Effect of lemborexant on pharmacokinetics of clozapine: A potential drug-drug interaction mediated by time-dependent inhibition of CYP3A4.

Clozapine (CLZ) is extensively used for treatment-resistant schizophrenia (TRS) with caution to avoid serious adverse events such as agranulocytosis and drug-drug interactions (DDIs). In the current report, we present a case of a 35-year-old male non-smoking TRS patient whose steady-state plasma trough concentrations (Ctrough ) of CLZ and its active metabolite, N-desmethylclozapine (NDMC), were significantly increased after initiating oral administration of lemborexant (LEM), a dual orexin receptor antagonist, for the treatment of insomnia. The patient experienced oversedation with sleepiness and fatigue while maintaining high levels of Ctrough of CLZ. The increased concentrations of CLZ returned to normal ranges after the discontinuation of LEM dosing, implying a pharmacokinetic DDI between CLZ and LEM. To gain insight into possible mechanisms, we performed in vitro assays of CYP1A2- and CYP3A4-mediated CLZ metabolism by measuring the formations of NDMC and clozapine N-oxide (CNO). In accordance with previous studies, the incubation of CLZ with each enzyme resulted in the production of both metabolites. LEM had only a weak inhibitory effect on CYP1A2- and CYP3A4-mediated CLZ metabolism. However, the preincubation of LEM with CYP3A4 in the presence of NADPH showed a significant enhancement of inhibitory effects on CLZ metabolism with IC50 values for the formations of CNO and NDMC of 2.8 µM and 4.1 µM, respectively, suggesting that LEM exerts as a potent time-dependent inhibitor for CYP3A4. Taken together, the results of the current study indicate that co-medication of CLZ with LEM may lead to increase in exposure to CLZ and risks of CLZ-related adverse events.

Is Japan at low risk for PFAS immunotoxicity?: human biomonitoring study in contaminated areas in Japan.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are now considered global contaminants posing health risks. Recent human biomonitoring data in Japan are presented. METHODS: Human biomonitoring data from Japan, dating back to 2000, were reviewed. In addition, 399 serum samples collected in a primary care clinic in Urayasu City, Okinawa Island-one of the highest PFAS-exposed areas in Japan-between 2021 and 2022 were analyzed. Serum levels of four PFAS were compared with risk levels based on the assessment by Sonne et al. and the European Food Safety Agency. RESULTS: The PFAS levels in the general population from various areas other than Hokkaido (16.1-43.5 ng/mL) are classified at moderate to severe risk for immunotoxicity based on the assessment. CONCLUSIONS: A portion of the Japanese population has had high exposure to PFAS and was at high risk of immunotoxicity, and this situation remained in PFAS-contaminated areas in the 2020s.

[Clinical Features of Endocrine Disorders with Immune Checkpoint Inhibitor in Patients with Non-Small Cell Lung Cancer].

Immune checkpoint inhibitors(ICIs)could cause immune-related adverse events(irAEs), of which endocrine disorders are relatively common. Symptoms include fatigue, anorexia, and shock, making diagnosis and treatment difficult. This study aimed to analyze the characteristics of patients with non-small cell lung cancer concomitant with endocrine disorders as irAEs. In total, 83 patients who were administered ICIs for advanced or postoperative recurrent non-small cell lung cancer between February 2016 and February 2021 were identified. We retrospectively studied the clinical course and findings of 7 patients who developed endocrine disorders after treatment. Four patients had hypopituitarism, and 3 patients had thyroid dysfunctions. There were 6 male patients and 1 female patient. Regarding anticancer agents, 5 patients received ICI alone, and 2 patients received ICI plus cytotoxic chemotherapies. The patients received treatment from the irAE treatment team in our hospital, and 5 of 7 patients could were able to be readministered ICIs. Endocrine disorders as irAEs require collaboration with specialized departments for early diagnosis and treatment.

[A Case of Advanced Esophagogastric Junction Cancer Responding to S-1 Neoadjuvant Chemotherapy].

A 56-year-old man was diagnosed with advanced adenocarcinoma of the esophagogastric junction. He received 1 course of neoadjuvant chemotherapy with S-1. After neoadjuvant chemotherapy, the primary tumor showed a remarkable decrease in size. Subtotalesophagectomy, D2 lymph node dissection, and reconstruction with a gastric tube through the posterior mediastinal route were performed. Pathological examination showed that most of the cancer cells had been destroyed, with a part where adenocarcinoma mucosa was seen. We successfully treated a case of advanced adenocarcinoma of the esophagogastric junction, with neoadjuvant S-1 chemotherapy and surgicalresection.

Relationship between Hemorrhagic Complications and Target Vessels in Acute Thrombectomy.

PURPOSE: Intracranial hemorrhage after thrombectomy using a catheter to treat acute major cerebral artery occlusion is known to exacerbate patient outcomes. This study was performed to determine the relationship between middle cerebral artery (MCA) tortuosity and postoperative hemorrhage. METHODS: We examined 111 consecutive patients who underwent acute thrombectomy for major intracranial artery occlusion in the anterior circulation at our hospital between September 2013 and June 2016. Patients in whom intracranial hemorrhage or subarachnoid hemorrhage was seen on head computed tomography 12-24 hours after surgery were assigned to the hemorrhagic group, whereas all the other patients were assigned to the nonhemorrhagic group. The groups were compared for tortuosity of the MCA, which was evaluated by finding the top-to-bottom (TB) distance of the M1 segment on anterior-posterior view angiograms. A modified Rankin scale score of 0-2 at 3 months after onset was considered a favorable prognosis. RESULTS: The hemorrhagic group comprised 28 patients (25.2%) and the nonhemorrhagic group comprised 83 patients (74.8%). No significant difference in patient characteristics was seen between the groups. The hemorrhagic group displayed significantly fewer patients with a favorable prognosis (17.9% versus 43.4%, P = .016). The TB distance was significantly greater in the hemorrhagic group (hemorrhagic group, 9.7 mm; nonhemorrhagic group, 7.6 mm; P = .002); multivariate analysis also identified a TB distance over 8.8 mm as a factor independently associated with postoperative intracranial hemorrhage (P = .001). CONCLUSIONS: Post-thrombectomy hemorrhage was significantly correlated with TB distance. A solution is needed for selecting and combining devices used in patients with a TB distance over 8.8 mm.

Introduction of 2-octyl cyanoacrylate (Dermabond®) for incisional hernia mesh repair.

PURPOSE: We developed a new technique, sutureless mesh fixation, using 2-octyl cyanoacrylate (Dermabond®, a surgical tissue adhesive) for incisional hernia repair. The objective of this article is to introduce the new technique and to examine whether the technique provides sufficient resistance to abdominal pressure. METHODS: We conducted two tests using a porcine model, a traction experiment and artificial pneumoperitoneum test. In the traction experiment, the adherence properties of Dermabond® with mesh and peritoneum were examined using a tissue fragment from a pig. In the artificial pneumoperitoneum test, which used an incisional hernia porcine model, mesh was implanted on the peritoneum in the abdominal cavity with Dermabond®. It was then determined whether sutureless mesh fixation could bear artificial abdominal air pressure. RESULTS: In the traction experiment, Dermabond®, which bonded the mesh to the peritoneum, tolerated pressure up to 2.45 × 103 mmHg. In the artificial pneumoperitoneum test, the mesh was strongly fastened to the peritoneum by means of only Dermabond®, and there was little air circulation even without closing the wound over the mesh. CONCLUSIONS: Sutureless mesh fixation with Dermabond® is technically feasible and promises to provide sufficient resistance to abdominal pressure.

Initial clinical trial of a novel hemostat, TDM-621, in the endoscopic treatments of the gastric tumors.

BACKGROUND AND AIM: The feasibility of TDM-621, the synthetic infectious agent-free peptides, was tested in hemostasis of the bleeding after endoscopic treatments of the gastric tumors. METHODS: The patients who underwent endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) were enrolled in the present study. The subject of hemostasis was the oozing after the EMR or ESD. The hemostatic effect, the secondary hemorrhage from one postoperative day to the day before discharge and operability were studied. RESULTS: The hemostatic effects were assessed in 12 patients. It was "remarkably effective" in 11 patients and "effective" in 1 patient. The operability was "very easy" in two patients, "easy" in eight patients and "acceptable" in two patients. No secondary hemorrhage was observed in all of 12 patients. No adverse effect considered to be related to TDM-621 was observed. CONCLUSION: It was shown that hemostasis using TDM-621 was feasible after endoscopic treatments of the gastric tumors without any technical trouble or adverse event.

Erratum to "Crossing double stent retriever technique for refractory terminal internal carotid artery occlusion" [Radiology Case Reports 17 (2022) 1848-1852].

[This corrects the article DOI: 10.1016/j.radcr.2022.03.023.].

Modified gastroduodenostomy in laparoscopy-assisted distal gastrectomy: a 'tornado' anastomosis.

BACKGROUND/AIMS: This study was to examine the utility of a modified double-stapling end-to-end gastroduodenostomy method ('Tornado' anastomosis) compared to a method with an additional gastrotomy ('Anterior Incision' method) in laparoscopy-assisted distal gastrectomy. METHODOLOGY: Forty-two patients with gastric cancer who underwent laparoscopy-assisted distal gastrectomy were analyzed retrospectively. Billroth-I using an additional gastrotomy was performed in 24 patients (AI group) and Billroth-I without an additional gastrotomy was performed in 18 (TOR group). Clinicopathological features, operative outcomes (lymph node dissection, operative time, operative blood loss) and postoperative outcomes (complications, postoperative hospital stay, and body weight loss at one year after surgery) were evaluated and compared between groups. RESULTS: Operative time was significantly shorter in the TOR group (251 min) than in the AI group (282 min) (p < 0.01). There were no statistically significant differences in operative blood loss, postoperative complications, and hospital stay between the 2 study groups. Body weight loss at one year after surgery was -5.8 kg in the TOR group and -6.5 kg in the AI group, without a statistically significant difference. CONCLUSIONS: Completion time for Billroth-I anastomosis was significantly shorter with Tornado anastomosis than with the Anterior Incision method, with safety equal between the two methods.

Surgical therapy and chemoradiotherapy for postoperative recurrent esophageal cancer.

BACKGROUND/AIMS: A retrospective analysis of therapeutic modalities used in postoperative recurrent esophageal cancer. METHODOLOGY: Among 43 esophageal cancer patients who underwent esophagectomy between 2003 and 2010, recurrence was found in 15. Best supportive care was given to two patients and another patient was referred to another hospital. The remaining 12 patients were treated by the following modalities: Surgical resection: 2 cases; chemoradiotherapy: 7 cases; chemotherapy: 2 cases; and radiotherapy: 1 case. The median survival time, 1-year survival rates, and response rates were examined. Data from 13 esophageal cancer patients who underwent chemoradiotheray as an initial therapy in the same period were collected and compared with recurrent cases treated with chemoradiotherapy. RESULTS: For all 12 patients, the median overall survival time was 19.5 months, and the 1-year survival rate was 83%. Among 7 chemoradiotherapy patients, the response rate was 57%. The median survival time was 23 months, and the 1-year survival rate was 86%. The response rate of 13 patients receiving chemoradiotherapy as an initial therapy was 69%. The median overall survival time was 12 months and the 1-year survival rate was 54%. CONCLUSIONS: Re-operation and chemoradiotherapy for recurrent esophageal cancer might be as effective as the same treatment used initially.

Application of the HyperEye Medical System for esophageal cancer surgery: a preliminary report.

The HyperEye Medical System is a newly developed device that allows for the visualization of the fluorescent image of indocyanine green enhanced by near-infrared light among the surrounding vivid color images. We recently applied this system to confirm the blood flow of an esophageal substitute, and for sentinel node navigation during esophagectomy. Five consecutive patients with thoracic esophageal cancer who underwent a subtotal esophagectomy between June 2010 and May 2011 were enrolled in the study. The esophageal substitute used for reconstruction was the stomach and ileocecum in four and one cases, respectively. In all cases with a reconstructive stomach, fine arterial blood flow and venous perfusion were observed. The blood flow of the reconstructive colon was poor before microvascular anastomosis, however, it dramatically increased after anastomosis. Concerning the sentinel node navigation, the fluorescence of lymph nodes, lymphatic vessels, and the tumor site were detected. The postoperative courses of all cases were uneventful, with no mortalities or anastomotic leakage occurring.

Acute internal carotid artery occlusion due to dissection of the paraclinoid segment: Diagnostic usefulness of angiographic findings during stent retriever deployment.

Intracranial artery dissection is an uncommon but possible cause of ischemic stroke, and is usually diagnosed based on imaging findings such as mural hematoma and dissection flap. However, it is challenging to recognize the underlying dissection in cases of acute large vessel occlusion. In this report, we present a case of acute internal carotid artery occlusion, in which the underlying dissection of the paraclinoid segment was found during the thrombectomy procedure. Two thrombectomy procedures failed to recanalize the acute internal carotid artery occlusion without removing any clot. Angiography performed during a Trevo stent retriever deployment in the first pass showed obscure contrast defects in the stent strut with temporary flow restoration. In the next pass, the appearance of the contrast defects changed and a parallel linear contrast appeared on the outside of the vessel wall. These angiographic findings were identified as mural hematoma and dissection flap, indicating dissection of the paraclinoid as the cause of the occlusion. During antiplatelet loading and preparation of a dedicated intracranial stent, the Trevo stent retriever was left deployed again at the occlusion site to maintain the blood flow. After permanent stenting with an Enterprise stent, angiography revealed complete recanalization. The patient recovered fully after the procedure. In the present case, stent retriever deployment revealed the hallmarks of dissection on angiography, such as mural hematoma, dissection flap, and temporal morphological changes, by restoring the blood flow temporarily. Such angiographic findings can provide useful information on the occlusion characteristics and real-time feedback for optimal treatment strategy.

Cardiac cycle-related volume change in unruptured cerebral aneurysms: a detailed volume quantification study using 4-dimensional CT angiography.

BACKGROUND AND PURPOSE: The hemodynamic factors of aneurysms were recently evaluated using computational fluid dynamics in a static vessel model in an effort to understand the mechanisms of initiation and rupture of aneurysms. However, few reports have evaluated the dynamic wall motion of aneurysms due to the cardiac cycle. The objective of this study was to quantify cardiac cycle-related volume changes in aneurysms using 4-dimensional CT angiography. METHODS: Four-dimensional CT angiography was performed in 18 patients. Image data of 1 cardiac cycle were divided into 10 phases and the volume of the aneurysm was then quantified in each phase. These data were also compared with intracranial vessels of normal appearance. RESULTS: The observed cardiac cycle-related volume changes were in good agreement with the sizes of the aneurysms and normal vessels. The cardiac cycle-related volume changes of the intracranial aneurysms and intracranial normal arteries were 5.40%±4.17% and 4.20±2.04%, respectively, but these did not differ statistically (P=0.12). CONCLUSIONS: We successfully quantified the volume change in intracranial aneurysms and intracranial normal arteries in human subjects. The data may indicate that cardiac cycle-related volume changes do not differ between unruptured aneurysms and normal intracranial arteries, suggesting that the global integrity of an unruptured aneurysmal wall is not different from that of normal intracranial arteries.

Role of the lesion scar in the response to damage and repair of the central nervous system.

Traumatic damage to the central nervous system (CNS) destroys the blood-brain barrier (BBB) and provokes the invasion of hematogenous cells into the neural tissue. Invading leukocytes, macrophages and lymphocytes secrete various cytokines that induce an inflammatory reaction in the injured CNS and result in local neural degeneration, formation of a cystic cavity and activation of glial cells around the lesion site. As a consequence of these processes, two types of scarring tissue are formed in the lesion site. One is a glial scar that consists in reactive astrocytes, reactive microglia and glial precursor cells. The other is a fibrotic scar formed by fibroblasts, which have invaded the lesion site from adjacent meningeal and perivascular cells. At the interface, the reactive astrocytes and the fibroblasts interact to form an organized tissue, the glia limitans. The astrocytic reaction has a protective role by reconstituting the BBB, preventing neuronal degeneration and limiting the spread of damage. While much attention has been paid to the inhibitory effects of the astrocytic component of the scars on axon regeneration, this review will cover a number of recent studies in which manipulations of the fibroblastic component of the scar by reagents, such as blockers of collagen synthesis have been found to be beneficial for axon regeneration. To what extent these changes in the fibroblasts act via subsequent downstream actions on the astrocytes remains for future investigation.

Indocyanine green injection for detecting sentinel nodes using color fluorescence camera in the laparoscopy-assisted gastrectomy.

BACKGROUND AND AIM: We seek for the accurate and simple method for detecting sentinel nodes of gastric cancer which can be popularized in community hospitals. The indocyanine green (ICG) fluorescence-guided method is reported to be sensitive. However, the ordinal fluorescence cameras have gray scale imaging and require a dark room. We have developed a new device, Hyper Eye Medical System (HEMS) which can simultaneously detect color and near-infrared rays and can be used under room light. This study was planned to examine whether submucosal injection of 0.5 mL × 4 of 50 µg/mL ICG on the day before operation is the adequate administration for detecting sentinel nodes using HEMS in the gastric cancer surgery. METHODS: The patients underwent gastrectomy for clinical T1a (mucosa)-T2 (muscularis propria) and clinical N0 were enrolled in the present study. As a preliminary trial, one case each of the ICG 25 and 100 µg/mL, injected on the day before operation and intraoperative injection, was examined. Then, 10 cases injected 50 µg/mL ICG on the day before operation were examined. RESULTS: The ICG fluorescence of the patient injected 100 µg/mL was too intense and that of the patient injected 25 µg/mL was too faint. Sentinel lymph nodes were detected in all of 10 cases injected 50 µg/mL, the day before operation and number of sentinel lymph nodes per patient was 3.6 ± 2.1. Metastasis was observed in one case. All of ICG fluorescence-positive sentinel nodes were positive for the metastasis. In the patient who underwent intraoperative injection, sentinel lymphatic basins could be identified. CONCLUSION: The present study shows that HEMS-guided abdominal surgery is feasible under room light. Submucosal injection of 0.5 mL × 4 of 50 µg/mL ICG on the day before operation is the adequate administration for detecting sentinel nodes using HEMS in the gastric cancer surgery.

Utility of preoperative chemoradiotherapy for advanced esophageal carcinoma.

BACKGROUND AND AIMS: The most effective treatment would be neoadjuvant chemoradiotherapy (NACRT) plus surgery with three-field lymphadenectomy, if tolerability and complications are acceptable. The aim of this prospective study was to evaluate the tolerability of NACRT+ systematic three-field lymphadenectomy. METHODS: A total of 127 cases of advanced esophageal carcinoma were objected, among which 32 had NACRT, being the cases suspected to cT3-T4 or, < cT3 with multiple lymph node metastasis. ≥ T2 of 95 cases were treated by surgery alone (NACRT [-] case). The effect of NACRT was evaluated by histological examination and corrected with the clinicopathologic factors, including postoperative prognosis. After reports JCOG9907, we treated eight cases with neoadjuvant chemotherapy at stages II and III. We examined Musashi-1 staining for these eight cases. RESULTS: Histological good response to NACRT group showed good prognosis. Lymph node metastasis is a predictive factor for prognosis. In this additional study, Musashi-1 was positive after neoadjuvant chemotherapy in three cases. The histological response was grade 1 in all of them and recurrence was observed within a short period of time. Two cases of grade 3 were negative staining to Musashi-1 and showed no recurrence. CONCLUSIONS: This study shows that NACRT plus surgery with three-field lymphadenectomy is a feasible therapeutic approach for the cases with multiple lymph node metastases. Prognosis was significantly better in cases with marked histological improvement. It is important to find the predictive factors of histological improvement. Musashi-1 might be a candidate maker for histological response and prognosis, and further studies are needed to prove it.

Medical image analysis: computer-aided diagnosis of gastric cancer invasion on endoscopic images.

BACKGROUND: The aim of this study was to investigate the efficacy of diagnosing depth of wall invasion of gastric cancer on endoscopic images using computer-aided pattern recognition. METHODS: The back propagation algorithm was used for computer training. Data of 344 patients who underwent gastrectomy or endoscopic tumor resection between 2001 and 2010 and their 902 endoscopic images were collected. The images were divided into ten groups among which the number of patients and images were almost equally distributed according to T staging. The computer learning was performed using about 800 images from all but one group, and the accuracy rate of diagnosing the depth of wall invasion of gastric cancer was calculated using the remaining group of about 90 images. The various numbers of input layers, hidden layers, and learning counts were updated, and the ideal setting was decided. Similar learning and diagnostic procedures were repeated ten times using every group and all 902 images were tested. The accuracy rate was calculated based on the ideal setting. RESULTS: The most appropriate setting was a resolution of 16 × 16, a hidden layer of 240, and a learning count of 50. In the next step, using all the images on the ideal setting, the overall accuracy rate was 64.7%. The diagnostic accuracy was 77.2, 49.1, 51.0, and 55.3% in the T1, T2, T3, and T4 stagings, respectively. The accuracy was 68.9% in T1a(M) staging and 63.6% in T1b(SM) staging. The positive predictive values were 80.1, 41.6, 51.4, and 55.8% in the T1, T2, T3, and T4 staging, respectively. It was 69.2% in T1a(M) staging and 68.3% in T1b(SM) staging. CONCLUSION: Computer-aided diagnosis is useful for diagnosing depth of wall invasion of gastric cancer on endoscopic images.

[Safe and effective administration of carboplatin-based chemotherapy in a patient undergoing hemodialysis with cancer of unknown primary by monitoring observed AUC of carboplatin-a case report].

Here we report a case of successful treatment with combination chemotherapy of carboplatin(CBDCA)and paclitaxel for a patient undergoing hemodialysis(HD)with cancer of unknown primary, conducted by monitoring the observed AUC of ultrafilterable CBDCA. CBDCA was administered at a dose of 125 mg on day 1 in each course, an amount which had been calculated by the Calvert formula(GFR: 0, target AUC: 5). HD was started at a point in time one hour after the completion of each CBDCA administration, and performed for 5 hours in each course. Blood samples were collected during the first 3 courses of chemotherapy to measure the plasma concentration of free-platinum. The observed AUCs(o-AUC)of CBDCA in the first, second and third courses were 3. 03, 3. 44 and 3. 50mg·min/mL, respectively. The o-AUC in the first course was lower than that in the second course. The o-AUC in the second course was nearly equal to that in the third course, while each o-AUC was below the target AUC(t-AUC). Partial response was achieved after two courses of the CBDCA and paclitaxel combination chemotherapy, with adverse events of Grade 3 neutropenia and Grade 3 peripheral neuropathy observed in each course after the second course of chemotherapy. o-AUC of CBDCA administered to HD patients can not only be below t-AUC, as in this case, but also oppositely above t-AUC in cases with different doses of CBDCA or HD settings. Our results suggest that the monitoring of o-AUC of CBDCA is useful when practicing CBDCA-based chemotherapy safely and effectively in cancer patients undergoing HD.

Crossing double stent retriever technique for refractory terminal internal carotid artery occlusion.

Mechanical thrombectomy is highly effective for the recovery of acute ischemic stroke with large vessel occlusion. However, refractory occlusions are still encountered despite the use of currently available devices. In this article, we present a case of refractory terminal internal carotid artery occlusion treated with the "crossing double stent retriever technique." Two thrombectomy procedures with the combined technique using a stent retriever and aspiration catheter failed to recanalize the terminal internal carotid artery occlusion that involved the dominant anterior cerebral artery. We then applied the crossing double stent retriever technique as a rescue technique. Two microcatheters were advanced across the occlusion: one to the anterior cerebral artery and the other to the middle cerebral artery. First, a Trevo NXT 4 mm stent retriever was deployed from the anterior cerebral artery. Next, an additional Trevo NXT 4 mm stent retriever was deployed from the middle cerebral artery, and full immediate restoration of flow was achieved on angiography. Intraprocedural radiological images showed that the 2 microcatheters traversed different pathways, and the 2 stent retrievers completely covered the entire vessel with apparent in-stent clot sign. Both stent retrievers were then pulled back together, and a hard clot was retrieved. Subsequent angiography revealed complete recanalization. The crossing double stent retriever technique seems an effective rescue technique for treating refractory terminal internal carotid artery occlusion, especially with the anatomical feature of branching of the dominant anterior cerebral artery. This technique can facilitate the device-clot-vessel interaction by engaging the clot via 2 different device pathways.

Small molecule inhibitor of type I transforming growth factor-ß receptor kinase ameliorates the inhibitory milieu in injured brain and promotes regeneration of nigrostriatal dopaminergic axons.

Transforming growth factor-ß (TGF-ß), a multifunctional cytokine, plays a crucial role in wound healing in the damaged central nervous system. To examine effects of the TGF-ß signaling inhibition on formation of scar tissue and axonal regeneration, the small molecule inhibitor of type I TGF-ß receptor kinase LY-364947 was continuously infused in the lesion site of mouse brain after a unilateral transection of the nigrostriatal dopaminergic pathway. At 2 weeks after injury, the fibrotic scar comprising extracellular matrix molecules including fibronectin, type IV collagen, and chondroitin sulfate proteoglycans was formed in the lesion center, and reactive astrocytes were increased around the fibrotic scar. In the brain injured and infused with LY-364947, fibrotic scar formation was suppressed and decreased numbers of reactive astrocytes occupied the lesion site. Although leukocytes and serum IgG were observed within the fibrotic scar in the injured brain, they were almost absent in the injured and LY-364947-treated brain. At 2 weeks after injury, tyrosine hydroxylase (TH)-immunoreactive fibers barely extended beyond the fibrotic scar in the injured brain, but numerous TH-immunoreactive fibers regenerated over the lesion site in the LY-364947-treated brain. These results indicate that inhibition of TGF-ß signaling suppresses formation of the fibrotic scar and creates a permissive environment for axonal regeneration.