Anatomical Flow Diversion by Hybrid Strategy for Intractable Large Cerebral Aneurysms.

BACKGROUND AND IMPORTANCE: Flow diverters (FDs) provide curative endovascular treatment for wide-necked sidewall aneurysms. The efficacy of FDs for bifurcation or branching sidewall aneurysms is probably limited. We used anatomical flow diversion (AFD) for intractable large cerebral aneurysms. We report our experiences with AFD. METHODS: The concept of AFD is the transformation from the bifurcation or branching sidewall type to the nonbranching sidewall type. Linearization of the parent artery by stenting, intentional branch occlusion, and aneurysmal coil embolization were performed. Furthermore, bypass surgery is performed for patients intolerant to branch occlusions. We evaluated the clinical outcomes of intractable aneurysms treated with AFD. RESULTS: AFD was performed in seven unruptured large aneurysms. Aneurysmal locations were the top of the basilar artery (BA), BA-superior cerebellar artery (SCA), internal carotid artery (IC)-posterior communicating artery (PcomA), and IC terminal. The mean dome diameter was 17.0 ± 4.6 mm. Six patients underwent bypass surgery. The occluded branches were the PCA + SCA, PcomA, and anterior cerebral artery (ACA) A1. An FD was used in three patients and a neck bridge stent in four patients. No intraprocedural complications occurred. Two postprocedural ischemic complications occurred in one patient. Six (86%) patients demonstrated a modified Rankin Scale (mRS) 0 at the 3-month follow-up, and one with an ischemic complication showed an mRS 5. Complete occlusion of all aneurysms was maintained with a median follow-up duration of 60 months. CONCLUSION: AFD is useful for intractable large cerebral aneurysms with high curability, although safety verification is required.

Additional outlet occlusion as an important factor in avoiding retreatment after transvenous embolization for cavernous sinus dural arteriovenous fistulas.

BACKGROUND: Transvenous embolization (TVE), such as selective shunt occlusion, is the first line treatment for cavernous sinus dural arteriovenous fistula (CSDAVF). Despite the favorable outcomes of TVE, some cases necessitating retreatment due to recurrence or incomplete occlusion persist. Given the physical, psychological, and financial burden of multiple treatments, understanding the predictive factors for recurrence, spontaneous occlusion, or retreatment is important. However, few reports have addressed these factors, complicating decision making regarding the need for retreatment. This study analyzed predictive factors for retreatment and spontaneous occlusion to offer new insights into CSDAVF management. METHODS: This retrospective, observational study was conducted in two acute care hospitals. Patients aged 18-100 years undergoing endovascular treatment for CSDAVF from January 2011 to December 2022 were included. RESULTS: Of 65 patients treated with TVE, 29 experienced immediate complete occlusion. Meanwhile, 22 of 36 patients with incomplete occlusion had spontaneous occlusion, and retreatment was performed in 20% of patients. Additional outlet occlusion was negatively associated with retreatment (P=0.046), and it tended to promote spontaneous occlusion (P=0.056). Favorable functional outcomes were observed in all patients, and approximately 94% of patients showed complete occlusion at the latest follow-up. CONCLUSION: TVE is an effective treatment for CSDAVF. Outlet occlusion, when immediate complete occlusion is unattainable, is important to reduce retreatment and promote spontaneous occlusion. Substantially reducing shunt flow, carefully assessing dangerous drainage routes, and closely monitoring the residual shunt are crucial for preventing intracranial hemorrhage when outlet occlusion is performed.

Allogeneic Hematopoietic cell Transplantation Using Alemtuzumab in Asian Patients with Inborn Errors of Immunity.

Alemtuzumab is used with reduced-toxicity conditioning (RTC) in allogeneic hematopoietic cell transplantation (HCT), demonstrating efficacy and feasibility for patients with inborn errors of immunity (IEI) in Western countries; however, the clinical experience in Asian patients with IEI is limited. We retrospectively analyzed patients with IEI who underwent the first allogeneic HCT with alemtuzumab combined with RTC regimens in Japan. A total of 19 patients were included and followed up for a median of 18 months. The donors were haploidentical parents (n = 10), matched siblings (n = 2), and unrelated bone marrow donors (n = 7). Most patients received RTC regimens containing fludarabine and busulfan and were treated with 0.8 mg/kg alemtuzumab with intermediate timing. Eighteen patients survived and achieved stable engraftment, and no grade 3-4 acute graft-versus-host disease was observed. Viral infections were observed in 11 patients (58%) and 6 of them presented symptomatic. The median CD4+ T cell count was low at 6 months (241/µL) but improved at 1 year (577/µL) after HCT. Whole blood cells continued to exhibit > 80% donor type in most cases; however, 3/10 patients exhibited poor donor chimerism only among T cells and also showed undetectable levels of T-cell receptor recombination excision circles (TRECs) at 1 year post-HCT. This study demonstrated the efficacy and safety of alemtuzumab; however, patients frequently developed viral infections and slow reconstitution or low donor chimerism in T cells, emphasizing the importance of monitoring viral status and T-cell-specific chimerism. (238 < 250 words).

Total knee arthroplasty for knee osteoarthritis associated with abnormal patellar tendon deformity: a case report.

There have been no earlier reports of knee osteoarthritis with valgus knee deformity in which the patellar tendon infiltrates the tibial bone marrow instead of attaching to the tibial tubercle. This case report describes a total knee arthroplasty (TKA) performed for the treatment of a primary knee osteoarthritis resulting from a valgus knee joint position attributed to an abnormality of the patellar ligament attachment. During a TKA, the tendon tissue in the tibial medullary canal interfered with the reamer used to prepare for the stem extensions needed to improve the fixation of the component on the tibia, which had a cortical defect. The arthroplasty succeeded, and good clinical results have been maintained over the 3 years since the surgery. Surgeons should consider careful preoperative examinations by magnetic resonance imaging or CT when an abnormal bone defect is observed at the tibial tubercle on plain X-ray images.

The Number of Microbubbles Generated During Cardiopulmonary Bypass Can Be Estimated Using Machine Learning From Suction Flow Rate, Venous Reservoir Level, Perfusion Flow Rate, Hematocrit Level, and Blood Temperature.

GOAL: Microbubbles (MBs) are known to occur within the circuits of cardiopulmonary bypass (CPB) systems, and higher-order dysfunction after cardiac surgery may be caused by MBs as well as atheroma dispersal associated with cannula insertion. As complete MB elimination is not possible, monitoring MB count rates is critical. We propose an online detection system with a neural network-based model to estimate MB count rate using five parameters: suction flow rate, venous reservoir level, perfusion flow rate, hematocrit level, and blood temperature. METHODS: Perfusion experiments were performed using an actual CPB circuit, and MB count rates were measured using the five varying parameters. RESULTS: Bland-Altman analysis indicated a high estimation accuracy (R2 > 0.95, p < 0.001) with no significant systematic error. In clinical practice, although the inclusion of clinical procedures slightly decreased the estimation accuracy, a high coefficient of determination for 30 clinical cases (R2 = 0.8576) was achieved between measured and estimated MB count rates. CONCLUSIONS: Our results highlight the potential of this system to improve patient outcomes and reduce MB-associated complication risk.

Rare TCF3 variants associated with pediatric B cell acute lymphoblastic leukemia.

Germline genetic variants influence development of pediatric B cell acute lymphoblastic leukemia (B-ALL). Genome-wide association studies (GWAS) have identified several pediatric B-ALL susceptibility loci. IKZF1 and PAX5, transcription factors involved in B cell development, have been reported as susceptibility genes for B-ALL development. Therefore, we hypothesized that rare variants of genes involved in B cell development would be candidate susceptibility loci for pediatric B-ALL. Thus, we sequenced TCF3, a key transcription factor gene involving in B cell development. Saliva DNA from 527 pediatric patients with pediatric B-ALL in remission who were registered with the Tokyo Children's Cancer Study Group (TCCSG) were examined. As a TCF3 gene-based evaluation, the numbers of rare deleterious germline TCF3 sequence variants in patients with pediatric B-ALL were compared with those in cancer-free individuals using data in public databases. As a TCF3 single-variant evaluation, the frequencies of rare deleterious germline TCF3 sequence variants in patients with pediatric B-ALL were also compared with those in control data. TCF3 gene-based analysis revealed significant associations between rare deleterious variants and pediatric B-ALL development. In addition, TCF3 variant-based analysis showed particularly strong association between variant rs372168347 (three in 521 TCCSG and three in the 15780 gnomAD whole genome analysis cohort, p = 0.0006) and pediatric B-ALL development. TCF3 variants are known to influence B cell maturation and may increase the risk of preleukemic clone emergence.

Hidden Bow Hunter's Syndrome Diagnosed Using Dynamic Cerebral Angiography and Successfully Treated with Spinal Surgery: A Case Report and Review of the Literature.

Hidden bow hunter's syndrome (HBHS) is a rare disease in which the vertebral artery (VA) occludes in a neutral position but recanalizes in a particular neck position. We herein report an HBHS case and assess its characteristics through a literature review. A 69-year-old man had repeated posterior-circulation infarcts with right VA occlusion. Cerebral angiography showed that the right VA was recanalized only with neck tilt. Decompression of the VA successfully prevented stroke recurrence. HBHS should be considered in patients with posterior circulation infarction with an occluded VA at its lower vertebral level. Diagnosing this syndrome correctly is important for preventing stroke recurrence.

Simultaneous Control of Venous Reservoir Level and Arterial Flow Rate in Cardiopulmonary Bypass With a Centrifugal Pump.

Cardiopulmonary bypass (CPB) is an indispensable technique in cardiac surgery, providing the ability to temporarily replace cardiopulmonary function and create a bloodless surgical field. Traditionally, the operation of CPB systems has depended on the expertise and experience of skilled perfusionists. In particular, simultaneously controlling the arterial and venous occluders is difficult because the blood flow rate and reservoir level both change, and failure may put the patient's life at risk. This study proposes an automatic control system with a two-degree-of-freedom model matching controller nested in an I-PD feedback controller to simultaneously regulate the blood flow rate and reservoir level. CPB operations were performed using glycerin and bovine blood as perfusate to simulate flow-up and flow-down phases. The results confirmed that the arterial blood flow rate followed the manually adjusted target venous blood flow rate, with an error of less than 5.32%, and the reservoir level was maintained, with an error of less than 3.44% from the target reservoir level. Then, we assessed the robustness of the control system against disturbances caused by venting/suction of blood. The resulting flow rate error was 5.95%, and the reservoir level error 2.02%. The accuracy of the proposed system is clinically satisfactory and within the allowable error range of 10% or less, meeting the standards set for perfusionists. Moreover, because of the system's simple configuration, consisting of a camera and notebook PC, the system can easily be integrated with general CPB equipment. This practical design enables seamless adoption in clinical settings. With these advancements, the proposed system represents a significant step towards the automation of CPB.

Acute cerebral hemorrhage mimicking glioblastoma on intraoperative magnetic resonance imaging: A case report.

Intraoperative magnetic resonance imaging (iMRI) is important in neurosurgical practice, especially for glioma surgery. However, the well-reported possibility to mistake lesions for brain tumors (tumor mimics) with MRI also exists for iMRI. Here, we first report a case of glioblastoma with acute cerebral hemorrhage that mimicked a newly emerged brain tumor on iMRI. A 53-year-old man underwent a second surgery for recurrent glioblastoma. Intraoperatively, iMRI revealed a new, enhanced lesion near the resected area that was absent on preoperative MRI and difficult to differentiate from newly emerged tumors. Here, a recent preoperative MRI was helpful and the new lesion was actually a hematoma. Neurosurgeons must understand that, as acute intracerebral hemorrhaging can mimic brain tumors on iMRI, preoperative MRI should be conducted just before surgery to place iMRI findings in proper context and avoid unnecessary resections.

Clinical and Genetic Characterization of Patients with Artemis Deficiency in Japan.

PURPOSE: Artemis is an exonuclease essential for V(D)J recombination and repair of DNA double-stranded breaks. Pathogenic variants in DCLRE1C encoding Artemis cause T-B-NK+ severe combined immunodeficiency (SCID), and patients with Artemis-deficient SCID (ART-SCID) require definitive therapy with allogeneic hematopoietic cell transplantation (HCT). Here we describe the clinical and genetic characteristics of patients with ART-SCID who were diagnosed in Japan from 2003 to 2022. METHODS: Clinical data of ART-SCID patients who were diagnosed between 2003 and 2022 in Japan were collected from their physicians using a questionnaire. RESULTS: ART-SCID diagnosis was made in eight patients from seven families with severe infections within 6 months of life. Two patients had missense variants, five patients had large genomic deletions, and one patient was compound heterozygous for a missense variant and large genomic deletion. All eight underwent allogeneic HCT within 4 months after the diagnosis, 7 receiving a conditioning regimen containing alkylating agents, and one patient without conditioning due to uncontrolled infection. Two patients with poor performance status (PS) died of complications 410 days and 32 days post-HCT, respectively. Of the six surviving patients with a median follow-up time of 8.3 (0.5-17.9) years, three patients had growth retardation. The patients with PS of 0-2 showed a tendency for better overall survival than those with PS 3-4. CONCLUSION: Large deletions were the most common genetic cause of ART-SCID in Japan. To improve HCT outcome, early diagnosis with newborn screening for SCID is urgently needed.

Suramin prevents the development of diabetic kidney disease by inhibiting NLRP3 inflammasome activation in KK-Ay mice.

AIMS/INTRODUCTION: Nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasomes produce IL-18 upon being activated by various stimuli via the P2 receptors. Previously, we showed that serum and urine IL-18 levels are positively associated with albuminuria in patients with type 2 diabetes, indicating the involvement of inflammasome activation in the pathogenesis of diabetic kidney disease (DKD). In the present study, we investigated whether the administration of suramin, a nonselective antagonist of the P2 receptors, protects diabetic KK.Cg-Ay /TaJcl (KK-Ay) mice against DKD progression. MATERIALS AND METHODS: Suramin or saline was administered i.p. to KK-Ay and C57BL/6J mice once every 2 weeks for a period of 8 weeks. Mouse mesangial cells (MMCs) were stimulated with ATP in the presence or absence of suramin. RESULTS: Suramin treatment significantly suppressed the increase in the urinary albumin-to-creatinine ratio, glomerular hypertrophy, mesangial matrix expansion, and glomerular fibrosis in KK-Ay mice. Suramin also suppressed the upregulation of NLRP3 inflammasome-related genes and proteins in the renal cortex of KK-Ay mice. P2X4 and P2X7 receptors were significantly upregulated in the isolated glomeruli of KK-Ay mice and mainly distributed in the glomerular mesangial cells of KK-Ay mice. Although neither ATP nor suramin affected NLRP3 expression in MMCs, suramin inhibited ATP-induced NLRP3 complex formation and the downstream expression of caspase-1 and IL-18 in MMCs. CONCLUSIONS: These results suggest that the NLRP3 inflammasome is activated in a diabetic kidney and that inhibition of the NLRP3 inflammasome with suramin protects against the progression of early stage DKD.

Neural Network-based Estimation of Microbubbles Generated in Cardiopulmonary Bypass Circuit: A Clinical Application Study.

The cardiopulmonary bypass system used in cardiac surgery can generate microbubbles (MBs) that may cause complications, such as neurocognitive dysfunction, when delivered into the blood vessel. Estimating the number of MBs generated, thus, is necessary to enable the surgeons to deal with it. To this end, we previously proposed a neural network-based model for estimating the number of MBs from four factors measurable from the cardiopulmonary bypass system: suction flow rate, venous reservoir level, blood viscosity, and perfusion flow rate. However, the model has not been adapted to the data collected from actual surgery cases. In this study, the accuracy of MBs estimated by the proposed model was examined in four clinical cases. The results showed that the coefficient of determination between estimated MBs and the measured MBs throughout the surgeries was R2=0.558 (p<0.001). We found that the surgical treatments, such as administration of drugs, fluids and blood transfusions, increased the number of measured MBs. The coefficient of determination increased to R2= 0.8762 (p<0.001) by excluding the duration of these treatments. This result indicates that the model can estimate the number of MBs with high accuracy under the clinical environment.

Conditioning regimens for inborn errors of immunity: current perspectives and future strategies.

Inborn errors of immunity (IEI) are caused by germline genetic mutations, resulting in defects of innate or acquired immunity. Hematopoietic cell transplantation (HCT) is indicated for curative therapy especially in patients with IEI who develop fatal opportunistic infections or severe manifestations of immune dysregulation. The first successful HCT for severe combined immunodeficiency (SCID) was reported in 1968. Since then, the indications for HCT have expanded from SCID to various non-SCID IEI. In general, HCT for IEI differs from that for other hematological malignancies in that the goal is not to eradicate certain immune cells but to achieve immune reconstitution. European Society for Blood and Marrow Transplantation/European Society for Immunodeficiencies guidelines recommend reduced-intensity conditioning to avoid treatment-related toxicity, and the optimal conditioning regimen should be considered for each IEI. We review conditioning regimens for some representative IEI disorders in Japanese and worldwide cohort studies, and future strategies for treating IEI.

Brainstem anesthesia during removal operation of ventriculoperitoneal shunt - A case report.

Background: Brainstem anesthesia is a transient loss of brainstem function usually associated with retrobulbar block and rarely seen by neurosurgeons. Case Description: Here, we report a case of brainstem anesthesia during shunt revision operation in a 79-year-old woman. Local anesthesia administered at the end of surgery was thought to have infiltrated the subarachnoid space through a burr hole, causing prolonged unconsciousness and cranial nerves' impairment. Spontaneous resolution occurred during systemic support. Conclusion: As brainstem anesthesia may occur by leakage of local anesthetic through small burr holes, timing injections carefully can avoid this rare complication.

First phase 1 clinical study of olaparib in pediatric patients with refractory solid tumors.

BACKGROUND: The survival of patients with high-risk, refractory, relapsed, or metastatic solid tumors remains dismal. A poly(ADP-ribose) polymerase (PARP) inhibitor could be effective for the treatment of pediatric solid tumors with defective homologous recombination. METHODS: This open-label, multicenter phase 1 clinical trial evaluated the safety, tolerability, and efficacy of olaparib, a PARP inhibitor, in pediatric patients with refractory solid tumors to recommend a dose for Phase 2 trials. Olaparib (62.5, 125, and 187.5 mg/m2 twice daily) was administered orally every day (1 cycle = 28 days) using a standard 3 + 3 dose-escalation design. Patients aged 3-18 years with recurrent pediatric solid tumors were eligible. Pharmacokinetic and pharmacodynamic analyses were performed. RESULTS: Fifteen patients were enrolled and received olaparib monotherapy, which was well tolerated. The recommended phase 2 dose for daily administration was 187.5 mg/m2 twice daily. Pharmacokinetics were dose proportional. The area under the concentration-time curve from 0 to 12 h and the peak plasma concentration for 187.5 mg/m2 twice daily in children were comparable to previous data obtained in a 200-mg, twice-daily cohort and lower than those in the 300-mg twice-daily cohort in adults. Pharmacodynamic studies demonstrated substantial inhibition of PARP activity. Two partial responses were observed in patients with Wilms tumor and neuroblastoma. CONCLUSIONS: This report is the first clinical trial to describe the use of a PARP inhibitor as monotherapy in children. Olaparib was well tolerated, with preliminary antitumor responses observed in DNA damage response-defective pediatric tumors. LAY SUMMARY: This Phase 1 trial evaluated the efficacy and safety of olaparib in patients with refractory childhood solid tumors. Olaparib was well tolerated, achieving objective response in 2/15 patients. The DNA damage response was attenuated in nearly one-half of advanced neuroblastoma patients, demonstrating the utility of the PARP inhibitor. The results support further investigation of olaparib as a new treatment for DNA damage-response or repair-defective pediatric cancers.