Kumamoto University Hospital

Post-transplant acute limbic encephalitis (PALE) has been reported, and human herpesvirus 6 (HHV-6) is one of the causes. Reports of PALE in children are still limited. In the present study, the detailed clinico-radiological findings of PALE and the neurological outcomes of four children are reported. Four patients aged three to twelve years of 142 patients who underwent allogeneic hematopoietic stem cell transplantation developed PALE. Underlying disorders were neuroblastoma in three patients and acute lymphoblastic leukemia in one. All four patients showed disorientation, behavioral changes, emotional dysregulation, anterograde amnesia, or decreased level of consciousness between 12 and 22days after transplantation. None had clinical seizures. In all patients, MRI showed hyperintense signals in unilateral or bilateral hippocampi, especially in the CA1 area, on diffusion-weighted imaging (DWI), with a decreased apparent diffusion coefficient. Though the hippocampi were also hyperintense on T2-weighted and fluid-attenuated inversion recovery imaging, signal intensity was higher on DWI by visual inspection. Electroencephalograms showed poorly organized posterior dominant rhythm in all patients and left occipito-centro-parietal slow waves in one without epileptiform discharges. HHV-6 DNA was positive in both cerebrospinal fluid and whole blood by polymerase chain reaction in three of the four patients. Two patients had pharmaco-resistant epilepsy and cognitive impairment three years after PALE, but the other two recovered neurologically from PALE. A DWI abnormality of the hippocampal CA1 area is a good biomarker for the diagnosis of HHV-6-positive or -negative PALE in children. Glutamatergic dysregulation and hippocampal cytotoxic edema may be involved in PALE.

This study aimed to compare the dosimetric parameters of the simultaneous integrated boost (SIB) technique using volumetric modulated arc therapy (VMAT) guided by 99mTc-labeled diethylenetriamine pentaacetate-galactosyl human serum albumin (99mTc-GSA) single-photon emission computed tomography (SPECT) image with those of conventional three-dimensional conformal radiotherapy (3D-CRT). Five patients with diffuse liver metastases underwent 99mTc-GSA SPECT and computed tomography (CT) imaging before RT planning. A SPECT threshold was used for determining the functional liver structure (FLS). The 3D-CRT plan included anterior-posterior opposed beams. The prescribed dose was 8 Gy in one fraction, with a goal of 95% of the planning target volume (PTV), D95, receiving at least 95% of the prescribed dose. The absorbed dose received by 2 cm3 of organ at risk (OAR) volume (D2cc) was below 10 Gy. The VMAT plan comprised two or three arcs. The goals for the PTV and OARs matched those of 3D-CRT. The PTV dose in SIB (PTVboost) defined according to FLS was optimized at an isodose line [~80% of the maximum dose (Dmax)] received at D95 of PTVboost. Two plans were compared using the dose-volume histogram parameters of PTV, PTVboost, FLS, and OARs. Dosimetric parameters including Dmean, Dmax, V110%, and V120% for PTV were significantly higher in the VMAT plan than in the 3D-CRT plan. Likewise, for PTVboost, the VMAT plan had significantly higher values of dosimetric parameters (D95, Dmean, Dmax, V110%, and V120%) than the 3D-CRT plan. The FLS and OAR parameters did not significantly differ between the two plans, except for the spinal cord. 99mTc-GSA SPECT image-guided VMAT planning using SIB allows selective target dose increase in palliative radiotherapy for diffuse liver metastases.

Giant cell tumor of bone (GCTB) induces overproduction of bone-resorbing osteoclasts through receptor activator of nuclear factor kappa B ligand (RANKL), leading to bone resorption and destruction. Consequently, denosumab, a neutralizing antibody against RANKL (a cytokine essential for osteoclast induction), is used to treat patients with GCTB. However, the activity of bone formation in GCTB remains poorly understood. Here, we show that GCTB antagonizes bone formation by expressing WNT5B, which inhibits bone formation. Co-culture of NCC-GCTB1-C1 (GCTB1s), a human GCTB cell line, with human adipose-derived stem cells (ADSCs) was performed with osteoblast induction medium. To identify the inhibitors of osteoblast differentiation, we reanalyzed the single-cell RNA sequencing data that was previously published. In addition, we performed spatial transcriptome analysis (Visium) against the section of paraffin block of GCTB. The targeted protein was knocked out using CRISPR/Cas9 and co-culture was performed. Co-culture of GCTB1s with ADSCs significantly inhibited mineralization of ADSCs. Reanalysis of single-cell RNA sequencing data indicated that GCTB tumors express WNT5B, and we observed that GCTB1s express WNT5B. We then knocked out WNT5B in GCTB1s using CRISPR/Cas9 and co-cultured them with ADSCs and observed significant rescue of mineralization in ADSCs relative to ADSCs cultured with GCTB1s expressing WNT5B. We also show that ADSC supernatants induce mineralization of GCTB1s. These studies indicate that GCTB not only induces osteoclasts, but also possesses activity that inhibits bone formation.

We evaluated atlas selection methods for multi-atlas-based segmentation (MABS) in breast cancer radiotherapy planning. Forty-five patients were divided into 30 atlas and 15 test cases. The 30 atlases were stratified into three groups based on breast separation, height, and volume. Firstly, MABS was performed on each of the 30 atlas cases using the remaining 29 atlases. Secondly, MABS was performed on 15 test cases using the 30 atlases. The Dice similarity coefficient (DSC) was calculated to assess the agreement between MABS and manual segmentation. The DSC was found to increase as more atlases were selected. Although this led to an increase in the computational time, the implementation of patient stratification reduced the computational time compared with using the entire dataset. Atlas selection from the height-matched and volume-matched tertile datasets provided median DSC values > 0.9. Breast height may be a practical surrogate for breast volume which is unknown before segmentation.

BackgroundTherapeutic hypothermia for moderate-to-severe hypoxic-ischemic encephalopathy in neonates effectively improves neurological outcomes when initiated within 6 hours of birth. However, coagulopathy is a potential side effect of therapeutic hypothermia and requires careful monitoring for signs of hemorrhage. Uncontrolled hemorrhage is the primary exclusion criterion for therapeutic hypothermia. Herein, we report two cases of intracranial hemorrhage that, despite being massive enough to cause hypovolemic shock with anemia, could not be detected by cranial ultrasonography before the initiation of therapeutic hypothermia for hypoxic-ischemic encephalopathy.Case presentationOne of the two Japanese newborn cases (one male and one female, 0 years old) was delivered by vacuum extraction and the other by forceps. Both infants presented with hypoxic-ischemic encephalopathy symptoms due to hypovolemic shock with anemia, without evidence of umbilical cord rupture or ultrasonographic evidence of ongoing bleeding such as intracranial or intraabdominal hemorrhage. Therapeutic hypothermia was initiated 5 hours after birth in both cases, alongside blood transfusion. One infant (male) presented with recurrent hypotension, while the other (female) developed hydrocephalus. Subsequent computed tomography or magnetic resonance imaging revealed a subdural hematoma. In one case (the male newborn), hypothermia was discontinued due to persistent bleeding, and a craniotomy was performed for hematoma evacuation.ConclusionThese cases show that even in massive intracranial hemorrhage causing hypovolemic shock, subdural hematoma may be undetectable on bedside imaging such as cranial ultrasonography. Therefore, when therapeutic hypothermia is considered for neonates with hypoxic-ischemic encephalopathy secondary to hypovolemic shock with anemia, clinicians should be cautious and not rely solely on ultrasonography to rule out intracranial hemorrhage. Early and proactive computed tomography imaging should be performed to investigate the cause of neonatal hypoxic-ischemic encephalopathy due to hypovolemic shock with anemia.

Background: In malignant pleural mesothelioma, epithelioid histology is traditionally considered a favorable prognostic marker. However, it remains clinically undetermined whether the intensity of an oncogenic insult can disrupt this link. Radiation-induced cases serve as an unconfounded biological model to dissect such trajectories masked by asbestos confounding. Methods: We performed an Individual Patient Data (IPD) synthesis of 20 strictly asbestos-unexposed human cases, applying clinically established dose stratification (intermediate: 20-45 Gy vs. high: >45 Gy). To confirm the observed pattern, we examined data from 829 dogs in the Colorado State University (CSU) Beagle Study. Results: In the intermediate-dose group (n = 13), a significant positive correlation persisted between age at radiotherapy and the latent period (ρ = 0.567, p = 0.043). Conversely, high-dose exposure (>45 Gy) showed a disruption of this age-dependent pattern, with a trend toward inverse correlation (ρ = -0.754, p = 0.084). Interaction analysis confirmed a statistically significant divergence between these dose-dependent trends (p = 0.005). The CSU Beagle Study (n = 829) demonstrated the physical basis of this phenomenon: in the canine model, high-dose exposure (≥0.74 Gy) triggered a "Step-Jump" in cumulative incidence (30.4% at 0.5 years), indicating instantaneous carcinogenic onset distinct from cumulative biological aging. Conclusions: This kinetic divergence points to a "Diagnostic Trap." We propose a 'Single- to Double-Brake' framework where intermediate doses preserve age-dependent progression, whereas high doses likely trigger catastrophic genomic failure (chromothripsis) that bypasses the time required for morphological dedifferentiation. Consequently, morphologically indolent epithelioid tumors in high-dose survivors may harbor aggressive molecular profiles not predicted by histology alone, necessitating risk-stratified precision surveillance.

Atherosclerosis is a chronic inflammatory disease wherein macrophage polarization critically influences lesion development. Dipeptidyl peptidase-4 (DPP4), a serine protease expressed on immune cells, has been implicated in vascular inflammation; however, its cell type-specific roles remain unclear. This study aimed to determine whether Dpp4 deficiency, particularly in hematopoietic cells, affects macrophage polarization and atherosclerosis progression. Using Apoe-knockout (ApoeKO) and Apoe- and Dpp4-double knockout mice as well as bone marrow transplantation models, we evaluated the impact of systemic and myeloid-specific Dpp4 deficiency on macrophage phenotype and atherogenesis. In bone marrow-derived macrophages, Dpp4 deficiency enhanced M2 marker expression (Arg1, Ym1, Mgl2, and Fizz1) and increased the proportion of CD206+ M2 macrophages without affecting M1 polarization, particularly after interleukin (IL)-4 stimulation. Furthermore, in vivo Dpp4 deficiency significantly reduced aortic lesion area and macrophage infiltration in ApoeKO mice. Real-time reverse transcription-polymerase chain reaction analysis of aortic tissue revealed upregulation of M2-related genes and Il4 expression, while M1-associated markers remained unchanged. Bone marrow transplantation experiments demonstrated that hematopoietic Dpp4 deficiency was sufficient to suppress atherosclerosis, independent of systemic glucose or lipid alterations. This protective effect was accompanied by enhanced M2 polarization, suggesting a role for DPP4 in regulating macrophage phenotype. Collectively, these findings identify hematopoietic DPP4 as a key modulator of macrophage polarization and atherogenesis. Dpp4 deficiency promotes the anti-inflammatory M2 phenotype and attenuates atherosclerosis regardless of metabolic effects, indicating that DPP4 may represent a promising therapeutic target for inflammatory cardiovascular diseases.