Targeting metabolic reprogramming to overcome drug resistance in advanced bladder cancer: insights from gemcitabine- and cisplatin-resistant models.

Gemcitabine plus cisplatin (GC) combination chemotherapy is the primary treatment for advanced bladder cancer (BC) with unresectable or metastatic disease. However, most cases develop resistance to this therapy. We investigated whether drug resistance could be targeted through metabolic reprogramming therapies. Metabolomics analyses in our lab's gemcitabine- and cisplatin-resistant cell lines revealed increased phosphoglycerate dehydrogenase (PHGDH) expression in gemcitabine-resistant cells compared with parental cells. Isocitrate dehydrogenase 2 (IDH2) gain of function stabilized hypoxia-inducible factor1α (HIF1α) expression, stimulating aerobic glycolysis. In gemcitabine-resistant cells, elevated fumaric acid suppressed prolyl hydroxylase domain-containing protein 2/Egl nine homolog 1 (PHD2) and stabilized HIF1α expression. PHGDH downregulation or inhibition in gemcitabine-resistant BC cells inhibited their proliferation, migration, and invasion. Cisplatin-resistant cells showed elevated fatty acid metabolism, upregulating fatty acid synthase (FASN) downstream of tyrosine kinase. Using the fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor erdafitinib, we inhibited malonyl-CoA production, which is crucial for fatty acid synthesis, and thereby suppressed upregulated HIF1α expression. Combination treatment with NCT503 and erdafitinib synergistically suppressed tumor cell proliferation and induced apoptosis in vitro and in vivo. Understanding these mechanisms could enable innovative BC therapeutic strategies to be developed.

LncRNA BCYRN1 as a Potential Therapeutic Target and Diagnostic Marker in Serum Exosomes in Bladder Cancer.

Bladder cancer (BC) is a common genitourinary malignancy that exhibits silent morbidity and high mortality rates because of a lack of diagnostic markers and limited effective treatments. Here, we evaluated the role of the lncRNA brain cytoplasmic RNA 1 (BCYRN1) in BC. We performed loss-of-function assays to examine the effects of BCYRN1 downregulation in T24 and BOY BC cells. We found that BCYRN1 downregulation significantly inhibited the proliferation, migration, invasion, and three-dimensional spheroid formation ability and induced apoptosis in BC cells. Additionally, gene set enrichment analysis (GSEA) using RNA sequences from tumor fractions showed that BCYRN1 downregulation decreased the expression of mRNAs associated with the cell cycle. These findings were supported by observations of G2/M arrest in flow cytometry assays. Finally, we examined the expression of serum exosomal BCYRN1 as a biomarker. Clinically, BCYRN1 expression in serum exosomes from patients with BC (n = 31) was significantly higher than that in healthy donors (n = 19; mean difference: 4.1-fold higher, p < 0.01). Moreover, in patients who had undergone complete resection of BC, serum exosomal BCYRN1 levels were significantly decreased (n = 8). Thus, serum exosomal BCYRN1 may be a promising diagnostic marker and therapeutic target in patients with BC.

Prevention of Postoperative Skin Disorders and Pressure Injuries in the Neurosurgical Park Bench Position Surgery: A Prospective Cohort Study.

Background In neurosurgical procedures where the park bench position is employed, the risk of perioperative pressure injuries is elevated due to the limited contact surface area, with the head and part of the upper torso extending beyond the surgical table. This study aimed to examine the effects of preventative measures against such injuries, proposing a potential standard for postural fixation in these surgeries. Methods Conducted at a medical center, from January 2017 to March 2023, this prospective cohort study involved participants aged 20 and above who underwent neurosurgical procedures in the park bench position under general anesthesia. The focus was on comparing the incidence of pressure injuries between intervention and control groups. The study adhered to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. Results Out of 65 patients enrolled, 28 were assigned to each of the intervention and control groups. The control group experienced 17 instances of postoperative pressure injuries and skin disorders in areas prone to pressure, such as the axillary and greater trochanter regions. Conversely, the intervention group reported no such incidents, underscoring the efficacy of meticulous surgical positioning and management of bodily pressure, temperature, humidity, and microclimate. Conclusion Implementing preventive measures in neurosurgical park bench procedures significantly reduces the incidence of postoperative pressure injuries and skin disorders. These findings advocate for the adoption of standardized postural fixation protocols in such surgeries, potentially influencing global clinical practices in neurosurgery.

Potential therapeutic target secretogranin II might cooperate with hypoxia-inducible factor 1α in sunitinib-resistant renal cell carcinoma.

Multitargeted receptor tyrosine kinase inhibitors, including vascular endothelial growth factor (VEGF) inhibitors, such as sunitinib, have been used as the primary targeted agents for patients with recurrent or distant metastasis of advanced renal cell carcinoma (RCC). However, endogenous or acquired sunitinib resistance has become a significant therapeutic problem. Therefore, we focused on mechanisms of sunitinib resistance in RCC. First, we undertook RNA sequencing analysis using previously established sunitinib-resistant RCC (SUR-Caki1, SUR-ACHN, and SUR-A498) cells. The results showed increased expression of secretogranin II (SCG2, chromogranin C) in SUR-RCC cells compared to parental cells. The Cancer Genome Atlas database showed that SCG2 expression was increased in RCC compared to normal renal cells. In addition, the survival rate of the SCG2 high-expression group was significantly lower than that of the RCC low-expression group. Thus, we investigated the involvement of SCG2 in sunitinib-resistant RCC. In vitro analysis showed that migratory and invasive abilities were suppressed by SCG2 knockdown SUR cells. As SCG2 was previously reported to be associated with angiogenesis, we undertook a tube formation assay. The results showed that suppression of SCG2 inhibited angiogenesis. Furthermore, coimmunoprecipitation assays revealed a direct interaction between SCG2 and hypoxia-inducible factor 1α (HIF1α). Expression levels of VEGF-A and VEGF-C downstream of HIF1α were found to be decreased in SCG2 knockdown SUR cells. In conclusion, SCG2 could be associated with sunitinib resistance through VEGF regulation in RCC cells. These findings could lead to a better understanding of the VHL/HIF/VEGF pathway and the development of new therapeutic strategies for sunitinib-resistant RCC.

[Internal carotid artery stenosis with repeated ischemic stroke recurrence due to mechanical stimulation by the hyoid bone and thyroid cartilage: a case report].

We present a case of internal carotid artery (ICA) stenosis caused by mechanical stimulation by the hyoid bone (HB) and thyroid cartilage (TC). A 78-year-old man with a history of right ICA stenting four years previously was admitted for abrupt onset of dysarthria and left hemiparesis and diagnosed with ischemic stroke by magnetic resonance imaging. Three-dimensional computed tomographic angiography revealed internal carotid in-stent restenosis. Furthermore, the HB and TC contacted with the right ICA. Treatment involved antiplatelet therapy, partial HB and TC resection, and carotid artery restenting. Posttreatmently, the ICA was restored and stenosis improved. Since restenosis may occur posttreatmently in patients with carotid artery stenosis caused by mechanical stimulation of the HB and TC, it is necessary to consider treatments including not only carotid artery stenting but also partial bone structures resection and carotid endarterectomy.

Case report: Unruptured small middle cerebral artery aneurysm with perianeurysmal edema.

Background: Perianeurysmal edema (PAE) has a tendency to occur in embolized aneurysms but also in partially thrombosed, large, or giant aneurysms. However, there are only a few cases recorded in which PAE was detected in untreated or small aneurysms. We suspected that PAE might be an impending sign of aneurysm rupture in these cases. Herein, we presented a unique case of PAE that was related to an unruptured small middle cerebral artery aneurysm. Case description: A 61-year-old woman was referred to our institute due to a newly formed abnormal fluid-attenuated inversion recovery (FLAIR) hyperintense lesion in the right medial temporal cortex. Upon admission, the patient did not present with any symptoms or complaints; however, FLAIR and CT angiography (CTA) suggested an increased risk of aneurysm rupture. Aneurysm clipping was conducted, and no evidence of subarachnoid hemorrhage and hemosiderin deposits around the aneurysm and brain parenchyma was noted. The patient was discharged home without any neurological symptoms. MRI taken at eight months post-clipping revealed complete regression of the FLAIR hyperintense lesion around the aneurysm. Conclusion: PAE in unruptured, small aneurysm is thought to be an impending sign of aneurysm rupture. Early surgical intervention is critical even for small aneurysms with PAE.

Exosomal microRNA-1 and MYO15A as a target for therapy and diagnosis in renal cell carcinoma.

Exosomes are 40-100 nm nano-sized extracellular vesicles and are receiving increasing attention as novel structures that participate in intracellular communication. We previously found that miRNA-1 (miR-1) functions as a tumor suppressor in renal cell carcinoma (RCC). In this study, we investigated the function of exosomal miR-1 and the possibility that the exosome constitutes a tumor maker in RCC. First, we established the method to collect exosomes from cell lysates and human serum by a spin column-based method. Next, we assessed exosomes using Nanosight nanoparticle tracking analysis and Western blot analysis with exosome marker CD63. We confirmed that exosomes labeled with PKH26 fused with recipient cells. Moreover, miR-1 expression was elevated in RCC cells treated with exosomes derived from miR-1-transfected cells. Functional analyses showed that exosomal miR-1 significantly inhibited cell proliferation, migration and invasion compared to control treatment. Our analyses with TCGA database of RCCs showed that miR-1 expression was significantly downregulated in clinical RCC samples compared to that in normal kidney samples, and patients with low miR-1 expression had poorer overall survival in comparison to patients with high expression. Furthermore, RNA sequence analyses showed that expression levels of several genes were altered by exposure to exosomal miR-1. The analyses with TCGA database indicated that high expression of MYO15A was associated with a poorer outcome in RCC. In addition, RT-qPCR analysis of exosomes from clinical patients' sera showed that MYO15A was significantly upregulated in RCC patients compared to that in healthy controls. This study showed that treatment with exosomal miR-1 might be an effective approach to treating RCCs. In addition, exosomal MYO15A could be a diagnostic tumor marker in RCCs.

Endovascular treatment of an aneurysm arising from the minor limb of an upper basilar artery fenestration: illustrative case.

BACKGROUND: An aneurysm arising in an upper basilar artery (BA) fenestration is extremely rare. The authors reported a case involving successful endovascular treatment of an aneurysm arising from the minor limb of an upper BA fenestration. OBSERVATIONS: A 65-year-old woman presented with an incidentally detected upper BA aneurysm arising from the minor limb of an upper BA fenestration. The irregularly shaped aneurysm was 6.0 × 2.7 mm in diameter, and the minor limb had several perforators. The aneurysm was nearly completely occluded with a catheter-assisted technique. The authors preserved both limbs of the BA fenestration. The postoperative course was uneventful, and the patient had an excellent clinical course with no neurological deficits or aneurysmal recanalization. LESSONS: The case is the first report of an unruptured aneurysm arising at the minor limb of an upper BA fenestration. In this case, the authors preserved the minor limb with endovascular treatment. The authors believe catheter-assisted coil embolization to be a feasible endovascular technique in such cases.

Endovascular Coil Embolization for Recurrent Bow Hunter's Stroke.

Bow hunter's stroke is a rare cause of vertebrobasilar infarction. There is no consensus regarding the optimal treatment. We herein report a case of bow hunter's stroke successfully treated by endovascular treatment. A 70-year-old man presented with central vertigo. Magnetic resonance imaging (MRI) showed posterior circulation infarcts. Dynamic angiography revealed thrombus formation and hypoperfusion of the right vertebral artery upon head rotation to the left. Endovascular parent artery occlusion of the right vertebral artery was performed, and there was no recurrence at follow-up MRI. Endovascular parent artery occlusion might be a useful treatment for bow hunter's stroke.

Unruptured cerebral aneurysms with the segmental duplicated middle cerebral artery formed a fenestrated structure at origin.

BACKGROUND: Middle cerebral artery (MCA) has a significantly lower incidence of anatomical variations than other intracranial arteries. We present an extremely rare case of unruptured aneurysms with the segmental duplicated MCA (d-MCA) formed a fenestrated structure at origin. CASE DESCRIPTION: A 55-year-old female underwent direct surgery for the unruptured aneurysms at the top of the right internal cerebral artery with d-MCA. The d-MCA branches separated at the right internal cerebral artery top and had comparable with that of the main MCA trunk. Moreover, there was an anastomosis between the d-MCA branches. We diagnosed this anastomosis as segmental d-MCA. Two aneurysmal domes were identified during surgery at the origin of the d-MCA, which the main dome protruding backward was wide necked and another small one was collapsed or thrombosed protruding forward. We used a fenestrated clip for the posterior projecting dome, and the aneurysms were successfully obliterated. CONCLUSION: Although cerebral aneurysms associated with d-MCA are rare, there are technical difficulties in the surgical management. A fenestrated clip might be most reasonable to obtain patency of the parent arteries for the posterior projecting aneurysms if the perforators can be avoided.

Subarachnoid hemorrhage due to a craniocervical junction arteriovenous fistula associated with thrombus formation in the internal jugular vein: illustrative case.

BACKGROUND: A craniocervical junction arteriovenous fistula (CCJAVF) is a rare vascular malformation, and its etiology remains unclear. Here, to the best of the authors' knowledge, they present the first case of CCJAVF associated with thrombus formation in the ipsilateral internal jugular vein. OBSERVATIONS: An 80-year-old man presented with a sudden occipital headache. Computed tomography revealed a subarachnoid hemorrhage surrounding the brainstem and upper cervical cord. Digital subtraction angiography showed a CCJAVF fed by the left C2 radiculomeningeal artery with ascending intracranial drainage and epidural plexus. After endovascular treatment, the authors retrospectively found that his ipsilateral internal jugular vein and innominate vein were occluded with a huge thrombus at admission. LESSONS: This case suggested a restricted antegrade venous flow due to thrombus-induced progressive retrograde intracranial drainage causing hemorrhage. Venous hypertension should be considered one of the causes of hemorrhage due to CCJAVF as well as intracranial arteriovenous fistulas.

Successful Endovascular Treatment for Middle Cerebral Artery Occlusion Caused by the Thrombus Formation in the Pulmonary Vein Stump Following Left Upper Lung Lobectomy.

Thrombus formation in the pulmonary vein (PV) stump after lung resection can cause rare cases of cerebral infarction. These infarctions can result in embolism and ischemia in the relatively large intracranial vessels, severely impacting the quality of life (QOL) of these patients. We performed endovascular thrombectomy successfully for this rare complication after lung lobectomy. A 73-year-old woman with paroxysmal atrial fibrillation (AF) suffered from sudden left complete hemiplegia 19 days after undergoing a left upper lung lobectomy (LUL). Magnetic resonance imaging (MRI) showed middle cerebral artery occlusion. Her left hemiplegia improved after the endovascular thrombectomy. Cardiogenic embolism was first suspected, but contrast-enhanced computed tomography (CECT) showed thrombus formation in the PV stump. We continued anticoagulant therapy, and the thrombus resolved completely two months after the stroke. Our patient had a relatively good outcome due to the immediate reperfusion of the affected area. This embolic source may be overlooked because AF frequently occurs after thoracic surgeries. Care should be taken during the postoperative phase to avoid overlooking these emboli. All thoracic surgeons should be informed about mechanical thrombectomy as an effective treatment for postoperative cerebral infarction.

Unusual course of the vagus nerve passing anterior to the internal carotid artery during carotid endarterectomy.

BACKGROUND: Carotid endarterectomy (CEA) is a conventional surgical technique to prevent ischemic stroke and the effectiveness for advanced lesions is established in many large studies. The vagus nerve is one of the cranial nerves that we usually encounter during CEA manipulation, which is identified as located posterior to the vessels in a position posterolateral to the carotid artery and posteromedial to the internal jugular vein. CASE DESCRIPTION: We experienced an extremely rare case of the vagus nerve passing anterior to the internal carotid artery during CEA. CONCLUSION: We should be careful not to accidentally cut off because the variation of the vagus nerve can be mistaken for an ansa cervicalis. A delicate and complete dissection to understand the variation of the vagus nerve is crucial to minimize the risk of cranial nerve injury during CEA.

[Asymptomatic Aplastic or Twig-Like Middle Cerebral Artery Associated with Unruptured Cerebral Aneurysms at the Origin (A1) of a Collateral Artery and the Anterior Communicating Artery: A Case Report with Multiple Intracranial Atherosclerotic Stenoses].

We report a rare case of asymptomatic aplastic or twig-like middle cerebral artery (Ap/T-MCA) with small unruptured aneurysms at the origin (A1) of the anomalous collateral artery containing plexiform (twig-like) networks and in the anterior communicating artery. In Ap/T-MCA, other cerebrovascular systems are usually considered to exhibit normal findings not associated with atherosclerosis. At first admission, atherosclerotic M1 occlusion was suspected because of the patient's risk factors and multiple stenoses in major intracranial arteries. Cerebral blood flow (CBF) studies revealed reduction of resting CBF and vascular reserve in the ipsilateral MCA territory. After 5 years, a diagnosis of Ap/T-MCA was reached based on detailed image examination and intraoperative findings during aneurysm clipping in combination with extracranial-intracranial (EC-IC) bypass. It should be noted that atherosclerosis can coexist with Ap/T-MCA, which is considered a congenital anomaly in which bleeding often occurs due to a ruptured aneurysm within the fragile collateral vessels. In previous reports, A1 aneurysms at the origins of the collateral arteries ruptured even when they were small. Aggressive radical surgery using EC-IC bypass can be considered for the treatment of unruptured aneurysms associated with Ap/T-MCA, but further research is needed. (Received September 14, 2020; Accepted November 4, 2020; Published 1 April, 2021).

A1 Segment Unruptured Aneurysm of Persistent Primitive Olfactory Artery Coexisted with Accessory Middle Cerebral Artery.

A persistent primitive olfactory artery (PPOA) is a rare anomaly of anterior cerebral artery (ACA), which generally arises from the internal carotid artery (ICA), runs along the olfactory tract, and makes a hairpin bend to supply the territory of the distal ACA. PPOA is also associated with cerebral aneurysms. An accessory MCA is a variant of the middle cerebral artery (MCA) that arises from either the proximal or distal portion of the A1 segment of the ACA, which runs parallel to the course of the MCA and supplies some of the MCA territory. We experienced a rare case of coexistence of PPOA with an unruptured aneurysm and accessory MCA. Three-dimensional computed tomographic angiography (3D-CTA) has an excellent picture of the spatial relationship of the surrounding bony and vascular structure.

Carotid Endarterectomy Using Lone Star Retractor System.

Cervical carotid disease is typical atherosclerosis, which is responsible for ischemic stroke. The effectiveness of carotid endarterectomy (CEA) for advanced carotid stenosis has been established in many large studies, and CEA is the gold standard in surgical treatment. On the other hand, endovascular carotid artery stenting (CAS) has become increasingly popular recently. It is very important to avoid any complications to maintain the effectiveness of CEA. The retractor device is important for the exposure of carotid arteries and for the safe surgical manipulation. We have started to use lone star retractor system (LSRS) to deploy the surgical field. LSRS provides the usability to handle and a shallower surgical field without the disturbance of surgical manipulation. And it can facilitate exposure of the distal internal carotid artery because surgeon can retract freely in whole circumference by towing with moderate strength. LSRS may bring the smoother and easier surgical manipulations in CEA.

Current status of a helicopter transportation system on remote islands for patients undergoing mechanical thrombectomy.

BACKGROUND: Mechanical thrombectomy (MT) is standard treatment for acute ischemic stroke (AIS) with large-vessel occlusion within 6 h of symptom onset to treatment initiation (OTP). Recent trials have extended the therapeutic time window for MT to within 24 h. However, MT treatment remains low in remote areas. Nagasaki Prefecture, Japan has many inhabited islands with no neurointerventionalists. Our hospital on the mainland is a regional hub for eight island hospitals. We evaluated clinical outcomes of MT for patients with AIS on these islands versus on the mainland. METHODS: During 2014-2019, we reviewed consecutive patients with AIS who received MT at our hospital. Patients comprised the Islands group and Mainland group. Patient characteristics and clinical outcomes were compared between groups. RESULTS: We included 91 patients (Islands group: 15 patients, Mainland group: 76 patients). Seven patients (46.7%) in the Islands group versus 43 (56.6%) in the Mainland group achieved favorable outcomes. Successful recanalization was obtained in 11 patients (73.3%) on the islands and 67 (88.2%) on the mainland. The median OTP time in the Islands was 365 min. In both the Islands and Mainland groups, the OTP time and successful recanalization were associated with functional outcome. The modified Rankin Scale (mRS) score at 90 days ≤2 was obtained in two patients and mRS = 3 in four patients among eight patients with OTP time >6 h. CONCLUSIONS: Few patients with AIS on remote islands have received MT. Although patients who underwent MT on the islands had longer OTP, the clinical outcomes were acceptable. OTP time on remote islands must be shortened, as this is related to functional outcome. In some cases with successful recanalization, a favorable outcome can still be obtained even after 6 h. Even if OTP exceeds 6 h, it is desirable to appropriately select patients and actively perform MT.

[Orbital Compartment Syndrome Perhaps Secondary to Intra-Orbital Fluid Retention and Orbital/Palpebral Emphysema Following Frontotemporal Craniotomy for an Unruptured Cerebral Aneurysm:A Case Report].

A 58-year-old woman underwent left frontotemporal craniotomy for clipping of an unruptured cerebral aneurysm. A small defect was accidentally created in the orbital roof intraoperatively. The patient developed left eyelid edema and ocular pain after recovery from anesthesia. The following day, the eyelid edema worsened, and she had difficulty opening her eyes. On the 9th postoperative day, she noticed diminished visual acuity and diplopia in her left eye when she was able to spontaneously open her eyes. Ophthalmological evaluation revealed mild left visual loss, decreased light reflex, ophthalmoplegia, ptosis, and chemosis. Computed tomography(CT)/magnetic resonance imaging revealed left proptosis, optic nerve stretching, intra-orbital fluid retention, and orbital/palpebral emphysema. She was diagnosed with orbital compartment syndrome(OCS)and received conservative treatment;however, her visual acuity did not improve. OCS observed after cerebral aneurysm surgery is rare;to date, only 24 cases have been reported in the available literature. Although the mechanism of OCS after craniotomy is unclear, it may be attributed to ocular compression by a muscle flap or increased intra-orbital pressure secondary to venous congestion. In the present case, the left superior ophthalmic vein and cavernous sinus were not clearly visualized on CT angiography. Therefore, we concluded that the right superior ophthalmic vein and superficial facial veins underwent dilatation and served as collateral circulation of the left orbital venous system. We speculate that OCS occurred secondary to increased intra-orbital pressure, possibly caused by inflow of cerebrospinal fluid with air into the orbit through a small bone defect that was accidentally created during craniotomy in a setting of orbital venous congestion.

[A Case of M2 Segment Dissection of the Middle Cerebral Artery Presenting with Deep White Matter Infarction Triggered by Minor Head Injury].

Herein, we report a rare case of a dissecting aneurysm of the M2 segment of the middle cerebral artery(MCA), presenting with a deep white matter infarction triggered by minor head injury. A 31-year-old woman was admitted to our hospital with headache and vomiting 3 hours after a mild head impact. A magnetic resonance angiogram obtained 10 months earlier, when the patient had complained of sudden headache, showed mild fusiform dilatation of the left M2 segment. On admission, computed tomography angiography(CTA)revealed irregular fusiform dilatation of the superior trunk of the left M2. Magnetic resonance imaging showed an intramural hematoma on the wall of the left M2 and acute infarction in the left deep white matter. Eight days after admission, CTA revealed further dilation of the aneurysm, and it was diagnosed as a dissecting aneurysm. The patient was successfully treated with proximal clipping and superficial temporal artery(STA)-MCA(M4)bypass on day 15. Bypass to a cortical M4 recipient was performed after the efferent M4 was identified using indocyanine green videoangiography. Four weeks postoperatively, the patient was discharged without any neurological deficits. The M2 dissecting aneurysm gradually regressed, and the bypass remained patent for 10 months postoperatively. To our knowledge, this is the first case of a dissecting M2 aneurysm treated by proximal clipping and STA-MCA bypass. This procedure seems a feasible option when the distal portion of the dissected MCA is difficult to expose.