Chb-M', an Inhibitor of the RUNX Family Binding to DNA, Induces Apoptosis in p53-Mutated Non-Small Cell Lung Cancer and Inhibits Tumor Growth and Repopulation In Vivo.

Runt-related transcription factor (RUNX) proteins are considered to play various roles in cancer. Here, we evaluated the anticancer activity of Chb-M', a compound that specifically and covalently binds to the consensus sequence for RUNX family proteins, in p53-mutated non-small cell lung cancer cells. Chb-M' killed the cancer cells by inducing apoptosis. The compound showed an anticancer effect comparable to that of the clinically used drugs alectinib and ceritinib in vivo. Notably, Chb-M' extended the cancer-free survival of mice after ending treatment more effectively than did the other two drugs. The results presented here suggest that Chb-M' is an attractive candidate as an anticancer drug applicable to the treatment of non-small cell lung cancer and various other types of cancers.

[Aortic Arch:Embryology and Remodeling].

A right aortic arch and aberrant subclavian artery result from an interruption in the remodeling of the pharyngeal arch arteries. We occasionally encounter this anatomical variation during angiography. Patients with disorders such as Down syndrome and congenital heart disease show a high incidence of an aberrant right subclavian artery, and this anomaly can cause symptomatic esophageal or tracheal compression. The root of the aberrant artery may show dilatation(referred to as a Kommerell diverticulum), dissection, intramural hematoma, or rupture necessitating cardiac intervention using a surgical or endovascular approach. Neurointerventionalists should have working knowledge of the anatomy to rapidly understand the anatomy and ensure a safe procedure. A left transradial approach should be considered if prior knowledge of the aberrant subclavian anatomy is available.

Gas Gangrene of the Spleen Caused by Clostridium perfringens After Mild Blunt Trauma.

Splenic gas gangrene caused by Clostridium perfringens is rare. A 73-year-old woman was referred to our hospital because of fatigue, dyspnea, and left hypochondrial pain. She had a history of blunt trauma to the left abdomen eight days ago. She presented with hypoxemia and a high inflammatory response on blood tests. A CT showed left pleural effusion and gas in the spleen. She was treated with antimicrobials and underwent splenectomy. C. perfringens was identified from blood and intraoperative ascites cultures. She recovered and was discharged on day 34 of hospitalization. As C. perfringens is part of the normal gut microbiota and can translocate to other parts of the body, this bacterium should be considered a splenic abscess pathogen when an intracorporeal anaerobic environment is suspected.

Perioperative Management of Spinal Arteriovenous Malformation Embolization: Delayed Venous Thrombosis and Implications for Severe Back Pain.

BACKGROUND AND PURPOSE: The prognosis of untreated spinal arteriovenous malformations (SAVMs) is poor. Embolization plays an important role in the management of intramedullary SAVMs. Delayed aggravation due to spinal venous thrombosis following successful embolization has been reported; however, perioperative management strategies to prevent thrombosis have not been explored. We present our single-center experience of SAVM embolization and perioperative management, including anticoagulation. MATERIAL AND METHODS: We retrospectively evaluated 18 patients with SAVMs who underwent transarterial embolization. Perioperative anticoagulation therapy was administered to selected patients. We compared the characteristics of the patients, including perioperative management procedures, between those with and without postoperative worsening following embolization. RESULTS: Acute postoperative worsening within 1 week occurred in 4 (22.2%) patients. Of these, immediate worsening was observed in one patient as a procedure-related complication. Delayed worsening after 24 h was observed in 3 patients, caused by delayed venous thrombosis with severe back pain. Rescue anticoagulation for delayed worsening improved symptoms in two patients. A comparison between patients with and without acute postoperative worsening revealed significant differences in age (median 46.5 vs. 26.5 years, p = 0.009) and the presence of postoperative back pain (75.0% vs. 0%, p = 0.005); however, there was no significant difference in use of selective anticoagulation (p = 0.274). CONCLUSION: The results of this study suggest that SAVM embolization can cause acute worsening due to postoperative venous thrombosis with severe back pain, which may be reversed by anticoagulation therapy. Back pain is an important finding that suggests venous thrombosis, and anticoagulation should be urgently administered.

Systemic inflammation score as a predictor of death within one year after esophagectomy.

BACKGROUND: After radical resection for esophageal cancer, death within 1 year of surgery can occur due both to recurrence and to other diseases, even after postoperative complications have been overcome. This study identified risk factors for early death within 1 year of esophagectomy for reasons other than death in hospital in patients undergoing esophagectomy for esophageal cancer or esophagogastric junction cancer. METHODS: We reviewed 366 patients who underwent esophagectomy without adjuvant treatment between January 2009 and July 2022 for thoracic esophageal cancer or esophagogastric junction cancer. Patients who died within 1 year excluding in-hospital death were compared with those who did not. Multivariable logistic regression analysis was used to identify predictors of death within 1 year after surgery. RESULTS: Death within 1 year occurred in 32 of 366 patients, 24 from primary disease and 8 from other diseases. Deaths within 1 year were significantly older than the other cases, had significantly lower % vital capacity (%VC), and occurred significantly more often in cases in advanced stages of disease. In a multivariable analysis, a systemic inflammation score (SIS) based on serum albumin level and lymphocyte-to-monocyte ratio was identified as an independent predictor of death within 1 year. As SIS increased, %VC decreased significantly, and CRP level and neutrophil-lymphocyte ratio increased significantly. There was no relationship between SIS and pN. Death within 1 year increased as SIS increased (p = 0.001 for trend). CONCLUSION: SIS assessment undertaken before beginning esophageal cancer treatment is a useful predictor of death within 1 year of surgery.

Comparison of efficacy between clazosentan and fasudil hydrochloride-based management of vasospasm after subarachnoid hemorrhage focusing on older and WFNS grade V patients: a single-center experience in Japan.

Subarachnoid hemorrhage often leads to poor outcomes owing to vasospasm, even after successful aneurysm treatment. Clazosentan, an endothelin receptor inhibitor, has been proven to be an effective treatment for vasospasms in a Japanese randomized controlled trial. However, its efficacy in older patients (≥ 75 years old) and those with World Federation of Neurosurgical Societies (WFNS) grade V has not been demonstrated. We retrospectively evaluated the efficacy of clazosentan in older patients and those with WFNS grade V, using real-world data. Patients with subarachnoid hemorrhage treated before and after the introduction of clazosentan were retrospectively evaluated. The patients were categorized into two groups (clazosentan era versus pre-clazosentan era), in which vasospasm management and outcomes were compared. Vasospasms were managed with fasudil hydrochloride-based (pre-clazosentan era) or clazosentan-based treatment (clazosentan era). Seventy-eight patients were included in this study: the clazosentan era (n = 32) and pre-clazosentan era (n = 46). Overall, clazosentan significantly reduced clinical vasospasms (clazosentan era: 31.3% versus pre-clazosentan era: 60.9%, p = 0.01), delayed cerebral ischemia (DCI) (9.4% versus 39.1%, p = 0.004), and vasospasm-related morbidity and mortality (M/M) (3.1% versus 19.6%, p = 0.03). In subgroup analysis of older patients or those with WFNS grade V, no significant difference was observed in clinical outcomes, although both DCI and vasospasm-related M/M were lower in the clazosentan era. Clazosentan was more effective than fasudil-based management in preventing DCI and reducing vasospasm-related M/M. Clazosentan could be used safely in older patients and those with WFNS grade V, although clinical outcomes in these patients were comparable to those of conventional treatment.

A case of delayed dyspnea after corrective posterior fusion of the middle and lower cervical spine for dropped head syndrome.

Dyspnea has been reported to occur following posterior occipitocervical fusion. However, there are no documented cases of dyspnea following posterior fixation of the middle and lower cervical spine without posterior occipitocervical fusion. An 80-year-old woman underwent corrective fusion from T4 to the ilium for kyphoscoliosis. Sixteen months later, the patient developed cervical kyphosis (dropped head syndrome) with proximal junctional kyphosis, leading to a pedicle subtraction osteotomy at T4 and an extended fixation to C2. On the sixth postoperative day, the patient experienced respiratory arrest, prompting a reoperation to reduce cervical lordosis, ultimately resolving the respiratory dysfunction. Excessive correction of cervical kyphosis should be avoided to prevent the occurrence of postoperative dyspnea, even in cases where posterior occipitocervical fusion has not been performed.

Recurrence-free survival as a surrogate endpoint for overall survival after neoadjuvant chemotherapy and surgery for oesophageal squamous cell carcinoma.

BACKGROUND: Overall survival is considered as one of the most important endpoints of treatment efficacy but often requires long follow-up. This study aimed to determine the validity of recurrence-free survival as a surrogate endpoint for overall survival in patients with surgically resectable advanced oesophageal squamous cell carcinoma (OSCC). METHODS: Patients with OSCC who received neoadjuvant cisplatin and 5-fluorouracil, or docetaxel, cisplatin and 5-fluorouracil, at 58 Japanese oesophageal centres certified by the Japan Esophageal Society were reviewed retrospectively. The correlation between recurrence-free and overall survival was assessed using Kendall's τ. RESULTS: The study included 3154 patients. The 5-year overall and recurrence-free survival rates were 56.6 and 47.7% respectively. The primary analysis revealed a strong correlation between recurrence-free and overall survival (Kendall's τ 0.797, 95% c.i. 0.782 to 0.812) at the individual level. Subgroup analysis showed a positive relationship between a more favourable pathological response to neoadjuvant chemotherapy and a higher τ value. In the meta-regression model, the adjusted R2 value at the institutional level was 100 (95% c.i. 40.2 to 100)%. The surrogate threshold effect was 0.703. CONCLUSION: There was a strong correlation between recurrence-free and overall survival in patients with surgically resectable OSCC who underwent neoadjuvant chemotherapy, and this was more pronounced in patients with a better response to neoadjuvant chemotherapy.

Sinus reconstruction therapy for superior sagittal sinus dural arteriovenous fistula caused by parasagittal meningioma invasion: a case report.

A dural arteriovenous fistula (dAVF) involving the superior sagittal sinus (SSS) is relatively rare, and its clinical course is usually aggressive. Its concomitance with a tumor has rarely been reported. Here, we present a case of SSS dAVF due to meningioma invasion, which was treated with sinus reconstruction and endovascular embolization. A 75-year-old man who had undergone tumor resection for parasagittal meningioma 4 years prior presented with intra-ventricular hemorrhage. Computed tomography angiography and magnetic resonance imaging revealed recurrent tumor invasion into the SSS causing occlusion. Cerebral angiography revealed multiple shunts along the occluded segment of the SSS, diffuse deep venous congestion, and cortical reflux. Borden type 3 SSS dAVF was diagnosed. We first performed direct tumor resection, followed by stenting for the occluded SSS and partial embolization of the shunts. After a 6-month interval, transvenous occlusion of the SSS was performed along the stent, resulting in complete obliteration of the dAVF. Sinus reconstruction therapy was effective in the immediate improvement of venous hypertension, obtaining the access route to the fistulas, and eradicating the shunts.

The impact of contour maps on estimating the risk of gastrointestinal stromal tumor recurrence: indications for adjuvant therapy: an analysis of the Kinki GIST registry.

INTRODUCTION: Contour maps enable risk classification of GIST recurrence in individual patients within 10 postoperative years. Although contour maps have been referred to in Japanese guidelines, their usefulness and role in determining indications for adjuvant therapy is still unclear in Japanese patients. The aims of this study are to investigate the validity of contour maps in Japanese patients with GIST and explore the new strategy for adjuvant therapy. MATERIALS AND METHODS: A total of 1426 Japanese GIST patients who were registered to the registry by the Kinki GIST Study Group between 2003 and 2012 were analyzed. Patients who had R0 surgery without perioperative therapy were included in this study. The accuracy of contour maps was validated. RESULTS: Overall, 994 patients have concluded this study. Using contour maps, we validated the patients. The 5-year recurrence-free survival rates of patients within the GIST classification groups of 0-10%, 10-20%, 20-40%, 40-60%, 60-80%, 80-90%, and 90-100% were 98.1%, 96.6%, 92.3%, 48.0%, 37.3%, 41.0% and 42.4%, respectively. We confirmed that this classification by contour maps was well reflected recurrence prediction. Further, in the high-risk group stratified by the modified National Institutes of Health consensus criteria (m-NIHC), the 10-year RFS rate was remarkably changed at a cutoff of 40% (0-40% group vs. 40-100% group: 88.7% vs. 50.3%, p < 0.001). CONCLUSION: Contour maps are effective in predicting individual recurrence rates. And it may be useful for the decision of individual strategy for high-risk patients combined with m-NIHC.

Re-appraisal of the universal definition of tumor rupture among patients with high-risk gastrointestinal stromal tumors.

Aim: Tumor rupture has been indicated as a risk factor for recurrence of gastrointestinal stromal tumors (GISTs). The universal definition of tumor rupture was proposed. This study evaluated whether the universal definition was more accurate in identification of GISTs with high recurrent risk than subjective judgment. Methods: The study included 507 patients with high-risk GISTs who underwent complete resection between December 2012 and December 2015. We conducted a questionnaire survey in participating institutes to re-diagnose tumor rupture based on the universal definition according to their surgical and pathological findings. We compared the clinical outcomes of tumor rupture based on the definition to those based on the surgeon's judgment and clarified the clinical importance of the rupture. Results: Sixty-four patients were initially registered to have tumor rupture by surgeon's judgment, and it became 90 patients who had tumor rupture after reevaluation. Although there were significant differences in recurrence-free survival (RFS) between no rupture and rupture for both initial registration and reevaluation (p = 0.002, <0.001, respectively), a significant difference in overall survival was only observed after reevaluation (p = 0.011). Tumor rupture was significantly associated with large tumor size, mixed cell type in histology, R1 resection, frequent adjuvant therapy and recurrence, but not with location, mitosis, and genotype. Adjuvant therapy more than 3 years improved RFS of patients with tumor rupture. Conclusion: This study suggested that tumor rupture based on the universal definition more accurately identified GISTs with poor prognostic outcomes than the subjective judgment.

A Case of Remote Cerebellar Hemorrhage in Spinal Surgery without Dural Injury: Case Report.

Introduction: Remote cerebellar hemorrhage (RCH) has been reported as a serious complication of spine surgery and is considered to be caused by dural injury. However, we have experienced a case in which intracranial hemorrhage occurred immediately after lumbar spine surgery without dural tear. There were no reports of RCH in spinal surgery without dural injury as far as we could find. Case Report: We described a rare presentation of an 80-year-old male who suffered a loss of consciousness after lumbar surgery. He was diagnosed with impaired consciousness due to chronic and acute intracranial hemorrhage. He went through two hematoma removal surgeries and his consciousness improved. Conclusion: RCH can occur in spinal surgery in patients with predicted cerebrovascular fragility, even in the absence of dural injury. Pre-operative imaging evaluation could be useful in assessing cerebrovascular fragility.

De Novo Radicular Arteriovenous Fistula After Treatment of Spinal Arteriovenous Fistula: A Case Report and Literature Review.

De novo spinal dural arteriovenous fistulas (AVFs) have been reported as metachronous AVFs However, metachronous spinal AVFs are extremely rare, and their pathogenesis remains uncertain. We report a case of de novo radicular AVF (RAVF) following treatment for spinal AVF at the craniocervical junction (CCJ). We also reviewed the literature and discussed the pathogenesis of metachronous spinal AVF. A 64-year-old male patient diagnosed with spinal AVF at the CCJ supplied from the right C1 segmental artery was treated with Onyx-18 (eV3 Inc, CA, USA) trans-arterial embolization, resulting in partial occlusion. Angiography showed a slight residual shunt two weeks after the embolization without another shunt lesion. A five-year follow-up spinal angiography showed de novo RAVF at the C4 level and complete occlusion of the first AVF. The second AVF was not treated because it was asymptomatic, and the patient remained asymptomatic. De novo RAVF was found to develop five years after the embolization of a CCJ-spinal AVF in a patient. This is the first case of de novo RAVF post-treatment of a spinal AVF. This case demonstrated that RAVF could develop as an acquired disease.

Successful embolization of ventricular arteriovenous malformation supplied by the choroidal artery: A case report and literature review.

Background: Ventricular arteriovenous malformations (AVMs) are localized in the ventricles and are mainly fed by the anterior choroidal artery (AChoA) and posterior choroidal artery (PChoA). Surgical resection of ventricular AVMs is difficult as the lesions are localized deep in the brain. Therefore, endovascular treatment is expected to treat ventricular AVMs. However, embolization from the AChoA and PChoA carries the risk of ischemic complications. Even though there are some major reports on embolization strategies from the choroidal arteries, embolization of these arteries remains technically challenging. In this article, we report two successful cases of ventricular AVM embolization using AChoA and PChoA. Case Description: Case 1: A 34-year-old male presented with intraventricular hemorrhage (IVH). Subsequently, ventricular AVM embolization in the anterior horn was performed using n-butyl-2-cyanoacrylate (NBCA) through the AChoA and medial PChoA, and complete obliteration was observed without neurological deterioration. Case 2: A 71-year-old female presented with IVH. Subsequently, ventricular AVM embolization in the lateral ventricle was performed through the AChoA and lateral PChoA with Onyx and NBCA, and partial obliteration was observed without complications. Furthermore, Gamma Knife surgery for residual lesions resulted in complete obliteration. Conclusion: Embolization through the choroidal arteries for ventricular AVMs is an effective curative or adjunctive treatment.

Anticancer Activities of DNA-Alkylating Pyrrole-Imidazole Polyamide Analogs Targeting RUNX Transcription Factors against p53-Mutated Pancreatic Cancer PANC-1 Cells.

The runt-related transcription factor (RUNX) family is known to play important roles in the progression of cancer. Conjugate 1, which covalently binds to the RUNX-binding sequences, was reported to inhibit the binding of RUNX proteins to their target sites and suppress cancer growth. Here, we evaluated the anticancer effects of 1 and its analogs 2-4 against p53-mutated PANC-1 pancreatic cancer cells. We found that they possessed different DNA-alkylating properties in vitro. And conjugates 1-3 were shown to have anticancer effects by inducing apoptosis in PANC-1 cells. Furthermore, conjugates 2 and 3 suppressed cancer growth in PANC-1 xenograft mice, with activity equivalent to a 50-fold dose of gemcitabine. Especially, 3 showed the highest alkylation efficiency, specificity, and better anticancer effects against pancreatic cancer than 1 in vivo without significant body weight loss. Our results revealed the potential of our compounds as new candidates for cancer therapy.

Incomplete Atypical Femoral Fracture With Severe Bowing Treated by Intramedullary Nail and Corrective Osteotomy.

We present the case of an 82-year-old female who had difficulty walking due to right thigh pain caused by incomplete atypical femoral fracture (AFF). The femoral bowing was so severe that intramedullary nail insertion was impossible, so we performed a corrective osteotomy of the femur and inserted the intramedullary nail. Postoperatively, the femoral pain disappeared, and bone fusion was achieved at one year and two months postoperatively. In cases of incomplete AFF with very severe femoral bowing, internal fixation with an intramedullary nail combined with corrective osteotomy of the femur is useful.

IL-1ß Derived Th17 Immune Responses Are a Critical Factor for Neutrophilic-Eosinophilic Airway Inflammation on Psychological Stress-Induced Immune Tolerance Breakdown in Mice.

INTRODUCTION: Asthma is an inflammatory reaction mediated by type 2 helper T (Th2) cells and is known to increase eosinophil levels. Our previous study showed that stress-related asthma can cause neutrophilic and eosinophilic airway inflammation by suppressing immune tolerance. However, the mechanism of stress-induced neutrophilic and eosinophilic airway inflammation remains unclear. Therefore, to elucidate the cause of neutrophilic and eosinophilic inflammation, we investigated the immune response during the induction of airway inflammation. In addition, we focused on the relationship between immune response modulation immediately after stress exposure and the development of airway inflammation. METHODS: Asthmatic mice were induced by three phases using female BALB/c mice. During the first phase, the mice were made to inhale ovalbumin (OVA) to induce immune tolerance before sensitization. Some mice were exposed to restraint stress during the induction of immune tolerance. In the second phase, the mice were sensitized with OVA/alum intraperitoneal injections. In the final phase, onset of asthma was induced through OVA exposure. Asthma development was evaluated based on airway inflammation and T-cell differentiation. Microarray and qPCR analyses were used to enumerate candidate factors to investigate the starting point of immunological modification immediately after stress exposure. Furthermore, we focused on interleukin-1ß (IL-1ß), which initiates these immune modifications, and performed experiments using its receptor blocker interleukin-1 receptor antagonist (IL-1RA). RESULTS: Stress exposure during immune tolerance induction increased eosinophil and neutrophil airway infiltration. This inflammation was associated with decreased T regulatory cell levels and increased Th2 and Th17 levels in bronchial lymph node cells. Microarray and qPCR analyses showed that the initiation of Th17 differentiation might be triggered by stress exposure during tolerance induction. IL-1RA administration during stress exposure suppressed neutrophilic and eosinophilic airway inflammation via Th17 reduction and Treg increase. CONCLUSIONS: Our results show that psychological stress causes both eosinophilic and neutrophilic inflammatory responses due to the breakdown of immune tolerance. Furthermore, stress-induced inflammation can be abolished using IL-1RA.

Complete Regression of an 8-cm Desmoid Fibromatosis After Treatment With Tamoxifen.

We report a case of a relatively large desmoid fibromatosis that responded completely to tamoxifen as a single drug therapy. A 47-year-old Japanese man underwent laparoscopy-assisted endoscopic submucosal dissection for a duodenal polyp. He developed postoperative generalized peritonitis and underwent an emergency laparotomy. Sixteen months after the surgery, a subcutaneous mass was found on the abdominal wall. Biopsy of the mass revealed estrogen receptor alpha-negative desmoid fibromatosis. The patient underwent total tumor resection. Two years after the initial surgery, he was found to have multiple intra-abdominal masses, with the largest mass measuring 8 cm in diameter. Biopsy revealed fibromatosis, as in the case of the subcutaneous mass. Complete resection was impossible due to the proximity of the duodenum and superior mesenteric artery. Tamoxifen was administered for three years, resulting in complete regression of the masses. No recurrence was observed for the following three years. This case indicates that relatively large desmoid fibromatosis can be successfully treated with a selective estrogen receptor modulator alone and that its effect is not dependent on the estrogen receptor alpha status of the tumor.

Descriptions of two new Celticecis species (Diptera: Cecidomyiidae) that induce leaf galls on Celtis boninensis (Cannabaceae) in Japan.

Two new species Celticecis insulicola Sato and Yukawa and Celticecis gracilicornis Sato and Yukawa (Diptera: Cecidomyiidae) are described from Japan based on morphological comparison with other congeners in the world. The definition of the genus Celticecis is broadened to include the two new species. Molecular phylogenetic analysis supported the results of identification. C. insulicola induces bullet-shaped galls, and C. gracilicornis induces slender conical galls on the leaves of Celtis boninensis Koidzumi (Cannabaceae), a plant of the southern part of Japan, mainly on the Nansei Islands in Kagoshima and Okinawa Prefectures. Both species are univoltine, mature larvae overwintering in the galls on the ground and adults emerging in early spring. C. insulicola was found on Amami, Uke and Okinoerabu Islands, Kagoshima Prefecture, and Okinawa Island, Okinawa Prefecture. C. gracilicornis was found on Amami and Okinawa Islands.

Postsurgical dural supply to the spinal cord arteriovenous malformation in spinal arteriovenous metameric syndrome.

Dural supply from the external carotid system in cerebral arteriovenous malformations (AVMs) is well known, but actual angiographic evidence of dural supply to spinal cord AVMs (SCAVMs) has not been reported. Here, we report a case of dural supply to the conus SCAVM in the spinal arteriovenous metameric syndrome segment 25-30. Thirteen years after spinal surgery (T12-L2 laminoplasty), spinal angiography showed multiple dural supplies from the dorsal somatic branches, prelaminar arteries, and radiculomeningeal arteries to the SCAVM at the level of the previous spinal surgery. To the best of our knowledge, this is the first reported case with dural supply to the spinal cord. This case demonstrates that the extradural and extraspinal branches can supply the spinal cord in rare instances of spinal dural adhesions following repeated hemorrhages and surgical intervention under a metameric link background.