Current and Future States of Natural Killer Cell-Based Immunotherapy in Hepatocellular Carcinoma.

Natural killer (NK) cells are innate lymphoid cells that exhibit high levels of cytotoxicity against NK-specific targets. NK cells also produce various cytokines, and interact with T cells, B cells, and dendritic cells to effectively serve as frontliners of the innate immune system. Produce various cytokines, and interact with T cells, B cells, and dendritic cells to effectively serve as frontliners of the innate immune system. Moreover, NK cells constitute the second most common immune cell in the liver. These properties have drawn significant attention towards leveraging NK cells in treating liver cancer, especially hepatocellular carcinoma (HCC), which accounts for 75% of all primary liver cancer and is the fourth leading cause of cancer-related death worldwide. Notable anti-cancer functions of NK cells against HCC include activating antibody-dependent cell cytotoxicity (ADCC), facilitating Gasdermin E-mediated pyroptosis of HCC cells, and initiating an antitumor response via the cGAS-STING signaling pathway. In this review, we describe how these mechanisms work in the context of HCC. We will then discuss the existing preclinical and clinical studies that leverage NK cell activity to create single and combined immunotherapies.

Constitutional balanced translocations involving SMARCB1: A rare cause of rhabdoid tumor predisposition syndrome.

Rhabdoid Tumor Predisposition Syndrome 1 (RTPS1) confers an increased risk of developing rhabdoid tumors and is caused by germline mutations in SMARCB1. RTPS1 should be evaluated in all individuals with rhabdoid tumor and is more likely in those with a young age at presentation (occasionally congenital presentation), multiple primary tumors, or a family history of rhabdoid tumor or RTPS1. Proband genetic testing is the standard method for diagnosing RTPS1. Most known RTPS1-related SMARCB1 gene mutations are copy number variants (CNVs) or single nucleotide variants/indels, but structural variant analysis (SVA) is not usually included in the molecular evaluation. Here, we report two children with RTPS1 presenting with atypical teratoid/rhabdoid tumor (ATRT) who had constitutional testing showing balanced chromosome translocations involving SMARCB1. Patient 1 is a 23-year-old female diagnosed with pineal region ATRT at 7 months who was found to have a de novo, constitutional t(16;22)(p13.3;q11.2). Patient 2 is a 24-month-old male diagnosed with a posterior fossa ATRT at 14 months, with subsequent testing showing a constitutional t(5;22)(q14.1;q11.23). These structural rearrangements have not been previously reported in RTPS1. While rare, these cases suggest that structural variants should be considered in the evaluation of children with rhabdoid tumors to provide more accurate genetic counseling on the risks of developing tumors, the need for surveillance, and the risks of passing the disorder on to future children. Further research is needed to understand the prevalence, clinical features, and tumor risks associated with RTPS1-related constitutional balanced translocations.

Capmatinib is an effective treatment for MET-fusion driven pediatric high-grade glioma and synergizes with radiotherapy.

BACKGROUND: Pediatric-type diffuse high-grade glioma (pHGG) is the most frequent malignant brain tumor in children and can be subclassified into multiple entities. Fusion genes activating the MET receptor tyrosine kinase often occur in infant-type hemispheric glioma (IHG) but also in other pHGG and are associated with devastating morbidity and mortality. METHODS: To identify new treatment options, we established and characterized two novel orthotopic mouse models harboring distinct MET fusions. These included an immunocompetent, murine allograft model and patient-derived orthotopic xenografts (PDOX) from a MET-fusion IHG patient who failed conventional therapy and targeted therapy with cabozantinib. With these models, we analyzed the efficacy and pharmacokinetic properties of three MET inhibitors, capmatinib, crizotinib and cabozantinib, alone or combined with radiotherapy. RESULTS: Capmatinib showed superior brain pharmacokinetic properties and greater in vitro and in vivo efficacy than cabozantinib or crizotinib in both models. The PDOX models recapitulated the poor efficacy of cabozantinib experienced by the patient. In contrast, capmatinib extended survival and induced long-term progression-free survival when combined with radiotherapy in two complementary mouse models. Capmatinib treatment increased radiation-induced DNA double-strand breaks and delayed their repair. CONCLUSIONS: We comprehensively investigated the combination of MET inhibition and radiotherapy as a novel treatment option for MET-driven pHGG. Our seminal preclinical data package includes pharmacokinetic characterization, recapitulation of clinical outcomes, coinciding results from multiple complementing in vivo studies, and insights into molecular mechanism underlying increased efficacy. Taken together, we demonstrate the groundbreaking efficacy of capmatinib and radiation as a highly promising concept for future clinical trials.

Cerebellar Mutism Syndrome and Dentato-Thalamo-Cortical Tract Disruption in Diffusion Tractography Following Surgery for Medulloblastoma.

Background Cerebellar mutism syndrome (CMS), a complication following medulloblastoma surgery, has been linked to dentato-thalamo-cortical tract (DTCT) injury; the association of the degree of DTCT injury with severity of CMS-related symptoms has not been investigated. Purpose To investigate the association between severity of CMS-related symptoms and degree and patterns of DTCT injury with use of diffusion tensor imaging (DTI), and if laterality of injury influences neurologic symptoms. Materials and Methods This retrospective case-control study used prospectively collected clinical and DTI data on patients with medulloblastoma enrolled in a clinical trial (between July 2016 and February 2020) and healthy controls (between April and November 2017), matched with the age range of the participants with medulloblastoma. CMS was divided into types 1 (CMS1) and 2 (CMS2). Multivariable logistic regression was used to investigate the relationship between CMS likelihood and DTCT injury. Results Overall, 82 participants with medulloblastoma (mean age, 11.0 years ± 5.2 [SD]; 53 male) and 35 healthy controls (mean age, 18.0 years ± 3.06; 18 female) were included. In participants with medulloblastoma, DTCT was absent bilaterally (AB), absent on the right side (AR), absent on the left side (AL), or present bilaterally (PB), while it was PB in all healthy controls. Odds of having CMS were associated with higher degree of DTCT damage (AB, odds ratio = 272.7 [95% CI: 269.68, 275.75; P < .001]; AR, odds ratio = 14.40 [95% CI: 2.84, 101.48; P < .001]; and AL, odds ratio = 8.55 [95% CI: 1.15, 74.14; P < .001). Left (coefficient = -0.07, χ2 = 12.4, P < .001) and right (coefficient = -0.15, χ2 = 33.82, P < .001) DTCT volumes were negatively associated with the odds of CMS. More participants with medulloblastoma with AB showed CMS1; unilateral DTCT absence prevailed in CMS2. Lower DTCT volumes correlated with more severe ataxia. Unilateral DTCT injury caused ipsilateral dysmetria; AB caused symmetric dysmetria. PB indicated better neurologic outcome. Conclusion The severity of CMS-associated mutism, ataxia, and dysmetria was associated with DTCT damage severity. DTCT damage patterns differed between CMS1 and CMS2. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Dorigatti Soldatelli and Ertl-Wagner in this issue.

Effects of a comprehensive brain computed tomography deep learning model on radiologist detection accuracy.

OBJECTIVES: Non-contrast computed tomography of the brain (NCCTB) is commonly used to detect intracranial pathology but is subject to interpretation errors. Machine learning can augment clinical decision-making and improve NCCTB scan interpretation. This retrospective detection accuracy study assessed the performance of radiologists assisted by a deep learning model and compared the standalone performance of the model with that of unassisted radiologists. METHODS: A deep learning model was trained on 212,484 NCCTB scans drawn from a private radiology group in Australia. Scans from inpatient, outpatient, and emergency settings were included. Scan inclusion criteria were age ≥ 18 years and series slice thickness ≤ 1.5 mm. Thirty-two radiologists reviewed 2848 scans with and without the assistance of the deep learning system and rated their confidence in the presence of each finding using a 7-point scale. Differences in AUC and Matthews correlation coefficient (MCC) were calculated using a ground-truth gold standard. RESULTS: The model demonstrated an average area under the receiver operating characteristic curve (AUC) of 0.93 across 144 NCCTB findings and significantly improved radiologist interpretation performance. Assisted and unassisted radiologists demonstrated an average AUC of 0.79 and 0.73 across 22 grouped parent findings and 0.72 and 0.68 across 189 child findings, respectively. When assisted by the model, radiologist AUC was significantly improved for 91 findings (158 findings were non-inferior), and reading time was significantly reduced. CONCLUSIONS: The assistance of a comprehensive deep learning model significantly improved radiologist detection accuracy across a wide range of clinical findings and demonstrated the potential to improve NCCTB interpretation. CLINICAL RELEVANCE STATEMENT: This study evaluated a comprehensive CT brain deep learning model, which performed strongly, improved the performance of radiologists, and reduced interpretation time. The model may reduce errors, improve efficiency, facilitate triage, and better enable the delivery of timely patient care. KEY POINTS: • This study demonstrated that the use of a comprehensive deep learning system assisted radiologists in the detection of a wide range of abnormalities on non-contrast brain computed tomography scans. • The deep learning model demonstrated an average area under the receiver operating characteristic curve of 0.93 across 144 findings and significantly improved radiologist interpretation performance. • The assistance of the comprehensive deep learning model significantly reduced the time required for radiologists to interpret computed tomography scans of the brain.

Pigs as Clinically Relevant Models for Synergizing Interventional Oncology and Immunotherapy.

Traditionally, rodent cancer models have driven preclinical oncology research. However, they do not fully recapitulate characteristics of human cancers, and their size poses challenges when evaluating tools in the interventional oncologists' armamentarium. Pig models, however, have been the gold standard for validating surgical procedures. Their size enables the study of image-guided interventions using human ultrasound (US), computed tomography (CT), and magnetic resonance (MR) imaging platforms. Furthermore, pigs have immunologic features that are similar to those of humans, which can potentially be leveraged for studying immunotherapy. Novel pig models of cancer are being developed, but additional research is required to better understand both the pig immune system and malignancy to enhance the potential for pig models in interventional oncology research. This review aims to address the main advantages and disadvantages of using a pig model for interventional oncology and outline the specific characteristics of pig models that make them more suitable for investigation of locoregional therapies.

Characterization of Microwave Generator Energy and Ablation Volumes following Transarterial Embolization in an In Vivo Porcine Liver Model.

PURPOSE: To characterize the relationship between ablation zone volume (AZV) and microwave ablation (MWA) energy in an in vivo porcine liver model following arterial embolization. MATERIALS AND METHODS: With Institutional Animal Care and Use Committee (IACUC) approval, 11 female swine underwent either right (n = 5) or left (n = 6) hepatic artery embolization under fluoroscopic guidance. Subsequently, ultrasound (US)-guided MWA was performed in each liver segment (left lateral, left medial, right medial, and right lateral) at either 30 W (n = 4 lobes), 60 W (n = 4), 65 W (n = 20), 90 W (n = 8), 120 W (n = 4), or 140 W (n = 4) continuously for 5 minutes. Postprocedural volumetric segmentation was performed on standardized multiphase T1 magnetic resonance (MR) imaging sequences. RESULTS: Mean AZVs in embolized lobes (15.8 mL ± SD 10.6) were significantly larger than those in nonembolized lobes (11.2 mL ± SD 6.5, P < .01). MWA energy demonstrated significant positive linear correlation with both embolized (R2 = 0.66, P < .01) and nonembolized (R2 = 0.64, P < .01) lobes. The slope of the linear models corresponded to a 0.95 mL/kJ (SD ± 0.16) and 0.54 mL/kJ (SD ± 0.09) increase in ablation volume per applied kilojoule of energy (E) in embolized and nonembolized lobes, respectively. In the multivariate model, embolization status significantly modified the relationship between E and AZV as described by the following interaction term: 0.42∗E∗(embolization status) (P = .031). CONCLUSIONS: Linear models demonstrated a near 1.8-fold increase in ratio of AZV per unit E, R(AZV:E), when applied to embolized lobes relative to nonembolized lobes. Absolute AZV differences between embolized and nonembolized lobes were greater at higher-power MWA.

Dynamic Contrast-Enhanced MR Imaging Evaluation of Perfusional Changes and Ablation Zone Size after Combination Embolization and Ablation Therapy.

PURPOSE: The objectives of this study were to assess the utility of dynamic contrast-enhanced magnetic resonance (MR) imaging in quantifying parenchymal perfusional changes after embolization and to characterize the association between pharmacokinetic (PK) parameters and final microwave ablation volume. MATERIALS AND METHODS: PK parameters from dynamic contrast-enhanced MR imaging were used to quantify perfusional changes in the liver after transarterial embolization of the right or left lobe in a swine liver model (n = 5). Each animal subject subsequently underwent microwave ablation (60 W for 5 minutes) of the embolized and nonembolized liver lobes. Changes in PK parameters from dynamic contrast-enhanced MR imaging were correlated with their respective final microwave ablation volumes in each liver lobe. RESULTS: Microwave ablation volumes of embolized liver lobes were significantly larger than those of nonembolized liver lobes (28.0 mL ± 6.2 vs 15.1 mL ± 5.2, P < .001). PK perfusion parameters were significantly lower in embolized liver lobes than in nonembolized liver lobes (Ktrans = 0.69 min-1 ± 0.15 vs 1.52 min-1 ± 0.37, P < .001; kep = 0.69 min-1 ± 0.19 vs 1.54 min-1 ± 0.42, P < .001). There was a moderate but significant correlation between normalized kep and ablation volume, with each unit increase in normalized kep corresponding to a 9.8-mL decrease in ablation volume (P = .035). CONCLUSIONS: PK-derived parameters from dynamic contrast-enhanced MR imaging can be used to quantify perfusional changes after transarterial embolization and are directly inversely correlated with final ablation volume.

Central Nervous System Tumor With BCL6 Corepressor Internal Tandem Duplication: Treatment Course of a Long-term Survivor.

Central nervous system (CNS) tumor with BCL6 corepressor (BCOR) internal tandem duplication (ITD) is a newly described CNS tumor, characterized by in-frame ITDs of the BCOR gene. There is no standard practice regarding the management of this tumor. We report the clinical course of a 6-year-old boy who presented to the hospital with worsening headaches. Computed tomography scan showed a large right-sided parietal supratentorial mass and brain magnetic resonance imaging confirmed a 6×8×6.7 cm lobulated, solid but heterogeneous mass in the right parieto-occipital region. While initial pathology suggested a WHO grade 3 anaplastic meningioma, additional investigation with molecular analysis confirmed the diagnosis of high-grade neuroepithelial tumor with BCOR exon 15 ITD. This diagnosis was renamed CNS tumor with BCOR ITD in the 2021 WHO CNS tumor classification. The patient received 54 Gy of focal radiation and has no evidence of disease recurrence after 48 months from the end of treatment. As this is a newly discovered entity with only a few previous reports in the scientific literature, this report presents a unique treatment for this CNS tumor compared with those previously described.

CSF cytology of common primary CNS neoplasms categorized by CNS WHO 2021.

OBJECTIVE: The detection of neoplastic cells in cerebral spinal fluid (CSF) is pivotal for the management of patients with central nervous system (CNS) tumours. This article delves into the CSF cytological characteristics of common CNS neoplasms, aligning with the 2021 World Health Organization (WHO) classification of CNS tumours. METHODS: A retrospective review of CSF specimens positive for primary CNS neoplasms was performed at three tertiary medical centres. Only cases that had histopathologic confirmation and/or molecular workup were included. RESULTS: Common primary CNS neoplasms seen in CSF cytology specimens include medulloblastoma, (non-WNT/non-SHH as well as SHH-activated and TP53 mutant), pineoblastoma, atypical teratoid/rhabdoid tumour (AT/RT), IDH-wildtype glioblastoma, and primary diffuse large B-cell lymphoma of the CNS. Ependymomas and germinomas can also have CSF involvement but are less common. Although the typical histologic architecture of these tumours may not be preserved in the CSF, unique cytomorphologic features such as nuclear moulding, nuclear pleomorphism, rhabdoid cells, prominent nucleoli and rosette formation can still be appreciated. CONCLUSION: Adopting the updated terminology and correlating cytologic observations with molecular findings will streamline the diagnostic process, reducing the complexities and ambiguities pathologists often encounter when analysing CSF specimens for potential primary CNS neoplasms.

Contrast-Enhanced Ultrasound Findings in Patients with Rare Solitary Necrotic Nodule of the Liver - a Multicenter Report.

PURPOSE: This multicenter retrospective study highlights the contrast-enhanced ultrasound (CEUS) findings in a series of histologically proven solitary necrotic nodules (SNN) of the liver, a poorly understood pathologic entity of uncertain origin that mimics malignancy. MATERIALS AND METHODS: 22 patients (M/F 13/9; mean age 59.4 years, SD ±â€Š10.7, range 35-81) with histological diagnosis of SNN and CEUS were selected from clinical, imaging, and pathological archives of 7 US interventional centers, each of which provided 1 to 6 cases (mean 2.8). Pathological diagnosis was made on 20 US-guided biopsies and 2 surgical specimens. 2 patients had 2 SNNs with identical CEUS findings so that imaging analysis was carried out on 24 nodules. RESULTS: SNN was an incidental finding in healthy people in 10 cases (45.5 %), and it was discovered during follow-up for either known extrahepatic malignancies (9 cases = 41 %) or chronic liver disease (3 cases = 13.5 %). SNNs had a mean size of 19.3 mm (SD ±â€Š6.5, range 9-40). On B-mode US, SNNs appeared hypoechoic in 14 cases (66.7 %), "target-like" in 7 cases (29.2 %), and homogeneously hyperechoic in 1 case (4.1 %). On CEUS, all lesions appeared devoid of contrast enhancement ("punched out" aspect) in the arterial, portal venous, and late phases after US contrast agent injection. A uniformly thin, hyperenhancing ring in the early arterial phase and isoenhanced with the surrounding parenchyma in the portal venous and late phases was found in 10 nodules (41.6 %). Clinical and imaging follow-up (mean duration 42.2 months, SD ±â€Š34.9, range 2-108) was available in 15 patients with 16 SNNs: no changes in size and echostructure were seen. CONCLUSION: CEUS can contribute to the diagnosis of SNN when a "punched out" appearance in all vascular phases with or without thin rim enhancement in the very early arterial phase is present in healthy subjects in whom a focal liver lesion is incidentally found. In patients with a history of chronic liver disease or malignancy, US-guided biopsy represents the unavoidable first-line diagnostic modality.

The molecular characteristics of low-grade and high-grade areas in desmoplastic infantile astrocytoma/ganglioglioma.

AIMS: Desmoplastic infantile astrocytomas and gangliogliomas (DIA/DIGs) are rare brain tumours of infancy. A distinctive feature of their histopathology is a combination of low-grade and high-grade features. Most DIA/DIGs can be surgically resected and have a good prognosis. However, high-grade features often dominate recurrent tumours, some of which have a poor outcome. In this study, we test the hypothesis that low-grade and high-grade areas in DIA/DIGs have distinct molecular characteristics. METHODS: Tissue samples from microdissected low-grade and high-grade areas in 12 DIA/DIGs were analysed by DNA methylation profiling, whole exome sequencing, RNA sequencing and immunohistochemistry to search for potential differences at multiple molecular levels. RESULTS: Copy number variants among tumours and between the two morphologically distinct areas were infrequent. No recurrent genetic alterations were identified across the tumour series, and high-grade areas did not have additional genetic alterations to explain their distinct morphology or biological behaviour. However, high-grade areas showed relative hypomethylation in genes downstream of the transcription factors SOX9 and LEF1 and evidence of a core SOX9 transcription network alongside activation of the BMP, WNT and MAPK signalling pathways. CONCLUSIONS: This study contributes to our knowledge of molecular genetic alterations in DIA/DIGs, uncovers molecular differences between the two distinct cell populations in these tumours and suggests potential therapeutic targets among the more proliferative cell population in DIA/DIGs.

A CTNNB1-altered medulloblastoma shows the immunophenotypic, DNA methylation and transcriptomic profiles of SHH-activated, and not WNT-activated, medulloblastoma.

Recent advancements in molecular characterisation have identified four principal molecular groups of medulloblastoma: WNT, SHH, group 3 and group 4. Each has its characteristic clinical features, signature genetic alterations and distinct DNA methylome profiles. Thus far, CTNNB1 mutations have been considered pathognomonic of WNT-activated medulloblastoma. Furthermore, it has been shown that CTNNB1 mutations dominantly drive the WNT-activated phenotype in medulloblastoma, even in the presence of alterations in the SHH pathway. We herein report an illustrative case that challenges this belief-a medulloblastoma with a pathogenic CTNNB1 mutation that otherwise showed the histopathology, immunophenotype and methylation and transcriptomic profiles of an SHH-activated medulloblastoma. Detailed molecular analyses, including whole exome sequencing, transcriptome analysis and DNA methylation profiling with DKFZ brain tumour classifier and St. Jude MLPnet neural network classifier analyses, have been performed on the tumour. Our example emphasises the diagnostic value of the immunohistochemistry panel with YAP1, GAB1 and ß-catenin and DNA methylation profiling, combined with exome sequencing, in the characterisation of medulloblastoma. CTNNB1 mutations are not specific for WNT-activated medulloblastoma, and different CTNNB1 mutations have diverse oncogenic potential.

Molecular classification and outcome of children with rare CNS embryonal tumors: results from St. Jude Children's Research Hospital including the multi-center SJYC07 and SJMB03 clinical trials.

Methylation profiling has radically transformed our understanding of tumors previously called central nervous system primitive neuro-ectodermal tumors (CNS-PNET). While this marks a momentous step toward defining key differences, reclassification has thrown treatment into disarray. To shed light on response to therapy and guide clinical decision-making, we report outcomes and molecular features of children with CNS-PNETs from two multi-center risk-adapted studies (SJMB03 for patients ≥ 3 years; SJYC07 for patients < 3 years) complemented by a non-protocol institutional cohort. Seventy patients who had a histological diagnosis of CNS-PNET or CNS embryonal tumor from one of the new categories that has supplanted CNS-PNET were included. This cohort was molecularly characterized by DNA methylation profiling (n = 70), whole-exome sequencing (n = 53), RNA sequencing (n = 20), and germline sequencing (n = 28). Clinical characteristics were detailed, and treatment was divided into craniospinal irradiation (CSI)-containing (SJMB03 and SJMB03-like) and CSI-sparing therapy (SJYC07 and SJYC07-like). When the cohort was analyzed in its entirety, no differences were observed in the 5-year survival rates even when CSI-containing therapy was compared to CSI-sparing therapy. However, when analyzed by DNA methylation molecular grouping, significant survival differences were observed, and treatment particulars provided suggestions of therapeutic response. Patients with CNS neuroblastoma with FOXR2 activation (CNS-NB-FOXR2) had a 5-year event-free survival (EFS)/overall survival (OS) of 66.7% ± 19.2%/83.3% ± 15.2%, and CIC rearranged sarcoma (CNS-SARC-CIC) had a 5-year EFS/OS both of 57.1% ± 18.7% with most receiving regimens that contained radiation (focal or CSI) and multidrug chemotherapy. Patients with high-grade neuroepithelial tumor with BCOR alteration (HGNET-BCOR) had abysmal responses to upfront chemotherapy-only regimens (5-year EFS = 0%), but survival extended with salvage radiation after progression [5-year OS = 53.6% ± 20.1%]. Patients with embryonal tumor with multilayered rosettes (ETMR) or high-grade glioma/glioblastoma multiforme (HGG/GBM) did not respond favorably to any modality (5-year EFS/OS = 10.7 ± 5.8%/17.9 ± 7.2%, and 10% ± 9.0%/10% ± 9.0%, respectively). As an accompaniment, we have assembled this data onto an interactive website to allow users to probe and query the cases. By reporting on a carefully matched clinical and molecular cohort, we provide the needed insight for future clinical management.

Cost-effectiveness of professional-mode flash glucose monitoring in general practice among adults with type 2 diabetes: Evidence from the GP-OSMOTIC trial.

AIM: To assess the cost-effectiveness of professional-mode flash glucose monitoring in adults with type 2 diabetes in general practice compared with usual clinical care. METHODS: An economic evaluation was conducted as a component of the GP-OSMOTIC trial, a pragmatic multicentre 12-month randomised controlled trial enrolling 299 adults with type 2 diabetes in Victoria, Australia. The economic evaluation was conducted from an Australian healthcare sector perspective with a lifetime horizon. Health-related quality of life (EQ-5D) and total healthcare costs were compared between the intervention and the usual care group within the trial period. The 'UKPDS Outcomes Model 2' was used to simulate post-trial lifetime costs, life expectancy and quality-adjusted life years (QALYs). RESULTS: No significant difference in health-related quality of life and costs was found between the two groups within the trial period. Professional-mode flash glucose monitoring yielded greater QALYs (0.03 [95% CI: 0.02, 0.04]) and a higher cost (A$3807 [95% CI: 3604, 4007]) compared with usual clinical care using a lifetime horizon under the trial-based monitoring frequency, considered not cost-effective (incremental cost-effectiveness ratio = A$120,228). The intervention becomes cost-effective if sensor price is reduced to lower than 50%, or monitoring frequency is decreased to once per year while maintaining the same treatment effect on HbA1c . CONCLUSIONS: Including professional-mode flash glucose monitoring every 3 months as part of a management plan for people with type 2 diabetes in general practice is not cost-effective, but could be if the sensor price or monitoring frequency can be reduced.

Creation of a successful multidisciplinary course in pediatric neuro-oncology with a systematic approach to curriculum development.

BACKGROUND: The St Jude Global Academy Neuro-Oncology Training Seminar (NOTS) is a hybrid course in pediatric neuro-oncology specifically designed for physicians from low-income and middle-income countries. METHODS: The curriculum for the course was created by conducting a targeted needs assessment that evaluated 11 domains of care for children with central nervous system (CNS) tumors. The targeted needs assessment was completed by 24 institutions across the world, and the data were used to define 5 core elements included in the 2 components of the NOTS: a 9-week online course and a 7-day in-person workshop. Participant acquisition of knowledge and changes in clinical behavior were evaluated as measures of success. RESULTS: Teams from 8 institutions located in 8 countries enrolled in the online course, and it was successfully completed by 36 participants representing 6 specialties. On the basis of their performance in the online course, 20 participants from 7 institutions took part in the on-site workshop. The participants exhibited improved knowledge in core elements of treating children with CNS tumors, including barriers of care, possible solutions, and steps for project implementation (P < .0001). All participants expressed a belief that they acquired new concepts and knowledge, leading to changes in their clinical practice. Those present at the workshop created an international multidisciplinary group focused on treating CNS tumors in low-income and middle-income countries. CONCLUSIONS: By using a hybrid online and in-person approach, the authors successfully created a multidisciplinary course focused on pediatric CNS tumors for resource-limited settings. Their experience supports this strategy as a feasible mechanism for driving further global collaborations.

Case 286: Sarcoidlike Granulomatosis and Lymphadenopathy-Thoracic Manifestations of Nivolumab Drug Toxicity.

History A 70-year-old man had a posterior left thigh lesion confirmed to be biopsy-proven melanoma. The patient underwent wide excision and sentinel node biopsy, which showed absence of residual melanoma. Two years later, the patient noticed a subcentimeter subcutaneous lump in his thigh. Repeat excisional biopsy showed involvement of the surrounding soft tissue, consistent with a satellite lesion. Follow-up combined PET/CT revealed satellite nodules around the primary lesion, enabling confirmation of subcutaneous metastatic disease. The patient was subsequently started on nivolumab, an anti-programmed cell death 1 (PD-1) immune checkpoint inhibitor that blocks PD-1 and is approved as a first-line treatment in patients with advanced metastatic melanoma. On the baseline scan prior to starting nivolumab, there were no CT findings that suggested metastatic disease, nor were there enlarged mediastinal or hilar lymph nodes. Five months after initiation of nivolumab treatment, the first follow-up chest CT scan was performed and showed new findings in the mediastinum and bilateral lungs. The patient remained asymptomatic during the treatment period. Furthermore, the subcutaneous metastatic disease remained stable during the treatment period, and no other site of metastatic disease was noted on follow-up CT scans obtained during the first 5 months of treatment. The patient had no prior history of infectious or occupational exposures. During the nivolumab treatment cycle, his pertinent laboratory values and physical examination findings were unremarkable.

Radiohistogenomics of pediatric low-grade neuroepithelial tumors.

PURPOSE: In addition to histology, genetic alteration is now required to classify many central nervous system (CNS) tumors according to the most recent World Health Organization CNS tumor classification scheme. Although that is still not the case for classifying pediatric low-grade neuroepithelial tumors (PLGNTs), genetic and molecular features are increasingly being used for making treatment decisions. This approach has become a standard clinical practice in many specialized pediatric cancer centers and will likely be more widely practiced in the near future. This paradigm shift in the management of PLGNTs necessitates better understanding of how genetic alterations influence histology and imaging characteristics of individual PLGNT phenotypes. METHODS: The complex association of genetic alterations with histology, clinical, and imaging of each phenotype of the extremely heterogeneous PLGNT family has been addressed in a holistic approach in this up-to-date review article. A new imaging stratification scheme has been proposed based on tumor morphology, location, histology, and genetics. Imaging characteristics of each PLGNT entity are also depicted in light of histology and genetics. CONCLUSION: This article reviews the association of specific genetic alteration with location, histology, imaging, and prognosis of a specific tumor of the PLGNT family and how that information can be used for better imaging of these tumors.

Use of Contrast-Enhanced Ultrasound in Ablation Therapy of HCC: Planning, Guiding, and Assessing Treatment Response.

Contrast-enhanced ultrasonography (CEUS) plays an important role in the management of patients treated with ablation therapies, in the diagnostic, therapeutic and monitoring phases. Compared to contrast-enhanced computed tomography and contrast-enhanced magnetic resonance imaging, CEUS presents several advantages in imaging HCC, including real time imaging capability, high sensitivity for tumor vascularity, absence of renal toxicity, no ionizing radiation, repeatability of injections, good compliance by the patient and low cost. The purpose of this review is to evaluate the role of CEUS in the management of the patients with HCC treated with ablation therapies and describe how in our protocol CEUS is integrated with the other imaging modalities such as contrast-enhanced computed tomography and contrast-enhanced magnetic resonance imaging.

Multimorbidity, mortality, and HbA1c in type 2 diabetes: A cohort study with UK and Taiwanese cohorts.

BACKGROUND: There is emerging interest in multimorbidity in type 2 diabetes (T2D), which can be either concordant (T2D related) or discordant (unrelated), as a way of understanding the burden of disease in T2D. Current diabetes guidelines acknowledge the complex nature of multimorbidity, the management of which should be based on the patient's individual clinical needs and comorbidities. However, although associations between multimorbidity, glycated haemoglobin (HbA1c), and mortality in people with T2D have been studied to some extent, significant gaps remain, particularly regarding different patterns of multimorbidity, including concordant and discordant conditions. This study explores associations between multimorbidity (total condition counts/concordant/discordant/different combinations of conditions), baseline HbA1c, and all-cause mortality in T2D. METHODS AND FINDINGS: We studied two longitudinal cohorts of people with T2D using the UK Biobank (n = 20,569) and the Taiwan National Diabetes Care Management Program (NDCMP) (n = 59,657). The number of conditions in addition to T2D was used to quantify total multimorbidity, concordant, and discordant counts, and the effects of different combinations of conditions were also studied. Outcomes of interest were baseline HbA1c and all-cause mortality. For the UK Biobank and Taiwan NDCMP, mean (SD) ages were 60.2 (6.8) years and 60.8 (11.3) years; 7,579 (36.8%) and 31,339 (52.5%) were female; body mass index (BMI) medians (IQR) were 30.8 (27.7, 34.8) kg/m2 and 25.6 (23.5, 28.7) kg/m2; and 2,197 (10.8%) and 9,423 (15.8) were current smokers, respectively. Increasing total and discordant multimorbidity counts were associated with lower HbA1c and increased mortality in both datasets. In Taiwan NDCMP, for those with four or more additional conditions compared with T2D only, the mean difference (95% CI) in HbA1c was -0.82% (-0.88, -0.76) p < 0.001. In UK Biobank, hazard ratios (HRs) (95% CI) for all-cause mortality in people with T2D and one, two, three, and four or more additional conditions compared with those without comorbidity were 1.20 (0.91-1.56) p < 0.001, 1.75 (1.35-2.27) p < 0.001, 2.17 (1.67-2.81) p < 0.001, and 3.14 (2.43-4.03) p < 0.001, respectively. Both concordant/discordant conditions were significantly associated with mortality; however, HRs were largest for concordant conditions. Those with four or more concordant conditions had >5 times the mortality (5.83 [4.28-7.93] p <0.001). HRs for NDCMP were similar to those from UK Biobank for all multimorbidity counts. For those with two conditions in addition to T2D, cardiovascular diseases featured in 18 of the top 20 combinations most highly associated with mortality in UK Biobank and 12 of the top combinations in the Taiwan NDCMP. In UK Biobank, a combination of coronary heart disease and heart failure in addition to T2D had the largest effect size on mortality, with a HR (95% CI) of 4.37 (3.59-5.32) p < 0.001, whereas in the Taiwan NDCMP, a combination of painful conditions and alcohol problems had the largest effect size on mortality, with an HR (95% CI) of 4.02 (3.08-5.23) p < 0.001. One limitation to note is that we were unable to model for changes in multimorbidity during our study period. CONCLUSIONS: Multimorbidity patterns associated with the highest mortality differed between UK Biobank (a population predominantly comprising people of European descent) and the Taiwan NDCMP, a predominantly ethnic Chinese population. Future research should explore the mechanisms underpinning the observed relationship between increasing multimorbidity count and reduced HbA1c alongside increased mortality in people with T2D and further examine the implications of different patterns of multimorbidity across different ethnic groups. Better understanding of these issues, especially effects of condition type, will enable more effective personalisation of care.