Anatomical Comparison of Endoscopic and Microscopic Exposure of the Petroclinal Core Area Through the Extended Middle Skull Base Approach.

OBJECTIVE: To compare the range of endoscopic and microscopic exposure of the petroclival core area through the middle skull base and to observe the corresponding anatomical structures. METHODS: Ten intact adult cadaveric head specimens fixed with formaldehyde were craniotomized through an expanded middle skull base epidural approach on 20 sides. The distance from the greater superficial petrosal nerve to the petrous ridge was measured. When different degrees (1-3 degrees) of the Kawase triangle bone were removed, the exposed anatomical structure was observed, and the exposed core area of the rock slope was measured under an endoscope and microscope. RESULTS: The average distance from the greater superficial petrosal nerve to the petrous ridge was 14.26 mm. During 1 to 2 degrees of bone removal, the petrous segment of the internal carotid artery (ICA) was not exposed, whereas during 3 degrees of bone removal, the petrous segment of the ICA was exposed. At 1 degree of bone removal, 400.62 ± 15.73 mm2 of the area was exposed by endoscopy and 170.87 ± 8.93 mm2 by microscopy, and the abducens nerve was not exposed. However, there was a significant difference between the two areas (P < 0.001). During 2 degrees of bone removal, 689.30 ± 32.06 mm2 of the abducens nerve was exposed by endoscopy, but 366.84 ± 30.30 mm2 of the abducens nerve could not be exposed by microscopy; moreover, there was a significant difference in the area of exposure between the two (P < 0.001). At 3 degrees of bone removal, the endoscopic exposure area was 875.92 ± 31.87 mm2, the microscopic exposure area was 699.26 ± 48.00 mm2, and the abducens nerves were exposed. There were significant differences between the two areas (P < 0.001). However, the difference between the 2-degree endoscopic exposure area and the 3-degree microscopic exposure area was studied by using paired t tests, and there was no difference (P > 0.05). CONCLUSION: When the same degree of the Kawase triangle bone was removed, the extent of endoscopic exposure of the petroclival core area was significantly greater than the extent of microscopic exposure. At 2 degrees of bone removal, an endoscopic application can maximally expose the petroclival core area, thus reducing the probability of exposure damage to the ICA and abductor nerve.

Surgical Treatment Strategies for Residual or Recurrent Intracranial Aneurysms Following Endovascular Embolization.

OBJECTIVE: To explore how to effectively manage the residual or recurrent intracranial aneurysms after embolization. METHODS: The authors retrospectively reviewed our experience of endovascular interventional therapy, surgical clipping, and cerebrovascular bypass surgery in the treatment of residual or recurrent aneurysms after embolization at the authors' institution from 2018 to 2022. RESULTS: The Glasgow Outcome Scale of 28 patients after the procedure and at discharge showed that 24 recovered well, 3 had severe disability, and 1 died. During the 24-month follow-up, 26 had a good recovery, 1 suffered from disability, and 1 died. Two cases of aneurysm recurrence were detected, and both were treated through endovascular therapy. Among them, 1 case underwent a repeat endovascular embolization, and 1 case was switched to surgical clipping. No residual aneurysms were observed in the remaining patients who underwent bypass surgery, and their bypass grafts were all patent. CONCLUSION: Based on the clinical status of patients, aneurysmal characteristics, surgical risk, and possibility of rerupture of aneurysms, an individualized strategy was proposed for residual or recurrent aneurysms after embolization. The use of endovascular interventional therapy or surgical clipping can be safely and effectively managed, and cerebrovascular bypass surgery can effectively manage complex aneurysms.

Surgical treatment of carotid blowout syndrome after radiotherapy for head and neck malignant tumors: a single-center experience.

To explore the treatments for and manifestations of carotid blowout syndrome (CBS) and to further explore the critical role of high-flow bypass combined with parent artery isolation. The clinical data of nine patients with radiotherapy-related CBS who were admitted to our hospital from March 2020 to March 2023 were retrospectively analyzed. Relevant literature was reviewed. From March 2020 to March 2023, nine CBS patients were admitted to Tianjin Huanhu Hospital, including eight males and one female. Digital subtraction angiography was performed for all the patients; all the pseudoaneurysms were located at the petrous segment of the internal carotid artery. A balloon occlusion test was performed on four patients, which was tolerated by all patients. CT and MRI scans showed seven cases of osteonecrosis combined with infection and two cases of tumor recurrence. Emergency permanent parent artery occlusion was performed on six patients, aneurysm embolization was completed in one case, covered stent implantation was performed in one patient, and three cases were treated by cerebral bypass surgery (including two patients with failed interventional treatment). Rebleeding was found in two patients, and no rebleeding was found in the bypass group. Paralysis was found in three patients, and asymptomatic cerebral infarction without permanent neurologic impairment was found in three patients. Two patients died due to tumor progression. Emergency occlusion surgery is lifesaving in the acute phase of CBS. Endovascular therapy cannot prevent the progression of pseudoaneurysms or lower the recurrence rate of bleeding events. High-flow bypass combined with parent artery isolation is a safe and effective method that may facilitate further surgical treatment. Further research is warranted.

Clinical characteristics and individualized treatment of intracranial aneurysms in young adults: a single-center experience.

This study aimed to investigate the clinical characteristics of intracranial aneurysms in young adults and summarize our treatment experiences. We performed a retrospective review of young patients (15-24 years old) with intracranial aneurysms examined in the Fifth Ward of the Neurosurgery Department of Tianjin Huanhu Hospital between January 2015 and November 2022. Data was reviewed for age, sex, presentation, type and size, treatment modalities, location, postoperative complications, and clinical and imaging outcomes. Among the 23 patients, there were 11 males and 12 females (1:1.09). Their presentations included headache, neurological deficits, aneurysmal subarachnoid hemorrhage, incidental or asymptomatic aneurysm, and traumatic subarachnoid hemorrhage. Twenty-five cases of intracranial aneurysms in 25 patients were identified. The aneurysms were saccular (32%, 8/25), dissecting (52%, 13/25), and fusiform (16%, 4/25) in shape. Treatment modalities included direct clipping, embolization, bypass, trapping, resection, coarctation of internal carotid artery (ICA), and endovascular vessel sacrifice. Of the 25 aneurysms, 16 (64%, 16/25) aneurysms were located in anterior circulation, and 9 (36%, 9/25) were located in the posterior circulation, while multiple aneurysms were identified in two patients. A preoperative magnetic resonance perfusion (MRP) examination was performed in 15 patients with unruptured complex aneurysms, of whom 13/15 (86.67%) showed hypoperfusion. Eighteen (78.26%, 18/23) patients had no postoperative complications, temporary complications occurred in 4 (17.39%, 4/23) patients, and 1 patient died postoperatively. The intracranial aneurysms in young adults (15 ~ 24 years old) are rare. The posterior circulation is more commonly involved than adults, giant and huge aneurysms are frequent, and fusiform and dissecting pathologic features are common. Headache is the most common clinical manifestation. Individualized treatment should be performed, and bypass is an effective treatment for young patients with intracranial aneurysms.

Cerebral revascularization for complex middle cerebral artery aneurysms: surgical strategies and outcomes in a single center.

Cerebral revascularization is the ultimate treatment for a subset of complex middle cerebral artery (MCA) aneurysms. The decision for the revascularization strategy should be made during the treatment process. This study aimed to summarize the revascularization strategies for different types of complex MCA aneurysms and their outcomes. The clinical data of patients with complex MCA aneurysms who underwent cerebral revascularization since 2015 were analyzed retrospectively. The aneurysms were classified according to the location and other main characteristics that affect the selection of surgical modalities. The corresponding surgical modalities and treatment outcomes were summarized. A total of 29 patients with 29 complex MCA aneurysms were treated with cerebral revascularization from 2015 to 2022. Treated aneurysms were located at the prebifurcation segment in 7 patients, bifurcation segment in 12 patients, and postbifurcation segment in 10 patients. Surgical modalities in the prebifurcation segment included four high-flow extracranial-to-intracranial (EC-IC) bypasses with aneurysm trapping or proximal occlusion, two IC-IC bypasses with aneurysm excision, and one combination bypass with aneurysm excision. In the bifurcation segment, surgical modalities included two low-flow EC-IC bypasses with aneurysm excision or trapping, six IC-IC bypasses with aneurysm excision, three combination bypasses with aneurysm excision, and one constructive clipping with IC-IC bypass. In the postbifurcation segment, surgical modalities included nine IC-IC bypasses with aneurysm excision and low-flow EC-IC bypass with aneurysm trapping. The revascularization strategy for prebifurcation aneurysms was determined based on the involvement of lenticulostriate arteries, whereas the strategy for bifurcation aneurysms was determined based on the number of distal bifurcations and the shape of the aneurysm. The location of the aneurysm determined the revascularization strategy for aneurysms in the postbifurcation segments. Angiography demonstrated that aneurysms were completely obliterated in 26 cases and shrank in 3 cases, and all bypasses except one were patent. The mean follow-up period was 47.5 months. Three patients developed hemiplegic paralysis, and one developed transient aphasia postoperatively due to cerebral ischemia. No new neurological dysfunction occurred in the other 25 patients with no recurrence or enlargement of aneurysms during the follow-up. Prebifurcation aneurysms involving the lenticulostriate arteries require proximal occlusion with high-flow bypass. Most of the other aneurysms can be safely excised or trapped by appropriate revascularization strategies according to their location and orientation.

Study on Microsurgical Anatomy of External Branch of Superior Laryngeal Nerve Related to Carotid Endarterectomy.

OBJECTIVE: To explore the methods of protecting the external branch of the superior laryngeal nerve during carotid endarterectomy through microsurgical anatomic study of the external branch of the superior laryngeal nerve in cadaveric specimens. METHODS: A total of 30 cadaveric specimens (60 sides) were dissected to measure the thickness of the external branch of the superior laryngeal nerve. A triangular area was exposed, bounded by the lower border of the digastric muscle superiorly, the medial edge of the sternocleidomastoid muscle laterally, and the upper border of the superior thyroid artery inferiorly. The probability of the occurrence of the external branch of the superior laryngeal nerve in this area was observed and recorded. The distance among the midpoint of the external branch of the superior laryngeal nerve in this area with the tip of the mastoid process and the angle of the mandible as well as the bifurcation of the common carotid artery was measured and recorded. RESULTS: Among 30 specimens of cadaveric heads (60 sides) examined 53 external branches of the superior laryngeal nerve were observed while 7 were absent. Of the 53 branches observed, 5 were located outside the anatomic triangle region mentioned above, while the remaining 48 branches were located within the anatomic triangle region with a probability of ~80%. The thickness of the midpoint of the external branches of the superior laryngeal nerve within the anatomic triangle region was 0.93 mm (0.72-1.15 mm [±0.83 SD]), located 0.34 cm [-1.62-2.43 cm (±0.96 SD)] posterior to the angle of the mandible, 1.28 cm (-1.33 to 3.42 cm (±0.93 SD)] inferiorly; 2.84 cm (0.51-5.14 cm±1.09 SD) anterior to the tip of the mastoid process, 4.51 cm (2.82-6.39 cm±0.76 SD) inferiorly; 1.64 cm [0.57-3.78 cm (±0.89 SD)] superior to the bifurcation of the carotid artery. CONCLUSIONS: During carotid endarterectomy procedure, using the cervical anatomic triangle region, as well as the angle of the mandible, the tip of the mastoid process, and the bifurcation of the carotid artery as anatomic landmarks, is of significant clinical importance for protecting the external branches of the superior laryngeal nerve.

Bypass Surgery to Treat Giant Cavernous Carotid Artery Aneurysms.

BACKGROUND: With the development of bypass technique, more and more complex aneurysms can be treated with bypass surgery. The goal of this study is to evaluate the efficacy and safety of bypass in patients with giant cavernous carotid aneurysms (GCCAs). To further discuss the treatment of asymptomatic GCCAs. METHODS: The authors retrospectively reviewed our experience of the internal carotid artery (ICA) ligation/constriction combined with high/low-flow bypass surgery in the treatment of GCCAs. RESULTS: Among the entire cohort, 4 patients underwent ICA ligation combined with high-flow bypass, 7 patients underwent ICA ligation/constriction combined with low-flow bypass. The postoperative symptom improvement: of 9 patients with preoperative ophthalmoplegia, the symptom resolved in 2 patients, improved in 7 patients, of 7 patients with preoperative pain, the symptom resolved in 2 patients, improved in 4 patients and was unchanged in 1 patient. The results of following-up were measured using the modified Rankin scale (mRS). During the follow-up, there were 9 patients with mRS score 0 to 1, 1 patient with mRS score 2, and 1 patient with mRS score 3. The long-term graft patency rate was 100%. All patients had no recurrence of intracranial aneurysm. CONCLUSIONS: Bypass surgery is a safe and effective method to treat GCCAs. Because of the risk of GCCAs and the improvement of bypass surgery technology, active surgical strategies should be adopted for asymptomatic or mild symptomatic GCCAs.

IDH1 Arg-132 mutant promotes tumor formation through down-regulating p53.

Resistance to apoptosis and uncontrolled proliferation are two hallmarks of cancer cells. p53 is crucial for apoptosis triggered by a broad range of stresses and a well-known gatekeeper for neoplastic transformation. Here we show that oncogenic IDH1 R132H/R132Q mutants robustly inhibit p53 expression and such an effect is attributed to 2-HG production. Mechanistically, 2-hydroxyglutarate (2-HG) stabilizes hypoxia-inducible factor-2α, which in turn activates the expression of miR-380-5p, a characterized microRNA against p53 expression. Rescue expression of p53 can inhibit the proliferation rate and impair the resistance of apoptosis induced by doxorubicin in IDH1 R132Q mouse embryonic fibroblast cells. Furthermore, p53 protein levels correlates negatively with IDH1 R132H levels in human glioma samples. Our results thus shed a new light on how p53 is down-regulated by 2-HG and suggests that impairment of p53-mediated apoptosis contributes to the tumorigenesis driven by IDH1 mutants.

Petrous Carotid to Upper Posterior Circulation Bypass for the Treatment of Basilar Trunk Aneurysm: A Novel High-Flow Intracranial-Intracranial Skull Base Bypass for Posterior Circulation.

BACKGROUND: Basilar trunk aneurysms are the most surgically challenging, and the spectrum covers small fusiform to dolichoectatic aneurysms and may lead to rupture, brain ischemia, or direct brainstem compression. The current strategy remains cerebral revascularization coupled with aneurysm trapping. Available bypass options for upper posterior circulation (UPC) are based on (1) different flow volumes from diverse blood supplies and (2) distinct modulation purposes for cerebral revascularization; however, the potential compromise of eloquent perforators of the basilar trunk and the occurrence of fatal brainstem infarcts remain unacceptable. OBJECTIVE: To innovate a high-flow intracranial-intracranial skull base bypass for posterior circulation to afford robust retrograde flow and shorten the graft length. METHODS: We retrospectively reviewed our experience in the treatment of a patient with basilar trunk aneurysm and reported a novel bypass alternative supplied by petrous internal carotid artery to augment blood flow to the UPC by a pretemporal approach. RESULTS: The postoperative course was uneventful, and there was no pons or midbrain ischemia or other complications. Postoperative computed tomography angiogram revealed the patency of bypass. There was no further development or rerupture observed during follow-up. CONCLUSION: Petrous internal carotid artery as a donor site is a reliable bypass modality for UPC. This approach provides the utmost retrograde flow to alleviate the development of dissecting aneurysms, preserves eloquent perforators of the basilar trunk, maintains bypass patency, and shortens the graft course. Therefore, this novel therapeutic alternative could be beneficial for improving the prognosis of basilar trunk aneurysms.

Superficial Temporal Artery-Posterior Cerebral Artery Bypass Through Zygomatic Anterior Temporal Approach for Complex Posterior Cerebral Artery Aneurysm.

BACKGROUND: Posterior cerebral artery (PCA) aneurysms are rare, and most are giant, dissecting, or fusiform in morphology. Proximal occlusion of the PCA without revascularization causes high risk of ischemic complications. This study aimed to evaluate the safety and validity of using superficial temporal artery (STA)-PCA bypass through zygomatic anterior temporal approach in complex PCA aneurysms. METHODS: Trapping or resecting of aneurysms and reconstruction of distal PCA through a zygomatic anterior temporal approach were performed in 6 patients from June 2017 to August 2020. Postoperative angiography confirmed obliteration of aneurysms and patency of bypass artery. Neurological function was assessed by the modified Rankin Scale (mRS). RESULTS: Patients were 4 men and 2 women with a mean age of 43.8 years (range, 21-58 years). Subarachnoid hemorrhage occurred in 5 patients. Hunt and Hess grade was IV in 3 patients, III in 2 patients, and I in 1 patient. All PCA aneurysms were treated with trapping or resection of the aneurysms and revascularization of distal PCA. Postoperatively, all aneurysms were eliminated, and no new permanent neurological deficit was found. During follow-up, mRS score of all patients improved: 2 patients had mRS score 0, 1 patient had mRS score 1, 1 patient had mRS score 3, and 2 patients had mRS score 4. Long-term graft patency rate was 100%. CONCLUSIONS: STA-PCA bypass appears to be safe and effective for the treatment of complex PCA aneurysms requiring supplementation of blood flow in the area of the PCA. We established a surgical route, allowing the procedure to be done through the zygomatic anterior temporal approach. This approach provides adequate operative field exposure and reduces retraction of temporal lobe.

Internal Carotid Artery Constriction with or without Superficial Temporal Artery-Middle Cerebral Artery Bypass for Patients with Giant Internal Carotid Aneurysms.

BACKGROUND: The optimal management of giant internal carotid aneurysms (GICAs) is disputed owing to their low incidence. The aim of this study was to describe the use of internal carotid artery (ICA) constriction as therapeutic management of GICAs. METHODS: This retrospective cohort study analyzed data from medical histories and follow-up of 14 patients with GICAs. Before surgery, the patients underwent balloon test occlusion and magnetic resonance perfusion evaluation. ICA constriction was considered only for patients with negative balloon test occlusion. A transverse incision of about 50% of the initial part of the ICA was done, and the free margins on both sides were sutured, causing 70%-90% stenosis. ICA constriction alone was selected (11 cases) if both anterior communicating artery and posterior communicating artery compensatory blood flow existed and magnetic resonance perfusion was ≤II1 on the affected side. If there was only 1 compensatory vessel from the anterior communicating artery and posterior communicating artery, and/or magnetic resonance perfusion was >II1, ICA constriction was combined with low-flow bypass (3 cases). RESULTS: The mean follow-up time of the 14 patients was 43.5 months (interquartile range: 38.8-51.3 months). Of these 14 patients, 5 achieved O'Kelly-Marotta grades C and D. Clinical improvement occurred in 12 of 14 patients. No patients experienced new-onset stroke. CONCLUSIONS: ICA constriction exhibits a perforator protective effect. This procedure could be a promising alternative to ICA ligation in patients with GICAs and negative balloon test occlusion.

Tailored Communicating Bypass for the Management of Complex Anterior Communicating Artery Aneurysms: "Flow-Counteraction" In Situ Bypass and Interposition Bypass Using Contralateral A2 Orifice as Donor Site.

BACKGROUND: The use of bypass surgery for anterior communicating artery (ACOM) aneurysms is technically challenging. Communicating bypass (COMB), such as pericallosal artery side-to-side anastomosis, is the most frequently used and anatomically directed reconstruction option. However, in many complex cases, this technique may not afford a sufficient blood supply or necessitate sacrificing the ACOM and the eloquent perforators arising from it. OBJECTIVE: To evaluate tailored COMB and propose a practical algorithm for the management of complex ACOM aneurysms. METHODS: For 1 patient with an aneurysm incorporating the entire ACOM, conventional in Situ A3-A3 bypass was performed as the sole treatment in order to create competing flow for aneurysm obliteration, sparing the sacrifice of eloquent perforators. In situations in which A2s were asymmetric in the other case, the contralateral A2 orifice was selected as the donor site to provide adequate blood flow by employing a short segment of the interposition graft. RESULTS: The aneurysm was not visualized in patients with in Situ A3-A3 bypass because of the "flow-counteraction" strategy. The second patient, who underwent implementation of the contralateral A2 orifice for ipsilateral A3 interposition bypass, demonstrated sufficient bypass patency and complete obliteration of the aneurysm. CONCLUSION: The feasibility of conventional COMB combined with complete trapping may only be constrained to selected ideal cases for the treatment of complex ACOM aneurysms. Innovative modifications should be designed in order to create individualized strategies for each patient because of the complexity of hemodynamics and the vascular architecture. Flow-counteraction in Situ bypass and interposition bypass using the contralateral A2 orifice as the donor site are 2 novel modalities for optimizing the advantages and broadening the applications of COMB for the treatment of complex ACOM aneurysms.

Occipital Artery to Extradural Vertebral Artery Bypass for Posterior Circulation Ischemia.

BACKGROUND: Posterior circulation ischemic strokes can have devastating consequences, despite medical therapies. Extracranial-intracranial bypass for the augmentation of flow is a treatment option for selected patients with hemodynamic compromise and recurrent ischemia. However, posterior circulation bypass carries a higher risk and lower patency rate than bypass with anterior circulation. OBJECTIVE: To present the occipital artery to the extradural vertebral artery (OA-eVA) bypass for posterior circulation ischemia. METHODS: We retrospectively reviewed our experience of the OA-eVA bypass surgery in the treatment of bilateral vertebral steno-occlusive disease. RESULTS: Seventeen patients were identified. Thirteen patients had bilateral vertebral artery (VA) occlusion (type I), while 4 patients had VA occlusion with contralateral VA severe stenosis (type II). All patients had cerebellar or pons infarction, for which the postoperative bypass patency rate was 100%, with carotid angiogram demonstrating excellent filling of the rostral basilar system or the posterior inferior cerebellar artery territory. The long-term follow-up outcome was favorable (modified Rankin score of 0-2) in 82% of patients (7 patients had complete resolution and 7 had improvement of symptoms) and unfavorable in 18%. One type II case without previous endovascular therapy developed recurrent ischemic onset associated with bypass occlusion. CONCLUSION: OA-eVA bypass is a minimally invasive and effective alternative to posterior circulation ischemia. It provides sufficient blood flow augmentation to the vertebrobasilar territory. The advantages of this novel therapeutic strategy include avoiding performing craniotomy and deep bypass and achieving shorter operative times compared to conventional bypass surgery.

Treatment of Symptomatic Dolichoectatic Vertebrobasilar Aneurysms: A Single-Center Experience with 12 Patients.

OBJECTIVE: To report our single-center experience in the treatment of dolichoectatic vertebrobasilar aneurysms. METHODS: We retrospectively reviewed the data, including clinical features, strategies of managing aneurysms, and follow-up results, of 12 patients who were treated at the Tainjin Huanhu Hospital. RESULTS: Of the 12 patients, 1 patient was treated with medication, 4 patients were treated using stent reconstruction, and 7 patients were treated via revascularization (open surgery). The clinical symptoms of the patients who were treated with medication and stent reconstruction were stable. The patients who were treated with revascularization suffered from pneumonia, and 1 patient who presented with intracranial hematoma was treated via a second craniotomy. One patient suffered from new cerebral infraction. Postoperative follow-up from 5 to 67 months indicated that 2 patients (16.7%) had died (modified Rankin Scale [mRS] score of 6), and both were treated with revascularization. Seven patients had mRS scores of 0-2, and the other 3 patients had mRS scores of 4-5. CONCLUSIONS: If the condition of the patients is stable and benign, they can be treated with medication or stent reconstruction. Given the serious complications that can be caused by open surgery, care must be taken when selecting the patients to be treated using open surgery, but more studies are needed to support this conclusion. The key points are to avoid aneurysm thrombosis and maintain patency of the perforators.

2-HG Inhibits Necroptosis by Stimulating DNMT1-Dependent Hypermethylation of the RIP3 Promoter.

2-hydroxyglutarate-(2-HG)-mediated inhibition of TET2 activity influences DNA hypermethylation in cells harboring mutations of isocitrate dehydrogenases 1 and 2 (IDH1/2). Here, we show that 2-HG also regulates DNA methylation mediated by DNA methyltransferase 1 (DNMT1). DNMT1-dependent hypermethylation of the RIP3 promoter occurred in both IDH1 R132Q knockin mutant mouse embryonic fibroblast (MEFs) and 2-HG-treated wild-type (WT) MEFs. We found that 2-HG bound to DNMT1 and stimulated its association with the RIP3 promoter, inducing hypermethylation that reduces RIP3 protein and consequently impaired RIP3-dependent necroptosis. In human glioma samples, RIP3 protein levels correlated negatively with IDH1 R132H levels. Furthermore, ectopic expression of RIP3 in transformed IDH1-mutated MEFs inhibited the growth of tumors derived from these cells following transplantation into nude mice. Thus, our research sheds light on a mechanism of 2-HG-induced DNA hypermethylation and suggests that impaired necroptosis contributes to the tumorigenesis driven by IDH1/2 mutations.

IDH1 Mutation Promotes Tumorigenesis by Inhibiting JNK Activation and Apoptosis Induced by Serum Starvation.

Two hallmarks of cancer cells are their resistance to apoptosis and ability to thrive despite reduced levels of vital serum components. c-jun N-terminal kinase (JNK) activation is crucial for apoptosis triggered by serum starvation (SS), and isocitrate dehydrogenase 1 (IDH1) mutations are tumorigenic, in part, because they produce the abnormal metabolite 2-hydroxyglutarate (2-HG). However, it is unknown whether 2-HG-induced tumorigenesis is partially due to JNK inhibition and thus defective SS-induced apoptosis. We show here, using IDH1-R132Q knockin mutant mouse cells, that 2-HG inhibits JNK activation induced only by SS and not by UV or doxorubicin, and thus can block apoptosis. Upon SS, Cdc42 normally disrupts mixed lineage kinase 3's (MLK3's) auto-inhibition, triggering the MLK3-MKK4/7-JNK-Bim apoptotic cascade. 2-HG binds to Cdc42 and abolishes its association with MLK3, inactivating MLK3 and apoptosis. Allograft tumor assays in mice demonstrate that this mechanism contributes to tumorigenesis driven by mutant IDH1, a result confirmed by detection of JNK inactivation in human gliomas harboring IDH1-R132H mutations.

[Experimental study of combination therapy against human glioma xenograft by differentiation-inducing agent and cytotoxic chemotherapeutic drug].

BACKGROUND & OBJECTIVE: Cytotoxic agent remains the main chemotherapeutic drug for glioma, although it has many limitations. It is not known whether differentiation-inducing agent can enhance antitumor efficiency of cytotoxic agent. This study was designed to investigate anti-tumor effects of differentiation-inducing agent in combination with cytotoxic chemotherapeutic drug against glioma. METHODS: Poorly-differentiated human brain glioma xenografted nude mice were treated with carmustine(1, 3-bis-(2-chloroethyl)-1-nitrosourea, BCNU) and sodium phenylbutyrate (SPB). The therapeutic effects were determined by measuring of tumor size, pathological changes, different phases of cell cycle of tumor cell proliferation, expression of differentiation antigen, and tumor cell apoptosis. RESULTS: The therapeutic effects of SPB plus BCNU group were much better than that of SPB or BCNU group alone, which were proved by lower growth rate of the tumor, cellularity decreasing, appearance of astroid-like polyglonal cells, G0/G1 ratio increasing, upregulation of GFAP expression. CONCLUSION: Combined application of SPB and BCNU can obviously inhibit proliferation of glioma, and promote differentiation of tumor cells.