Unyielding progress: recent advances in the treatment of central nervous system neoplasms with radiosurgery and radiation therapy

In the past decade, our understanding of the roles of external beam radiotherapy (EBRT) and stereotactic radiosurgery (SRS) in the management of brain tumors has dramatically improved. To highlight the changes and contemporary treatment approaches, we review the indications and outcomes of ionizing radiation for benign intracranial tumors and brain metastases. For nonfunctioning pituitary adenomas, SRS is able to achieve radiographic tumor control in at least 90 % of cases. The rate of SRS-induced endocrine remission for functioning pituitary adenomas depends on the tumor subtype, but it is generally lower than the rate of radiographic tumor control. The most common complications from pituitary adenoma SRS treatment are hypopituitarism and cranial neuropathies. SRS has become the preferred treatment modality for vestibular schwannomas and skull base meningiomas less than 3 cm in size. Large vestibular schwannomas and meningiomas remain best managed with initial surgical resection or EBRT for surgically ineligible patients. For small to moderately sized brain metastases, there has been a shift toward treatment of newly diagnosed patients with SRS alone due to similar local control rates compared with surgical resection. RCTs have shown combined SRS and whole brain radiation therapy (WBRT) for brain metastases to decrease rates of local and distant intracranial recurrence compared to SRS alone. However, the improved intracranial control comes at the expense of poorer neurocognitive outcomes and without prolonging overall survival. Therefore, WBRT is generally reserved for salvage therapy. While EBRT has been frequently supplanted by SRS for the treatment pituitary adenomas and brain metastases, it still proves useful in selected cases of large lesions which are not amenable to surgical debulking or for those with widespread disease, poor performance status, and short life expectancy. In recent years, the scope of SRS has extended beyond the intracranial space to include extradural and intradural spinal tumors.     

Stereotactic radiosurgery of benign intracranial tumors

Stereotactic radiosurgery is a frequently performed procedure for patients with benign intracranial tumors. Benign tumors are good candidates for radiosurgery because they are generally non-invasive, are well visualized by magnetic resonance imaging, and their slow rate of proliferation makes conventional radiation dose fractionation unnecessary. Stereotactic radiosurgery is now an important part of both neurosurgical and radiation oncology training. This chapter will review the indications and results of radiosurgery for patients with intracranial meningiomas, vestibular schwannomas, and pituitary adenomas having single-fraction radiosurgery at the Mayo Clinic since 1990.     

Radiosurgery of Benign Lesions

The use of stereotactic radiosurgery is increasing at an accelerated rate throughout the United States and the rest of the world. The greatest success for radiosurgery has been in the treatment of benign intracranial mass lesions and arteriovenous malformations (AVM) in particular. The majority of large radiosurgery series report that AVM obliteration rates exceed 74% and serious complication rates (permanent brain injury) exceed less than 5%. Radiosurgery is being investigated as a treatment for high-risk angiographically occult vascular malformations (cavernous angiomas) with a history of hemorrhages, but is contraindicated in asymptomatic patients. Radiosurgery has been successfully established as an alternative to surgical resection of vestibular schwannomas (acoustic neuromas). Long-term tumor control rates with radiosurgery are above 85%. Radiosurgery offers tumor control comparable to surgery with better preservation of hearing and facial nerve function. Radiosurgery has also been found to be equally effective in controlling nonacoustic schwannomas and meningiomas. Radiosurgery offers the potential of faster and higher response rates in treating functional pituitary adenomas than fractionated radiotherapy with a greater chance of preserving normal pituitary function. Long-term studies with 10 to 15-year follow-up are still needed to fully compare the efficacy of radiosurgery with other modern techniques for treating pituitary adenomas and meningiomas (such as cranial base microsurgery and fractionated large-field radiotherapy). Overall, radiosurgery is a relatively safe and effective alternative to surgical resection of small AVMs and most benign intracranial tumors.     

Trends in the incidence of primary intracranial tumors in Kumamoto, Japan

Background. The introduction of modern neuro-imaging techniques, as well as various environmental factors, have been changing the incidence and the proportions of the types of clinically diagnosed intracranial tumors. The aim of this study was to determine recent trends in the occurrence of primary intracranial tumors in the residents of Kumamoto Prefecture, Japan. Methods. We surveyed 2129 patients who were diagnosed with primary intracranial tumors between 1989 and 1998, with histological diagnosis being obtained in 71% of the patients. Results. Of the 2129 patients, 710 (33.3%) had meningiomas, 390 (18.3%) had pituitary adenomas, 315 (14.8%) had malignant gliomas, and 208 (9.8%) had schwannomas. The overall age-adjusted incidence rates were 10.97/100 000/year (males, 9.70; females, 11.86). One hundred and nine patients (5.1%) were younger than 15 years, and 480 patients (22.5%) were older than 70 years. The most common tumors in children were astrocytomas (37.6%), followed by germ-cell tumors (16.5%) and craniopharyngiomas (11.9%), medulloblastomas (11.0%), and ependymomas (4.6%). Meanwhile, the most common tumors in elderly residents were meningioma (51.7%), followed by malignant glioma (13.7%), pituitary adenoma (11.4%), schwannoma (7.7%), malignant lymphoma (4.6%), and astrocytoma (2.7%). The proportion of asymptomatic tumors increased, from 24.6% in 1989–1994 to 33.0% in 1995–1998; 169 (62.8%) were meningiomas, followed by pituitary adenomas (14.1%). Conclusion. The detection rate of asymptomatic intracranial tumors, particularly that of meningiomas, and the incidence of brain lymphoma are on the increase. Differences in the incidence of gliomas, pituitary adenomas, medulloblastomas, and germ-cell tumors between the Japanese population and populations in Western countries may be attributable to ethnic differences. Received: February 19, 2001 / Accepted: May 25, 2001     

A study on the radiation tolerance of the optic nerves and chiasm after stereotactic radiosurgery

PURPOSE: To evaluate the risk of clinically significant radiation optic neuropathy (RON) for patients having stereotactic radiosurgery of benign tumors adjacent to the optic apparatus. METHODS AND MATERIALS: We reviewed the dose plans and clinical outcomes of 218 gamma knife procedures (215 patients) for tumors of the sellar and parasellar region (meningiomas, n = 122; pituitary adenomas, n = 89; craniopharyngiomas, n = 7 patients). Previous surgery or radiation therapy was performed in 156 (66%) and 24 (11%) patients, respectively. Median follow-up was 40 months (range 4-115). RESULTS: The median maximum radiation dose to the optic nerve was 10 Gy (range 0.4-16.0). Four patients (1.9%) developed RON at a median of 48 months after radiosurgery. All had prior surgery, and 3 of 4 had external beam radiotherapy (EBRT) in their management either before (n = 2) or adjuvantly (n = 1). The risk of developing a clinically significant RON was 1.1% for patients receiving 12 Gy or less. Patients receiving prior or concurrent EBRT had a greater risk of developing RON after radiosurgery (p = 0.004). CONCLUSION: RON occurred in less than 2% of our patients, despite the majority (73%) receiving more than 8 Gy to a short segment of the optic apparatus. Knowledge of the dose tolerance of these structures permits physicians to be more aggressive in treating patients with sellar or parasellar tumors, especially those with hormone-producing pituitary adenomas that appear to require higher doses to achieve biochemical remission.     

Clinical uses of radiosurgery

Radiosurgery uses stereotactic targeting methods to precisely deliver highly focused, large doses of radiation to small intracranial tumors and arteriovenous malformations (AVMs). This article reviews the most common clinical applications of radiosurgery and the clinical results reported from a number of series using either a cobalt-60 gamma knife or linear accelerator as radiation sources. Radiosurgery is used to treat malignant tumors, such as selected cases of brain metastases and malignant gliomas (for which stereotactic radiosurgical boosts are utilized in conjunction with fractionated radiation therapy), as well as benign tumors, such as meningiomas, acoustic neuromas, and pituitary adenomas. Treatment of small AVMs is also highly effective. Although radiosurgery has the potential to produce complications, the majority of patients experience clinical improvement with less morbidity than occurs with surgical resection.     

Visual outcome after fractionated stereotactic radiation therapy of benign anterior skull base tumors

To determine visual outcome including the occurrence of radiation induced optic neuropathy (RION) as well as tumor control after fractionated stereotactic radiation therapy (FSRT) of benign anterior skull base meningiomas or pituitary adenomas. Thirty-nine patients treated with FSRT for anterior skull base meningiomas and 55 patients treated with FSRT for pituitary adenomas between January 1999 and December 2009 with at least 2 years follow-up were included. Patients were followed up prospectively with magnetic resonance imaging scans, visual acuity and visual field examinations. RION was found in four (10 %) patients with anterior skull base meningiomas and seven patients (13 %) with pituitary adenomas. The five-year actuarial freedom from 25 % RION visual field loss was 94 % following FSRT. Actuarial 2-, 5- and 10-year tumor control rates were 100, 88.4 and 64.5 % for anterior skull base meningiomas and 100, 98.2 and 94.9 % for pituitary adenomas, respectively. Patients with an impaired visual field function pre-FSRT were more likely to experience worsened function (p = 0.016). We found that RION, was a relatively uncommon event, in a large prospective cohort of patients that were systematically monitored following FSRT of benign anterior skull base tumors. Long term tumor control was favorable, especially for pituitary adenomas.     

Chemotherapy,hormonal therapy,and immunotherapy for recurrent meningiomas

Meningioma is a common intracranial tumor, originating from the meninges of the skull or spinal canal. Most meningiomas are benign tumors, however atypical or anaplastic tumors can be found in 6% of cases. Patients with asymptomatic small benign meningiomas can be followed without therapy, but in symptomatic patients complete surgical resection should be performed. For recurrent previously resected tumors re-resection is recommended followed by radiotherapy in selected cases. Antiprogesterone treatment can also be considered in recurrent benign meningiomas. Immunotherapy with interferon-alpha and chemotherapy should be reserved for all cases of recurrent meningiomas (benign, atypical, and malignant) when all the standard therapies have failed or contraindicated.     

Stereotactic radiosurgery for benign neoplasms

Over the last decade, the use of stereotactic radiosurgery (SRS) for the treatment of intracranial lesions has grown significantly. In addition to malignant brain tumors and vascular malformations, benign tumors have also been treated with SRS. Although surgical resection has long been considered the gold standard in the management of such benign lesions, the outcomes of SRS in various benign neoplasms appears to be comparable. In this review, we will examine the literature as it pertains to the treatment of benign brain tumors with SRS. Of particular note, we will examine the results of SRS in acoustic neuromas, meningiomas, pituitary adenomas, and other benign tumors.     

脑膜瘤的放射治疗

脑膜瘤是常见的颅内肿瘤之一,主要的治疗方法为手术治疗。近30年来大量文献证明放射治疗已成为脑膜瘤治疗的重要方法之一。良性脑膜瘤次全切除术后,不典型增生型及恶性脑膜瘤术后均需辅助放疗。脑膜瘤术后复发可再行放射治疗。对于特殊部位的脑膜瘤可首选放疗。本文将略述有关脑膜瘤放射治疗的资料,并对近年来脑膜瘤放射治疗的进展进行综述。     

Pathological analysis of 1458 cases of tumor in the sella turcica region

The sella turcica region is an anatomical site preferential for various types of intracranial tumors. Pathological analysis of 1458 cases of tumor in this region is presented. They comprised 20.16% of the intracranial tumors. Among them, 846(59.1%) were pituitary adenomas, 433(29.7%) craniopharyngiomas, 91(6.2%) meningiomas and 42(2.9%) germinomas. In pituitary adenomas, chromophobe adenoma was predominant, mixed cell adenoma next and no basophilic adenoma was observed. Of craniopharyngiomas they were divided into cystic, partly solid and cystic, and calcified types grossly and histologically into adamantinomatous, squamous and calcified types. In this kind of tumor, well differentiated cells were consistent to the clinical benign course. For meningiomas, histologically meningotheliomatous type was most common in this region. In previous reports, germinomas in the sella turcica region were so-called ectopic pinealoma. Now it is well known that this tumor arises from germ cells, hence, the synonym "ectopic pinealoma" is obsolete. The germinomas in the sella turcica region accounted for 44.68% of all intracranial germinomas. Microscopic picture of this tumor was similar to those of seminoma of the testicle and dysgerminoma of the ovary. Although gliomas, teratomas, giant cell tumors and chondromas were uncommon in the sella turcica region, the authors believe that they should be considered in the differential diagnosis of tumors in the sella turcica region.     

侵袭性在垂体腺瘤术后残留再生长与复发中的评价及临床现状

垂体腺瘤是颅内肿瘤中较常见的一种,约占颅内肿瘤的10%。垂体腺瘤虽然为良性肿瘤,但由于肿瘤侵袭性生长特性、设备条件和手术者技术有限等因素影响,使得肿瘤镜下全切和复发问题仍然较突出,复发垂体腺瘤比例逐年升高,治疗难度也随之增大。本文旨在总结本中心的侵袭性或复发性垂体腺瘤的病例资料,对复发性垂体腺瘤的诊治,包括再次经蝶手术适应证、手术技巧以及术后并发症的预防和处理等进行述评,为临床医师提供参考。     

Neurotoxicity of Radiosurgery

Radiosurgery is a technique to deliver (in most cases) a single fraction of ionizing radiation, usually in the range of 10 to 25 Gy, to a precisely localized intracranial volume of pathological tissue. The radiobiological principles that govern the practice of single-fraction radiosurgery differ from those of conventional fractionated external beam radiation therapy. Rather, the results are primarily a consequence of either vascular effects or antiproliferative effects. The neurotoxicity of radiosurgery can be described according to its time course (immediate, acute, or chronic) and severity (mild, moderate, severe, life-threatening, or fatal( based on existing definitions established by the Radiation Therapy Oncology Group. Current indications for radiosurgery include arteriovenous malformations, acoustic neuromas, brain metastases, high-grade and other gliomas, meningiomas, and pituitary adenomas. The efficacy of radiosurgery and the time course and severity of radiosurgical neurotoxicity are dependent both on the nature of the lesion being treated and the normal tissue milieu which the lesion resides. This article describes the spectrum of neurotoxicity reported in the medical literature pertaining to the current variety of space-occupying lesions, benign tumors, and malignant neoplasms for which radiosurgery currently is being used.     

Comparison of 68Ga-DOTATOC-PET/CT and PET/MRI hybrid systems in patients with cranial meningioma: Initial results

Background⁶⁸Ga-DOTATOC-PET/CT is a well-established method for detecting and targeting the volume definition of meningiomas prior to radiotherapy. Moreover, there is evidence that this method is able to detect meningiomas with higher sensitivity than the goldstandard MRI. Since the hybrid PET/MRI scanner became available in the past few years, the next stage of development could consequently evolve by evaluating the feasibility of a hybrid PET/MRI scanner using ⁶⁸Ga-DOTATOC for detecting meningiomas.MethodsFifteen patients received ⁶⁸Ga-DOTATOC-PET/CT (0.5 h post injection [p.i.]) followed by PET/MRI 2 hours p.i. Both investigations were analyzed separately and then compared with respect to image quality, detection of intracranial meningiomas, and radiotracer uptake values (RUVs). In addition, ratios between radiotracer uptake in meningiomas and pituitary glands were compared between both PET/CT and PET/MRI.ResultsOverall, 33 intracranial meningiomas were detected. All were visible with high contrast in both PET/CT and PET/MRI. ⁶⁸Ga-DOTATOC-PET/MRI provided flawless image quality without artefacts. Calculated RUV in meningiomas, as well as the ratios of RUVs in meningiomas to those of pituitary glands, were higher in PET/CT. As a result, meningiomas can be distinguished from pituitary glands better in early images.Conclusions⁶⁸Ga-DOTATOC-PET/MRI provided flawless image quality and presented an ideal combination of high sensitivity/specificity (PET) and the best possible morphological visualization of meningiomas (MRI). In addition, excellent detection of meningiomas is already possible at 0.5 hours p.i. Later images do not improve the distinction between pituitary gland and adjacent meningiomas. However, RUVs need to be carefully compared between both imaging modalities.     

Incidental uptake of 18F-fluorocholine (FCH) in the head or in the neck of patients with prostate cancer

Background

Positron emission tomography-computed tomography (PET/CT) with ¹⁸F-fluorocholine (FCH) is routinely performed in patients with prostate cancer. In this clinical context, foci of FCH uptake in the head or in the neck were considered as incidentalomas, except for those suggestive of multiple bone metastases.

Results

In 8 patients the incidental focus corresponded to a benign tumour. The standard of truth was histology in two cases, correlative imaging with MRI in four cases, ^99mTc-SestaMIBI scintigraphy, ultrasonography and biochemistry in one case and biochemistry including PTH assay in one case. The final diagnosis of benign tumours consisted in 3 pituitary adenomas, 2 meningiomas, 2 hyperfunctioning parathyroid glands and 1 thyroid adenoma.Malignancy was proven histologically in 2 other patients: 1 papillary carcinoma of the thyroid and 1 cerebellar metastasis.

Conclusions

To the best of our knowledge, FCH uptake by pituitary adenomas or hyperfunctioning parathyroid glands has never been described previously. We thus discuss whether there might be a future indication for FCH PET/CT when one such tumour is already known or suspected: to detect a residual or recurrent pituitary adenoma after surgery, to guide surgery or radiotherapy of a meningioma or to localise a hyperfunctioning parathyroid gland. In these potential indications, comparative studies with reference PET tracers or with ^99mTc-sestaMIBI in case of hyperparathyroidism could be undertaken.     

Radiothérapie en conditions stéréotaxiques des tumeurs bénignes intracrâniennes

Stereotactic radiotherapy can be delivered in one fraction or in multiple fractions schedule. It is used in benign tumours such as meningiomas, mainly localized in the base of the skull, for acoustic schwannoma and pituitary tumours. Whatever the tumour, results with the Gamma Knife^® are the most numerous, but those obtained by linear accelerators, adapted or dedicated, are comparable. The peripheral dose is preferred to the dose delivered to the isocentre. One fraction stereotactic irradiation should be proposed in small lesions and fractionated treatment for tumours larger. Whatever the tumour, the results are satisfactory with a control rate of 90%. However, this value reflects a disparity assessment, radiological stability for meningiomas, radiological stability and preservation of useful hearing in schwannoma and radiological stability and a decrease in hormonal secretions for pituitary adenomas. Overall complication rates are low. In total, the treatment of benign lesions with stereotactic irradiation gives satisfactory results with few complications.     

The CyberKnife®

Stereotactic radiosurgery has emerged as an accepted treatment for many types of intracranial tumors. Based on the understanding of the limitations of prior radiosurgical systems, image-guided robotic radiosurgery was developed to overcome many of these restrictions. The CyberKnife® is a commercially available frameless image-guided radiosurgical system that provides state-of-the-art radiosurgery for intracranial tumors, and has also revolutionized the use of radiosurgery to treat tumors in other parts of the body. This review focuses on the current use of the CyberKnife® to treat cranial and spinal tumors. Brain metastases have long been treated with other radiosurgical systems, but the CyberKnife® allows patients with brain metastases to be treated multiple times as successive tumors are discovered, without the repetitive placement of a stereotactic head frame. Benign tumors such as acoustic neuromas, pituitary tumors, and meningiomas are also easily treated with the CyberKnife®, with radiographic tumor-control rates of >90% for pituitary tumors and 95% for acoustic neuromas and meningiomas. A subset of meningiomas and pituitary tumors surround the optic nerves and are considered to be perioptic tumors. Historically, these tumors have not been treatable with radiosurgery because of the risk of visual loss. The frameless nature of the CyberKnife® allows the radiosurgery treatment to be delivered in separate stages (typically 24 hours apart); this has been shown to significantly reduce the risk of visual loss, and thus allows effective radiosurgery treatment to be delivered. Staged radiosurgery treatment has also been used at our institution to treat acoustic neuromas, with the understanding that several stages of radiation delivery may be associated with a higher level of hearing preservation than a single-staged radiosurgery treatment. Malignant gliomas and nasopharyngeal carcinoma tumors have historically been treated with conventional radiotherapy techniques. However, we have learnt that supplementing these radiotherapy treatments with a CyberKnife® stereotactic boost after radiotherapy can improve response rates to treatment. Spinal radiosurgery is a novel development; prior frame-based radiosurgery devices did not allow treatment of lesions outside the brain and neck. We have observed high rates of tumor control when treating benign spinal tumors with the CyberKnife®, and have noted excellent pain relief and tumor-control rates in patients with spinal metastases. Future CyberKnife® stereotactic applications will focus on the continual expansion of this technology to treat tumors outside the CNS, including cancers of the lung, pancreas, liver, and prostate.     

质子放射治疗颅内肿瘤66例近期疗效分析

背景与目的:颅内肿瘤的放射治疗大多是手术后的辅助治疗,高能质子束有尾部剂量快速降落现象,其物理特性和生物特性均优于光子,颅内肿瘤是质子放射治疗的最佳适应证之一,特别是对部分颅底肿瘤的疗效优于开颅手术,而无手术的风险和并发症。本文通过观察质子放射治疗颅内肿瘤的近期疗效,总结和探讨质子放射治疗颅内肿瘤的剂量、分割方法和疗效。方法:2004年12月至2006年10月,共收治各类脑瘤66例,其中胶质瘤46例,脑膜瘤5例,脊索瘤8例,其他良恶性肿瘤7例。恶性肿瘤总剂量为54～70CGE,单次剂量1.8～3CGE;良性肿瘤总剂量为45～72CGE,单次剂量1.8～5CGE。疗效判断标准为:显效、有效、无效三组。观察时间胶质瘤为9.8个月(1~20个月),良性肿瘤10.5个月(3~22个月)。结果:质子放射治疗66例的总有效率90.9%。胶质瘤显效13例,占27.1%,有效29例,占60.4%,其他恶性肿瘤1例显效,1例死亡。48例恶性肿瘤总有效率89.6%。良性肿瘤显效5例,占27.8%,有效12例,占66.7%,18例良性肿瘤总有效率94.4%。结论:质子因其优越的物理特性,适用于所有需放射治疗的患者,特别是对放疗后复...     

Statin immunolocalization in human brain tumors. Detection of noncycling cells using a novel marker of cell quiescence.

Surgical specimens of 35 human brain tumors were examined with a novel monoclonal antibody, S-44, immunoreactive to statin, a nuclear protein specifically expressed in quiescent (noncycling) G0-phase cells. Benign tumors typically were statin positive with labeling indices (LI) between 22% and 96%: acoustic schwannomas (n = 3, mean = 29.9 +/- 19.4%); meningiomas (n = 4, mean = 59.0 +/- 15.1%); pituitary adenomas (n = 3, mean = 79.9 +/- 28.2%), and an epidermoid cyst (41.0%). By contrast, the statin LI of 18 of 24 (75%) malignant brain tumors was less than or equal to 2%: medulloblastomas (n = 7, mean = 0.3 +/- 0.2%); anaplastic astrocytomas (n = 3, mean = 1.6 +/- 2.7%); glioblastomas (n = 10, mean = 10.3 +/- 14.4%); metastatic carcinomas (n = 3, mean = 3.0 +/- 4.6); and a germinoma (0.2%). The vascular endothelium among diverse tumors typically was statin positive. All 21 tumors with a statin LI less than 10% were malignant, and all nine tumors with a statin LI greater than 40% were benign. The statin LI of benign tumors (n = 11, mean = 55.1 +/- 26.7%) was significantly higher than that of the malignant tumors (n = 24, mean = 5.2 +/- 10.5%, P less than 0.001). The absence of statin expression is a new way to determine the malignancy of human brain tumors. The statin LI may be useful to guide the prognosis and treatment of individual patients. The mechanisms that control statin expression are important in therapy seeking to shift the proliferating, cycling cells to the quiescent, G0 compartment.     

Effets tardifs de la radiothérapie externe sur la glande thyroïde

The thyroid is the purest endocrine gland in the body and is likely to produce clinically significant abnormalities after external radiotherapy. Functional clinical modifications after direct irradiation exceeding 30 Gy are essentially related to hypothyroidism which may be clinically overt or subclinical with normal serum free thyroxine levels and high thyrotropin concentrations; the risk of hyperthyroidism, silent thyroiditis and Hashimoto's disease is also increased. Secondary hypothyroidism related to irradiation of the hypothalamus and the pituitary gland may arise with doses over 40–50 Gy following treatment for brain and nasopharyngeal tumors — Morphological glandular modifications induced by radiotherapy are responsible for the appearance of benign adenomas, more rarely cystic degenerations and specially well differentiated papillary or follicular carcinomas among children and adults. After irradiation during childhood for benign or malignant tumors, thyroid cancers are more frequent, higher for younger children, and the relative excess risk is increased from 15.6-to 53-fold; tumors can belatedly occur, more than 35 years after initial therapy. Thereby, in order to limit excess morbidity, it is evident that long term supervision with careful clinical and biological evaluations is necessary for patients who previously received neck, upper mediastinum and pituitary radiation therapy.