescriptions/patient [$0 PT copayment] versus 1.07 prescriptions/patient [$50-74 PT copayment]; 1.15 prescriptions/patient [$75+ PT copayment]). Among patients with known opioid and PT copayments, higher PT copayments were correlated with faster opioid use while higher opioid copayments were correlated with faster PT use (Spearman p<.05). For multivariable whole-cohort analyses, incidence of PT initiation among patients with inferred copayments in the 50-75th and 75-100th percentiles was significantly lower than those below the 50th percentile (HR=0.893 [95%CI 0.887-0.899] and HR=0.905 [95%CI 0.899-0.912], respectively). CONCLUSIONS: Higher PT copayments correlated with reduced PT utilization; higher PT copayments and lower opioid copayments were independent contributors to delayed PT initiation and higher opioid use. In patients covered by plans charging high PT copayments, opioid use was significantly higher. Copays may impact long-term adherence to PT.

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.

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.

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].