Long-term outcomes of robot-assisted versus minimally invasive esophagectomy in patients with thoracic esophageal cancer: a propensity score-matched study.

BACKGROUND: Recently, robot-assisted minimally invasive esophagectomy (RAMIE) has gained popularity worldwide. Some studies have compared the long-term results of RAMIE and minimally invasive esophagectomy (MIE). However, there are no reports on the long-term outcomes of RAMIE in Japan. This study compared the long-term outcomes of RAMIE and MIE. METHODS: This retrospective study included 86 patients with thoracic esophageal cancer who underwent RAMIE or MIE at our hospital from June 2010 to December 2016. Propensity score matching (PSM) was employed, incorporating co-variables such as confounders or risk factors derived from the literature and clinical practice. These variables included age, sex, body mass index, alcohol consumption, smoking history, American Society of Anesthesiologists stage, comorbidities, tumor location, histology, clinical TNM stage, and preoperative therapy. The primary endpoint was 5-year overall survival (OS), and the secondary endpoints were 5-year disease-free survival (DFS) and recurrence rates. RESULTS: Before PSM, the RAMIE group had a longer operation time (min) than the MIE group (P = 0.019). RAMIE also exhibited significantly lower blood loss volume (mL) (P < 0.001) and fewer three-field lymph node dissections (P = 0.028). Postoperative complications (Clavien-Dindo: CD ≥ 2) were significantly lower in the RAMIE group (P = 0.04), and postoperative hospital stay was significantly shorter than the MIE group (P < 0.001). After PSM, the RAMIE and MIE groups consisted of 26 patients each. Blood loss volume was significantly smaller (P = 0.012), postoperative complications (Clavien-Dindo ≥ 2) were significantly lower (P = 0.021), and postoperative hospital stay was significantly shorter (P < 0.001) in the RAMIE group than those in the MIE group. The median observation period was 63 months. The 5-year OS rates were 73.1% and 80.8% in the RAMIE and MIE groups, respectively (P = 0.360); the 5-year DFS rates were 76.9% and 76.9% in the RAMIE and MIE groups, respectively (P = 0.749). Six of 26 patients (23.1%) in each group experienced recurrence, with a median recurrence period of 41.5 months in the RAMIE group and 22.5 months in the MIE group. CONCLUSIONS: Compared with MIE, RAMIE led to no differences in long-term results, suggesting that RAMIE is a comparable technique.

[Significance of Colorectal Cancer Resection for the Elderly].

INTRODUCTION: Elderly patients requiring surgical treatment is increasing in Japan, and while surgical treatment is expected to be effective even in the very elderly, there is a lack of evidence for the safety and efficacy of surgical resection due to problems with perioperative management and operative tolerance. We therefore retrospectively examined the short-term and long-term outcomes of colorectal cancer surgery for the very elderly at our hospital. SUBJECTS: The study included 14 cases of colorectal cancer in the very elderly who underwent radical resection at our hospital between January 2010 and March 2020. RESULTS: The mean age was 92 years, PS; 1/2=8/6, ASA-PS; 2/3/4=8/4/2, primary site was C/A/T/S/R= 2/5/2/2/3, pStage; 1/2/3=1/9/4, and only 1 case of decompression with ileus tube due to obstructive symptoms was treated before surgery. All patients underwent radical surgery. Median blood loss was 61 mL, median operation time was 190.5 min, and median postoperative hospital stay was 16 days. 5 patients had CD≥2 complications. All patients did not receive adjuvant chemotherapy, and recurrence in was observed 3 patients. CONCLUSION: Surgical treatment of very elderly patients seems to be acceptable under appropriate patient selection.

Prospective evaluation of common hepatic duct histopathology at the time of choledochal cyst excision ranging from children to adults.

PURPOSE: To evaluate common hepatic duct just distal to the HE anastomosis (d-CHD) prospectively for mucosal damage, inflammation, fibrosis, dysplasia, carcinoma in situ, malignant transformation, effects of serum amylase, and symptoms at presentation in CC cases ranging from children to adults. METHODS: Cross-sections of d-CHD obtained at cyst excision 2018-2023 from 65 CC patients; 40 children (< 15 years old), 25 adults (≥ 15) were examined with hematoxylin and eosin, Ki-67, S100P, IMP3, p53, and Masson's trichrome to determine an inflammation score (IS), fibrosis score (FS), and damaged mucosa rate (DMR; damaged mucosa expressed as a percentage of the internal circumference). RESULTS: Mean age at cyst excision ("age") was 18.2 years (range: 3 months-74 years). Significant inverse correlations were found for age and DMR (p = 0.002), age and IS (p = 0.011), and age and Ki-67 (p = 0.01). FS did not correlate with age (p = 0.32) despite significantly increased IS in children. Dysplasia was identified in a 4-month-old girl with cystic CC. Serum amylase was elevated in high DMR subjects. CONCLUSIONS: High DMR, high IS, and evidence of dysplasia in pediatric CC suggest children are at risk for serious sequelae best managed by precise histopathology, protocolized follow-up, and awareness that premalignant histopathology can arise in infancy.

Incidence of anastomotic stricture after hepaticojejunostomy with continuous sutures in patients who underwent laparoscopic pancreaticoduodenectomy.

PURPOSE: Laparoscopic hepatojejunostomy (HJ) with continuous sutures is commonly performed in laparoscopic pancreaticoduodenectomy (LPD). This study aimed to investigate the long-term surgical outcomes of HJ in LPD. METHODS: We retrospectively evaluated 103 consecutive patients who underwent pancreaticoduodenectomy via laparoscopic HJ with continuous suturing using multifilament (n = 48) or monofilament-absorbable sutures (n = 47). RESULTS: During follow-up, anastomotic stricture of HJ was identified in 8 (7.8%) patients via balloon enteroscopy-assisted cholangiography. The median time from surgery to confirmation of stricture formation was 7.6 months (range 3.6-19.4). The incidence of HJ stricture was significantly higher in patients with a thin bile duct (diameter < 6.0 mm) than in those with a thick bile duct (diameter ≥ 6.0 mm) [7/27 (25.9%) vs. 1/76 (1.3%), respectively, p < 0.01]. Similarly, it was significantly higher in the monofilament group than in the multifilament group [7/54 (13.0%) vs. 1/49 (2.0%), respectively, p = 0.04]. In the monofilament suture group, 37.5% of patients with thin bile ducts developed stricture after HJ. A multivariate analysis revealed that a thin bile duct was an independent risk factor for HJ stricture (hazard ratio: 25.3, p < 0.01). CONCLUSIONS: Stricture after laparoscopic HJ using continuous sutures frequently occurs in patients with thin bile ducts, particularly when monofilament-absorbable suture is used.

Receptor Tyrosine Kinases: Principles and Functions in Glioma Invasion.

Protein tyrosine kinases are enzymes that are capable of adding a phosphate group to specific tyrosines on target proteins. A receptor tyrosine kinase (RTK) is a tyrosine kinase located at the cellular membrane and is activated by binding of a ligand via its extracellular domain. Protein phosphorylation by kinases is an important mechanism for communicating signals within a cell and regulating cellular activity; furthermore, this mechanism functions as an "on" or "off" switch in many cellular functions. Ninety unique tyrosine kinase genes, including 58 RTKs, were identified in the human genome; the products of these genes regulate cellular proliferation, survival, differentiation, function, and motility. Tyrosine kinases play a critical role in the development and progression of many types of cancer, in addition to their roles as key regulators of normal cellular processes. Recent studies have revealed that RTKs such as epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), c-Met, Tie, Axl, discoidin domain receptor 1 (DDR1), and erythropoietin-producing human hepatocellular carcinoma (Eph) play a major role in glioma invasion. Herein, we summarize recent advances in understanding the role of RTKs in glioma pathobiology, especially the invasive phenotype, and present the perspective that RTKs are a potential target of glioma therapy.

[Multiple Tentorial Dural Arteriovenous Fistulas with Acquired Pial Arteriovenous Fistula Presented with Unilateral Eye Symptoms Successfully Treated by Transarterial Embolization and Direct Surgery:A Case Report].

A 58-year-old man presented with slowly progressive chemosis, exophthalmos, and blepharedema of the left eye. Digital subtraction angiography revealed multiple dural arteriovenous fistulas(dAVFs)involving the bilateral tentorium, superior sagittal sinus, and right frontal convexity. In addition, occlusion of the left cavernous sinus and left sigmoid sinus were observed, which could lead to venous hypertension and might be associated with the occurrence of multiple dAVFs. Along with the congestion of the left ophthalmic vein, increased intracranial pressure due to the left tentorial dAVF with cortical venous reflux could have caused the left eye symptoms; therefore, the tentorial lesion was treated first. Although the proximal occlusion of the vein of Labbe, drainer of the left tentorial dAVF, was achieved after embolization using n-butyl cyanoacrylate via the external carotid artery, an arteriovenous shunt between the middle cerebral artery and the distal site of the vein of Labbe was newly visualized after embolization. The newly visualized lesion was treated with further surgical intervention. A pial AVF arising from several peripheral branches of the left middle cerebral artery with drainage into the distal site of the vein of Labbe was confirmed during the surgery, and interruption of the vein of Labbe was performed. The left eye symptoms of the patient significantly improved after the surgery, and postoperative angiogram revealed no residual shunt. Thus, the patient was treated using a combined approach of endovascular and direct surgeries, after which he recovered uneventfully.

Prediction of carotid artery in-stent restenosis by quantitative assessment of vulnerable plaque using computed tomography.

BACKGROUND AND PURPOSE: To assess the relationship between plaque volume evaluated by multidetector computed tomographic angiography (MDCT) and in-stent restenosis (ISR) after carotid artery stenting (CAS). MATERIALS AND METHODS: From a retrospectively maintained database, data were collected for 52patients with carotid artery stenosis treated with CAS between 2007 and 2012. We defined ISR of≥50% as a peak systolic velocity≥200cm/s on echo-duplex scan. Carotid plaques were subdivided into four components according to radiodensity in Hounsfield units (HU) as follows: <0, 0-60, 60-130, and>600HU. Risk factors that influenced ISR were compared using univariate and multivariate Cox regression analyses. RESULTS: During a median follow-up period of 36months, ISR of≥50% was detected in five patients (9.6%). In the univariate Cox proportional hazard regression analysis, renal insufficiency, coronary artery disease, total plaque volume, and plaque volumes with radiodensities<0 and≥600HU increased the risk for ISR (P<0.10). When the significant risk factors determined from the univariate analysis were subjected to a multivariate analysis, only the volumes of the plaque components with radiodensities<0 HU independently predicted the development of ISR (hazard ratio: 1.041; 95% confidence interval: 1.006-1.078; P=0.021). CONCLUSION: Our data suggest that the high volume of the plaque components with radiodensities<0HU was independently associated with the increased risk of ISR after CAS. Quantitative and qualitative tissue characterizations of carotid plaques using MDCT might be a useful predictive tool of the development of ISR.

[Intraluminal Thrombus in Internal Carotid Artery Successfully Treated with Adjuvant Anticoagulant Therapy Followed by Carotid Endarterectomy:A Case Report].

BACKGROUND: An intraluminal thrombus in the carotid artery is relatively rare. A high frequency of perioperative symptomatic stroke has been reported in patients undergoing carotid endarterectomy, and no standard therapy has yet been developed. CASE PRESENTATION: A 69-year-old woman, with no history of trauma, presented with ischemic stroke and mild right hemiparesis. Computed tomography and MRI showed an infarction in the left parietal region. A carotid Doppler study showed carotid stenosis on the left side. Further investigation with digital subtraction angiography confirmed significant carotid artery stenosis with an intraluminal thrombus in the left internal carotid artery. She was treated with initial intravenous anticoagulant therapy followed by carotid endarterectomy with thrombus removal 14 days after admission(subacute phase). There was no postoperative complication and she had uneventful course over 3 years of follow-up. CONCLUSION: Initial adjuvant anticoagulant therapy for symptomatic intraluminal thrombus followed by carotid revascularization is an effective surgical strategy. A meticulous surgical procedure is required to perform a carotid endarterectomy in patients with an intraluminal thrombus.

Deletion of Atf6α impairs astroglial activation and enhances neuronal death following brain ischemia in mice.

To dissect the role of endoplasmic reticulum (ER) stress and unfolded protein response in brain ischemia, we investigated the relevance of activating transcription factor 6α (ATF6α), a master transcriptional factor in the unfolded protein response, after permanent middle cerebral artery occlusion (MCAO) in mice. Enhanced expression of glucose-regulated protein78, a downstream molecular chaperone of ATF6α, was observed in both neurons and glia in the peri-infarct region of wild-type mice after MCAO. Analysis using wild-type and Atf6α(-/-) mice revealed a larger infarct volume and increased cell death in the peri-ischemic region of Atf6α(-/-) mice 5 days after MCAO. These phenotypes in Atf6α(-/-) mice were associated with reduced levels of astroglial activation/glial scar formation, and a spread of tissue damage into the non-infarct area. Further analysis in mice and cultured astrocytes revealed that signal transducer and activator of transcription 3 (STAT3)-glial fibrillary acidic protein signaling were diminished in Atf6α(-/-) astrocytes. A chemical chaperone, 4-phenylbutyrate, restored STAT3-glial fibrillary acidic protein signaling, while ER stressors, such as tunicamycin and thapsigargin, almost completely abolished signaling in cultured astrocytes. Furthermore, ER stress-induced deactivation of STAT3 was mediated, at least in part, by the ER stress-responsive tyrosine phosphatase, TC-PTP/PTPN2. These results suggest that ER stress plays critical roles in determining the level of astroglial activation and neuronal survival after brain ischemia.

Strong therapeutic potential of γ-secretase inhibitor MRK003 for CD44-high and CD133-low glioblastoma initiating cells.

The Notch signal regulates both cell viability and apoptosis, and maintains stemness of various cancers including glioblastoma (GBM). Although Notch signal inhibition may be an effective strategy in treating GBM initiating cells (GICs), its applicability to the different subtypes of GBM remains unclear. Here, we analyzed the effectiveness of MRK003, a preclinical γ-secretase inhibitor, on GICs. Nine patient-derived GICs were treated by MRK003, and its efficacy on cell viability, apoptosis, sphere forming ability and Akt expression level which might be related to Notch downstream and be greatly important signals in GBM was evaluated. MRK003 suppressed viability and sphere-formation ability, and induced apoptosis in all GICs in varying doses of MRK003. Based on their sensitivities to MRK003, the nine GICs were divided into "relatively sensitive" and "relatively resistant" GICs. Sensitivity to MRK003 was associated with its inhibitory effect on Akt pathway. Transgenic expression of the myristoylated Akt vector in relatively sensitive GICs partially rescued the effect of MRK003, suggesting that the effect of MRK003 was, at least in part, mediated through inhibition of the Akt pathway. These GICs were differentiated by the expression of CD44 and CD133 with flow cytometric analysis. The relatively sensitive GICs are CD44-high and CD133-low. The IC50 of MRK003 in a set of GICs exhibited a negative correlation with CD44 and positive correlation with CD133. Collectively, MRK003 is partially mediated by the Akt pathway and has strong therapeutic potential for CD44-high and CD133-low GICs.

A 15-month-old boy with congenital duodenal stenosis due to food impaction.

Duodenal stenosis is a type of congenital intestinal atresia syndrome. Most patients are diagnosed during the neonatal period based on recurrent vomiting, but some cases develop symptoms at an older age. We report a case with an unusual pathogenic mechanism: sudden ileus due to food impaction.A 15-month-old boy was admitted to our institution with a history of recurrent vomiting and diarrhea for 7 days and fever for 2 days. Abdominal distention was found upon physical examination but other congenital anomalies were not. He was initially treated for acute gastroenteritis, but vomiting resumed after starting oral ingestion. Congenital membranous duodenal stenosis and impaction of a shimeji mushroom into the narrow section of the duodenum was recognized upon endoscopy. Dilatation was successful and restenosis was not seen. Food impaction is a rare (but important) initial event in congenital duodenal stenosis, and this disorder should be included in the differential diagnosis, especially for infants/toddlers with recurrent vomiting that develops at the time of eating solid and more diverse types of food.

Prognostic paradox: brain damage around the glioblastoma resection cavity.

Hyperintense lesions around the resection cavity on magnetic resonance diffusion-weighted imaging (MR-DWI) frequently appear after brain tumor surgery due to the damage of surrounding brain. The putative connection between the lesion and the prognosis for patients with glioblastoma (GBM) was explored. This retrospective study reviewed consecutive sixty-one patients with newly diagnosed GBM. Postoperative MRI was performed within 2 weeks after the initial surgery. We classified the cases into two groups depending on whether DWI hyperintense lesions were observed or not [DWI(+) group and DWI(-) group]. Progression-free survival (PFS) and overall survival (OS) were compared between the two groups. Forty-two patients were identified. The various extents of hyperintense lesions around the resection cavity were observed in 28/42 (66.7%) cases. In the DWI(+) and DWI(-) groups, median PFS was 10.0 [95% confidence interval (CI) 8.4-11.5] and 6.7 (95% CI 4.9-8.5) months, respectively (p = 0.042), and median OS was 18.0 (95% CI 12.2-23.8) and 17.0 (95% CI 15.7-18.3) months, respectively (p = 0.254). On multivariate analysis, the presence of DWI hyperintense lesion was more likely to be an independent predictor for 6-month PFS (p = 0.019; HR, 0.038; 95% CI 0.002-0.582). Tumor recurrence appeared outside the former DWI hyperintense lesion. Hyperintense lesions surrounding the resected GBM on MR-DWI might be a favorable prognostic factor in patients with GBM.

A 7-dimethylallyl tryptophan synthase from a fungal Neosartorya sp.: biochemical characterization and structural insight into the regioselective prenylation.

A putative 7-dimethylallyl tryptophan synthase (DMATS) gene from a fungal Neosartorya sp. was cloned and overexpressed as a soluble His6-fusion protein in Escherichia coli. The enzyme was found to catalyze the prenylation of L-tryptophan at the C7 position of the indole moiety in the presence of dimethylallyl diphosphate; thus, it functions as a 7-DMATS. In this study, we describe the biochemical characterization of 7-DMATS from Neosartorya sp., referred to as 7-DMATS(Neo), and the structural basis of the regioselective prenylation of L-tryptophan at the C7 position by comparison of the three-dimensional structural models of 7-DMATS(Neo) with FgaPT2 (4-DMATS) from Aspergillus fumigatus.

Reversible acute bilateral blindness resulting from a frontal brain tumor: a case report.

We experienced an unusual case of a 15-year-old girl who suffered acute bilateral blindness caused by a frontal lobe tumour. She underwent emergent operation, after which her vision recovered. This case emphasizes that a brain mass can cause sudden onset blindness and an emergency intervention might save the patient's sight.

Clinical Limitations of Vasoreactivity Testing as a Diagnostic Tool in Patients with Vasospastic Angina.

The Japanese Circulation Society guidelines recommend a class I vasoreactivity test to diagnose patients with vasospastic angina (VSA). However, the acetylcholine or ergonovine test has been established as the gold standard for variant angina (VA). The sensitivity and specificity of intracoronary vasoreactivity testing in patients with VA were acceptable. Cardiologists have employed these vasoreactivity tests to conveniently diagnose the presence of coronary spasms in patients with all VSA. The majority of VSAs may have lower disease activity than VA cases. We have summarized the usefulness of spasm provocation tests in patients with VA and VSA. A positive-provoked spasm diagnosed by standard vasoreactivity testing may indicate a disease state similar to that of VA, whereas a negative-provoked spasm after standard vasoreactivity testing may indicate a lower disease state than that of VA. Cardiologists should reconsider the limited usefulness of vasoreactivity testing when diagnosing the presence of coronary spasms in all VSAs, but not VA.

Importance of provoked spasms at the sites of nonobstructive stenosis as well as at the sites of obstructive stenosis in patients with obstructive coronary arteries and coronary spasm.

OBJECTIVES: There are few reports regarding the prognosis in patients with obstructive coronary artery disease (OCAD) and vasospastic angina (VSA). This study investigated the clinical characteristics and clinical outcomes in patients with VSA and OCAD, especially regarding provoked spasm phenotypes and sites. METHODS: This was a retrospective, observational, single-center study of 403 patients with typical or atypical angina-like chest pain undergoing acetylcholine (ACH) spasm provocation testing and OCAD. An obstructed coronary artery was defined as ≥50% luminal narrowing. We defined positive epicardial spasm as ≥90% transient stenosis and usual chest symptoms or ischemic ECG changes. RESULTS: Among these 403 patients with OCAD, positive spasm by intracoronary ACH testing was observed in 196 patients (49%), whereas negative spasm was found in the remaining 207 patients (51%). The clinical outcomes in the patients with OCAD and provoked spasm were not different according to the provoked-spasm phenotypes. Furthermore, the clinical outcomes were unsatisfactory in the patients with spasm at the site of nonobstructive lesion alone compared with those with spasm at the site of obstructive and nonobstructive lesions. CONCLUSION: We should precisely diagnose patients with OCAD who have provoked spasm by using intracoronary ACH testing and medicate the nonobstructive vessels in patients with OCAD and VSA under optimal coronary vasodilators.

Clinical complete response after trastuzumab deruxtecan 6th-line treatment for postoperative gastric cancer recurrence: a case report.

BACKGROUND: Despite the recent developments in the treatment of advanced or recurrent gastric cancer, the median survival time remains shorter than 15 months. Herein, we report a case of postoperative gastric cancer recurrence in which a complete clinical response was achieved with trastuzumab deruxtecan as 6th-line treatment. CASE PRESENTATION: A 70-year-old man underwent abdominal contrast-enhanced computed tomography (CT) during follow-up after rectal cancer surgery. The CT revealed an enlarged perigastric lymph node. After further examination, the patient's condition was diagnosed as gastric cancer cT2N1H0P0M0 cStage IIA. The patient underwent distal gastrectomy and D2 lymph node dissection. The resulting pathological diagnosis was pT1bN3aH0P0 pStageIIB, HER2 score 3+. Abdominal contrast-enhanced CT 19 months postoperatively revealed para-aortic lymph node recurrence, thus systemic chemotherapy courses were planned. The primary treatment was a combination of S-1, cisplatin, and trastuzumab administered in 11 courses. However, there was an enlargement of the para-aortic lymph node which was evaluated as progressive disease. Systematic chemotherapy with various regimens was continued until the 5th-line treatment. However, therapeutic benefits were not achieved and lung metastasis was observed. Trastuzumab deruxtecan (TDXD) was initiated as 6th-line treatment. Abdominal contrast-enhanced CT at 4 months after the start of treatment showed marked shrinkage of the enlarged para-aortic lymph node and disappearance of the lung metastasis in the right upper lung lobe, which was evaluated as partial response (PR). The para-aortic lymph node metastasis was evaluated as PR with only a slight accumulation of SUV-Max 2.66 with a shrinking trend by positron emission tomography-computed tomography (PET-CT) performed after 1 year. Tumor markers CEA, CA19-9, and CA125 also improved significantly. PET-CT after 1 year and 4 months showed no lymph node enlargement or accumulation, indicating a complete response (CR). All tumor markers also normalized. The patient has maintained clinical CR without additional treatment to date. CONCLUSIONS: We report the apparent first case of postoperative gastric cancer recurrence successfully treated with TDXD, achieving clinical CR with TDXD as a 6th-line treatment.

Glycogen synthase kinase 3ß inhibition sensitizes human glioblastoma cells to temozolomide by affecting O6-methylguanine DNA methyltransferase promoter methylation via c-Myc signaling.

Glycogen synthase kinase 3ß (GSK3ß) is a serine/threonine protein kinase involved in human cancers including glioblastoma. We have previously demonstrated that GSK3ß inhibition enhances temozolomide effect in glioma cells. In this report, we investigated the molecular mechanisms of sensitization of glioblastoma cells to temozolomide by GSK3ß inhibition, focusing on O(6)-methylguanine DNA methyltransferase (MGMT) gene silencing. Glioblastoma tissues from patients treated with the GSK3ß-inhibiting drugs were subjected to immunohistochemistry and methylation-specific PCR assay. Human glioblastoma cell lines T98G, U138, U251 and U87 were treated with a small-molecule GSK3ß inhibitor, AR-A014418 or GSK3ß-specific small interfering RNA. The combined effect of temozolomide and AR-A014418 on cell proliferation was determined by AlamarBlue assay and an isobologram method. MGMT promoter methylation was estimated by methylation-specific PCR and MethyLight assay. MGMT gene expression was evaluated by real-time quantitative reverse transcriptase-PCR. c-Myc and DNA (cytosine-5)-methyltransferase 3A binding to the MGMT promoter was estimated by chromatin immunoprecipitation assay. GSK3ß inhibition decreased phosphorylation of glycogen synthase and reduced MGMT expression and increased MGMT promoter methylation in clinical tumors. In glioblastoma cell lines, GSK3ß inhibition decreased cell viability, enhanced temozolomide effect and downregulated MGMT expression with relevant changes in the methylation levels of the MGMT promoter. Here, we showed for the first time that c-Myc binds to the MGMT promoter with consequent recruitment of DNA (cytosine-5)-methyltransferase 3A, regulating the levels of MGMT promoter methylation. The results of this study suggest that GSK3ß inhibition enhances temozolomide effect by silencing MGMT expression via c-Myc-mediated promoter methylation.

Receptor tyrosine kinases: principles and functions in glioma invasion.

Protein tyrosine kinases are enzymes that are capable of adding a phosphate group to specific tyrosines on target proteins. A receptor tyrosine kinase (RTK) is a tyrosine kinase located at the cellular membrane and is activated by binding of a ligand via its extracellular domain. Protein phosphorylation by kinases is an important mechanism for communicating signals within a cell and regulating cellular activity; furthermore, this mechanism functions as an "on" or "off" switch in many cellular functions. Ninety unique tyrosine kinase genes, including 58 RTKs, were identified in the human genome; the products of these genes regulate cellular proliferation, survival, differentiation, function, and motility. Tyrosine kinases play a critical role in the development and progression of many types of cancer, in addition to their roles as key regulators of normal cellular processes. Recent studies have revealed that RTKs such as epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), c-Met, Tie, Axl, discoidin domain receptor 1 (DDR1), and erythropoietin-producing human hepatocellular carcinoma (Eph) play a major role in glioma invasion. Herein, we summarize recent advances in understanding the role of RTKs in glioma pathobiology, especially the invasive phenotype, and present the perspective that RTKs are a potential target of glioma therapy.

Percutaneous transjugular approach without arterial monitoring for the treatment of a direct carotid-cavernous fistula with vascular Ehlers-Danlos syndrome: illustrative case.

BACKGROUND: Vascular Ehlers-Danlos syndrome (vEDS) because of COL3A1 mutations is a rare inherited collagen vascular disease associated with spontaneous arterial dissections, aneurysms, vessel rupture, and organ rupture. A direct carotid-cavernous fistula (CCF) is the most common central nervous system vascular anomaly in vEDS; however, its treatment is challenging due to extremely fragile arteries and veins. OBSERVATIONS: A 22-year-old woman presented with pulsatile tinnitus and mild diplopia. CCF formation without trauma, cervical dissecting aneurysms, thin skin, and multiple ligament tears, as well as a genetic analysis, led to a diagnosis of vEDS. To minimize the risk of vascular injury in the thoracoperitoneal cavity, the internal jugular vein was directly punctured and the CCF was embolized transvenously using the triple-overlay road-mapping technique without arterial monitoring. The CCF was completely occluded, and the patient showed an excellent clinical course without neurological or vascular complications. LESSONS: Physicians and neurosurgeons should consider vEDS when treating younger patients with spontaneous CCF without trauma and investigate the possibility of genetic abnormalities and systemic vascular pathology. Transvenous embolization of a CCF through the transjugular route using the triple-overlay road-mapping technique can minimize the risk of vascular injury in a patient with vEDS.