Crotonoside exhibits selective post-inhibition effect in AML cells via inhibition of FLT3 and HDAC3/6.

Targeted therapies for the treatment of acute myeloid leukemia (AML), specifically the FLT3 inhibitors, have shown promising results. Nevertheless, it is very unlikely that inhibitors which target a single pathway will provide long-term disease control. Here, we report the characterization of crotonoside, a natural product extracted from Chinese medicinal herb, Croton, for the treatment of AML via inhibition of FLT3 and HDAC3/6. In vitro, crotonoside exhibited selective inhibition in AML cells. In vivo, crotonoside treatment at 70 and 35 mg/kg/d produced significant AML tumor inhibition rates of 93.5% and 73.6%, respectively. Studies on the anti-AML mechanism of crotonoside demonstrated a significant inhibition of FLT3 signaling, cell cycle arrest in G0/G1 phase, and apoptosis. In contrast to classic FLT3 inhibitor; sunitinib, crotonoside was able to selectively suppress the expression of HDAC3 and HDAC6 without altering the expression of other HDAC isoforms. Inhibitors of HDAC3 and HDAC6; RGFP966 and HPOB, respectively, also exhibited selective inhibition in AML cells. Furthermore, we established novel signaling pathways including HDAC3/NF-κB-p65 and HDAC6/c-Myc besides FLT3/c-Myc which are aberrantly regulated in the progression of AML. In addition, crotonoside alone or the combination of sunitinib/RFP966/HPOB exhibited a significant post-inhibition effect in AML cells by the inhibition of FLT3 and HDAC3/6. Inhibitors targeting the FLT3 and HDAC3/6 might provide a more effective treatment strategy for AML. Taken together, the present study suggests that crotonoside could be a promising candidate for the treatment of AML, and deserves further investigations.

Parenchymal Infiltration in Primary Diffuse Leptomeningeal Gliomatosis: Dynamic Changes in Brain MRI.

Primary diffuse leptomeningeal gliomatosis (PDLG) is a rare and fatal disease with no special clinical manifestations. Here, we report the dynamic brain magnetic resonance imaging (MRI) changes in a 30-year-old female PDLG patient over a 10-month period. MRI showed aggressive dilation of the subarachnoid space and the ventricular system, numerous encapsulated cysts in the subarachnoid space and the dilated cerebral sulci, diffuse reticulated or focal nodular enhancement in the subarachnoid space, as well as overall enhancement in the cystic walls. In addition to the aforementioned PDLG pathological findings, MRI also revealed non-contrasted solid lesions and a contrasted cyst-like lesion in the paraventricular areas. The dynamic and multiform neuroradiological changes help us to understand the pathological process of PDLG. Of particular interest is the discovery that parenchymal infiltration can occur in PDLG.

Anatomic study of the anterior skull base via an endoscopic transnasal approach.

OBJECTIVES: With rapid advances in endoscopic neurosurgery, it has become possible to treat some lesions located in the anterior skull base through a transnasal approach. This anatomic study was undertaken to describe the area of surgical exposure of the anterior skull base afforded by transnasal approaches with an endoscope, as well as to provide references for clinical practice. METHODS: Thirty bony skull base specimens (all Chinese) were used, and 10 injected adult cadaver heads (all Chinese) were dissected for a simulated endoscopic transnasal approach to the anterior skull base. The distance between the bilateral optic canals was measured in skull base specimens and the distance between the columella and anterior ethmoid artery or posterior ethmoid artery was measured on both sides in adult cadaver heads. RESULTS: The optic canals were 15.13±1.69 mm apart. The distance between the columella and posterior ethmoid artery was 71.01±3.99 mm on the left side and 72.27±3.97 mm on the right side. The distance between the columella and anterior ethmoid artery was 64.811±3.74 mm on the left side and 64.18±3.74 mm on the right side. The endoscopic transnasal approach to the anterior skull base exposed the optic protuberance, sellar floor, crista galli, anterior ethmoid artery, and posterior ethmoid artery. In addition, bilateral olfactory bulbs, olfactory tracts, and optic nerves beneath the dura mater were also revealed. CONCLUSIONS: The anatomic data as well as established anatomic landmarks associated with endoscopic surgery would benefit clinical practice.

Endoscopic transsphenoidal treatment of pituitary adenomas.

OBJECTIVE: To explore the techniques and methods of endoscopic transnasal transsphenoid surgery for pituitary adenoma. METHOD: We treated 678 cases with pituitary adenoma by endoscopic transsphenoidal surgery between May 2000 and May 2006. All cases were operated through a transnasal transsphenoid approach between the nasal septum and middle nasal concha, first to enlarged sphenoid ostium and opened sellar floor with a high-speed drill and then removed the tumor step by step. Sixty-two percent of cases (420 cases) got 6-24 months of follow-up. RESULTS: Among the 678 pituitary adenomas, tumor removal was total in 543 (80.1%), subtotal in 118 (17.4%) and partial in 17 (2.5%). Ninety-eight percent (643 of 655 cases) obtained an improvement in clinical symptoms at some extent after the operation. Post-operative complication (including subarachnoid hemorrhage, nasal cavity bleed, nostril infection, nasal wing deformation and cerebrospinal fluid nasal leakage) occurred in 21 patients (3%). Among the 420 follow-up patients, tumor in four cases recurred 2 years after the first operation. CONCLUSION: Endoscopic transsphenoidal surgery of pituitary adenomas is a valuable microinvasive neurosurgery technique of minimal invasiveness, being effective and safe, yet requiring simple manipulation. With technological and scientific advancements, endoscopic transsphenoidal surgery will improve and develop step by step.

[Endoscopic treatment of suprasellar arachnoid cysts].

OBJECTIVE: To analyze the clinical manifestation and neuroendoscopic techniques in treatment of suprasellar arachnoid cysts. METHODS: Between October 2000 and June 2006, 42 patients (22 male and 20 female with a mean age of 10.4 years) with suprasellar arachnoid cysts were treated by endoscopy. All patients presented with hydrocephalus in CT and MRI scanning before operation. Endoscopic ventriculocystostomy was performed in 39 patients and cystocisternostomy was also performed in the other 3 patients. The mean duration of follow-up was 20.8 months. RESULTS: There was no surgery-related death and only two patients (4.8%) had postoperative complications. 25 cases (59.5%) recovered completely and 14 cases (33.3%) improved clinically. Ventriculoperitoneal shunting was performed in 3 patients because of recurrent hydrocephalus. Postoperative CT or/and MRI showed cyst volume decreased in all cases. Cine-MR imaging was performed in 21 patients that confirmed CSF could flow through all fenestration sites and aqueduct fluently. CONCLUSIONS: Endoscopic ventriculocystostomy (ventriculocystocisternostomy) is an effective and safe method in the treatment of suprasellar arachnoid cysts.

[Experimental research of myogenic motor evoked potentials to transcranial magnetic stimulation for spinal cord monitoring].

OBJECTIVE: To evaluate the validity of intraoperative magnetic MEP (motor evoked potentials) monitoring in a spinal-cord-menaced surgery. METHODS: 32 rabbits were employed in weight-drop spinal cord contusion model. After anesthetized with a combination of Ketamine and Droperidol the spinal cords were surgically exposed with the dura intact, and the contusion injuries were delivered except the rabbits in control group. The MEPs were recorded and the relationship between the variation of the MEPs and the residual locomotor capacity after spinal cord injury was analyzed. RESULTS: The 6 rabbits in mild-spinal-cord-injury group experienced transient attenuation of their TMS-MEPs, and the locomotor capacity remained intact (scores of 5) in almost all rabbits (5 of 6) when assessed 24 hours later; In the moderate-spinal-cord-injury group the 8 rabbits lost their TMS-MEP immediately after the weight-drop contusion, but they regained them partly in 1 hour one after another and scored 4 or 5 in the assessment of muscle power next day except for one score of 2; 8 rabbits had their spinal cords impaired severely in the contusion procedure and lost their TMS-MEP too but without recovery, their locomotor capacity outcomes were very poor, 5 of them had no response to transcranial magnetic stimulation next day, and in the other 3 rabbits we only found some polyphase waves with variant latency and lower amplitude which did not resemble common compound muscle action potential (CMAPs) evoked by TMS. CONCLUSIONS: Myogenic TMS-MEPs was very sensitive to the spinal cord injury and should be a valid technique for intraoperative monitoring, and a slight change of them, even if a transient lose, should be unnecessarily related to a severe movement disorder. The warning threshold for a given patient should depend on the malady itself.