Gamma Knife Radiosurgery in Recurrent Glioblastoma.

BACKGROUND: We evaluated Gamma Knife radiosurgery (GKRS) as a treatment option for patients with recurrent glioblastoma. PATIENTS AND METHODS: 42 patients with histopathologically diagnosed recurrent grade IV tumor were treated with GKRS. All patients had undergone standard multimodal first-line treatment. The average time from diagnosis to GKRS was 17.0 months. The median target volume was 5.1 cm3. The median margin dose was 10 Gy and the median central dose 20 Gy. In a subset of patients, O6-methylguanine methyltransferase (MGMT) promoter methylation analysis by pyrosequencing was performed. RESULTS: Most patients did not develop complications after GKRS. Time to radiological progression after initial GKRS was 4.4 months (95% CI: 3.1-5.7 months). Radiological progression mainly occurred beyond the GKRS-irradiated area. The median survival time after initial GKRS was 9.6 months (95% CI: 7.7-11.5 months). The median overall survival time from diagnosis was 25.6 months (95% CI: 21.8-29.3 months). Patients with MGMT promoter methylation survived significantly longer (33.4 months; 95% CI: 21.2-45.5 months) compared to patients without MGMT promoter methylation (16.0 months; 95% CI: 8.0-23.9 months). CONCLUSION: GKRS seems to be a relatively safe salvage treatment option for recurrent glioblastoma for highly selected patients but must be seen as part of a multimodal treatment algorithm.

Multimodality Management of Cerebral Arteriovenous Malformations with Special Reference to AVM-Related Hemorrhages During Ongoing Staged Treatment.

In this study we report and analyze the results of a multimodality management concept for intracranial arteriovenous malformations (AVMs), including microsurgery, embolization, and gamma knife radiosurgery. The study population consists of a consecutive series of 294 patients treated for 304 intracranial AVMs over a 10-year period.

Radiosurgery as a Stand-Alone Treatment Option for Cerebral Dural Arteriovenous Fistulas: the Vienna Series.

BACKGROUND: Gamma Knife radiosurgery (GKRS) has been demonstrated to be an effective and safe treatment method for dural arteriovenous fistulas (DAVFs). However, only few studies, mostly with limited patient numbers, have evaluated radiosurgery as a sole and upfront treatment option for DAVFs. METHODS: Thirty-three DAVF patients treated with GKRS as a stand-alone management at our institution between January 1992 and January 2020 were included in this study. Obliteration rates, time to obliteration, neurologic outcome, and complications were evaluated retrospectively. RESULTS: Complete overall obliteration was achieved in 20/28 (71%) patients. The postradiosurgery actuarial rates of obliteration at 2, 5, and 10 years were 53, 71, and 85%, respectively. No difference in time to obliteration between carotid-cavernous fistulas (CCFs; 14/28, 50%, 17 months; 95% confidence interval [CI]: 7.4-27.2) and non-CCFs (NCCFs; 14/28, 50%, 37 months; 95% CI: 34.7-38.5; p = 0.111) were found. Overall, the neurologic outcome in our series was highly favorable at the time of the last follow-up. A complete resolution of symptoms was seen in two-thirds (20/30, 67%) of patients. One patient with multiple DAVFs suffered from an intracranial hemorrhage of the untreated lesion and died during the follow-up period, resulting in a yearly bleeding risk of 0.5%. No complications after radiosurgery were observed in our series. CONCLUSION: Our results show that GKRS is a safe and effective stand-alone management option for selected DAVF patients.

Extracerebral metastases determine the outcome of patients with brain metastases from renal cell carcinoma.

BACKGROUND: In the era of cytokines, patients with brain metastases (BM) from renal cell carcinoma had a significantly shorter survival than patients without. Targeted agents (TA) have improved the outcome of patients with metastatic renal cell carcinoma (mRCC) however, their impact on patients with BM is less clear. The aim of this analysis was to compare the outcome of patients with and without BM in the era of targeted agents. METHODS: Data from 114 consecutive patients who had access to targeted agent were analyzed for response rates (ORR), progression free survival (PFS) and overall survival (OS). All patients diagnosed with BM underwent local, BM-specific treatment before initiation of medical treatment. RESULTS: Data of 114 consecutive patients who had access to at least one type of targeted agents were analyzed. Twelve out of 114 renal cell carcinoma (RCC) patients (10.5%) were diagnosed with BM. Systemic treatment consisted of sunitinib, sorafenib, temsirolimus or bevacizumab. The median PFS was 8.7 months (95% CI 5.1 - 12.3) and 11.4 months (95% CI 8.7 - 14.1) for BM-patients and non-BM-patients, respectively (p = 0.232). The median overall survival for patients with and without BM was 13.4 (95% CI 1- 43.9) and 33.3 months (95% CI 18.6 - 47.0) (p = 0.358), respectively. No patient died from cerebral disease progression. ECOG Performance status and the time from primary tumor to metastases (TDM) were independent risk factors for short survival (HR 2.74, p = 0.001; HR: 0.552, p = 0.034). CONCLUSIONS: Although extracerebral metastases determine the outcome of patients with BM, the benefit from targeted agents still appears to be limited when compared to patients without BM.

Multimodality treatment of cerebral AVMs in children: a single-centre 20 years experience.

PURPOSE: The purpose of this study was to review our experience with a multimodality treatment approach in the management of cerebral arteriovenous malformation (AVM) in children. METHODS: We retrospectively analysed a consecutive series of 56 children who harboured a cerebral AVM and were treated at our institution between 1988 and 2008. During the whole treatment period, a combined treatment strategy, including microsurgery, endovascular treatment and gamma knife radiosurgery, was used. RESULTS: Of the 56 patients (median age, 14.0; range, 3 months-18 years) reported, 36 (64.3%) were admitted after AVM rupture; of these, only one AVM (1.8%) was considered untreatable. In 30.9% (17/55) of the treated patients, a single treatment measure was sufficient to attain angiographic cure of the AVM. Among these, six patients (10.9%) had microsurgical AVM resection, four patients (7.3%) underwent endovascular treatment, and another seven patients (12.7%) underwent radiosurgical management of the AVM. The majority of the population (38/55; 69.1%) underwent combined treatment: 21 patients (38.2%) received embolisation followed by radiosurgery of the remnant nidus, ten patients (18.2%) underwent embolisation with subsequent surgical resection of the residual AVM, three patients (5.5%) had radiosurgery after incomplete surgical AVM nidus resection and another four patients (7.3%) required a combination of all three treatment modalities to achieve permanent angiographic cure of the AVM. We observed good clinical outcomes (Glasgow Outcome Scale 5 and 4) in 94.6% of the children. Complete angiographic obliteration was achieved in 93.3% of the patients treated. CONCLUSION: A multimodality treatment approach in children harbouring cerebral AVMs leads to excellent angiographic and clinical outcomes.

Evaluation of the radiosurgical treatment of cerebral arteriovenous malformations: a retrospective single-center analysis of three decades.

BACKGROUND: Gamma Knife radiosurgery (GKRS) in the treatment of arteriovenous malformations (AVMs) is still controversially discussed. OBJECTIVE: To present long-term follow-up data on patients after Gamma Knife radiosurgery for cerebral AVMs. METHODS: Overall, 516 patients received radiosurgery for cerebral AVMs between 1992 and 2018 at our department, of whom 265 received radiosurgery alone and 207 were treated with a combined endovascular-radiosurgical approach. Moreover, 45 patients were treated with a volume-staged approach. Two eras were analyzed, the pre-modern era between 1992 and 2002 and the modern era thereafter. RESULTS: In GKRS-only treated patients, median time to nidus occlusion was 3.8 years. Spetzler-Ponce (SP) class was a significant predictor for time to obliteration in the whole sample. Median time to obliteration for the combined treatment group was 6.5 years. Patients in the pre-modern era had a significantly higher obliteration rate than those treated in the modern era. Overall, the calculated yearly hemorrhage risk in the observation period after first GKRS was 1.3%. Permanent post-radiosurgical complications occurred in 4.9% of cases but did not differ between the treatment groups or treatment eras. The obliteration rate was significantly lower and the hemorrhage rate was higher in volume-staged treated patients than in conventionally treated patients. CONCLUSION: GKRS is an effective treatment option for SP class A and B cerebral AVMs. After combined endovascular-radiosurgical treatment, the outcome of selected SP class C AVMs aligns with that of SP class B lesions. Both the combined therapy and radiosurgery alone constitute sound methods for treatment of cerebral AVMs.

Long-term outcome after Gamma Knife radiosurgery for acoustic neuroma of all Koos grades: a single-center study.

OBJECTIVE The authors present long-term follow-up data on patients treated with Gamma Knife radiosurgery (GKRS) for acoustic neuroma. METHODS Six hundred eighteen patients were radiosurgically treated for acoustic neuroma between 1992 and 2016 at the Department of Neurosurgery, Medical University Vienna. Patients with neurofibromatosis and patients treated too recently to attain 1 year of follow-up were excluded from this retrospective study. Thus, data on 557 patients with spontaneous acoustic neuroma of any Koos grade are presented, as are long-term follow-up data on 426 patients with a minimum follow-up of 2 years. Patients were assessed according to the Gardner-Robertson (GR) hearing scale and the House-Brackmann facial nerve function scale, both prior to GKRS and at the times of follow-up. RESULTS Four hundred fifty-two patients (81%) were treated with radiosurgery alone and 105 patients (19%) with combined microsurgery-radiosurgery. While the combined treatment was especially favored before 2002, the percentage of cases treated with radiosurgery alone has significantly increased since then. The overall complication rate after GKRS was low and has declined significantly in the last decade. The risk of developing hydrocephalus after GKRS increased with tumor size. One case (0.2%) of malignant transformation after GKRS was diagnosed. Radiological tumor control rates of 92%, 91%, and 91% at 5, 10, and 15 years after GKRS, regardless of the Koos grade or pretreatment, were observed. The overall tumor control rate without the need for additional treatment was even higher at 98%. At the last follow-up, functional hearing was preserved in 55% of patients who had been classified with GR hearing class I or II prior to GKRS. Hearing preservation rates of 53%, 34%, and 34% at 5, 10, and 15 years after GKRS were observed. The multivariate regression model revealed that the GR hearing class prior to GKRS and the median dose to the cochlea were independent predictors of the GR class at follow-up. CONCLUSIONS In small to medium-sized spontaneous acoustic neuromas, radiosurgery should be recognized as the primary treatment at an early stage. Although minimizing the cochlear dose seems beneficial for hearing preservation, the authors, like others before, do not recommend undertreating intracanalicular tumors in favor of low cochlear doses. For larger acoustic neuromas, radiosurgery remains a reliable management option with tumor control rates similar to those for smaller acoustic neuromas; however, careful patient selection and counseling are recommended given the higher risk of side effects. Microsurgery must be considered in acoustic neuromas with significant brainstem compression or hydrocephalus.

Multimodal treatment of parasagittal meningiomas: a single-center experience.

OBJECTIVE Treatment of parasagittal meningiomas is still considered a challenge in modern microsurgery. The use of microsurgical resection, radiosurgery, or a microsurgery-radiosurgery combination treatment strategy is often debated. The aim of this study was to evaluate the treatment of parasagittal meningioma and provide evidence that a multimodal approach reduces complication rates and achieves good tumor control rates. METHODS The authors retrospectively reviewed long-term follow-up data on 117 patients who had been treated for parasagittal meningiomas at their institution between 1993 and 2013. Treatment included microsurgery, Gamma Knife radiosurgery (GKRS), and radiotherapy. RESULTS The median tumor volume prior to the first microsurgical resection was largest in the microsurgery-radiosurgery combination treatment group. Invasion of the superior sagittal sinus was significantly associated with a Simpson Grade IV resection and subsequent radiosurgery treatment. The Simpson resection grade did not influence time to progression or recurrence in benign meningioma cases. Complete sinus occlusion was followed by microsurgical resection of the occluded sinus, by tumor resection without resection of the sinus, or by GKRS. Histopathology revealed WHO Grade I tumors in most patients. However, a high percentage (33%) of atypical or malignant meningiomas were diagnosed after the last microsurgical resection. The time to recurrence or progression after microsurgery was significantly longer in patients with WHO Grade I meningiomas than in those with Grade II or III meningiomas. At follow-up, tumor control rates after GKRS were 91% for presumed meningioma, 85% for benign meningioma, 71% for atypical meningioma, and 38% for malignant meningioma. CONCLUSIONS A multimodal treatment approach to parasagittal meningiomas reduces the rate of complications. Thus, microsurgery, radiotherapy, and radiosurgery are complementary treatment options. Gamma Knife radiosurgery is safe and effective in patients with meningiomas invading the superior sagittal sinus. The procedure can be part of a multimodal treatment plan or administered as a single treatment in well-selected patients.

Intensified local treatment and systemic therapy significantly increase survival in patients with brain metastases from advanced breast cancer - a retrospective analysis.

BACKGROUND: Brain metastases have evolved from a rare to a frequently encountered event in advanced breast cancer due to advances in palliative systemic treatment. PATIENTS AND METHODS: All Patients treated at our centre from 1994 to 2004 with WBRT for brain metastases from breast cancer were included. We performed a multivariate analysis (Cox regression) to explore which factors are able to influence significantly cerebral time to progression (TTP) and overall survival (metastatic sites [visceral versus non-visceral], Karnofsky performance score [KPS], age, intensified local treatment [boost irradiation, neuro-surgical resection] further systemic treatment). RESULTS: Overall 174 patients, median age 51 years, range 27-76 years, were included. Median TTP was 3 months (m), range 1-33+ m. Median overall survival was 7 m, range 1-44 m. Factors significantly influencing TTP were KPS (p = 0.002), intensified local treatment (p < 0.001), and palliative systemic treatment (p = 0.001). Factors significantly influencing survival were intensified local treatment (p = 0.004), metastatic sites (p = 0.008), KPS (p = 0.006), and palliative systemic treatment (p < 0.001). CONCLUSION: As shown by the significant influence of metastatic sites, some patients die from their advanced systemic tumour situation before they would die from cerebral progression. In other individuals however, intensified local treatment and systemic treatment appear to influence cerebral time to progression and overall survival.

Evaluation of Dose-Staged Gamma Knife Radiosurgical Treatment Method for High-Risk Brain Metastases.

OBJECTIVES: The study aim was to evaluate the utility of 2-fraction, dose-staged Gamma Knife radiosurgery (GKRS) in patients with large, high-risk brain metastases (BMs). METHODS: A total of 63 large BMs in eloquent areas in 61 patients were treated with GKRS in 2 reduced doses. Treatment planning was conducted on the 50% isodose line and included the whole tumor volume as seen on T1 contrast-enhanced and T2-weighted magnetic resonance imaging sections. The median margin and central dose were 12 Gy and 24 Gy, respectively, for both fractions. Patients were assessed using the Graded Prognostic Assessment, Recursive Partitioning Analysis, and Score Index for Radiosurgery. RESULTS: Thirty-two patients (53%) had been diagnosed with multiple BMs, and extracranial metastases were present in a majority of patients before GKRS treatment. Significant decreases in tumor volume were observed between the first and second treatment stages. At 3-month follow-up, a majority of patients presented with stable or decreased lesion volumes. The remaining patients showed intralesional hemorrhaging or increasing edema that was managed conservatively. Three patients were diagnosed with tumor progression at the last follow-up and received microsurgical treatment. The median time to radiologic progression was 7 months. The median survival time after initial BM diagnosis was 6 months. Survival times were significantly longer than 3 of 4 calculated prognostic survival estimates. CONCLUSION: The new 2-fraction, dose-staged GKRS concept seems to be a well-tolerated and effective treatment option for large BMs. This method may be indicated in elderly patients or patients with surgical contraindications with large or high-risk brain metastases.

Topoisomerase II alpha as a reliable proliferation marker in meningiomas.

The value of DNA Topoisomerase IIalpha expression as a proliferation marker in meningiomas was investigated. The correlation to MIB-1 expression and tumor grade in 85 meningiomas (60 classical, 19 atypical and 6 anaplastic) was analysed by immunohistochemistry. MIB-1 labeling indices (LI) were 1.1% (+/- 0.85) for classical meningiomas, 1.9% (+/- 1.5) for atypical meningiomas and 5.6% (+/- 4.1) for anaplastic meningiomas, differences statistically significant (p = 0.03, < 0.0001, < 0.0001). Topoisomerase IIalpha LIs were 1.4% (+/- 1.2) for classical, 3.2% (+/- 2.4) for atypical and 9.7% (+/- 6.6) for anaplastic meningiomas, differences statistically significant (p = 0.003, < 0.0001, < 0.0001). Proliferation indices based on cells staining for MIB-1 and Topoisomerase IIalpha correlated highly with one another (r= 0.906, p <0.0001). Topoisomerase IIalpha exhibited a more distinct, less variable nuclear staining pattern compared to MIB-1 expression. DNA Topoisomerase IIalpha LI represents a reliable alternative to MIB-1 as a proliferation marker in human meningiomas, especially for computer assisted assessment, where a distinct uniform staining pattern is required.

High diagnostic accuracy of cytologic smears of central nervous system tumors. A 15-year experience based on 4,172 patients.

OBJECTIVE: To investigate the diagnostic accuracy and current role of intraoperative cytologic smears of central nervous system tumors. STUDY DESIGN: Retrospective analysis of 4,172 patients operated on during 1985-1999, with 3,541 intraoperative smears performed during open procedures and 631 during stereotactic biopsies. RESULTS: Complete correlation with the final diagnosis was achieved in a mean of 89.8% (range, 83-93.7% per year). Diagnostic accuracy increased to 95% on average (range, 91.5-96.7% per year) when cases of partial correlation, mainly due to grading deviations, were included. The most accurate intraoperative diagnoses were obtained in cases of meningioma (97.9%), metastasis (96.3%) and glioblastoma (95.7%). A significant reduction in diagnostic accuracy was observed in cases of oligodendroglioma (80.9%) and ependymoma (77.7%). Besides diagnosis and grading, smear cytology provided resection guidance in cases of well-delineated tumors. CONCLUSION: Intraoperative smears in neurosurgery are easy to obtain and inexpensive and have high diagnostic accuracy. In addition to stereotactic biopsy procedures, intraoperative smears permit reliable intraoperative guidance during lesion targeting and resection.

Microsurgery and radiosurgery for brainstem cavernomas: effective and complementary treatment options.

OBJECTIVE: To evaluate treatment options for brainstem cavernous malformations (BSCMs) using the results from a center with long-standing experience in microsurgical resection and Gamma Knife radiosurgery (GKRS) treatment of BSCMs. METHODS: Study participants were 67 symptomatic patients with BSCMs who were treated either microsurgically (n = 29) or radiosurgically (n = 38). Patients were followed for a minimum of 2 years (median, 7.7 years). A recent follow-up was performed. RESULTS: Patients receiving surgical treatment had mainly large, superficially seated lesions and experienced preoperative hemorrhages more often and presented with higher preoperative modified Rankin Scale scores. Patients receiving GKRS harbored smaller, deep-seated lesions, reflecting a selection bias. In both treatment groups, patients presented with significantly better modified Rankin Scale scores at follow-up than before intervention. Overall annual preoperative hemorrhage rates were 3.2% in microsurgery patients and 2.3% in radiosurgery patients. In the preoperative observation period, the rehemorrhage rate was 25.1% for microsurgery patients and 7.2% for radiosurgery patients. Hemorrhage rate after GKRS decreased significantly to 0.6% after 2 years. The postoperative hemorrhage rate was 8.8% but only for microsurgery patients with residual lesions. Advancements in microsurgical techniques improved surgical outcomes, resulting in a high total excision rate in the modern era. CONCLUSIONS: In the treatment of BSCM, patient selection and timing of surgery are crucial. If applied in a multidisciplinary neurosurgical center, microsurgery and radiosurgery are complementary treatment options that both result in reduced bleeding rates and improvement of clinical outcome.

Susceptibility-weighted imaging at 7 T: Improved diagnosis of cerebral cavernous malformations and associated developmental venous anomalies.

BACKGROUND AND AIM: In the diagnosis of cerebral cavernous malformations (CCMs) magnetic resonance imaging is established as the gold standard. Conventional MRI techniques have their drawbacks in the diagnosis of CCMs and associated venous malformations (DVAs). The aim of our study was to evaluate susceptibility weighted imaging SWI for the detection of CCM and associated DVAs at 7 T in comparison with 3 T. PATIENTS AND METHODS: 24 patients (14 female, 10 male; median age: 38.3 y (21.1 y-69.1 y) were included in the study. Patients enrolled in the study received a 3 T and a 7 T MRI on the same day. The following sequences were applied on both field strengths: a T1 weighted 3D GRE sequence (MP-RAGE) and a SWI sequence. After obtaining the study MRIs, eleven patients underwent surgery and 13 patients were followed conservatively or were treated radio-surgically. RESULTS: Patients initially presented with haemorrhage (n = 4, 16.7%), seizures (n = 2, 8.3%) or other neurology (n = 18, 75.0%). For surgical resected lesions histopathological findings verified the diagnosis of CCMs. A significantly higher number of CCMs was diagnosed at 7 T SWI sequences compared with 3 T SWI (p < 0.05). Additionally diagnosed lesions on 7 T MRI were significantly smaller compared to the initial lesions on 3 T MRIs (p < 0.001). Further, more associated DVAs were diagnosed at 7 T MRI compared to 3 T MRI. CONCLUSION: SWI sequences at ultra-high-field MRI improve the diagnosis of CCMs and associated DVAs and therefore add important pre-operative information.

Long-term tumor control of benign intracranial meningiomas after radiosurgery in a series of 4565 patients.

BACKGROUND: Radiosurgery is the main alternative to microsurgical resection for benign meningiomas. OBJECTIVE: To assess the long-term efficacy and safety of radiosurgery for meningiomas with respect to tumor growth and prevention of associated neurological deterioration. Medium- to long-term outcomes have been widely reported, but no large multicenter series with long-term follow-up have been published. METHODS: From 15 participating centers, we performed a retrospective observational analysis of 4565 consecutive patients harboring 5300 benign meningiomas. All were treated with Gamma Knife radiosurgery at least 5 years before assessment for this study. Clinical and imaging data were retrieved from each center and uniformly entered into a database by 1 author (A.S.). RESULTS: Median tumor volume was 4.8 cm³, and median dose to tumor margin was 14 Gy. All tumors with imaging follow-up < 24 months were excluded. Detailed results from 3768 meningiomas (71%) were analyzed. Median imaging follow-up was 63 months. The volume of treated tumors decreased in 2187 lesions (58%), remained unchanged in 1300 lesions (34.5%), and increased in 281 lesions (7.5%), giving a control rate of 92.5%. Only 84 (2.2%) enlarging tumors required further treatment. Five- and 10-year progression-free survival rates were 95.2% and 88.6%, respectively. Tumor control was higher for imaging defined tumors vs grade I meningiomas (P < .001), for female vs male patients (P < .001), for sporadic vs multiple meningiomas (P < .001), and for skull base vs convexity tumors (P < .001). Permanent morbidity rate was 6.6% at the last follow-up. CONCLUSION: Radiosurgery is a safe and effective method for treating benign meningiomas even in the medium to long term.

Gamma-knife radiosurgery for cranial base meningiomas: experience of tumor control, clinical course, and morbidity in a follow-up of more than 8 years.

OBJECTIVE: Surgical resection of cranial base meningiomas is often limited owing to involvement of crucial neural structures. Within the last 2 decades Gamma Knife radiosurgery (GKRS) has gained increasing importance as an adjunct treatment after incomplete resection and as an alternative treatment to open surgery. However, reports of long-term results are still sparse. We therefore performed this study to analyze the long-term results of GKRS treatment of cranial base meningiomas, following our previously published early follow-up experience. METHODS: A retrospective analysis of the medical files for Gamma Knife and surgical treatments, clinicoradiological findings, and outcome was carried out focusing on tumor control, clinical course, and morbidity. RESULTS: Between 1992 and 1995, we treated 36 patients with cranial base meningiomas using GKRS (male:female ratio, 1:5; mean age, 59 yr; range, 44-89 yr). Twenty-five patients were treated with GKRS after open surgery, and 11 patients received GKRS alone. Tumor control, neurological outcomes, and adverse effects were analyzed after a long-term follow-up period (mean, 103 mo; range, 70-133 mo) and compared with our previous results after an early follow-up period (mean, 48 mo; range, 36-76 mo). Control of tumor growth was achieved in 94% of patients. Compared with the early follow-up period, the late neuroradiological effects of GKRS on cranial base meningiomas were continuing tumor shrinkage in 11 patients (33%), stable tumor size in 20 patients (64%) and tumor progression in two meningiomas (6%). The neurological status improved in 16 patients (44%), remained stable in 19 patients (52%), and deteriorated in one patient (4%). Adverse side effects of GKRS were found only during the early follow-up period. CONCLUSION: Our data confirm that GKRS is not only a safe and effective treatment modality for cranial base meningiomas in short-term observation, but also in a mean long-term follow-up period of more than 8 years. Tumor shrinkage and clinical improvement also continued during the longer follow-up period.