[Prevalences of Trigeminal Neuralgia and Hemifacial Spasm].

Neurosurgeons must have knowledge about the epidemiology of trigeminal neuralgia and facial spasm. The annual incidence of trigeminal neuralgia is 4.3-28.9 per 100,000 persons, with a prevalence of 76.8 per 100,000 persons, increasing with age. It is more common in women and on the right side, with SCA being the most common causative vessel. The long-term efficacy of MVD for trigeminal neuralgia is 80% with complete resolution of pain and 5.2% with complications, which is safe and highly effective when performed by an expert surgeon. Hemifacial spasm has an annual incidence of 0.78/100,000 with a prevalence of approximately 10 per 100,000, increasing with age. It is more common in women and on the left side. AICA alone is the most common causative vessel. The long-term efficacy of MVD for facial spasms is 87.1% with complete resolution of facial spasms and 3.0% with complications. As with trigeminal neuralgia, safe and highly effective treatment can be expected when treated by an expert surgeon.

A Novel Approach to Microvascular Decompression for Hemifacial Spasm: Method Description and Associated Outcomes.

BACKGROUND: Microvascular decompression (MVD) is the only potential cure for hemifacial spasm (HFS). However, traditional techniques such as the interposition method may have limited effect in some cases. Alternative techniques have been proposed; however, they can be more complex or difficult to perform than the standard approach. OBJECTIVE: To describe a safe decompression technique-the "shelter method"-which involves creating a shelter-like space around the facial nerve root exit zone and present associated outcomes. METHODS: Medical records and intraoperative findings of 92 patients with HFS who underwent MVD using the shelter method between April 1997 and March 2017 were retrospectively reviewed. As a historical control group, we included 53 patients who had undergone MVD by the traditional interposition method before March 1989. The patients were divided into 3 subgroups according to the arteries involved and degree or direction of arterial compression to the seventh nerve. Patient outcomes were assessed as excellent, good, fair, and poor according to the MVD scoring system of the Japan Society for MVD Surgery. RESULTS: In the shelter method group, complete disappearance of HFS was achieved in 87 patients (94.6%). The curative rate of the shelter method group was significantly higher than that of the interposition method group. The overall complication rates were significantly lower in the shelter method group than in the interposition method group. CONCLUSION: Our findings indicate high curative and low complication rates of the shelter method, suggesting that it helps treat HFS caused by various types of arterial compression.

Microvascular Decompression for Trigeminal Neuralgia: A Prospective, Multicenter Study.

BACKGROUND: Microvascular decompression (MVD) is the most effective procedure for the long-term management of trigeminal neuralgia (TGN). However, retrospective and single-center studies are inherently biased, and there are currently no prospective, multicenter studies. OBJECTIVE: To evaluate the short- and long-term outcomes and complications in patients with TGN who underwent MVD at specialized Japanese institutions. METHODS: We enrolled patients with TGN who underwent MVD between April 2012 and March 2015. We recorded their facial pain grade and complications at 7 d (short term), 1 yr (mid-term), and 3 yr (long term) postoperatively. RESULTS: There were 166 patients, comprising 60 men and 106 women (mean age 62.7 yr). Furthermore, 105 patients were aged over 60 yr. We conducted neuromonitoring in 84.3% of the cases. The complete pain relief, mortality, and complication rates at the short-term follow-up were 78.9%, 0%, and 16.3%, respectively. Overall, 155 patients (93.4%) completed the long-term follow-up, with the complete pain relief and complication rates of 80.0% and 5.2%, respectively. CONCLUSION: In the hands of experienced neurosurgeons, MVD for TGN can achieve high long-term curative effects. In addition, complications are uncommon and usually transient. Our results indicate that MVD is an effective and safe treatment for patients with TGN, including elderly patients.

Prospective, Multicenter Clinical Study of Microvascular Decompression for Hemifacial Spasm.

BACKGROUND: Microvascular decompression (MVD) is the most effective procedure for hemifacial spasm (HFS). MVD results from nonspecialized or low-volume institutes are not always reliable. Most studies on MVD for HFS are retrospective and single centered; to the best of our knowledge, no prospective, multicenter studies exist. OBJECTIVE: To evaluate short- and long-term outcomes and complications in patients who underwent MVD for HFS in specialized Japanese institutions, in this multicenter, prospective, cohort study. METHODS: Included patients had undergone MVD for HFS in study centers between April 2012 and March 2015. Patients' postoperative grade of involuntary movements and complications were recorded postoperatively at 7 d (short-term) and at 1 (mid-term) and 3 (long-term) yr. RESULTS: A total of 486 patients (150 men, 336 women; mean age 53.9 yr with 181 patients over 60 yr) were enrolled during the study period. Neuromonitoring was used in 96.3% of the cases. The complete cure rate of symptom relief, mortality rate, and complication rate at short-term follow-up were 70.6%, 0%, and 15%, respectively. The long-term follow-up was completed by 463 patients (95.3%); the complete cure rate of symptom relief and complication rate were 87.1% and 3.0%, respectively. CONCLUSION: Our study revealed that under expert guidance and intraoperative neuromonitoring, the long-term curative effect rate of MVD for HFS is high, while complications are uncommon and usually transient. Our results indicate that MVD is an effective and safe treatment for patients with HFS, including elderly patients.

Efficacy of intraarterial superselective indocyanine green videoangiography in cerebral arteriovenous malformation surgery in a hybrid operating room.

OBJECTIVE: Although intravenous indocyanine green (ICG) videoangiography has been reported to be useful when applied to cerebral arteriovenous malformation (AVM) surgery, the ICG that remains after the procedure makes it difficult to understand the anatomy, to evaluate nidus blood flow changes, and to repeat ICG videoangiography within a short time. Intraarterial ICG videoangiography has emerged as a way to overcome these limitations. The current study presents the results of intraarterial ICG videoangiography undertaken in patients with cerebral AVMs. METHODS: Intraarterial ICG videoangiography was performed in 13 patients with cerebral AVMs. Routine intraoperative digital subtraction angiography at the authors' institution is performed in a hybrid operating room during AVM surgery and includes the added step of injecting ICG to the contrast medium that is administered through a catheter. RESULTS: Predissection studies were able to visualize the feeder in 12 of 13 cases. The nidus was visualized in 12 of 13 cases, while the drainer was visualized in all cases. After total dissection of the nidus, there was no ICG filling in the drainers found in any of the cases. Washout of the ICG took 4.4 ± 1.3 seconds in the feeders, 9.2 ± 3.5 seconds in the drainers, and 20.9 ± 3.4 seconds in all of the vessels. Nidus flow reduction was confirmed during dissection in 9 of 9 cases. Flow reduction was easy to recognize due to each span being very short. Color-encoded visualization and objective data obtained by Flow 800 analysis reinforced these findings. CONCLUSIONS: The results showed that intraarterial ICG videoangiography was more useful than intravenous ICG videoangiography in cerebral AVM surgery. This was especially effective in the identification of the feeder, nidus, and drainer and in the assessment of the flow dynamics of the nidus. Use of Flow 800 made it simpler and easier to evaluate these findings.

The risk of hemorrhage in stereotactic biopsy for brain tumors.

Objective : One major complication associated with STB is intratumoral hematoma, which is also the most common cause of morbidity related to permanent paralysis and mortality in STB. The risk of perioperative hemorrhage is generally between 1% and 10%, but this could be an underestimation since it is not common for many neurosurgeons to perform CT scans after uncomplicated STBs. In this study, we describe the incidence of cerebral hemorrhage, including asymptomatic cerebral hemorrhage. Methods : We recently reviewed data on the diagnosis rate and occurrence of complications, including symptomatic and asymptomatic cerebral hemorrhage, in 80 patients who underwent STB at our facility between 2005 and 2014. Results : Histological diagnosis was established for 75 cases (93.8%), glioma was the most frequently encountered tumor. Symptomatic hemorrhage was observed in two cases (2.6%), with the symptoms subsiding within two days. The morbidity and mortality rate was 0%. However, asymptomatic hemorrhages were observed in 23 cases (28.8%). Conclusion : Stereotactic biopsy is a less invasive procedure for obtaining samples of brain tumors for diagnosis. The bleeding of the tissue-resection cavity that includes asymptomatic hemorrhage occurs at a constant rate. It is important to reduce the symptomatic bleeding associated with stereotactic biopsy. J. Med. Invest. 66 : 314-318, August, 2019.

Prosthesis Used in Microvascular Decompressions: A Multicenter Survey in Japan Focusing on Adverse Events.

OBJECTIVE: To investigate the characteristics of materials used as prostheses for microvascular decompression surgery (MVDs) in Japan and their possible adverse events (AEs) to determine preferable materials for MVDs. METHODS: A questionnaire was sent to all members of the Japanese Society for MVDs, and answers were obtained from 59 institutions. RESULTS: Among a total of 2789 MVDs, 1088 operations for trigeminal neuralgia, 1670 for hemifacial spasm, and 31 others, including 117 reoperations, were performed between April 2011 and March 2014. Nonabsorbable material was used in 96.5% of MVDs, including polytetrafluoroethylene (PTFE) (80.5%), polyurethane (11.9%), expanded PTFE (2.1%), and silk thread (1.47%). The use of absorbable materials, including fibrin glue (87.5%), cellulose (13.5%), gelatin (4,77%), and collagen (1.76%), was reported. The major combinations were PTFE with fibrin glue (58.7%) followed by PTFE alone (7.60%). Eighty-eight AEs in 85 (3.2%) cases were reported among 2672 first operations. AEs included 51 central nervous system dysfunctions, 15 wound infections/dehiscence, and 10 others, which were presumed to be related to the intraoperative procedure. Among relatively high-, moderate-, and low-volume centers, there were no significant differences in the frequency of AEs (P = 0.077). Tissue-prosthesis adhesion and/or granuloma formation were reported in 13 cases of 117 reoperations. The incidence of adhesion-related recurrence was 11.1% of all reoperations. CONCLUSIONS: The number of AEs was quite low in this survey, and intradural use of any prosthesis reported in this paper might be justified; however, further development of easily handled and less-adhesive prosthesis materials is awaited.

Flow Alteration Therapy for Ruptured Vertebral Artery Dissecting Aneurysms Involving the Posterior Inferior Cerebellar Artery.

Surgery for- and endovascular treatment of vertebral artery (VA) dissecting aneurysms involving the origin of the posterior inferior cerebellar artery (PICA) remain challenging. Their ideal treatment is complete isolation of the aneurysm by surgical or endovascular trapping plus PICA reconstruction. However, postoperative lower cranial nerve palsy and medullary infarction are potential complications. We report four patients with VA dissecting aneurysms involving the PICA origin who were treated by occipital artery (OA)-PICA bypass followed by proximal occlusion of the VA and clip ligation of the PICA origin instead of trapping. There were no procedural or ischemic complications. In all patients, angiography performed 2-3 weeks later showed good patency of the bypass graft and complete obliteration of the aneurysm. During the follow-up period ranging from 1 to 14 years, none experienced bleeding. Although retrograde blood flow to the dissecting aneurysm persisted in the absence of trapping, iatrogenic lower cranial nerve injury could be avoided. The decrease in aneurysmal flow might elicit spontaneous thrombosis and prevent aneurysmal rerupture. Our technique might be less invasive than aneurysmal trapping and help to prevent rebleeding.

Posttraumatic Cerebrospinal Fluid Leak Associated with an Upper Cervical Meningeal Diverticulum.

BACKGROUND: Spontaneous intracranial hypotension (SIH) has been increasingly recognized as a phenomenon caused by cerebrospinal fluid (CSF) leaks; however, its pathogenesis remains unclear. CASE DESCRIPTION: We report 2 cases of SIH resulting from CSF leak from a meningeal diverticulum at the C2 nerve root sleeve. The first case is that of a 46-year-old man who experienced orthostatic headache after a bicycle accident at age 45. Computed tomography (CT) myelography revealed CSF leaks at the C1-2 level. He underwent epidural blood patch therapy, but it was unsuccessful. Next, we performed direct surgery and found a meningeal diverticulum originating from the left C2 nerve root; therefore, we ligated the diverticulum. His symptoms and image findings strikingly improved after surgery. The second case is that of a 45-year-old man who experienced orthostatic headache 1 month after jumping into a river. Magnetic resonance imaging of the head showed bilateral subdural hematoma. CT myelography revealed CSF leaks at the C1-2 level and multiple cyst formations at the cervical and thoracic nerve root sleeves. epidural blood patch was performed, and his symptoms immediately improved. CONCLUSIONS: Recent studies have reported that meningeal diverticulum is involved in various cases of CSF leaks. The 2 cases indicate that traumatic accidents, such as back-and-forth neck movement or falls, presumably induce an increase in CSF pressure, followed by the rupture of an existing meningeal diverticulum, leading to CSF leak.

Down-regulation of MDR1 by Ad-DKK3 via Akt/NFκB pathways augments the anti-tumor effect of temozolomide in glioblastoma cells and a murine xenograft model.

BACKGROUND: Glioblastoma multiforme (GBM) is the most malignant of brain tumors. Acquired drug resistance is a major obstacle for successful treatment. Earlier studies reported that expression of the multiple drug resistance gene (MDR1) is regulated by YB-1 or NFκB via the JNK/c-Jun or Akt pathway. Over-expression of the Dickkopf (DKK) family member DKK3 by an adenovirus vector carrying DKK3 (Ad-DKK3) exerted anti-tumor effects and led to the activation of the JNK/c-Jun pathway. We investigated whether Ad-DKK3 augments the anti-tumor effect of temozolomide (TMZ) via the regulation of MDR1. METHODS: GBM cells (U87MG and U251MG), primary TGB105 cells, and mice xenografted with U87MG cells were treated with Ad-DKK3 or TMZ alone or in combination. RESULTS: Ad-DKK3 augmentation of the anti-tumor effects of TMZ was associated with reduced MDR1 expression in both in vivo and in vitro studies. The survival of Ad-DKK3-treated U87MG cells was inhibited and the expression of MDR1 was reduced. This was associated with the inhibition of Akt/NFκB but not of YB-1 via the JNK/c-Jun- or Akt pathway. CONCLUSIONS: Our results suggest that Ad-DKK3 regulates the expression of MDR1 via Akt/NFκB pathways and that it augments the anti-tumor effects of TMZ in GBM cells.

Idiopathic and Chronic Epidural Hematoma in the Lumbar Spine: A Case Report and Review of Literatures.

Spontaneous and chronic epidural hematoma (SSEH) in the lumbar spine is rare, and idiopathic and chronic SSEH in the lumbar spine is extremely rare disease. Most of lumbar SSEH were acute and secondary with trauma, hematologic disorders, drug, and surgical procedure. Only 20 cases of chronic SSEH in the lumbar spine have been reported and 14 cases among them were considered to be idiopathic. Definitive guidelines for management of this condition are not clear and surgical total evacuation was performed in most of the cases. Some authors reported the epidural bleeding originates in the rupture of Batson's plexus due to a rise in intra-abdominal pressure, but the mechanism is not clearly clarified. We report a surgical case of idiopathic and chronic SSEH. A 61-year-old woman suffered a sudden onset of severe lumbar pain during sleep. She had no history of trauma, spinal surgery, or hypertension. Magnetic resonance imaging revealed a lumbar chronic epidural hematoma which compressed the dural sac behind and extended from L2 to L5. This patient underwent the partial evacuation of the hematoma with partial hemilaminectomy on left at L2/3, resulting in immediate pain relief and resolution of symptoms and almost absorption of the hematoma within 1 week of the procedure. We presented this rare case and reviewed idiopathic and chronic epidural hematoma in the lumbar spine.

Coloring Technique of Magnetic Resonance Angiography for Superficial Temporal Artery to Middle Cerebral Artery Bypass Surgery.

OBJECTIVE: Superficial temporal artery (STA)-to-middle cerebral artery (MCA) bypass is an established surgical technique for achieving revascularization. It is important to select the proper recipient artery of the MCA. Three-dimensional computed tomographic angiography (3D-CTA) and conventional angiography are useful in the selection process but need contrast agents. The authors have designed a coloring MRA technique that needs no agents to visualize the recipient artery. Retrospective evaluation of the efficacy and limitation for selection of the recipient artery and decision of the place and size of the craniotomy were carried out. METHODS: The authors performed the coloring MRA before operation since January 2013. Ninety-two patients underwent STA-MCA bypass for atherosclerotic stenosis or occlusion of internal carotid artery (ICA), MCA with reference to the coloring MRA. To evaluate the efficacy of coloring MRA, the control group consisted of 75 patients who underwent STA-MCA bypass between January 2012 to November 2013 with reference to 3D-CTA. The size of craniotomy was retrospectively calculated and compared. RESULTS: Neither additional craniotomy nor wrong selection of the recipient artery was done in either group. There was no significant difference in size between the 2 groups in both single and double bypass. CONCLUSIONS: The coloring MRA technique was not inferior to 3D-CTA with respect to the size of craniotomy. This novel technique was found to be very helpful not only for the virtual identification of the proper recipient artery but also for preoperative simulation such as decisions about length of donor artery, location, and size of craniotomy.

Correction to: Treatment with the PPARγ Agonist Pioglitazone in the Early Post-ischemia Phase Inhibits Pro-inflammatory Responses and Promotes Neurogenesis Via the Activation of Innate- and Bone Marrow-Derived Stem Cells in Rats.

In the original publication of the article, the second author (Keiko T. Kitazato) was missing.

Diagnostic Performance of Arterial Spin Labeling for Grading Nonenhancing Astrocytic Tumors.

PURPOSE: We evaluated the utility of arterial spin labeling (ASL) imaging of tumor blood flow (TBF) for grading non-enhancing astrocytic tumors. MATERIALS AND METHODS: Thirteen non-enhancing astrocytomas were divided into high-grade (n = 7) and low-grade (n = 6) groups. Both ASL and conventional sequences were acquired using the same magnetic resonance machine. Intratumoral absolute maximum TBF (TBFmax), absolute mean TBF (TBFmean), and corresponding values normalized to cerebral blood flow (TBFmax and TBFmean ratios) were measured. The Mann-Whitney U test and receiver operating characteristic (ROC) curve analysis were used to assess the accuracy of TBF variables for tumor grading. RESULTS: Compared with low-grade astrocytoma, high-grade astrocytoma exhibited significantly greater absolute TBFmax (90.93 ± 24.96 vs 46.94 ± 20.97 ml/100 g/min, P < 0.001), TBFmean (58.75 ± 19.89 vs 31.16 ± 17.63 ml/100 g/min, P < 0.001), TBFmax ratio (3.34 ± 1.22 vs 1.35 ± 0.5, P < 0.001), and TBFmean ratio (2.15 ± 0.94 vs 0.88 ± 0.41, P < 0.001). The TBFmax ratio yielded the highest diagnostic accuracy (sensitivity 100%, specificity 86.3%), while absolute TBFmean yielded the lowest accuracy (sensitivity 85.7%, specificity 70.1%) by ROC analysis. CONCLUSION: Parameters from ASL perfusion imaging, particularly TBFmax ratio, may be useful for distinguishing high-grade from low-grade astrocytoma in cases with equivocal conventional MRI findings.

Treatment with the PPARγ Agonist Pioglitazone in the Early Post-ischemia Phase Inhibits Pro-inflammatory Responses and Promotes Neurogenesis Via the Activation of Innate- and Bone Marrow-Derived Stem Cells in Rats.

Neurogenesis is essential for a good post-stroke outcome. Exogenous stem cells are currently being tested to promote neurogenesis after stroke. Elsewhere, we demonstrated that treatment with the PPARγ agonist pioglitazone (PGZ) before cerebral ischemia induction reduced brain damage and activated survival-related genes in ovariectomized (OVX) rats. Here, we tested our hypothesis that post-ischemia treatment with PGZ inhibits brain damage and contributes to neurogenesis via activated stem cells. Bone marrow (BM) cells of 7-week-old Wistar female rats were replaced with BM cells from green fluorescent protein-transgenic (GFP+BM) rats. Three weeks later, they were ovariectomized (OVX/GFP+BM rats). We subjected 7-week-old Wistar male and 13-week-old OVX/GFP+BM rats to 90-min cerebral ischemia. Male and OVX/GFP+BM rats were divided into two groups, one was treated with PGZ (2.5 mg/kg/day) and the other served as the vehicle control (VC). In both male and OVX/GFP+BM rats, post-ischemia treatment with PGZ reduced neurological deficits and the infarct volume. In male rats, PGZ decreased the mRNA level of IL-6 and M1-like macrophages after 24 h. In OVX/GFP+BM rats, PGZ augmented the proliferation of resident stem cells in the subventricular zone (SVZ) and the recruitment of GFP+BM stem cells on days 7-14. Both types of proliferated stem cells migrated from the SVZ into the peri-infarct area. There, they differentiated into mature neurons, glia, and blood vessels in association with activated Akt, MAP2, and VEGF. Post-ischemia treatment with PGZ may offer a new avenue for stroke treatment through contribution to neuroprotection and neurogenesis.

The Current Status of Microvascular Decompression for the Treatment of Trigeminal Neuralgia in Japan: An Analysis of 1619 Patients Using the Japanese Diagnosis Procedure Combination Database.

Microvascular decompression (MVD) is a widely used, safe, and effective treatment for trigeminal neuralgia (TGN). However, the extent of application of this therapeutic method and its outcomes in Japan are currently unclear. To address these questions, the authors analyzed the use of MVD for the treatment of TGN during the 33-month period from July 2010 to March 2013, using data contained in the Diagnosis Procedure Combination database. The analysis revealed that MVD was used for the treatment of TGN in 1619 cases (608 men, 1011 women), with approximately 1.66 times more women treated than men. MVD for TGN was most frequently performed in individuals 60 to 79 years of age; of particular note was the remarkable increase in the number of women in this particular category. The overall number of procedures performed per 100,000 population/year in Japan was 0.46. The number of procedures was larger in prefectures with higher populations, with a tendency toward a higher number of MVD procedures performed in the area designated West than in the East. Discharge outcomes indicated that cure and improvement were achieved in 97.6% of cases, with a mortality rate of 0.2%, and no differences in discharge outcomes between men and women. The mean length of hospital stay in patients undergoing MVD for TGN was 14.8 days. This analysis revealed discernable trends in the use of MVD for the treatment of TGN in Japan.

Bazedoxifene, a selective estrogen receptor modulator, reduces cerebral aneurysm rupture in Ovariectomized rats.

BACKGROUND: Estrogen deficiency is thought to be responsible for the higher frequency of aneurysmal subarachnoid hemorrhage in post- than premenopausal women. Estrogen replacement therapy appears to reduce this risk but is associated with significant side effects. We tested our hypothesis that bazedoxifene, a clinically used selective estrogen receptor (ER) modulator with fewer estrogenic side effects, reduces cerebral aneurysm rupture in a new model of ovariectomized rats. METHODS: Ten-week-old female Sprague-Dawley rats were subjected to ovariectomy, hemodynamic changes, and hypertension to induce aneurysms (ovariectomized aneurysm rats) and treated with vehicle or with 0.3 or 1.0 mg/kg/day bazedoxifene. They were compared with sham-ovariectomized rats subjected to hypertension and hemodynamic changes (HT rats). The vasoprotective effects of bazedoxifene and the mechanisms underlying its efficacy were analyzed. RESULTS: During 12 weeks of observation, the incidence of aneurysm rupture was 52% in ovariectomized rats. With no effect on the blood pressure, treatment with 0.3 or 1.0 mg/kg/day bazedoxifene lowered this rate to 11 and 17%, almost the same as in HT rats (17%). In ovariectomized rats, the mRNA level of ERα, ERß, and the tissue inhibitor of metalloproteinase-2 was downregulated in the cerebral artery prone to rupture at 5 weeks after aneurysm induction; the mRNA level of interleukin-1ß and the matrix metalloproteinase-9 was upregulated. In HT rats, bazedoxifene restored the mRNA level of ERα and ERß and decreased the level of interleukin-1ß and matrix metalloproteinase-9. These findings suggest that bazedoxifene was protective against aneurysmal rupture by alleviating the vascular inflammation and degradation exacerbated by the decrease in ERα and ERß. CONCLUSIONS: Our observation that bazedoxifene decreased the incidence of aneurysmal rupture in ovariectomized rats warrants further studies to validate this response in humans.

MicroRNA-449a deficiency promotes colon carcinogenesis.

MicroRNAs have broad roles in tumorigenesis and cell differentiation through regulation of target genes. Notch signaling also controls cell differentiation and tumorigenesis. However, the mechanisms through which Notch mediates microRNA expression are still unclear. In this study, we aimed to identify microRNAs regulated by Notch signaling. Our analysis found that microRNA-449a (miR-449a) was indirectly regulated by Notch signaling. Although miR-449a-deficient mice did not show any Notch-dependent defects in immune cell development, treatment of miR-449a-deficient mice with azoxymethane (AOM) or dextran sodium sulfate (DSS) increased the numbers and sizes of colon tumors. These effects were associated with an increase in intestinal epithelial cell proliferation following AOM/DSS treatment. In patients with colon cancer, miR-449a expression was inversely correlated with disease-free survival and histological scores and was positively correlated with the expression of MLH1 for which loss-of function mutations have been shown to be involved in colon cancer. Colon tissues of miR-449a-deficient mice showed reduced Mlh1 expression compared with those of wild-type mice. Thus, these data suggested that miR-449a acted as a key regulator of colon tumorigenesis by controlling the proliferation of intestinal epithelial cells. Additionally, activation of miR-449a may represent an effective therapeutic strategy and prognostic marker in colon cancer.