Analysis of the risk factors for development of post-operative extradural hematoma after intracranial surgery.

OBJECTIVE: Post-operative extradural hematoma (EDH) is a relatively common complication in patients undergoing intracranial operations. The risk factors associated with the occurrence of EDH are not well described in the literature. The objective of this study was to identify the risk factors and the incidence of post-operative EDH adjacent and regional to the craniotomy or the craniectomy site. METHOD: This was a retrospective study of 24 (2.6% of total) patients who underwent extradural hematoma evacuation after primary intracranial supratentorial surgery between January 2005 and December 2011. During this period, 941 intracranial operations were performed. The control group (72 patients) was selected on the basis of having undergone the same pre-operative diagnosis and treatment within 2 months of the operations for the 24 hematoma patients. The Glasgow Coma Scale score and operation character (emergency or elective) of the hematoma and control group were individually matched to minimize pre-operative conditional bias. The ages of both groups were individually matched with similar ages within 10 years of each other to minimize age bias. RESULT: Univariate analysis showed that the significant pre-operative and intra-operative factors associated with post-operative EDH were an intra-operative blood loss of greater than 800 mL (p=0.007), maximal craniotomy length of greater than or equal to 100 mm (p=0.001), and craniotomy area of greater than or equal to 71.53 cm2 (p=0.018). In multivariate analysis, intra-operative blood loss exceeding 800 mL (median of total patients) placed a patient at significantly increased risk for post-operative EDH. CONCLUSION: The data did not examine established risk factors for post-operative hematoma, such as thrombocytopenia, anti-coagulant and anti-platelet therapy, and a history of heavy alcohol consumption and/or tobacco intake. Recognizing the limitations of the study, large intra-operative blood loss and wide craniotomy area are implicated with an increased risk of post-operative EDH after intracranial surgery.

HOX gene analysis of endothelial cell differentiation in human bone marrow-derived mesenchymal stem cells.

Human bone marrow-derived mesenchymal stem cells (hMSCs) have been shown to possess multilineage differentiation potential. HOX genes function in transcriptional regulators, and are involved in stem cell differentiation. The aim of the present study was to demonstrate HOX genes that are related to angiogenesis. To identify the expression patterns of 37 HOX genes in the endothelial cell differentiation of hMSCs, we analyzed HOX genes through profiling with multiplex RT-PCR. The results showed that the expression patterns of four HOX genes, HOXA7, HOXB3, HOXA3, and HOXB13, significantly changed during angiogenesis. The expression levels of HOXA7 and HOXB3 were dramatically increased, whereas those of HOXA3 and HOXB13 were decreased during endothelial cell differentiation. When further analysis of the expressions of these HOX genes was performed with real-time PCR and an immunoblot assay, the expression patterns were also found to be well-matched with the results of multiplex RT-PCR. Here, we report that HOXA7, HOXB3, HOXA3, and HOXB13 might be involved in the angiogenesis of hMSCs.

Identification of DNA copy number aberrations by array comparative genomic hybridization in patients with ruptured intracranial aneurysms.

We aimed to use array comparative genomic hybridization (CGH) to identify chromosomal loci that contribute to the pathogenesis of ruptured intracranial aneurysms (IAs) in a Korean population and to confirm the results using real-time polymerase chain reaction (PCR). Twenty-three patients with ruptured IAs were enrolled in this study. Array CGH revealed copy number aberrations in 19 chromosomal regions. Chromosomal gains were identified at a high frequency in regions 1p12, 4q24, 5p15.31, 5p15.33, 6p12.2, 6q22.33, 7p21.1, 9q22.1, 10q24.32, 10q26.3, 12q13.13, 17p12, 18q12.3, 18q23, 19p13.3, 20q13.33, 21q11.2, and 21q22.3, whereas chromosomal losses were identified at 15q11.2 and 22q11.21. Real-time PCR confirmed the results of the array CGH studies of the COL6A2, GRIN3B, MUC17, and PRODH genes. This is the first study to identify candidate regions by array CGH in patients with IAs. The identification of genes that may predispose an individual to the development of IAs may lead to a better understanding of the mechanism of IA formation. Multicenter studies comparing cohorts of patients of different ethnicities are needed to better understand the mechanism of IA formation.

The clinical efficacy of repeat brain computed tomography in patients with traumatic intracranial haemorrhage within 24 hours after blunt head injury.

This study was performed to determine the usefulness of repeated brain computed tomography (CT) within 24 hours of blunt head trauma in patients with traumatic intracranial haemorrhages (ICH) and who were initially treated nonsurgically. Factors associated with the worsening of lesions on repeat CT were evaluated. Medical records of all blunt head trauma patients with traumatic ICH admitted to our hospital from January 2003 to December 2006 were retrospectively reviewed. Patients older than 16 years of age with an initial Glasgow Coma Scale (GCS) of 8 or greater were included. From the results of the repeat CT, patients were categorized as Group 1 (improved or unchanged condition) or Group 2 (worsened condition). A total of 168 patients (mean age of 44.8 +/- 19.2; mean admission GCS of 13.42 +/- 2.07; male to female ratio 2.1:1) were included. In 161 patients, repeat CT was obtained on a routine basis. In the remaining 7, it was prompted by a worsening neurological condition. The mean time from initial to repeat CT was 10.10 +/- 7.25 hours. Based on the results of the repeat CT, 108 patients were included in Group 1 and 60 in Group 2. The mean initial GCS was lower in patients from Group 2 versus those from Group 1 (11.9 +/- 2.6 compared with 14.3 +/- 0.96; p < 0.001). After repeat CT, 28 (47%) of the patients in Group 2 underwent neurosurgical interventions. Of the 28 surgically treated patients from Group 2, 6 (10%) exhibited neurological worsening and 22 (37%) appeared neurologically stable. According to our data, we suggest that routine repeat CT within 24 hours after blunt head trauma might minimize potential neurological deterioration in patients with either a GCS lower than 12 or with an epidural haematoma or multiple lesions as indicated on initial CT.

Prognostic value of intra-operative lateral spread response monitoring during microvascular decompression in patients with hemifacial spasm.

Hemifacial spasm (HFS) has characteristic and specific electrophysiological features, primarily the lateral spread response (LSR). The aim of this study was to evaluate the correlation between changes in the lateral spread response during microvascular decompression (MVD) and the clinical outcome after MVD. Seventy-two patients with HFS who were treated with MVD were included in this study. Intra-operative facial electromyography (EMG) was performed and brainstem auditory evoked potentials were monitored. In 32 (44.4%) patients, the LSR persisted after MVD. Among these 32 patients, 11 had mild HFS at discharge and six had mild HFS at the 6 month follow up. Out of the 40 patients in whom the LSR disappeared intra-operatively after MVD, five had mild HFS at discharge and four had mild HFS at the 6-moth follow up. The clinical outcome of HFS after MVD does not always correlate with intra-operative EMG abnormality. Therefore, the prognostic value of intra-operative LSR monitoring with respect to long-term results is questionable.

Comparative genome hybridization array analysis for sporadic Parkinson's disease.

Parkinson disease (PD) is a common neurodegenerative disorder, characterized by the loss of midbrain dopamine neurons and Lewy body inclusions. We investigated array CGH to analyze gain or loss of genetic material from 30 patients with PD. We identified the frequent copy number variations in PD; gains in 1p21.1, 4p15.31, 5p15.33, 6q24.1, 7q35, 8q24.3, 10q26.3, 11p15.5-15.4, 12q21.2, 16p13.3, 18q12.3 and 22q13.31, and losses in 1p36.33, and 5q13.2. These findings enable a better description of genetic variations in PD, and could provide a foundation for understanding the critical regions of the genome that may be involved in the development of PD.

Altered DNA copy number in patients with different seizure disorder type: by array-CGH.

Epilepsy is one of the most common but genetically complex neurological disorders in children. Previous studies have showed that chromosomal abnormalities confer susceptibility to epilepsy. To identify new chromosomal abnormalities associated with epilepsy, DNA samples from patients with idiopathic generalized epilepsy (IGE), partial epilepsy (PE), and febrile seizures (FS) were analyzed using array comparative genome hybridization technique (array-CGH). Genomic aberrations were detected throughout whole chromosome. The most frequently altered loci were gains noted in: 1p (60%), 5p (55%), 8q (55%), 10q (55%), and losses in 7q (55%). The most frequent chromosomal aberrations for each seizure type were: IGE-1p (60%), 5p (55%), and 10q (55%), PE-11p (45%), 21q (45%) and FS-8q (55%), and losses in 7q (55%). To validate the array-CGH results, real time PCR was performed for several genes (EPM2AIP1, OSM, AFP, CYP19A1, SLC6A13, and COL6A2). The results from the real time PCR were consistent with those from the array-CGH. Therefore, we found that the three types of seizures disorder studied have different chromosomal aberrations. These results might be used for further investigation of the pathogenesis of epilepsy.

Bypass surgery versus medical treatment for symptomatic moyamoya disease in adults.

OBJECTIVE In this study the authors evaluated whether extracranial-intracranial bypass surgery can prevent stroke occurrence and decrease mortality in adult patients with symptomatic moyamoya disease (MMD). METHODS The medical records of 249 consecutive adult patients with symptomatic MMD that was confirmed by digital subtraction angiography between 2002 and 2011 at 8 institutions were retrospectively reviewed. The study outcomes of stroke recurrence as a primary event and death during the 6-year follow-up and perioperative complications within 30 days as secondary events were compared between the bypass and medical treatment groups. RESULTS The bypass group comprised 158 (63.5%) patients, and the medical treatment group comprised 91 (36.5%) patients. For 249 adult patients with MMD, bypass surgery showed an HR of 0.48 (95% CI 0.27-0.86, p = 0.014) for stroke recurrence calculated by Cox regression analysis. However, for the 153 patients with ischemic MMD, the HR of bypass surgery for stroke recurrence was 1.07 (95% CI 0.43-2.66, p = 0.887). For the 96 patients with hemorrhagic MMD, the multivariable adjusted HR of bypass surgery for stroke recurrence was 0.18 (95% CI 0.06-0.49, p = 0.001). For the treatment modality, indirect bypass and direct bypass (or combined bypass) did not show any significant difference for stroke recurrence, perioperative stroke, or mortality (log rank; p = 0.524, p = 0.828, and p = 0.616, respectively). CONCLUSIONS During the treatment of symptomatic MMD in adults, bypass surgery reduces stroke recurrence for the hemorrhagic type, but it does not do so for the ischemic type. The best choice of bypass methods in adult patients with MMD is uncertain. In adult ischemic MMD, a prospective randomized study to evaluate the effectiveness and safety of bypass surgery to prevent recurrent stroke is necessary.

Proper Management of Posttraumatic Tension Pneumocephalus.

Pneumocephalus is commonly seen after craniofacial injury. The pathogenesis of pneumocephalus has been debated as to whether it was caused by ball valve effect or combined episodic increased pressure within the nasopharynx on coughing. Discontinuous exchange of air and cerebrospinal fluid due to "inverted bottle" effect is assumed to be the cause of it. Delayed tension pneumocephalus is not common, but it requires an active management in order to prevent serious complication. We represent a clinical case of a 57-year-old male patient who fell down from 3 m height, complicated by tension pneumocephalus on 5 months after trauma. We recommend a surgical intervention, but the patient did not want that so we observe the patient. The patient was underwent seizure and meningitis after 7 months after trauma, he came on emergency room on stupor mentality. Tension pneumocephalus may result in a neurologic disturbance due to continued air entrainment and it significantly the likelihood of intracranial infection caused by continued open channel. Tension pneumocephalus threat a life, so need a neurosurgical emergency surgical intervention.

The merlin tumor suppressor interacts with Ral guanine nucleotide dissociation stimulator and inhibits its activity.

Neurofibromatosis type 2 (NF2) is the most commonly mutated gene in benign tumors of the human nervous system such as schwannomas and meningiomas. The NF2 gene encodes a protein called schwannomin or merlin, which is involved in regulating cell growth and proliferation through protein-protein interactions with various cellular proteins. In order to better understand the mechanism by which merlin exerts its function, yeast two-hybrid screening was performed and Ral guanine nucleotide dissociation stimulator (RalGDS), a downstream molecule of Ras, was identified as a merlin-binding protein. The direct interaction between merlin and RalGDS was confirmed both in vitro and in the NIH3T3 cells. The domain analyses revealed that the broad C-terminal region of merlin (aa 141-595) is necessary for the interaction with the C-terminal Ras-binding domain (RBD) of RalGDS. Functional studies showed that merlin inhibits the RalGDS-induced RalA activation, the colony formation and the cell migration in mammalian cells. These results suggest that merlin can function as a tumor suppressor by inhibiting the RalGDS-mediated oncogenic signals.

A molecular basis for the efficacy of magnesium treatment following traumatic brain injury in rats.

Magnesium ions have been shown to be a promising treatment for brain lesions caused by traumatic brain injury (TBI), as well as for the associated acute neurodegeneration and progressive functional deficits. This study investigated the effects of magnesium on the expression of the cell death/survival related proteins following TBI. Male Sprague-Dawley (SD) rats (n = 66, 280-320 g body weight) were subjected to sham surgery alone (n = 14), or to the surgery followed by a lateral fluid percussion brain injury of moderate severity (n = 52, 2.4-2.7 atm). The injured rats were randomly treated with an intravenous bolus of magnesium chloride (n = 26, 125 micromol) or saline vehicle (n = 26). The coronal brain sections were quantitatively analyzed for cell apoptosis and the expression of p53-related proteins, Bcl-2, cyclin D1 and PCNA at 1, 2, and 4 days post-injury by immunohistochemistry or in situ hybridization. Tissue damage was observed primarily in the ipsilateral cortex of the injured region with the induction of apoptosis and p53 mRNA level at 2 days after TBI. The expression of p53 and responding proteins (p21(WAF1/CIP1), Mdm2 and Bax) showed a temporal pattern similar to the apoptotic events in the time course experiments. They were induced in the early time points of days 1-2, decreasing by day 4 after TBI. In contrast, the expression of the cell survival related proteins - Bcl-2, cyclin D1, and PCNA - was most significant at day 4 post-injury, when the rate of apoptosis decreased. Magnesium treatment resulted in a reduction in apoptosis and expression of p53-related proteins. However, it had only a slight additive effect on the expression of the survival related proteins in the same time-course. These results provide a molecular basis for the efficiency of magnesium in treating TBI-induced tissue damage.

TAK1 mediates lipopolysaccharide-induced RANTES promoter activation in BV-2 microglial cells.

Lipopolysaccharide (LPS), a part of the outer membrane of gram-negative bacteria activates the expression of the regulated upon activation, normal T cell expressed and secreted (RANTES), which plays an important role in the chemo-attraction of leukocytes during the inflammatory response. Recently, we found that LPS-induced RANTES production is mediated by the activation of NF-kappaB, but, the upstream regulatory mechanism involved in mediating this NF-kappaB activation was unclear. In this study, we investigated signal transducing molecules that mediate LPS-induced RANTES promoter activation and found the followings. First, LPS activates the RANTES gene promoter through NF-kappaB binding sites. Second, the expression of dominant negative mutants of TGF-beta-activated kinasel (TAK1) and NF-kappaB-inducing kinase (NIK), blocked the LPS-induced transcriptional activation of RANTES promoter. Moreover, the overexpression of TAK1 along with TAK1-binding protein 1 (TAB1), or NIK stimulated the transcriptional activation of RANTES in the absence of external stimuli. Third, we showed that endogenous TAK1 is phosphorylated by LPS stimulation, and that the association between TAK1 and tumour necrosis factor receptor-associated factor 6 (TRAF6) is constitutive and not induced by LPS treatment. These results indicate that NF-kappaB mediates LPS-triggered RANTES induction and that TAK1 as well as NIK, as NF-kappaB activators participates in LPS-triggered RANTES induction.

Inhibition of ras-mediated activator protein 1 activity and cell growth by merlin.

The neurofibromatosis type2 (NF2) gene encodes an intracellular-associated protein that is referred to as either merlin or schwannomin. Merlin/Schwannomin is a tumor suppressor protein that has been reported to block the Ras-mediated cell proliferation and -anchorage-independent cell growth. However, its inhibitory mechanism is uncertain. In this report, merlin was demonstrated to be effective in suppressing Ras-induced foci-formation and its associated AP-1 activity in NIH3T3cells. In addition, merlin blocked Ras-induced Rb phosphorylation, and inhibited the increase of cyclin D1 levels. It also blocked E2F-1-dependent transcription. These results suggest that merlin inhibits abnormal cell proliferation which is activated via Ras by repressing Rb phosphorylation, blocking the increase of the cyclin D1 protein level, and inhibiting the activation of AP-1- and E2F-1-dependent transcription in NIH3T3 cells.

Identification of the elements regulating the expression of the phospholipase C delta1.

Recently we cloned the phospholipase C deltal (PLC-delta1) promoter region and found that PLC-delta1 is selectively expressed in several tissues. In order to establish the common and cell-type specific transcriptional elements, 1.8 kilobase of the 5'-flanking region of PLC-delta1 was characterized in several cell lines. A transient transfection assay of the -1787-Luc construct in several cell lines demonstrated the potential transcriptional enhancement of reporter activities in the neuroblastoma cell [SK-N-BE(2)C] and kidney cell lines (Cos-7), but not in liver cell lines (Chang liver cell). Transient transfection assays of a series of 5' --> 3' deletion constructs of the PLC-delta1 promoter and electronic mobility shift assays suggested that the E-box and HFH3 binding sites are cell-type specific elements, and that Sp-1 is a major transcriptional activator of a majority of cell lines. Our findings, therefore, indicate that the combination of several elements within the 5'-flanking region of the PLC-delta1 gene dictates its restricted expression in several cell lines.

Brain Metastases of Papillary Thyroid Carcinoma with Horner's Syndrome.

Papillary thyroid carcinoma (PTC) is the most common type of thyroid malignancy and has relatively favorable prognosis. Blood-borne metastases of PTC are very rare among the thyroid malignancies. Moreover a case of blood-borne central nervous system metastasized PTC with only unilateral Horner's syndrome, and without any abnormalities in laboratory or physical examinations has not been described before. A 53-year-old female patient had been managed in ophthalmologic clinic due to vague symptoms of right monocular blurred vision with eye dryness for 3 months, but showed no signs of improvement. So it was performed a magnetic resonance imaging and magnetic resonance angiography to evaluate the possibilities of cerebral lesion. And a left frontal mass was incidentally found, and the tumor turned out to be a PTC that had metastasized to brain, regional lymph node, cervical, thoracic spine, and lung. We describe a PTC with extraordinary initial symptoms that metastasized to an unusual site. We recommend that if a papillary thyroid tumor with unusual symptoms or at an advanced stage is found, further investigation should be performed for distant metastasis.

Hinge Fracture during Cervical Open-door Laminoplasty: Does it Affect Clinical and Radiographic Outcomes?

OBJECTIVE: The purpose of this study was to determine whether the status of the hinge gutter affected clinical and radiographic outcomes of cervical open door laminoplasty. METHODS: We retrospectively analyzed 43 patients who had undergone cervical open door laminoplasty. 23 CT scans were performed at 2 days post-operation. The number of CT scans at 3, 6, 12 and 24 months were 16, 12, 21 and 11, respectively. We collected perioperative and follow-up data, including clinical and radiographic results. RESULTS: There were 7 patients without a hinge fracture and 16 patients with one or more hinge fractures at 2 days postoperation. There were 90 hinges, and the rate of ideal greenstick deformation of the hinge was 63% on 2-day-postoperative CT scans. Postoperative VAS scores of neck pain (p=0.012) in patients without a hinge fracture were higher than in patients with hinge fractures. The hinge healing rates were 37% at 3 months, 57.4% at 6 months, 86.4% at 12 months, and 85.4% at 24 months. Among the patients, 14 patients had healed hinges, and 7 patients had one or more hinge(s) that was/were not healed at 12 months post-operation. However, in clinical and radiographic outcomes, there was no difference between these patients. CONCLUSION: Cervical open door laminoplasty was safe and provided stable reconstruction of laminar expansion. In radiographs, the difference between hinges that had healed and hinges that had not healed was statistically negligible. Hinge fractures might not influence the clinical and radiographic outcomes of cervical open door laminoplasty.

Prevalence and epidemiological features of moyamoya disease in Korea.

OBJECTIVE: The objectives of the present study were to investigate the annual detection rate of patients with Moyamoya disease (MMD) and to describe the prevalence and epidemiological features of the Moyamoya patients in Korea. MATERIALS AND METHODS: The authors analyzed the epidemiological data of Korean patients taken from the National Health Insurance Corporation in Korea among Moyamoya patients who were treated from 2004 until 2008. RESULTS: Based on 2004 data, 2,539 MMD patients were treated in Korea and the prevalence rate was 5.2 per 100,000 people. There were 2,987 in 2005, 3,429 in 2006, 4,051 in 2007, and 4,517 cases in 2008, and the prevalence rates per 100.000 people were 6.3, 7.0, 8.6, and 9.1, for those respective years. This represents an annual increase of 15% of new cases during this period. In 2008, 466 people were newly diagnosed with MMD, representing an incidence rate of 1 per 100,000 persons. The gender ratio was 1,547 men (34%) and 2,970 women (66%). Women had a higher incidence rate than men (1.94 times). There were two age peaks: teenagers and those in their forties. CONCLUSION: The present study shows that the number of Moyamoya patients in Korea is increasing. This increase could partly be explained by a recent increase in newly diagnosed cases, suggesting that a more careful consideration of the disease and better diagnostic techniques should be promoted among clinicians.

Axial neck pain after cervical laminoplasty.

OBJECTIVE: It has been demonstrated that cervical laminoplasty is an effective and safe method of treating multi-level cervical spondylotic myelopathy and ossification of the posterior longitudinal ligament. However, recent reports have suggested that axial neck pain is frequently encountered after cervical laminoplasty. The aim of the present study was to determine clinical significance of the C7 spinous process on axial neck pain after cervical laminoplasty. METHODS: A total of 31 consecutive patients that underwent cervical laminoplasty between March 2002 and December 2008 were reviewed. The authors evaluated and compared axial neck pain and lordotic angle in patients that underwent C7 spinous process preserving surgery (group 1, n = 16) and in patients in which the C7 spinous process was sacrificed (group 2, n = 15). RESULTS: Severe or moderate early axial pain occurred in 56.2% of patients in group 1 and in 86.6% in group 2. Severe or moderate late axial pain occurred in 12.5% in group 1 and in 73.3% in group 2. Eighty-Six percent of patients in group 2 and 43% in group 1 experienced aggravation of their axial neck pain during the early postoperative period. Aggravation of axial neck pain during early postoperative period was less common in group 1 but not statistically significant (p = 0.073). Sixty-six percent of patients in group 2 and 12% in group 1 had aggravated axial neck pain at late postoperative period and aggravation of late axial neck pain was significantly less common in group 1 (p = 0.002). CONCLUSION: The present study demonstrates that C7 spinous process preserving laminoplasty decreases the incidence of aggravated axial neck pain after cervical laminoplasty.

Thalamic Deep Brain Stimulation for Writer's Cramp.

Writer's cramp is a type of idiopathic focal hand dystonia characterized by muscle cramps that accompany execution of the writing task specifically. There has been renewed interest in neurosurgical procedures for the treatment of dystonia over the past several years. In particular, deep brain stimulation (DBS) has received increasing attention as a therapeutic option for patients with dystonia. However, to date, limited reporters made investigations into DBS in relation to the Writer's cramp. In this case, unilateral Ventro-oralis complex (Vo) DBS resulted in a major improvement in patient's focal dystonic movement disorders. Her post-operative Burke-Fahn-Marsden Dystonia Rating (BFMDR) scale demonstrated 1 compared with pre-operative BFMDR scale 4. We conclude that thalamic Vo complex DBS may be an important neurosurgical therapeutic option for Writer's cramp.

Stereotactic Radiosurgery with the CyberKnife for Pituitary Adenomas.

OBJECTIVE: In recent years, CyberKnife has emerged as an important treatment modality in the management of pituitary adenomas. Treatment results after performing CyberKnife and the complications of this procedure are reviewed. METHODS: Twenty-six patients with pituitary adenomas received stereotactic radiosurgery with the CyberKnife (CKRS). The follow-up periods ranged from 7 months to 47 months (mean+/-SD : 30+/-12.7 months). The patients consisted of 17 with non-functioning adenomas, 3 with prolactinomas and 6 with acromegaly. The change in the tumor volume, visual acuity, hormonal function, and complications by this therapy were analyzed in each case. RESULTS: The tumor control rate was 92.3%. Hormonal function was improved in all of the 9 (100%) functioning adenomas. Hormonal normalization was observed in 4 of the 9 (44%) patients with a mean duration of 16 months. In two patients (7.6%), visual acuity worsened due to cystic enlargement of the tumor after CKRS. No other complications were observed. CONCLUSION: CyberKnife is considered safe and effective in selected patients with pituitary adenomas. However, longer follow-up is required for a more complete assessment of late toxicity and treatment efficacy.