The molecular interaction pattern of lenvatinib enables inhibition of wild-type or kinase-mutated FGFR2-driven cholangiocarcinoma.

Fibroblast growth factor receptor (FGFR)-2 can be inhibited by FGFR-selective or non-selective tyrosine kinase inhibitors (TKIs). Selective TKIs are approved for cholangiocarcinoma (CCA) with FGFR2 fusions; however, their application is limited by a characteristic pattern of adverse events or evocation of kinase domain mutations. A comprehensive characterization of a patient cohort treated with the non-selective TKI lenvatinib reveals promising efficacy in FGFR2-driven CCA. In a bed-to-bench approach, we investigate FGFR2 fusion proteins bearing critical tumor-relevant point mutations. These mutations confer growth advantage of tumor cells and increased resistance to selective TKIs but remain intriguingly sensitive to lenvatinib. In line with clinical observations, in-silico analyses reveal a more favorable interaction pattern of lenvatinib with FGFR2, including an increased flexibility and ligand efficacy, compared to FGFR-selective TKIs. Finally, the treatment of a patient with progressive disease and a newly developed kinase mutation during therapy with a selective inhibitor results in a striking response to lenvatinib. Our in vitro, in silico, and clinical data suggest that lenvatinib is a promising treatment option for FGFR2-driven CCA, especially when insurmountable adverse reactions of selective TKIs or acquired kinase mutations occur.

A novel fully automated method for measuring ASPECTS to improve stroke diagnosis: Comparison to traditional ASPECTS.

BACKGROUND AND PURPOSE: To compare the accuracy of subjective Alberta Stroke Program Early CT Score (sASPECTS) evaluation and that of an automated prototype software (aASPECTS) on nonenhanced CT (NECT) in patients with early anterior territory stroke and controls using side-to-side quantification of hypoattenuated brain areas. METHODS: We retrospectively analyzed the NECT scans of 42 consecutive patients with ischemic stroke before reperfusion and 42 controls using first sASPECTS and subsequently aASPECTS. We assessed the differences in Alberta Stroke Program Early CT Score (ASPECTS) and calculated the sensitivity and specificity of NECT with CT perfusion, whereas cerebral blood volume (CBV) served as the reference standard for brain infarction. RESULTS: The clot was located in the middle cerebral artery (MCA) in 47.6% of cases and the internal carotid artery (ICA) in 28.6% of cases. Ten cases presented combined ICA and MCA occlusions. The stroke was right sided in 52.4% of cases and left sided in 47.6%. Reader-based NECT analysis yielded a median sASPECTS of 10. The median CBV-based ASPECTS was 7. Compared to the area of decreased CBV, sASPECTS yielded a sensitivity of 12.5% and specificity of 86.8%. The software prototype (aASPECTS) yielded an overall sensitivity of 65.5% and a specificity of 92.2%. The interreader agreement for ASPECTS evaluation of admission NECT and follow-up CT was almost perfect (κ = .93). The interreader agreement of the CBV color map evaluation was substantial (κ = .77). CONCLUSIONS: aASPECTS of NECT can outperform sASPECTS for stroke detection.

Photon-counting computed tomography - clinical application in oncological, cardiovascular, and pediatric radiology. / Photon-Counting Computertomographie ­ klinische Anwendungen in der onkologischen, kardiovaskulären und pädiatrischen Radiologie.

BACKGROUND: Photon-counting detector computed tomography (PCD-CT) is a promising new technology with the potential to fundamentally change workflows in the daily routine and provide new quantitative imaging information to improve clinical decision-making and patient management. METHOD: The contents of this review are based on an unrestricted literature search of PubMed and Google Scholar using the search terms "photon-counting CT", "photon-counting detector", "spectral CT", "computed tomography" as well as on the authors' own experience. RESULTS: The fundamental difference with respect to the currently established energy-integrating CT detectors is that PCD-CT allows for the counting of every single photon at the detector level. Based on the identified literature, PCD-CT phantom measurements and initial clinical studies have demonstrated that the new technology allows for improved spatial resolution, reduced image noise, and new possibilities for advanced quantitative image postprocessing. CONCLUSION: For clinical practice, the potential benefits include fewer beam hardening artifacts, a radiation dose reduction, and the use of new or combinations of contrast agents. In particular, critical patient groups such as oncological, cardiovascular, lung, and head & neck as well as pediatric patient collectives benefit from the clinical advantages. KEY POINTS: · Photon-counting computed tomography (PCD-CT) is being used for the first time in routine clinical practice, enabling a significant dose reduction in critical patient populations such as oncology, cardiology, and pediatrics.. · Compared to conventional CT, PCD-CT enables a reduction in electronic image noise.. · Due to the spectral data sets, PCD-CT enables fully comprehensive post-processing applications.. CITATION FORMAT: · Hagen F, Soschynski M, Weis M et al. Photon-counting computed tomography - clinical application in oncological, cardiovascular, and pediatric radiology. Fortschr Röntgenstr 2024; 196: 25 - 34.

Imaging of Pathologies of the Temporal Bone and Middle Ear: Inflammatory Diseases, Their Mimics and Potential Complications-Pictorial Review.

Imaging of the temporal bone and middle ear is challenging for radiologists due to the abundance of distinct anatomical structures and the plethora of possible pathologies. The basis for a precise diagnosis is knowledge of the underlying anatomy as well as the clinical presentation and the individual patient's otological status. In this article, we aimed to summarize the most common inflammatory lesions of the temporal bone and middle ear, describe their specific imaging characteristics, and highlight their differential diagnoses. First, we introduce anatomical and imaging fundamentals. Additionally, a point-to-point comparison of the radiological and histological features of the wide spectrum of inflammatory diseases of the temporal bone and middle ear in context with a review of the current literature and current trends is given.

Myasthenia gravis as initial presentation of a pancreatic neuroendocrine tumor: A case report.

Myasthenia gravis (MG) is a heterogeneous autoimmune disease, which is characterized by a postsynaptic neuromuscular transmission defect, with antibodies directly targeting the acetylcholine receptor (AChR) or other structural proteins of the neuromuscular junction. The majority of MG cases are associated with thymic pathologies, including thymoma, thyroiditis, autoimmune diseases or malignant hematologic neoplasia. The present study reported a rare case of AChR-positive and late-onset ocular MG, which rapidly progressed to a generalized myasthenic syndrome as an initial presentation of a pancreatic neuroendocrine neoplasia (pNEN). Following complete surgical resection of the pNEN, the myasthenic syndrome was improved and the anti-AChR antibody titers were reduced. It has been reported that MG is a paraneoplastic syndrome in thymic neoplasms and less common in hematologic malignancies. However, currently, only few cases of MG as initial presentation of a solid tumor, and more particular of a neuroendocrine neoplasm, have been reported in the literature. In conclusion, surveillance for extrathymic solid malignancies in newly diagnosed patients with MG could promote the early diagnosis of associated tumor diseases.

Automated Intracranial Clot Detection: A Promising Tool for Vascular Occlusion Detection in Non-Enhanced CT.

(1) Background: to test the diagnostic performance of a fully convolutional neural network-based software prototype for clot detection in intracranial arteries using non-enhanced computed tomography (NECT) imaging data. (2) Methods: we retrospectively identified 85 patients with stroke imaging and one intracranial vessel occlusion. An automated clot detection prototype computed clot location, clot length, and clot volume in NECT scans. Clot detection rates were compared to the visual assessment of the hyperdense artery sign by two neuroradiologists. CT angiography (CTA) was used as the ground truth. Additionally, NIHSS, ASPECTS, type of therapy, and TOAST were registered to assess the relationship between clinical parameters, image results, and chosen therapy. (3) Results: the overall detection rate of the software was 66%, while the human readers had lower rates of 46% and 24%, respectively. Clot detection rates of the automated software were best in the proximal middle cerebral artery (MCA) and the intracranial carotid artery (ICA) with 88-92% followed by the more distal MCA and basilar artery with 67-69%. There was a high correlation between greater clot length and interventional thrombectomy and between smaller clot length and rather conservative treatment. (4) Conclusions: the automated clot detection prototype has the potential to detect intracranial arterial thromboembolism in NECT images, particularly in the ICA and MCA. Thus, it could support radiologists in emergency settings to speed up the diagnosis of acute ischemic stroke, especially in settings where CTA is not available.

CD19-Targeting CAR T Cells for Myositis and Interstitial Lung Disease Associated With Antisynthetase Syndrome.

Importance: Autoimmune disorders can affect various organs and if refractory, can be life threatening. Recently, CD19-targeting-chimeric antigen receptor (CAR) T cells were efficacious as an immune suppressive agent in 6 patients with refractory systemic lupus erythematosus and in 1 patient with antisynthetase syndrome. Objective: To test the safety and efficacy of CD19-targeting CAR T cells in a patient with severe antisynthetase syndrome, a complex autoimmune disorder with evidence for B- and T-cell involvement. Design, Setting, and Participants: This case report describes a patient with antisynthetase syndrome with progressive myositis and interstitial lung disease refractory to available therapies (including rituximab and azathioprine), who was treated with CD19-targeting CAR T cells in June 2022 at University Hospital Tübingen in Tübingen, Germany, with the last follow-up in February 2023. Mycophenolate mofetil was added to the treatment to cotarget CD8+ T cells, hypothesized to contribute to disease activity. Exposure: Prior to treatment with CD19-targeting CAR T cells, the patient received conditioning therapy with fludarabine (25 mg/m2 [5 days before until 3 days before]) and cyclophosphamide (1000 mg/m2 [3 days before]) followed by infusion of CAR T cells (1.23×106/kg [manufactured by transduction of autologous T cells with a CD19 lentiviral vector and amplification in the CliniMACS Prodigy system]) and mycophenolate mofetil (2 g/d) 35 days after CD19-targeting CAR T-cell infusion. Main Outcomes and Measures: The patient's response to therapy was followed by magnetic resonance imaging of the thigh muscle, Physician Global Assessment, functional muscle and pulmonary tests, and peripheral blood quantification of anti-Jo-1 antibody levels, lymphocyte subsets, immunoglobulins, and serological muscle enzymes. Results: Rapid clinical improvement was observed after CD19-targeting CAR T-cell infusion. Eight months after treatment, the patient's scores on the Physician Global Assessment and muscle and pulmonary function tests improved, and there were no detectable signs of myositis on magnetic resonance imaging. Serological muscle enzymes (alanine aminotransferase, aspartate aminotransferase, creatinine kinase, and lactate dehydrogenase), CD8+ T-cell subsets, and inflammatory cytokine secretion in the peripheral blood mononuclear cells (interferon gamma, interleukin 1 [IL-1], IL-6, and IL-13) were all normalized. Further, there was a reduction in anti-Jo-1 antibody levels and a partial recovery of IgA (to 67% of normal value), IgG (to 87%), and IgM (to 58%). Conclusions and Relevance: CD19-targeting CAR T cells directed against B cells and plasmablasts deeply reset B-cell immunity. Together with mycophenolate mofetil, CD19-targeting CAR T cells may break pathologic B-cell, as well as T-cell responses, inducing remission in refractory antisynthetase syndrome.

Is There Still a Role for Two-Phase Contrast-Enhanced CT and Virtual Monoenergetic Images in the Era of Photon-Counting Detector CT?

BACKGROUND: To compare the diagnostic characteristics between arterial phase imaging versus portal venous phase imaging, applying polychromatic T3D images and low keV virtual monochromatic images using a 1st generation photon-counting CT detector, of CT in patients with hepatocellular carcinoma (HCC). METHODS: Consecutive patients with HCC, with a clinical indication for CT imaging, were prospectively enrolled. Virtual monoenergetic images (VMI) were reconstructed at 40 to 70 keV for the PCD-CT. Two independent, blinded radiologists counted all hepatic lesions and quantified their size. The lesion-to-background ratio was quantified for both phases. SNR and CNR were determined for T3D and low VMI images; non-parametric statistics were used. RESULTS: Among 49 oncologic patients (mean age 66.9 ± 11.2 years, eight females), HCC was detected in both arterial and portal venous scans. The signal-to-noise ratio, the CNR liver-to-muscle, the CNR tumor-to-liver, and CNR tumor-to-muscle were 6.58 ± 2.86, 1.40 ± 0.42, 1.13 ± 0.49, and 1.53 ± 0.76 in the arterial phase and 5.93 ± 2.97, 1.73 ± 0.38, 0.79 ± 0.30, and 1.36 ± 0.60 in the portal venous phase with PCD-CT, respectively. There was no significant difference in SNR between the arterial and portal venous phases, including between "T3D" and low keV images (p > 0.05). CNRtumor-to-liver differed significantly between arterial and portal venous contrast phases (p < 0.005) for both "T3D" and all reconstructed keV levels. CNRliver-to-muscle and CNRtumor-to-muscle did not differ in either the arterial or portal venous contrast phases. CNRtumor-to-liver increased in the arterial contrast phase with lower keV in addition to SD. In the portal venous contrast phase, CNRtumor-to-liver decreased with lower keV; whereas, CNRtumor-to-muscle increased with lower keV in both arterial and portal venous contrast phases. CTDI and DLP mean values for the arterial upper abdomen phase were 9.03 ± 3.59 and 275 ± 133, respectively. CTDI and DLP mean values for the abdominal portal venous phase were 8.75 ± 2.99 and 448 ± 157 with PCD-CT, respectively. No statistically significant differences were found concerning the inter-reader agreement for any of the (calculated) keV levels in either the arterial or portal-venous contrast phases. CONCLUSIONS: The arterial contrast phase imaging provides higher lesion-to-background ratios of HCC lesions using a PCD-CT; especially, at 40 keV. However, the difference was not subjectively perceived as significant.

Prediction of Bone Marrow Biopsy Results From MRI in Multiple Myeloma Patients Using Deep Learning and Radiomics.

OBJECTIVES: In multiple myeloma and its precursor stages, plasma cell infiltration (PCI) and cytogenetic aberrations are important for staging, risk stratification, and response assessment. However, invasive bone marrow (BM) biopsies cannot be performed frequently and multifocally to assess the spatially heterogenous tumor tissue. Therefore, the goal of this study was to establish an automated framework to predict local BM biopsy results from magnetic resonance imaging (MRI). MATERIALS AND METHODS: This retrospective multicentric study used data from center 1 for algorithm training and internal testing, and data from center 2 to 8 for external testing. An nnU-Net was trained for automated segmentation of pelvic BM from T1-weighted whole-body MRI. Radiomics features were extracted from these segmentations, and random forest models were trained to predict PCI and the presence or absence of cytogenetic aberrations. Pearson correlation coefficient and the area under the receiver operating characteristic were used to evaluate the prediction performance for PCI and cytogenetic aberrations, respectively. RESULTS: A total of 672 MRIs from 512 patients (median age, 61 years; interquartile range, 53-67 years; 307 men) from 8 centers and 370 corresponding BM biopsies were included. The predicted PCI from the best model was significantly correlated ( P ≤ 0.01) to the actual PCI from biopsy in all internal and external test sets (internal test set: r = 0.71 [0.51, 0.83]; center 2, high-quality test set: r = 0.45 [0.12, 0.69]; center 2, other test set: r = 0.30 [0.07, 0.49]; multicenter test set: r = 0.57 [0.30, 0.76]). The areas under the receiver operating characteristic of the prediction models for the different cytogenetic aberrations ranged from 0.57 to 0.76 for the internal test set, but no model generalized well to all 3 external test sets. CONCLUSIONS: The automated image analysis framework established in this study allows for noninvasive prediction of a surrogate parameter for PCI, which is significantly correlated to the actual PCI from BM biopsy.