A case of bilateral vertebral artery dissection treated by bilateral surgical occlusion and low-flow bypass.

Background: Bilateral vertebral artery dissection aneurysm (VADA) is a rare condition that leads to severe stroke. However, the surgical strategy for its treatment is controversial because the pathology is very complicated and varies in each case. Here, we report a case of bilateral VADA that was successfully treated with staged bilateral VADA occlusion and low-flow bypass. Case Description: A Japanese man in his 40s presented with bilateral VADA with subarachnoid hemorrhage. He had only mild headaches without any other neurological deficits. Subsequently, the ruptured left VADA was surgically trapped. However, on postoperative day 11, the contralateral VADA enlarged. The right VADA was then proximally clipped via a lateral suboccipital approach. Furthermore, a superficial temporal artery-superior cerebellar artery bypass was performed through a subtemporal approach in advance to preserve cerebral flow in the posterior circulation. The bilateral VADA was obliterated, and the patient had an uneventful postoperative course during the 1-year and 6-month follow-up period. Conclusion: Bilateral VADA can be successfully treated with staged bilateral VADA obstruction and low-flow bypass. In this case, as the posterior communicating arteries were the fetal type and the precommunicating segments of the posterior cerebral arteries (P1) were hypoplastic, a low-flow bypass was used to supply the basilar and cerebellar arteries, except the posterior cerebral and posterior inferior cerebellar arteries. Furthermore, low-flow bypass is a less invasive option than high-flow bypass.

Characteristics of two different cryoballoon systems for treatment of paroxysmal atrial fibrillation: study protocol for a multicenter randomized controlled trial (CONTRAST-CRYO Trial).

BACKGROUND: Single-shot pulmonary vein isolation (PVI) utilizing cryothermal energy is an effective and safe treatment for atrial fibrillation (AF) patients. A novel cryoballoon system, POLARx™, has been recently introduced. The aim of this study was to compare the efficacy, safety, and biophysical parameters of PVI between the novel cryoballoon system, POLARx™, and the standard cryoballoon system, Arctic Front Advance Pro™ (AFA-Pro), in patients with paroxysmal AF. METHODS: The CONTRAST-CRYO trial is a prospective, multicenter, open-label, randomized controlled study performed at seven large cardiac centers. This study was approved by the central ethics committee or the local ethics committee of each participating hospital and has been registered at UMIN Clinical Trials Registry (UMIN000049948). The trial will assign 200 patients with paroxysmal AF undergoing PVI to POLARx™ and AFA-Pro in a 1:1 randomization. The primary endpoint is the one-shot acute success rate of the right inferior pulmonary vein. Second endpoints include freedom from documented atrial fibrillation, atrial flutter, or atrial tachycardia without antiarrhythmic drugs at 12 months after the procedure, freedom from re-do procedures, the incidence of procedure-related adverse events, freezing duration, and the biophysical parameters during applications for each PV, total procedure and fluoroscopy time, and PVI durability during re-do procedures. CONCLUSION: The CONTRAST-CRYO trial is a prospective, multicenter, randomized study designed to elucidate the difference in the efficacy, safety, and biophysical parameters between POLARx™ and AFA-Pro in paroxysmal AF patients undergoing PVI. The findings from this trial may provide a valuable indication for selecting the optimal cryoballoon system. CLINICAL TRIAL REGISTRATION:  UMIN000049948.

Long-term follow-up of task-specific tremor after thalamotomy: a retrospective observational study.

OBJECTIVE: This study aimed to report the long-term results of thalamotomy in 23 patients with task-specific tremor. METHODS: Data of 23 patients with task-specific tremor who underwent ventralis intermedius nucleus and posterior part of ventro-oral nucleus thalamotomy at the Tokyo Women's Medical University Hospital between 2010 and 2022 were retrospectively analyzed. To evaluate neurological conditions, the severity of task-specific tremor was divided into 0 (no tremor), 1 (slightly tremulous), 2 (moderately tremulous), 3 (accomplishing tasks with great difficulty), and 4 (unable to complete tasks). We also used the subscores "handwriting" (0-4) and "spiral drawing" (0-4) of the Clinical Rating Scales for Tremor. Evaluation scales were presented as medians and interquartile ranges. RESULTS: The severities of task-specific tremor were 3.0 (3.0-4.0) preoperatively and 0.0 (0.0-0.0, p < 0.0001) at the last available evaluation. The writing and spiral drawing of the Clinical Rating Scales for Tremor significantly improved from 3.0 (3.0-4.0) and 3.0 (2.0-3.0) preoperatively, respectively, to 0.0 (0.0-0.0, p < 0.0001) and 0.0 (0.0-0.0, p < 0.0001) at the last available evaluation, respectively. The mean clinical follow-up period was 62.7 ± 26.0 months. Seven (30.4%) patients had focal hand dystonia, which newly developed on the ipsilateral side of the tremor at 2-45 months after the surgery. No serious complications were observed. INTERPRETATION: Thalamotomy significantly improves task-specific tremor with high long-term efficacy, and long-term follow-up is important because focal hand dystonia can develop postoperatively.

Difference in tissue temperature change between two cryoballoons.

BACKGROUND: Cryoballoon ablation, especially Arctic Front Advance Pro (AFA-Pro) (Medtronic, Minneapolis, Minnesota, USA), has been widely recognised as a standard approach to atrial fibrillation (AF). Recently, Boston Scientific has released a novel cryoballoon system (POLARx). Despite comparable acute clinical outcomes of these two cryoballoons, the recent study reported a higher complication rate, especially for phrenic nerve palsy, with POLARx. However, their impact on biological tissue remains unclear. OBJECTIVE: The purpose of our study is to evaluate temperature change of biological tissue during cryoablation of each cryoballoon using a porcine experimental model. METHOD: A tissue-based pulmonary vein model was constructed from porcine myocardial tissue and placed on a stage designed to simulate pulmonary vein anatomy and venous flow. Controlled cryoablations of AFA-Pro and POLARx were performed in this model to evaluate the tissue temperature. A temperature sensor was set behind the muscle and cryoballoon ablation was performed after confirming the occlusion of pulmonary vein with cryoballoon. RESULTS: The mean tissue nadir temperature during cryoablation with AFA-Pro was -41.5°C±4.9°C, while the mean tissue nadir temperature during cryoablation with POLARx was -58.4°C±5.9°C (p<0.001). The mean balloon nadir temperature during cryoablation with AFA-Pro was -54.6°C±2.6°C and the mean balloon nadir temperature during cryoablation with POLARx was -64.7°C±3.8°C (p<0.001). CONCLUSION: POLARx could freeze the biological tissue more strongly than AFA-Pro.

Roles of TRPM4 in immune responses in keratinocytes and identification of a novel TRPM4-activating agent.

The skin is a protective interface between the internal organs and environment and functions not only as a physical barrier but also as an immune organ. However, the immune system in the skin is not fully understood. A member of the thermo-sensitive transient receptor potential (TRP) channel family, TRPM4, which acts as a regulatory receptor in immune cells, was recently reported to be expressed in human skin and keratinocytes. However, the function of TRPM4 in immune responses in keratinocytes has not been investigated. In this study, we found that treatment with BTP2, a known TRPM4 agonist, reduced cytokine production induced by tumor necrosis factor (TNF) α in normal human epidermal keratinocytes and in immortalized human epidermal keratinocytes (HaCaT cells). This cytokine-reducing effect was not observed in TRPM4-deficient HaCaT cells, indicating that TRPM4 contributed to the control of cytokine production in keratinocytes. Furthermore, we identified aluminum potassium sulfate, as a new TRPM4 activating agent. Aluminum potassium sulfate reduced Ca2+ influx by store-operated Ca2+ entry in human TRPM4-expressing HEK293T cells. We further confirmed that aluminum potassium sulfate evoked TRPM4-mediated currents, showing direct evidence for TRPM4 activation. Moreover, treatment with aluminum potassium sulfate reduced cytokine expression induced by TNFα in HaCaT cells. Taken together, our data suggested that TRPM4 may serve as a new target for the treatment of skin inflammatory reactions by suppressing the cytokine production in keratinocytes, and aluminum potassium sulfate is a useful ingredient to prevent undesirable skin inflammation through TRPM4 activation.

Pan-cancer gene expression analysis of tissue microarray using EdgeSeq oncology biomarker panel and a cross-comparison with HER2 and HER3 immunohistochemical analysis.

Molecular and protein biomarker profiling are key to oncology drug development. Antibody-drug conjugates (ADCs) directly deliver chemotherapeutic agents into tumor cells based on unique cancer cell biomarkers. A pan-cancer tissue microarray (TMA) data set and gene panel were validated and gene signature analyses were conducted on normal and cancer tissues to refine selection of ADC targets. Correlation of mRNA and protein levels, and human epidermal growth factor receptor (HER) expression patterns were assessed. An EdgeSeq biomarker panel (2862 genes) was used across 8531 samples (23 solid cancer types/subtypes; 16 normal tissues) with an established TMA data set, and immune cell and cell cycle gene signatures were analyzed. Discriminating gene expression signatures were defined based on pathological classification of cancer subtypes. Correlative analyses of HER2 and HER3 mRNA (EdgeSeq) and protein expression (immunohistochemistry [IHC]) were performed and compared with publicly available data (The Cancer Genome Atlas [TCGA]; Cancer Cell Line Encyclopedia [CCLE]). Gene expression patterns among cancer types in the TMA (EdgeSeq) and TCGA (RNA-seq) were similar. EdgeSeq gene signature analyses aligned with the majority of pathological cancer types/subtypes and identified cancer-specific gene expression patterns. TMA IHC H-scores for HER3 varied across cancer types/subtypes. In a few cancer types, HER3 mRNA and protein expression did not align, including lower liver hepatocellular carcinoma IHC H-score, compared with mRNA. Although all TNBC and ovarian cancer subtypes expressed mRNA, some had lower protein expression. This was seen in TMA and TCGA data sets, but not in CCLE. The EdgeSeq TMA data set can expand upon current biomarker data by including cancers not currently in TCGA. The primary analysis of EdgeSeq and IHC comparison suggested a unique protein-level regulation of HER3 in some tumor subtypes and highlights the importance of investigating protein levels of ADC targets in both tumor and normal tissues.

Patritumab deruxtecan (HER3-DXd), a novel HER3 directed antibody drug conjugate, exhibits in vitro activity against breast cancer cells expressing HER3 mutations with and without HER2 overexpression.

ErbB3 (HER3), a member of the HER family, is overexpressed in various cancers and plays an important role in cell proliferation and survival. Certain HER3 mutations have also been identified as oncogenic drivers, making them potential therapeutic targets. In the current study, antitumor activity of patritumab deruxtecan (HER3-DXd), a HER3 directed antibody drug conjugate, was evaluated in tumor models with clinically reported HER3 mutations. MDA-MB-231, a HER3-negative human triple-negative breast cancer cell line, was transduced with lentiviral vectors encoding HER3 wild type (HER3WT), one of 11 HER3 mutations, or HER3 empty vector (HER3EV), in the presence/absence of HER2 overexpression. Targeted delivery of HER3-DXd was assessed using cell-surface binding, lysosomal trafficking, and cell-growth inhibition assays. HER3-DXd bound to the surface of HER3WT and mutant cells in a similar, concentration-dependent manner but not to HER3EV. HER3-DXd was translocated to the lysosome, where time- and concentration-dependent signals were observed in the HER3 mutant and HER3WT cells. HER3-DXd inhibited the growth of HER3WT and HER3 mutant cells. HER3-DXd activity was observed in the presence and absence of HER2 overexpression. These data suggest that HER3-DXd may have activity against tumors expressing wild type HER3 or clinically observed HER3 mutations, supporting further clinical evaluation.

Characteristics of anatomical difficulty for cryoballoon ablation: insights from CT.

BACKGROUND: The limited availability of balloon sizes for cryoballoon leads to anatomical limitations for pulmonary vein (PV) isolation. We conducted a comprehensive systematic analysis on procedural success rate, atrial fibrillation (AF) recurrence rate and complications of cryoballoon ablation in association with the anatomy of the left atrium and PV based on preprocedural CT to gain insights into proper treatments of patients with AF using cryoballoon. METHOD: A systematic search of literature databases, including PubMed, Web of Science and Cochrane Library, from the inception of each database through February 2021 was conducted. Search keywords included 'atrial fibrillation', 'cryoballoon ablation' and 'anatomy'. RESULTS: Overall, 243 articles were identified. After screening, 16 articles comprising 1396 patients were included (3, 5 and 8 for acute success, AF recurrence and complications, respectively). Regarding acute success and AF recurrences, thinner width of the left lateral ridge, higher PV ovality, PV ostium-bifurcation distance, shorter distance from the non-coronary cusp to inferior PVs, shallower angle of right PVs against the atrial septum and larger right superior PV (RSPV) were associated with poor outcomes. Regarding complications, shorter distance between the RSPV ostium and the right phrenic nerve, larger RSPV-left atrium angle, larger RSPV area and smaller right carina width were associated with incidences of phrenic nerve injury. CONCLUSION: This study elucidated several key anatomical features of PVs possibly affecting acute success, AF recurrence and complications in patients with AF using cryoballoon ablation. CT analysis has helped to describe benefits and anatomical limitations for cryoballoon ablation.

Serum Globulin Is Associated with Endoscopic Findings and Mucosal Healing in Japanese Patients with Ulcerative Colitis.

BACKGROUND: Serum globulin is an inflammation marker. To date, no evidence regarding the association between serum globulin and disease activity in patients with ulcerative colitis has been reported. AIMS: We evaluated the association between serum globulin and endoscopic activity in patients with ulcerative colitis. METHODS: Serum globulin was divided into tertiles based on the distribution of study subjects (low globulin, ≤ 2.7 g/dl (reference); moderate globulin, 2.7-3.1 g/dl; and high globulin, > 3.1 g/dl). A single endoscopic specialist evaluated the endoscopic findings, and mucosal healing was based on Mayo endoscopic subscore. RESULTS: A total of 277 patients with ulcerative colitis were included in the study. Serum globulin was independently positively associated with diminished or absent vascular markings [moderate: adjusted odds ratio (OR) 3.70 (95% confidence interval, CI: 1.82-7.88) and high: adjusted OR 2.40 (95%CI: 1.20-4.94), p for trend = 0.005]. A similar positive association between globulin and erosion was found [high: adjusted OR 2.00 (95%CI: 1.05-3.86)]. Serum globulin was independently inversely associated with mucosal healing [moderate: adjusted OR 0.37 (95%CI: 0.18-0.73) and high: adjusted OR 0.31 (95%CI: 0.14-0.64), p for trend = 0.001] and adjusted partial mucosal healing [moderate: OR 0.51 (95%CI: 0.26-0.98), p for trend = 0.048]. The inverse association between globulin and mucosal healing was significant in the low but not the high C-reactive protein group. CONCLUSIONS: In patients with ulcerative colitis, serum globulin was significantly positively associated with endoscopic activity, and was significantly inversely associated with mucosal healing, especially in the low C-reactive protein group.

Horizontal stent deployment via extracranial-intracranial bypass in coil embolization of basilar apex aneurysms: technical report.

BACKGROUND: The endovascular treatment of large, wide-necked basilar apex aneurysms (BAAs) remains challenging. Although horizontal stent deployment across both P1 segments of the posterior cerebral arteries (PCAs) would be an optimal strategy in coil embolization of wide-necked BAAs, this is only feasible in cases with anatomically favorable access. In rare circumstances, large-diameter conduits of extracranial-intracranial (EC-IC) bypass can also provide a good access route for endovascular treatment of complex intracranial aneurysms. METHODS: We describe the technique of accessing the PCA via EC-IC bypass grafts and deploying a stent horizontally across the neck of BAA and its coil embolization. We provide a detailed technical review and describe some pitfalls of the procedure. RESULTS: Two patients underwent EC-IC bypass surgery prior to the treatment of a large, wide-necked BAA. The radial artery and saphenous vein were used as grafts, respectively. To facilitate coil embolization for a large BAA, a PCA-to-PCA horizontal stent was deployed via the bypass graft. Trans-cell and jailing techniques were used, respectively. Both aneurysms were completely occluded, and the patients were discharged without any neurological deficit. CONCLUSION: Horizontal stent deployment via EC-IC bypass grafts can be performed safely, providing proper closure of the aneurysmal neck and apposition to both PCAs, facilitating complete coil embolization.

Five-Day Bed Rest Reduces Postoperative Intracerebral Hemorrhage After Direct Bypass for Moyamoya Disease.

OBJECTIVE: Postoperative intracerebral hemorrhage (ICH) after direct bypass surgery for Moyamoya disease could contribute to neurologic deterioration. The aim of this study was to evaluate the effectiveness of 5-day bed rest in reducing the occurrence of postoperative ICH. METHODS: This study included 122 consecutive hemispheres in 87 Japanese adult MMD patients, composed of 80 control hemispheres from historical data and 42 hemispheres after 5-day bed rest. They all underwent direct bypass surgery. The incidence of postoperative ICH and neurologic deterioration assessed via the modified Rankin Scale were investigated and statistically analyzed. RESULTS: Postoperative ICH was observed in 9 out of the 80 (11.3%) control patients, but not in the 42 patients with 5-day bed rest. The incidence of postoperative ICH and neurologic deterioration via the modified Rankin Scale were significantly different between the 2 groups (P = 0.0268 and 0.0078, respectively). Univariate logistic analysis revealed that 5-day bed rest significantly reduced the incidence of postoperative ICH (P = 0.0048). CONCLUSIONS: Five-day bed rest after direct bypass surgery dramatically can reduce the incidence of postoperative ICH and neurologic deterioration after direct bypass surgery.

Case Report: Long-Term Suppression of Paroxysmal Kinesigenic Dyskinesia After Bilateral Thalamotomy.

Background: Paroxysmal kinesigenic dyskinesia (PKD) is a movement disorder characterized by transient dyskinetic movements, including dystonia, chorea, or both, triggered by sudden voluntary movements. Carbamazepine and other antiepileptic drugs (AEDs) are widely used in the treatment of PKD, and they provide complete remission in 80-90% of medically treated patients. However, the adverse effects of AEDs include drowsiness and dizziness, which interfere with patients' daily lives. For those with poor compatibility with AEDs, other treatment approaches are warranted. Case Report: A 19-year-old man presented to our institute with right hand and foot dyskinesia. He had a significant family history of PKD; his uncle, grandfather, and grandfather's brother had PKD. The patient first experienced paroxysmal involuntary left hand and toe flexion with left forearm pronation triggered by sudden voluntary movements at the age of 14. Carbamazepine (100 mg/day) was prescribed, which led to a significant reduction in the frequency of attacks. However, carbamazepine induced drowsiness, which significantly interfered with his daily life, especially school life. He underwent right-sided ventro-oral (Vo) thalamotomy at the age of 15, which resulted in complete resolution of PKD attacks immediately after the surgery. Four months after the thalamotomy, he developed right elbow, hand, and toe flexion. He underwent left-sided Vo thalamotomy at the age of 19. Immediately after the surgery, the PKD attacks resolved completely. However, mild dysarthria developed, which spontaneously resolved within three months. Left-sided PKD attacks never developed six years after the right Vo thalamotomy, and right-sided PKD attacks never developed two years after the left Vo thalamotomy without medication. Conclusion: The present case showed long-term suppression of bilateral PKDs after bilateral thalamotomy, which led to drug-free conditions.

Deep Brain Stimulation of the Forel's Field for Dystonia: Preliminary Results.

The field of Forel (FF) is a subthalamic area through which the pallidothalamic tracts originating from the globus pallidus internus (GPi) traverse. The FF was used as a stereotactic surgical target (ablation and stimulation) to treat cervical dystonia in the 1960s and 1970s. Although recent studies have reappraised the ablation and stimulation of the pallidothalamic tract at FF for Parkinson's disease, the efficacy of deep brain stimulation of FF (FF-DBS) for dystonia has not been well investigated. To confirm the efficacy and stimulation-induced adverse effects of FF-DBS, three consecutive patients with medically refractory dystonia who underwent FF-DBS were analyzed (tongue protrusion dystonia, cranio-cervico-axial dystonia, and hemidystonia). Compared to the Burke-Fahn-Marsden Dystonia Rating Scale-Movement Scale scores before surgery (23.3 ± 12.7), improvements were observed at 1 week (8.3 ± 5.9), 3 months (5.3 ± 5.9), and 6 months (4.7 ± 4.7, p = 0.0282) after surgery. Two patients had stimulation-induced complications, including bradykinesia and postural instability, all well controlled by stimulation adjustments.

Datopotamab Deruxtecan, a Novel TROP2-directed Antibody-drug Conjugate, Demonstrates Potent Antitumor Activity by Efficient Drug Delivery to Tumor Cells.

Trophoblast cell surface antigen 2 (TROP2) is highly expressed on various epithelial tumors and correlates with poor prognosis. We developed the novel TROP2-directed antibody-drug conjugate (ADC), datopotamab deruxtecan (Dato-DXd, DS-1062a), with a potent DNA topoisomerase I inhibitor (DXd), and evaluated its antitumor activity and safety profiles in preclinical models.The pharmacologic activity and mechanism of action of Dato-DXd were investigated in several human cancer cell lines and xenograft mouse models including patient-derived xenograft (PDX) models. Safety profiles were also assessed in rats and cynomolgus monkeys.Dato-DXd bound specifically to TROP2 and was internalized into tumor cells followed by intracellular trafficking to lysosome and DXd release, which induced DNA damage and apoptosis in TROP2-expressing tumor cells in vitro. Dato-DXd exhibited in vivo antitumor activity with DNA damage induced by the accumulated DXd in TROP2-expressing xenograft tumors, but neither isotype control IgG-ADC nor anti-TROP2 antibody had this effect. Dato-DXd also showed potent antitumor activity with tumor regression in several TROP2-expressing xenograft tumors including NSCLC PDX models. Safety profiles of Dato-DXd in rats and cynomolgus monkeys were acceptable.Dato-DXd demonstrated potent antitumor activity against TROP2-expressing tumors by efficient payload delivery into tumors and acceptable safety profiles in preclinical models. These results suggest Dato-DXd could be a valuable treatment option for patients with TROP2-expressing tumors in the clinical setting.

Association between platelet count and mucosal healing in Japanese patients with ulcerative colitis: a cross-sectional study.

BACKGROUND: Mucosal healing (MH) has been indicated as the therapeutic goal for ulcerative colitis (UC). Platelet count is known as an inflammation evaluation. However, the association between platelet count and MH among patients with UC is still scarce. We therefore assessed this issue among Japanese patients with UC. METHODS: The study subjects consisted of 345 Japanese patients with UC. Platelet count was divided into quartiles on the basis of the distribution of all study subjects (low, moderate, high, and very high). Several endoscope specialists were responsible for evaluating MH and partial MH, which was defined as a Mayo endoscopic subscore of 0 and 0-1, respectively. Estimations of crude odds ratios (ORs) and their 95% confidence intervals (CIs) for partial MH and MH in relation to platelet count were performed using logistic regression analysis. Age, sex, CRP, steroid use, and anti-Tumor necrosis factor α (TNFα) preparation were selected a priori as potential confounding factors. RESULTS: The percentage of partial MH and MH were 63.2 and 26.1%, respectively. Moderate and very high was independently inversely associated with partial MH (moderate: OR 0.40 [95%CI 0.19-0.810], very high: OR 0.37 [95%CI 0.17-0.77], p for trend = 0.034). Similarly, moderate, high, and very high were independently inversely associated with MH (moderate: OR 0.37 [95% CI 0.18-0.73], high: OR 0.41 [95% CI 0.19-0.83], and very high: OR 0.45 [95% CI 0.21-0.94], p for trend = 0.033) after adjustment for confounding factors. CONCLUSIONS: Among patients with UC, platelet count was independently inversely associated with MH.

Isolated Posterior Spinal Artery Aneurysm Presenting with Spontaneous Thrombosis After Subarachnoid Hemorrhage.

BACKGROUND: The cause of subarachnoid hemorrhage is more likely to be intracranial than spinal. Bleeding, although common with spinal arteriovenous malformations and spinal cord tumors, rarely occurs with ruptured isolated spinal artery aneurysms. Here, we report a case of isolated thoracic posterior spinal artery aneurysm presenting with thrombosis after subarachnoid hemorrhage. CASE DESCRIPTION: A 67-year-old woman presented with sudden-onset nausea and low back and right thigh pain that worsened with movement. Computed tomography (CT) and magnetic resonance imaging (MRI) scans of the head suggested a small subarachnoid hemorrhage in the high-convexity sulcus, and lumbar puncture showed bloody cerebrospinal fluid. There was no apparent intracranial aneurysm on CT angiography; however, spinal MRI showed a lesion on the right side of the spinal cord at Th10. Contrast-enhanced CT showed an enhancing lesion at this site on day 7 that was not present on day 15. Selective right Th10 intercostal artery angiography on day 22 showed no evidence of aneurysm. The lesion was suspected to be a thrombotic spinal artery aneurysm. Given the unclear natural history of this entity, surgery was performed on day 36. After right Th10 hemilaminectomy and opening the dura, the arachnoid and adhesions were found to be thickened. A fusiform-shaped thrombosed aneurysm continuous with the radiculopial artery was removed. The patient was discharged without neurologic deterioration. CONCLUSIONS: Isolated spinal artery aneurysm is a rare cause of subarachnoid hemorrhage. It is expected that additional cases will clarify the natural history and indications for treatment.

A conditional inducible JAK2V617F transgenic mouse model reveals myeloproliferative disease that is reversible upon switching off transgene expression.

Aberrant activation of the JAK/STAT pathway is thought to be the critical event in the pathogenesis of the chronic myeloproliferative neoplasms, polycythemia vera, essential thrombocythemia and primary myelofibrosis. The most frequent genetic alteration in these pathologies is the activating JAK2V617F mutation, and expression of the mutant gene in mouse models was shown to cause a phenotype resembling the human diseases. Given the body of genetic evidence, it has come as a sobering finding that JAK inhibitor therapy only modestly suppresses the JAK2V617F allele burden, despite showing clear benefits in terms of reducing splenomegaly and constitutional symptoms in patients. To gain a better understanding if JAK2V617F is required for maintenance of myeloproliferative disease once it has evolved, we generated a conditional inducible transgenic JAK2V617F mouse model using the SCL-tTA-2S tet-off system. Our model corroborates that expression of JAK2V617F in hematopoietic stem and progenitor cells recapitulates key hallmarks of human myeloproliferative neoplasms, and exhibits gender differences in disease manifestation. The disease was found to be transplantable, and importantly, reversible when transgenic JAK2V617F expression was switched off. Our results indicate that mutant JAK2V617F-specific inhibitors should result in profound disease modification by disabling the myeloproliferative clone bearing mutant JAK2.

A Novel HER3-Targeting Antibody-Drug Conjugate, U3-1402, Exhibits Potent Therapeutic Efficacy through the Delivery of Cytotoxic Payload by Efficient Internalization.

PURPOSE: HER3 is a compelling target for cancer treatment; however, no HER3-targeted therapy is currently clinically available. Here, we produced U3-1402, an anti-HER3 antibody-drug conjugate with a topoisomerase I inhibitor exatecan derivative (DXd), and systematically investigated its targeted drug delivery potential and antitumor activity in preclinical models. EXPERIMENTAL DESIGN: In vitro pharmacologic activities and the mechanisms of action of U3-1402 were assessed in several human cancer cell lines. Antitumor activity of U3-1402 was evaluated in xenograft mouse models, including patient-derived xenograft (PDX) models. Safety assessments were also conducted in rats and monkeys. RESULTS: U3-1402 showed HER3-specific binding followed by highly efficient cancer cell internalization. Subsequently, U3-1402 was translocated to the lysosome and released its payload DXd. While U3-1402 was able to inhibit HER3-activated signaling similar to its naked antibody patritumab, the cytotoxic activity of U3-1402 in HER3-expressing cells was predominantly mediated by released DXd through DNA damage and apoptosis induction. In xenograft mouse models, U3-1402 exhibited dose-dependent and HER3-dependent antitumor activity. Furthermore, U3-1402 exerted potent antitumor activity against PDX tumors with HER3 expression. Acceptable toxicity was noted in both rats and monkeys. CONCLUSIONS: U3-1402 demonstrated promising antitumor activity against HER3-expressing tumors with tolerable safety profiles. The activity of U3-1402 was driven by HER3-mediated payload delivery via high internalization into tumor cells.

Efficacy and safety of quizartinib in Japanese patients with FLT3-ITD positive relapsed or refractory acute myeloid leukemia in an open-label, phase 2 study.

FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutations in patients with acute myeloid leukemia (AML) are associated with early relapse and poor survival. This multicenter, single-arm, two-stage phase 2 study (NCT02984995) was conducted to evaluate the efficacy and safety of quizartinib hydrochloride (initial dose 20/30 mg/day), an oral, highly potent, selective FLT3 inhibitor in Japanese patients (median age 65 years) with FLT3-ITD positive relapsed/refractory (R/R) AML. The composite complete remission (CRc) rate (primary endpoint) was 53.8% (90% confidence interval 36.2-70.8%) for evaluable patients in the efficacy analysis set. The median duration of CRc and overall survival was 16.1 weeks and 34.1 weeks, respectively. The most frequent treatment-emergent adverse events (TEAEs) were febrile neutropenia (43.2%), platelet count decreased (37.8%), and QT prolonged (35.1%). Two (5.4%) patients experienced TEAEs associated with treatment discontinuation. All serious TEAEs (45.9%), except febrile neutropenia (16.2%), were reported in ≤ 2 patients. The incidence of QTcF 451-480 ms and 481-500 ms was 37.8% and 2.7%, respectively. No QTcF > 500 ms, events of torsade de pointes or arrhythmia with clinical symptoms were reported. Quizartinib monotherapy was well tolerated and resulted in clinically meaningful reductions in blast count in Japanese patients with FLT3-ITD R/R AML.

FGF401, A First-In-Class Highly Selective and Potent FGFR4 Inhibitor for the Treatment of FGF19-Driven Hepatocellular Cancer.

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and it is the third leading cause of cancer-related deaths worldwide. Recently, aberrant signaling through the FGF19/FGFR4 axis has been implicated in HCC. Here, we describe the development of FGF401, a highly potent and selective, first in class, reversible-covalent small-molecule inhibitor of the kinase activity of FGFR4. FGF401 is exquisitely selective for FGFR4 versus the other FGFR paralogues FGFR1, FGFR2, FGFR3, and all other kinases in the kinome. FGF401 has excellent drug-like properties showing a robust pharmacokinetic/pharmacodynamics/efficacy relationship, driven by a fraction of time above the phospho-FGFR4 IC90 value. FGF401 has remarkable antitumor activity in mice bearing HCC tumor xenografts and patient-derived xenograft models that are positive for FGF19, FGFR4, and KLB. FGF401 is the first FGFR4 inhibitor to enter clinical trials, and a phase I/II study is currently ongoing in HCC and other solid malignancies.