Quantitative assessment of gadolinium deposition in dentate nuclei with MR fingerprinting.

RATIONALE AND OBJECTIVES: Gadolinium deposition in the dentate nucleus (DN) has been evaluated by T1-weighted imaging (T1WI) and T1 (R1) mapping, but not MR fingerprinting (MRF). This study investigated associations between T1 and T2 values of DN and gadolinium-based contrast agents (GBCAs) using 2-dimensional MRF. MATERIALS AND METHODS: This study included 101 patients. Region of interest analysis was performed for T1 and T2 values of DN on MRF (T1-MRF, T2-MRF) and T1-weighted images (T1WI ratio). T1 and T2 ratios compared to normal cerebellar white matter (T1-MRF ratio, T2-MRF ratio) were calculated. The type of previous GBCA was confirmed in 79 patients, and linear regressions were performed between T1, T2 values and number of GBCAs. RESULTS: Good correlations were observed between T1-MRF and T1WI ratio (ρ = -0.69, P < 0.001) and between T1-MRF ratio and T1WI ratio (ρ = -0.76, P < 0.001). Mild correlations were observed between T2-MRF and T1WI ratio (ρ = -0.32, P < 0.001) and between T2-MRF ratio and T1WI ratio (ρ = -0.44, P < 0.001). The number of linear-type GBCAs was associated with T1-MRF (ß = -0.62, P < 0.001) and T1-MRF ratio (ß = -0.54, P < 0.001) in univariate linear regression analyses, and with T1-MRF (ß = -0.61, P < 0.001) and T1-MRF ratio (ß = -0.53, P < 0.001) in multivariate analysis. The number of linear-type GBCAs was associated with T2-MRF (ß = -0.30, P < 0.001) and T2-MRF ratio (ß = -0.29, P < 0.001) in univariate analyses, and with T2-MRF (ß = -0.31, P < 0.001) and T2-MRF ratio (ß = -0.32, P < 0.001) in multivariate analyses. No associations were observed between number of macrocyclic GBCAs and T1-MRF (ratio) or T2-MRF (ratio). CONCLUSION: The number of linear-type GBCA administrations was associated with lower T1 and T2 values (ratios) in DN.

The effect of Fc region affinity of protein-based antibody-recruiting molecules on antibody-dependent cellular cytotoxicity.

Previously, we reported anticancer molecules, Fc-binding antibody-recruiting molecules (Fc-ARMs), which crosslink proteins on cancer cells with endogenous immunoglobulin Gs (IgGs) via their Fc region. The mobilized IgGs on cancer cells can accommodate natural killer cells to induce antibody-dependent cellular cytotoxicity (ADCC). Because previous Fc-ARMs utilized Fc-binding peptides, their affinity to IgGs is weak, which resulted in the limited induction capability of ADCC. Previous Fc-ARMs also unitized small molecular ligands to cancer cells, which limited their universal applicability to any cancer cells. A recent study reported that protein-based Fc-ARMs might overcome the issues associated with non-proteinous Fc-ARMs. Here, we examined the universality of a protein-based Fc-ARM by replacing its tumor-binding domain with a human epidermal growth factor receptor 2 (HER2)-specific affibody (ZHER2:342). We also examined the requirement of its Fc-binding domain affinity. We found that the Fc-ARMs accepted an affibody as a tumor-binding domain to induce ADCC. Furthermore, the required residence time of the complex between Fc-ARM and IgG was ∼102 min, which was comparable to that when monoclonal antibodies bind to their specific antigens. However, we found that the extent of ADCC induced by Fc-ARM was lower than that of conventional IgG-mediated ADCC, indicating that further enhancement of the affinity of the antibody-binding terminus and tumor-binding terminus of Fc-ARM may be needed to achieve ADCC equivalent to that of conventional IgG-mediated ADCC.

Thin-slice reverse encoding distortion correction DWI facilitates visualization of non-functioning pituitary neuroendocrine tumor (PitNET)/pituitary adenoma and surrounding normal structures.

BACKGROUND: To evaluate the clinical usefulness of thin-slice echo-planar imaging (EPI)-based diffusion-weighted imaging (DWI) with an on-console distortion correction technique, termed reverse encoding distortion correction DWI (RDC-DWI), in patients with non-functioning pituitary neuroendocrine tumor (PitNET)/pituitary adenoma. METHODS: Patients with non-functioning PitNET/pituitary adenoma who underwent 3-T RDC-DWI between December 2021 and September 2022 were retrospectively enrolled. Image quality was compared among RDC-DWI, DWI with correction for distortion induced by B0 inhomogeneity alone (B0-corrected-DWI), and original EPI-based DWI with anterior-posterior phase-encoding direction (AP-DWI). Susceptibility artifact, anatomical visualization of cranial nerves, overall tumor visualization, and visualization of cavernous sinus invasion were assessed qualitatively. Quantitative assessment of geometric distortion was performed by evaluation of anterior and posterior displacement between each DWI and the corresponding three-dimensional T2-weighted imaging. Signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and apparent diffusion coefficient values were measured. RESULTS: Sixty-four patients (age 70.8 ± 9.9 years [mean ± standard deviation]; 33 females) with non-functioning PitNET/pituitary adenoma were evaluated. In terms of susceptibility artifacts in the frontal and temporal lobes, visualization of left trigeminal nerve, overall tumor visualization, and anterior displacement, RDC-DWI performed the best and B0-corrected-DWI performed better than AP-DWI. The right oculomotor and right trigeminal nerves were better visualized by RDC-DWI than by B0-corrected-DWI and AP-DWI. Visualization of cavernous sinus invasion and posterior displacement were better by RDC-DWI and B0-corrected-DWI than by AP-DWI. SNR and CNR were the highest for RDC-DWI. CONCLUSIONS: RDC-DWI achieved excellent image quality regarding susceptibility artifact, geometric distortion, and tumor visualization in patients with non-functioning PitNET/pituitary adenoma. RELEVANCE STATEMENT: RDC-DWI facilitates excellent visualization of the pituitary region and surrounding normal structures, and its on-console distortion correction technique is convenient. RDC-DWI can clearly depict cavernous sinus invasion of PitNET/pituitary adenoma even without contrast medium. KEY POINTS: • RDC-DWI is an EPI-based DWI technique with a novel on-console distortion correction technique. • RDC-DWI corrects distortion due to B0 field inhomogeneity and eddy current. • We evaluated the usefulness of thin-slice RDC-DWI in non-functioning PitNET/pituitary adenoma. • RDC-DWI exhibited excellent visualization in the pituitary region and surrounding structures. • In addition, the on-console distortion correction of RDC-DWI is clinically convenient.

Vessel wall MRI in moyamoya disease: arterial wall enhancement varies depending on age, arteries, and disease progression.

OBJECTIVE: To investigate the relationship of followings for patients with moyamoya disease (MMD): arterial wall enhancement on vessel wall MRI (VW-MRI), cross-sectional area (CSA), time-of-flight MR angiography (MRA), age, locations from intracranial internal carotid artery (ICA) to proximal middle cerebral artery (MCA), disease progression, and transient ischemic attack (TIA). METHODS: Patients who underwent VW-MRI between October 2018 and December 2020 were enrolled in this retrospective study. We measured arterial wall enhancement (enhancement ratio, ER) and CSA at five sections of ICA and MCA. Also, we scored MRA findings. Multiple linear regression (MLR) analysis was performed to explore the associations between ER, age, MRA score, CSA, history of TIA, and surgical revascularization. RESULTS: We investigated 102 sides of 51 patients with MMD (35 women, 16 men, mean age 31 years ± 18 [standard deviation]). ER for MRA score 2 (signal discontinuity) was higher than ER for other scores in sections D (end of ICA) and E (proximal MCA) on MLR analysis. ER in section E was significantly higher in patients for MRA score 2 with TIA history than without. ER significantly increased as CSA increased in section E, which suggests ER becomes less in decreased CSA due to negative remodeling. CONCLUSION: Arterial wall enhancement in MMD varies by age, location, and disease progression. Arterial wall enhancement may be stronger in the progressive stage of MMD. Arterial wall enhancement increases with history of TIA at proximal MCA, which may indicate the progression of the disease. CLINICAL RELEVANCE STATEMENT: Arterial wall enhancement in moyamoya disease varies by age, location of arteries, and disease progression, and arterial wall enhancement may be used as an imaging biomarker of moyamoya disease. KEY POINTS: It has not been clarified what arterial wall enhancement in moyamoya disease represents. Arterial wall enhancement in moyamoya disease varies by age, location of arteries, and disease progression. Arterial wall enhancement in moyamoya disease increases as the disease progresses.

Incidence of neurocutaneous melanosis in Japanese pediatric patients with congenital melanocytic nevi.

Neurocutaneous melanosis (NCM) is a rare, non-hereditary neurocutaneous disorder characterized by excessive melanocytic proliferation in the skin and central nervous system. As no major studies have covered the incidence of NCM among Japanese patients with congenital melanocytic nevi (CMN), we prospectively investigated the incidence of NCM among Japanese patients who underwent initial treatment for CMN. The relationship of CMN and NCM was also investigated. Japanese pediatric patients with CMN under 1 year of age were included between January 2020 and November 2022, and all patients underwent brain MRI to check for NCM in this study. NCM lesions were most frequently seen in the amygdala, followed by the cerebellum, brainstem, and cerebral hemispheres. NCM was diagnosed on brain MRI in 31.6% of the 38 patients with CMN and in 25.0% of patients with no prior examination or treatment. Distribution and size of CMN, number of satellite nevi, rugosity and nodules were strongly associated with the existence of NCM, and these findings may guide a future registry study with a large cohort of CMN patients.

Accuracy, repeatability, and reproducibility of T1 and T2 relaxation times measurement by 3D magnetic resonance fingerprinting with different dictionary resolutions.

OBJECTIVES: To assess the accuracy, repeatability, and reproducibility of T1 and T2 relaxation time measurements by three-dimensional magnetic resonance fingerprinting (3D MRF) using various dictionary resolutions. METHODS: The ISMRM/NIST phantom was scanned daily for 10 days in two 3 T MR scanners using a 3D MRF sequence reconstructed using four dictionaries with varying step sizes and one dictionary with wider ranges. Thirty-nine healthy volunteers were enrolled: 20 subjects underwent whole-brain MRF scans in both scanners and the rest in one scanner. ROI/VOI analyses were performed on phantom and brain MRF maps. Accuracy, repeatability, and reproducibility metrics were calculated. RESULTS: In the phantom study, all dictionaries showed high T1 linearity to the reference values (R2 > 0.99), repeatability (CV < 3%), and reproducibility (CV < 3%) with lower linearity (R2 > 0.98), repeatability (CV < 6%), and reproducibility (CV ≤ 4%) for T2 measurement. The volunteer study demonstrated high T1 reproducibility of within-subject CV (wCV) < 4% by all dictionaries with the same ranges, both in the brain parenchyma and CSF. Yet, reproducibility was moderate for T2 measurement (wCV < 8%). In CSF measurement, dictionaries with a smaller range showed a seemingly better reproducibility (T1, wCV 3%; T2, wCV 8%) than the much wider range dictionary (T1, wCV 5%; T2, wCV 13%). Truncated CSF relaxometry values were evident in smaller range dictionaries. CONCLUSIONS: The accuracy, repeatability, and reproducibility of 3D MRF across various dictionary resolutions were high for T1 and moderate for T2 measurements. A lower-resolution dictionary with a well-defined range may be adequate, thus significantly reducing the computational load. KEY POINTS: • A lower-resolution dictionary with a well-defined range may be sufficient for 3D MRF reconstruction. • CSF relaxation times might be underestimated due to truncation by the upper dictionary range. • Dictionary with a higher upper range might be advisable, especially for CSF evaluation and elderly subjects whose perivascular spaces are more prominent.

Hemosiderin Detection inside the Mammillary Bodies Using Quantitative Susceptibility Mapping on Patients with Wernicke-Korsakoff Syndrome.

Hemorrhage inside the mammillary bodies (MMBs) is known to be one of the findings of Wernicke encephalopathy. Brain MRI of two patients with Wernicke-Korsakoff syndrome (WKS) demonstrated high susceptibility values representing hemosiderin deposition in MMBs by using quantitative susceptibility mapping (QSM). QSM provided additional information of susceptibility values to susceptibility-weighted imaging in diagnosis of WKS.

Diagnostic advantage of thin slice 2D MRI and multiplanar reconstruction of the knee joint using deep learning based denoising approach.

The purpose of this study is to evaluate whether thin-slice high-resolution 2D fat-suppressed proton density-weighted image of the knee joint using denoising approach with deep learning-based reconstruction (dDLR) with MPR is more useful than 3D FS-PD multi planar voxel image. Twelve patients who underwent MRI of the knee at 3T and 13 knees were enrolled. Denoising effect was quantitatively evaluated by comparing the coefficient of variation (CV) before and after dDLR. For the qualitative assessment, two radiologists evaluated image quality, artifacts, anatomical structures, and abnormal findings using a 5-point Likert scale between 2D and 3D. All of them were statistically analyzed. Gwet's agreement coefficients were also calculated. For the scores of abnormal findings, we calculated the percentages of the cases with agreement with high confidence. The CV after dDLR was significantly lower than the one before dDLR (p < 0.05). As for image quality, artifacts and anatomical structure, no significant differences were found except for flow artifact (p < 0.05). The agreement was significantly higher in 2D than in 3D in abnormal findings (p < 0.05). In abnormal findings, the percentage with high confidence was higher in 2D than in 3D (p < 0.05). By applying dDLR to 2D, almost equivalent image quality to 3D could be obtained. Furthermore, abnormal findings could be depicted with greater confidence and consistency, indicating that 2D with dDLR can be a promising imaging method for the knee joint disease evaluation.

Comparative Evaluation of Natural Killer Cell-mediated Cell Killing Assay Based on the Leakage of an Endogenous Enzyme or a Pre-loaded Fluorophore.

A cell-killing ability of natural killer (NK) cells has been evaluated by the leakage of marker molecules from target cells. Lactate dehydrogenase (LDH) and calcein are two major non-radioisotope markers used for the killing assay. The spontaneous death of NK cells during the killing-assay of cells is a major issue in the assay because it provides background signals to increase errors. In this study, the effect of the spontaneous death of NK cells on the killing assays based on LDH and the calcein method was comparatively evaluated. We found that the calcein method is much less sensitive to the spontaneous death of NK cells to enable an accurate evaluation of the cell killing.

Fc-Binding Antibody-Recruiting Molecules Targeting Prostate-Specific Membrane Antigen: Defucosylation of Antibody for Efficacy Improvement*.

Synthetic small molecules that redirect endogenous antibodies to target cells are promising drug candidates because they overcome the potential shortcomings of therapeutic antibodies, such as immunogenicity and the need for intravenous delivery. Previously, we reported a novel class of bispecific molecules targeting the antibody Fc region and folate receptor, named Fc-binding antibody-recruiting molecules (Fc-ARMs). Fc-ARMs can theoretically recruit most endogenous antibodies, inducing antibody-dependent cell-mediated cytotoxicity (ADCC) to eliminate cancer cells. Herein, we describe new Fc-ARMs that target prostate cancer (Fc-ARM-Ps). Fc-ARM-Ps recruited antibodies to cancer cells expressing prostate-specific membrane antigen but did so with lower efficiency compared with Fc-ARMs targeting the folate receptor. Upon recruitment by Fc-ARM-P, defucosylated antibodies efficiently activated natural killer cells and induced ADCC, whereas antibodies with intact N-glycans did not. The results suggest that the affinity between recruited antibodies and CD16a, a type of Fc receptor expressed on immune cells, could be a key factor controlling immune activation in the Fc-ARM strategy.

Modification of nitric oxide donors onto a monoclonal antibody boosts accumulation in solid tumors.

Although monoclonal antibodies (mAbs) have revolutionized cancer treatment, their accumulation in solid tumors is limited and requires improvement to enhance therapeutic efficacy. Here we developed a strategy to modify mAb with a donor of nitric oxide (NO) because NO functions to vasodilate as well as to enhance the permeability of vascular endothelium, which will contribute to enhancing the tumor accumulation of mAb. We selected S-nitrosothiol as a NO donor and established the procedure to modify S-nitrosothiol group on mAb under ambient conditions. The modified mAb (Ab-SNO) thus obtained released NO in a preferable speed and maintained its original properties such as binding affinity to a target antigen and efficacy to induce antibody-dependent cellular cytotoxicity. We demonstrated that Ab-SNO enhanced the tumor accumulation of co-administered proteins such as antibody and serum albumin.

A 78-Year-Old Man With Repeated Dyspnea and Neutrophilia in Peripheral Blood and BAL.

CASE PRESENTATION: A 78-year-old man with asthma and COPD presented with shortness of breath, cough, and severe malaise for 4 days. Upon arrival, the patient was conscious and body temperature was 37.5°C. Arterial oxygen saturation (Spo2) was 80% on room air. Laboratory data demonstrated a WBC count of 17,400/µL (89.5% neutrophils) and C-reactive protein of 5.00 mg/dL. CT scan of chest revealed scattered ground-glass in the upper right lobe and thickening of the bronchial wall. Based on these findings, acute bronchopneumonia was diagnosed and antibacterial therapy was started. The day after admission, the patient's general condition and shortness of breath had gradually improved. We treated and observed him carefully for 10 days in the hospital on antibacterial therapy because of his underlying comorbidities (asthma and COPD) and his ongoing hypoxemia. Three days after discharge, the patient re-presented with shortness of breath, hypoxemia, and loss of appetite. The patient was hospitalized for a second time.

Induction of ADCC by a folic acid-mAb conjugate prepared by tryptophan-selective reaction toward folate-receptor-positive cancer cells.

We developed conjugates between monoclonal antibody (mAb) and folic acid (FA) by using a tryptophan (Trp)-selective reaction, which yields relatively homogenous products compared to conventional methods. The obtained mAb-FA conjugates showed significant cellular cytotoxicity toward folate receptor-expressing cancer cells, demonstrating that the conjugates retained the Fc region's original function.

Fc-binding antibody-recruiting molecules exploit endogenous antibodies for anti-tumor immune responses.

Redirecting endogenous antibodies in the bloodstream to tumor cells using synthetic molecules is a promising approach to trigger anti-tumor immune responses. However, current molecular designs only enable the use of a small fraction of endogenous antibodies, limiting the therapeutic potential. Here, we report Fc-binding antibody-recruiting molecules (Fc-ARMs) as the first example addressing this issue. Fc-ARMs are composed of an Fc-binding peptide and a targeting ligand, enabling the exploitation of endogenous antibodies through constant affinity to the Fc region of antibodies, whose sequence is conserved in contrast to the Fab region. We show that Fc-ARM targeting folate receptor-α (FR-α) redirects a clinically used antibody mixture to FR-α+ cancer cells, resulting in cancer cell lysis by natural killer cells in vitro. Fc-ARMs successfully interacted with antibodies in vivo and accumulated in tumors. Furthermore, Fc-ARMs recruited antibodies to suppress tumor growth in a mouse model. Thus, Fc-ARMs have the potential to be a novel class of cancer immunotherapeutic agents.

Development of Interstitial Lung Disease after Initiation of Apixaban Anticoagulation Therapy.

BACKGROUND: Nonvitamin K antagonist oral anticoagulants may cause interstitial lung disease (ILD) similar to that seen for other cardiovascular drugs. The aim of this study was to determine trends and medical conditions associated with ILD in patients taking apixaban. METHODS: A single-center observational survey conducted between February 2013 and May 2015 examined patients who developed ILD after initiation of apixaban administration. RESULTS: Chest computed tomography showed that 4 (~.45%) out of approximately 870 apixaban users developed ILD. All patients were elderly Japanese men with decreased creatinine clearance who had nonvalvular atrial fibrillation. Three of the four were confirmed smokers, whereas three had a history of lung disease. Dyspnea occurred during the initial week after starting apixaban administration in 3 patients and at 90 days in 1 patient. All patients underwent methylprednisolone pulse therapy, with three requiring mechanical ventilation. Although 2 patients recovered, the other two died of respiratory failure. CONCLUSIONS: Development of ILD during anticoagulation with apixaban is not rare. When apixaban is administered in elderly high-risk patients, subjects need to be carefully monitored for respiratory symptoms. As drug-induced ILD is often reported in Japan, further studies that clarify if these types of cases are common in countries other than Japan will also need to be undertaken.

[A case of metastatic cancer of unknown primary origin that progressed rapidly after complete remission via second-line chemotherapy].

Leptomeningeal metastasis occurs in approximately 5% of patients with metastatic solid carcinomas, and it is often diagnosed in patients with breast cancer, lung cancer, malignant melanoma, and digestive cancer. Herein, we report a case of a metastatic cancer of unknown primary origin. The leptomeningeal metastasis progressed quite rapidly, and the patient died despite achieving complete remission via second-line chemotherapy.

[An autopsy of a case of pulmonary hypertension secondary to pulmonary embolization of intrahepatic cholangiocarcinoma].

A 70-year-old woman was admitted to our hospital for one month because of progressive dyspnea. Her medical history included an operation for hepatolithiasis at age 47. She was a current smoker. Chest CT revealed emphysematous change and honeycombing in the lung and bilateral subpleural opacifications. Cardiac ultrasound examination showed pulmonary hypertension. Treatments with antibiotics, corticosteroids and heparin were unsuccessful. Despite mechanical ventilation, she died of respiratory failure. Autopsy revealed that intrahepatic cholangiocarcinoma had spread via the hematogeneous route, formed multiple emboli into the pulmonary small arteries, and led to severe pulmonary hypertension and lung infarction.

[Epidemic nosocomial keratoconjunctivitis caused by adenovirus type 4].

PURPOSE: To evaluate the clinical features of nosocomial epidemic keratoconjunctivitis(EKC) occurring in the ophthalmology ward of Sapporo Medical University Hospital and to devise preventive measures for it. MATERIALS AND METHODS: We studied the symptoms and clinical course of 2 patients who had EKC and 16 patients who had EKC caused by nosocomial infections in our hospital. We attempted to detect adenovirus antigen and viral DNA from conjunctival swabs and also to isolate the virus. RESULTS: The clinical symptoms of EKC were conjunctival hyperemia in 18 patients(100%), conjunctival follicles in 11 patients (61.1%), discharge in 8 patients(44.4%), superficial punctate keratopathy in 7 patients(38.9%), swelling of the eyelids in 3 patients(16.7%), and fever in 3 patients(16.7%). 72% were positive for Adeno-check. Adenovirus type 4 was isolated from the conjunctival swabs. We considered that the route of hospital infection was infection from the doctor's hands, from eye drops, and from contact lenses. We disclosed that nosocomical EKC had occurred in our hospital. The hospital infection was eliminated by closing the ophthalmology ward and sterilizing instruments and washing hands. CONCLUSIONS: The delay of proper measures increased the risk of nosocomical infection. We recognized the importance of careful observation of patients and immediate preventive efforts in nosocomical infection.