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.

Performance of GPT-4 on the American College of Radiology In-training Examination: Evaluating Accuracy, Model Drift, and Fine-tuning.

RATIONALE AND OBJECTIVES: In our study, we evaluate GPT-4's performance on the American College of Radiology (ACR) 2022 Diagnostic Radiology In-Training Examination (DXIT). We perform multiple experiments across time points to assess for model drift, as well as after fine-tuning to assess for differences in accuracy. MATERIALS AND METHODS: Questions were sequentially input into GPT-4 with a standardized prompt. Each answer was recorded and overall accuracy was calculated, as was logic-adjusted accuracy, and accuracy on image-based questions. This experiment was repeated several months later to assess for model drift, then again after the performance of fine-tuning to assess for changes in GPT's performance. RESULTS: GPT-4 achieved 58.5% overall accuracy, lower than the PGY-3 average (61.9%) but higher than the PGY-2 average (52.8%). Adjusted accuracy was 52.8%. GPT-4 showed significantly higher (p = 0.012) confidence for correct answers (87.1%) compared to incorrect (84.0%). Performance on image-based questions was significantly poorer (p < 0.001) at 45.4% compared to text-only questions (80.0%), with adjusted accuracy for image-based questions of 36.4%. When the questions were repeated, GPT-4 chose a different answer 25.5% of the time and there was no change in accuracy. Fine-tuning did not improve accuracy. CONCLUSION: GPT-4 performed between PGY-2 and PGY-3 levels on the 2022 DXIT, significantly poorer on image-based questions, and with large variability in answer choices across time points. Exploratory experiments in fine-tuning did not improve performance. This study underscores the potential and risks of using minimally-prompted general AI models in interpreting radiologic images as a diagnostic tool. Implementers of general AI radiology systems should exercise caution given the possibility of spurious yet confident responses.

Rogue AI: Cautionary Cases in Neuroradiology and What We Can Learn From Them.

Introduction In recent years, artificial intelligence (AI) in medical imaging has undergone unprecedented innovation and advancement, sparking a revolutionary transformation in healthcare. The field of radiology is particularly implicated, as clinical radiologists are expected to interpret an ever-increasing number of complex cases in record time. Machine learning software purchased by our institution is expected to help our radiologists come to a more prompt diagnosis by delivering point-of-care quantitative analysis of suspicious findings and streamlining clinical workflow. This paper explores AI's impact on neuroradiology, an area accounting for a substantial portion of recent radiology studies. We present a case series evaluating an AI software's performance in detecting neurovascular findings, highlighting five cases where AI interpretations differed from radiologists' assessments. Our study underscores common pitfalls of AI in the context of CT head angiograms, aiming to guide future AI algorithms.  Methods We conducted a retrospective case series study at Stony Brook University Hospital, a large medical center in Stony Brook, New York, spanning from October 1, 2021 to December 31, 2021, analyzing 140 randomly sampled CT angiograms using AI software. This software assessed various neurovascular parameters, and AI findings were compared with neuroradiologists' interpretations. Five cases with divergent interpretations were selected for detailed analysis. Results Five representative cases in which AI findings were discordant with radiologists' interpretations are presented with diagnoses including diffuse anoxic ischemic injury, cortical laminar necrosis, colloid cyst, right superficial temporal artery-to-middle cerebral artery (STA-MCA) bypass, and subacute bilateral subdural hematomas. Discussion The errors identified in our case series expose AI's limitations in radiology. Our case series reveals that AI's incorrect interpretations can stem from complexities in pathology, challenges in distinguishing densities, inability to identify artifacts, identifying post-surgical changes in normal anatomy, sensitivity limitations, and insufficient pattern recognition. AI's potential for improvement lies in refining its algorithms to effectively recognize and differentiate pathologies. Incorporating more diverse training datasets, multimodal data, deep-reinforcement learning, clinical context, and real-time learning capabilities are some ways to improve AI's performance in the field of radiology. Conclusion Overall, it is apparent that AI applications in radiology have much room for improvement before becoming more widely integrated into clinical workflows. While AI demonstrates remarkable potential to aid in diagnosis and streamline workflows, our case series highlights common pitfalls that underscore the need for continuous improvement. By refining algorithms, incorporating diverse datasets, embracing multimodal information, and leveraging innovative machine learning strategies, AI's diagnostic accuracy can be significantly improved.

Modeling of Charge-to-Breakdown with an Electron Trapping Model for Analysis of Thermal Gate Oxide Failure Mechanism in SiC Power MOSFETs.

The failure mechanism of thermal gate oxide in silicon carbide (SiC) power metal oxide semiconductor field effect transistors (MOSFETs), whether it is field-driven breakdown or charge-driven breakdown, has always been a controversial topic. Previous studies have demonstrated that the failure time of thermally grown silicon dioxide (SiO2) on SiC stressed with a constant voltage is indicated as charge driven rather than field driven through the observation of Weibull Slope ß. Considering the importance of the accurate failure mechanism for the thermal gate oxide lifetime prediction model of time-dependent dielectric breakdown (TDDB), charge-driven breakdown needs to be further fundamentally justified. In this work, the charge-to-breakdown (QBD) of the thermal gate oxide in a type of commercial planar SiC power MOSFETs, under the constant current stress (CCS), constant voltage stress (CVS), and pulsed voltage stress (PVS) are extracted, respectively. A mathematical electron trapping model in thermal SiO2 grown on single crystal silicon (Si) under CCS, which was proposed by M. Liang et al., is proven to work equally well with thermal SiO2 grown on SiC and used to deduce the QBD model of the device under test (DUT). Compared with the QBD obtained under the three stress conditions, the charge-driven breakdown mechanism is validated in the thermal gate oxide of SiC power MOSFETs.

Radiology advocacy: Promoting collaboration between trainees and professional societies.

From mammographic screening guidelines to resident work hour regulations, public policy affects every aspect of the practice of radiology and ultimately determines how radiological care is delivered to patients. Shaping public policy through advocacy is therefore critical to ensure patient access to equitable, high-quality radiological care. In advocacy, individual practicing radiologists and radiology trainees can increase the scope of their influence by collaborating with professional radiology societies. When radiology trainees participate in organized radiology advocacy, they learn about regulatory and legislative issues that will affect their careers, and they learn how to effect policy change. Radiology societies in turn benefit from trainee involvement, as engaging trainees early in their careers leads to more robust future participation and leadership. To encourage trainee involvement, radiology societies can engage individual residency programs and medical student radiology interest groups, invest in trainee-focused events, and maximize the number of positions of responsibility open to trainees. To circumvent the barriers to participation that many trainees face, radiology societies can make meeting proceedings free and available through virtual mediums. Through active collaboration, trainees and professional societies can help assure a bright future for radiologists and patients in need of radiological care.

An Investigation of Body Diode Reliability in Commercial 1.2 kV SiC Power MOSFETs with Planar and Trench Structures.

The body diode degradation in SiC power MOSFETs has been demonstrated to be caused by basal plane dislocation (BPD)-induced stacking faults (SFs) in the drift region. To enhance the reliability of the body diode, many process and structural improvements have been proposed to eliminate BPDs in the drift region, ensuring that commercial SiC wafers for 1.2 kV devices are of high quality. Thus, investigating the body diode reliability in commercial planar and trench SiC power MOSFETs made from SiC wafers with similar quality has attracted attention in the industry. In this work, current stress is applied on the body diodes of 1.2 kV commercial planar and trench SiC power MOSFETs under the off-state. The results show that the body diodes of planar and trench devices with a shallow P+ depth are highly reliable, while those of the trench devices with the deep P+ implantation exhibit significant degradation. In conclusion, the body diode degradation in trench devices is mainly influenced by P+ implantation-induced BPDs. Therefore, a trade-off design by controlling the implantation depth/dose and maximizing the device performance is crucial. Moreover, the deep JFET design is confirmed to further improve the body diode reliability in planar devices.

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.

A Review of COVID-19's Impact on Radiology Residents' Academics and Wellness in North America.

BACKGROUND: The COVID-19 pandemic caused major disruptions in radiology departments throughout North America. Radiology residency programs were forced to make dramatic changes to their training programs, which had major impacts on resident academics and wellness. The goal of this review is to evaluate the impact of COVID-19 on radiology residents' academics and wellness in North America, while also identifying effective measures taken by programs to mitigate the effects of the pandemic. METHODS: The search strategy involved database search via PubMed, Embase, and Web of Science with specific key words related to COVID-19, radiology residents, education, wellness, and virtual learning. Studies discussing the education and wellness of radiology residents in North America published after 2020 were included. The data were analyzed using a narrative synthesis approach. RESULTS: The three main domains affected by the pandemic include the residency curriculum, research, and resident wellness. The decline in case volume and diversity of cases had negative overall impact on education of radiology residents, but simulated cases and virtual learning proved its value during the pandemic and may have lasting implications for the postpandemic world. Research initiatives transitioned to a remote format with greater emphasis on quality improvement and COVID-19-related studies. Reduced face-to-face interaction opportunities made it difficult to establish strong and meaningful interpersonal connections and had a negative impact on resident wellness, mentorship, and professional development. Implementing mentorship programs and virtual "town hall meetings" were effective measures to maintain connections during times of social distancing. Finally, the COVID-19 pandemic introduced unprecedented stressors and challenges for radiology residents that negatively impacted their mental health and wellness. Incorporating wellness initiatives such as wellness hours and team-building activities and using social media were helpful in promoting wellness and mental health for radiology residents. CONCLUSION: The COVID-19 pandemic has had a significant impact on the academics and wellness of radiology residents across North America but has taught us many lessons that can help us navigate the ongoing challenges of the pandemic, the postpandemic world, and future pandemics.

Progenitor Cells Play a Role in Reinstatement of Ethanol Seeking in Adult Male and Female Ethanol Dependent Rats.

Female and male glial fibrillary acidic protein-thymidine kinase (GFAP-TK) transgenic rats were made ethanol dependent via a six-week chronic intermittent ethanol vapor (CIE) and ethanol drinking (ED) procedure. During the last week of CIE, a subset of male and female TK rats was fed valcyte to ablate dividing progenitor cells and continued the diet until the end of this study. Following week six, all CIE rats experienced two weeks of forced abstinence from CIE-ED, after which they experienced relapse to drinking, extinction, and reinstatement of ethanol seeking sessions. CIE increased ED in female and male rats, with females having higher ethanol consumption during CIE and relapse sessions compared with males. In both sexes, valcyte reduced the levels of Ki-67-labeled progenitor cells in the subgranular zone of the dentate gyrus and did not alter the levels in the medial prefrontal cortex (mPFC). Valcyte increased ED during relapse, increased lever responses during extinction and, interestingly, enhanced latency to extinguish ethanol-seeking behaviors in males. Valcyte reduced the reinstatement of ethanol-seeking behaviors triggered by ethanol cues in females and males. Reduced seeking by valcyte was associated with the normalization of cytokines and chemokines in plasma isolated from trunk blood, indicating a role for progenitor cells in peripheral inflammatory responses. Reduced seeking by valcyte was associated with increases in tight junction protein claudin-5 and oligodendrogenesis in the dentate gyrus and reduction in microglial activity in the dentate gyrus and mPFC in females and males, demonstrating a role for progenitor cells in the dentate gyrus in dependence-induced endothelial and microglial dysfunction. These data suggest that progenitor cells born during withdrawal and abstinence from CIE in the dentate gyrus are aberrant and could play a role in strengthening ethanol memories triggered by ethanol cues via central and peripheral immune responses.

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.

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.

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.

Call to Action: Creating Resources for Radiology Technologists to Capture Higher Quality Portable Chest X-rays.

Background Patient rotation, foreign body overlying anatomy, and anatomy out of field of view can have detrimental impacts on the diagnostic quality of portable chest x-rays (PCXRs), especially as the number of PCXR imaging increases due to the coronavirus disease 2019 (COVID-19) pandemic. Although preventable, these "quality failures" are common and may lead to interpretative and diagnostic errors for the radiologist. Aims In this study, we present a baseline quality failure rate of PCXR imaging as observed at our institution. We also conduct a focus group highlighting the key issues that lead to the problematic images and discuss potential interventions targeting technologists that can be implemented to address imaging quality failure rate. Materials and methods A total of 500 PCXRs for adult patients admitted to a large university hospital between July 12, 2021, and July 25, 2021, were obtained for evaluation of quality. The PCXRs were evaluated by radiology residents for failures in technical image quality. The images were categorized into various metrics including the degree of rotation and obstruction of anatomical structures. After collecting the data, a focus group involving six managers of the technologist department at our university hospital was conducted to further illuminate the key barriers to quality PCXRs faced at our institution.. Results  Out of the 500 PCXRs evaluated, 231 were problematic (46.2%). 43.5% of the problematic films with a repeat PCXR within one week showed that there was a technical problem impacting the ability to detect pathology. Most problematic films also occurred during the night shift (48%). Key issues that lead to poor image quality included improper patient positioning, foreign objects covering anatomy, and variances in technologists' training. Three interventions were proposed to optimize technologist performance that can lower quality failure rates of PCXRs. These include a longitudinal educational curriculum involving didactic sessions, adding nursing support to assist technologists, and adding an extra layer of verification by internal medicine residents before sending the films to the radiologist. The rationale for these interventions is discussed in detail so that a modified version can be implemented in other hospital systems.  Conclusion This study illustrates the high baseline error rate in image quality of PCXRs at our institution and demonstrates the need to improve on image quality. Poor image quality negatively impacts the interpretive accuracy of radiologists and therefore leads to wrong diagnoses. Increasing educational resources and support for technologists can lead to higher image quality and radiologist accuracy.

Comparison of Deep Learning and Classical Machine Learning Algorithms to Predict Postoperative Outcomes for Anterior Cervical Discectomy and Fusion Procedures With State-of-the-art Performance.

STUDY DESIGN: Retrospective cohort. OBJECTIVE: Due to anterior cervical discectomy and fusion (ACDF) popularity, it is important to predict postoperative complications, unfavorable 90-day readmissions, and two-year reoperations to improve surgical decision-making, prognostication, and planning. SUMMARY OF BACKGROUND DATA: Machine learning has been applied to predict postoperative complications for ACDF; however, studies were limited by sample size and model type. These studies achieved ≤0.70 area under the curve (AUC). Further approaches, not limited to ACDF, focused on specific complication types and resulted in AUC between 0.70 and 0.76. MATERIALS AND METHODS: The IBM MarketScan Commercial Claims and Encounters Database and Medicare Supplement were queried from 2007 to 2016 to identify adult patients who underwent an ACDF procedure (N=176,816). Traditional machine learning algorithms, logistic regression, and support vector machines, were compared with deep neural networks to predict: 90-day postoperative complications, 90-day readmission, and two-year reoperation. We further generated random deep learning model architectures and trained them on the 90-day complication task to approximate an upper bound. Last, using deep learning, we investigated the importance of each input variable for the prediction of 90-day postoperative complications in ACDF. RESULTS: For the prediction of 90-day complication, 90-day readmission, and two-year reoperation, the deep neural network-based models achieved AUC of 0.832, 0.713, and 0.671. Logistic regression achieved AUCs of 0.820, 0.712, and 0.671. Support vector machine approaches were significantly lower. The upper bound of deep learning performance was approximated as 0.832. Myelopathy, age, human immunodeficiency virus, previous myocardial infarctions, obesity, and documentary weakness were found to be the strongest variable to predict 90-day postoperative complications. CONCLUSIONS: The deep neural network may be used to predict complications for clinical applications after multicenter validation. The results suggest limited added knowledge exists in interactions between the input variables used for this task. Future work should identify novel variables to increase predictive power.