Abnormal neovascular and proliferative conjunctival phenotype in limbal stem cell deficiency is associated with altered microRNA and gene expression modulated by PAX6 mutational status in congenital aniridia.

PURPOSE: To evaluate conjunctival cell microRNA (miRNAs) and mRNA expression in relation to observed phenotype of progressive limbal stem cell deficiency in a cohort of subjects with congenital aniridia with known genetic status. METHODS: Using impression cytology, bulbar conjunctival cells were sampled from 20 subjects with congenital aniridia and 20 age and sex-matched healthy control subjects. RNA was extracted and miRNA and mRNA analyses were performed using microarrays. Results were related to severity of keratopathy and genetic cause of aniridia. RESULTS: Of 2549 miRNAs, 21 were differentially expressed in aniridia relative to controls (fold change ≤ -1.5 or ≥ +1.5). Among these miR-204-5p, an inhibitor of corneal neovascularization, was downregulated 26.8-fold in severely vascularized corneas. At the mRNA level, 539 transcripts were differentially expressed (fold change ≤ -2 or ≥ +2), among these FOSB and FOS were upregulated 17.5 and 9.7-fold respectively, and JUN by 2.9-fold, all being components of the AP-1 transcription factor complex. Pathway analysis revealed enrichment of PI3K-Akt, MAPK, and Ras signaling pathways in aniridia. For several miRNAs and transcripts regulating retinoic acid metabolism, expression levels correlated with keratopathy severity and genetic status. CONCLUSION: Strong dysregulation of key factors at the miRNA and mRNA level suggests that the conjunctiva in aniridia is abnormally maintained in a pro-angiogenic and proliferative state, and these changes are expressed in a PAX6 mutation-dependent manner. Additionally, retinoic acid metabolism is disrupted in severe, but not mild forms of the limbal stem cell deficiency in aniridia.

Quality of life in the follow-up of uveal melanoma patients after enucleation in comparison to CyberKnife treatment.

PURPOSE: To compare quality of life (QoL) in patients with uveal melanoma after enucleation and stereotactic radiosurgery to that in an age-matched patient collective. METHODS: QoL was assessed in a cross-sectional survey and compared among 32 uveal melanoma patients after enucleation, 48 patients after stereotactic radiosurgery (CyberKnife(®); Accuray(®) Incorporated, Sunnyvale, CA, USA), and an age-matched control group of 35 patients, using the SF-12 Health Survey. Statistical analysis was performed with Fisher's exact test, Student's t test, one-way ANOVA analysis, Wilcoxon rank-sum (Mann-Whitney test), and ordered logistic regression for multivariate analysis. RESULTS: There was no significant difference in QoL between patients treated by stereotactic radiosurgery and the age-matched control group. After enucleation, patients presented significantly lower values in Physical Functioning (PF), Role Physical (RP), and Role Emotional (RE) compared to the radiosurgery and control group. To control for the overall QoL lowering effect of visual loss, the QoL of the patients who underwent enucleation was compared with the QoL of patients suffering severe functional loss after CyberKnife radiosurgery in a subgroup analysis, which showed no statistically significant difference. The number of comorbidities had a significant impact on QoL in multivariate analysis. CONCLUSIONS: Superior performance in PF, RP, and RE suggests that CyberKnife represents a suitable first-line therapy for uveal melanoma. In cases with painful amaurosis or vast tumor recurrence, enucleation can be performed with an acceptable QoL outcome.

CyberKnife radiosurgery for the treatment of orbital metastases.

Purpose of this study is to evaluate radiographic therapy response, clinical outcome and adverse effects of CyberKnife radiosurgery in patients suffering from orbital metastases. Sixteen orbital metastases originating from different solid cancers in fourteen patients were treated by single fraction CyberKnife radiosurgery. Radiographic response and clinical outcome were evaluated. The treated tumor volume ranged from 0.2 to 35 cm3 (median 2.3 cm3, mean 7.0 cm3, SD 6 10.4 cm3, CI 0.9-9.4 cm3). The prescription dose ranged from 16.5-21 Gy (median 18 Gy, mean 18.2 Gy, SD 6 1.2 Gy, CI 17.0-18.4 Gy). A no change situation was observed in nine lesions, partial remission in four as well as complete remission in one metastasis. Tumor growth was stabilized or regressive following CyberKnife therapy in 87% of the cases. Recurrence was observed in two cases (13%). Before therapy, three patients suffered from visual disturbance and five patients reported diplopia. Six patients had no initial symptoms. After therapy, one patient indicated improvement of the present visual deficit and two patients no change. Out of the two patients with persistent diplopia, two reported improvement after therapy and three no change. No progression of symptoms was noted in any of the cases. Fourteen out of sixteen treated lesions were stable or regressive following CyberKnife radiosurgery (87%). As no serious adverse effects were reported in this series, CyberKnife therapy was shown to be of great value for local management of orbital metastases.

Radiosurgery of spinal meningiomas and schwannomas.

Purpose of this study is to analyze local control, clinical symptoms and toxicity after image-guided radiosurgery of spinal meningiomas and schwannomas. Standard treatment of benign spinal lesions is microsurgical resection. While a few publications have reported about radiosurgery for benign spinal lesions, this is the first study analyzing the outcome of robotic radiosurgery for benign spinal tumors, treated exclusively with a non-invasive, fiducial free, single-fraction setup. Thirty-six patients with spinal meningiomas or schwannomas were treated, utilizing a robotic radiosurgery system (CyberKnife®, Accuray Inc. Sunnyvale CA), and were followed prospectively. Medical history, histology, clinical symptoms and radiographic outcome were recorded. Thirty-nine spinal lesions were treated because of tumor recurrence, remnants after microsurgery, multiple lesions, or rejection of open surgery. Median age was 45 years (range 18-80 years). Median target volume was 3.4 cm(3) (range 0.2-43.4 cm(3)). Histology revealed 28 schwannomas and 11 meningiomas (WHO grade I). All spinal levels were affected. Median prescription dose was 14 Gray (95% C.I. 13.4-14 Gy) to the 70% isodose. After a median follow-up of 18 months (range 6-50 months) no local tumor progression was detected. 20 lesions (51%) remained stable, 19 tumors (49%) decreased in size. One patient with schwannomatosis was treated repeatedly for three new tumor locations. Pain was the initial symptom in 16 of 25 schwannoma patients, and in 3 of 11 patients with meningiomas. Pain levels decreased in 8/19 patients. All but one patient with motor deficits remained clinically stable. No myelopathic signs where found. Single-session radiosurgery for benign spinal tumors in selected patients has proven to inhibit tumor progression within the observed period without signs of early toxicity. Radiosurgery offers an additional treatment option, if microsurgery is not feasible in cases of tumor recurrence, post-resection remnants, multiple lesions, or medical comorbidity.

Technical description, phantom accuracy, and clinical feasibility for single-session lung radiosurgery using robotic image-guided real-time respiratory tumor tracking.

To describe the technological background, the accuracy, and clinical feasibility for single session lung radiosurgery using a real-time robotic system with respiratory tracking. The latest version of image-guided real-time respiratory tracking software (Synchrony, Accuray Incorporated, Sunnyvale, CA) was applied and is described. Accuracy measurements were performed using a newly designed moving phantom model. We treated 15 patients with 19 lung tumors with robotic radiosurgery (CyberKnife, Accuray) using the same treatment parameters for all patients. Ten patients had primary tumors and five had metastatic tumors. All patients underwent computed tomography-guided percutaneous placement of one fiducial directly into the tumor, and were all treated with single session radiosurgery to a dose of 24 Gy. Follow up CT scanning was performed every two months. All patients could be treated with the automated robotic technique. The respiratory tracking error was less than 1 mm and the overall shape of the dose profile was not affected by target motion and/or phase shift between fiducial and optical marker motion. Two patients required a chest tube insertion after fiducial implantation because of pneumothorax. One patient experienced nausea after treatment. No other short-term adverse reactions were found. One patient showed imaging signs of pneumonitis without a clinical correlation. Single-session radiosurgery for lung tumor tracking using the described technology is a stable, safe, and feasible concept for respiratory tracking of tumors during robotic lung radiosurgery in selected patients. Longer follow-up is needed for definitive clinical results.

Functional outcome after gamma knife treatment in vestibular schwannoma.

Radiosurgery (RS) is a noninvasive, ambulatory special neurosurgical procedure for the treatment of vestibular schwannoma (VS). We treated 123 patients with unilateral schwannomas between 1994 and 2000 at the gamma knife (GK) center in Munich using a primary stereotactic procedure. These patients were followed up until June 2004 in respect to audiological, neurological, neurootological and radiological features before and after radiosurgical intervention. The actual tumor control rate of 8.2 years (mean) after GK surgery for all patients and a single treatment was calculated to be 96.7%. The impairment of hearing was on average 18% after GK, ranking from 0% gain of hearing loss up to 90%. Facial nerve function, graded according to the House-Brackmann scale, deteriorated in none of the patients; 5.8% reported a trigeminal neuralgia. Tinnitus developed in 4.1% of the patients after RS; 13.3% had vertigo for the first time after the treatment, age apparently being a predisposing factor. Radiosurgical treatment for VS is an alternative to microsurgery (MS). It is associated with a lower rate of facial and trigeminal neuropathy, postoperative complications and hospital stay. The hearing preservation rate is equivalent to MS.

Development of a 3-D convolution/superposition algorithm for precise dose calculation in the skull.

In this paper an algorithm for calculating 3-D dose distributions within the brain is introduced and adapted to the demands of modem radiosurgery. The dose calculation with this model is based on a 3-D distribution of the primary photon intensity which is calculated with a ray casting algorithm. A prelocated matrix takes into account field sizes as well as modifying elements as collimator positions (MLC), blocks, wedges and compensators. Monte Carlo precalculated monoenergetic kernels from 0.1 MeV to 50 MeV were at our disposal. The components of the spectrum were either determined by deconvoluting depth dose curves measured in water or analyzed with a Ge-Li detector system in the case of 60Co. The calculated fluence distribution has to be superposed to the complete kernel containing the spatial energy deposition. Inhomogeneities and tissue interface phenomena (rhoe, Z) have been investigated. The divergence of the rays and the curved surface of the patient are taken into account. Assuming homogenous media, it is possible to shorten the computation time by using the Fast Fourier Transformation (FFT) delivering a first overview within seconds. The algorithm was evaluated and verified under specific conditions of small fields as used in radiosurgery and compared to dose measurements and Monte Carlo calculations. In using both the fast algorithm (FFT) for mainly homogenous conditions on one hand and the very precise superposition for inhomogeneous cases on the other, this algorithm can be a very helpful instrument especially for critical locations in the skull.

Gamma-knife surgery is effective in normalising plasma insulin-like growth factor I in patients with acromegaly.

OBJECTIVE: For patients in whom acromegaly persists despite pituitary surgery or drug treatment, gamma-knife surgery represents an additional treatment option. Considering carefully the different reported biochemical outcomes, the central point is whether gamma-knife radiosurgery has advantages compared to conventional radiotherapy or, furthermore, to newer medical therapies, such as long-acting somatostatin analogues or growth hormone receptor antagonists. DESIGN AND METHODS: We report the outcome of 44 patients with acromegaly, who received gamma-knife surgery with the Leksell gamma knife. The median follow-up time was 1.9 years (0.5-4.3 years) post-radiosurgery. 43 of 44 patients had previously undergone pituitary surgery. RESULTS: Immediately prior to gamma-knife surgery, median xULN of patients' serum IGF-I was 1.9 times above upper limit of normal (range: 0.5-8.9 xULN [multiple of upper limit of normal range]). There was a significant decline of serum IGF-I at patients' final follow-up. We found a normal age-adjusted IGF-I in 21/44 patients (xULN of IGF-I<1). Furthermore, as the number of treated patients increased, we found an improvement in remission rate, which let us assume that there was a learning effect for the gamma-knife performing team over time. In addition, the median adenoma size decreased from 1.5 ml (0.1-6.9 ml) prior to gamma-knife therapy to 0.3 ml (no rest vol. detectable-2.4 ml) at patients' last visit. CONCLUSION: We have shown that pituitary gamma-knife surgery is effective in lowering serum IGF-I levels. At the end of the follow-up period, 48 % of our cohort had normal age-adjusted IGF-I levels.

Stereotactic radiosurgery without radiation therapy providing high local tumor control of multiple brain metastases from renal cell carcinoma.

The aim of this study was to analyse treatment effects after stereotactic radiosurgery (SRS) without whole brain radiation therapy (WBRT) as primary treatment for patients harboring brain metastases of renal cell carcinoma (RCC). During an 8-year period, 85 patients with 376 brain metastases from RCC underwent 134 outpatient SRS procedures. 65 % of all patients had multiple brain metastases. The median tumor volume was 1.2 cm (3) (range: 0.1 - 14.2 cm (3)). Mean prescribed tumor dose was 21.2 (+/- 3.2) Gy. Local/distant tumor recurrences were treated by additional SRS in cases of stable systemic disease. Overall median survival was 11.1 months after SRS. The local tumor control rate after SRS was 94 %. Most patients (78 %) died because of systemically progressing cancer. A KPS > 70 and RTOG class I were related to prolonged survival time. Patients of the RTOG groups I, II and III survived for 24.2 months, 9.2 months and 7.5 months, respectively. There was no permanent morbidity after SRS. 11 patients (12.9 %) showed transient radiogenic complications and 3 patients (3.5 %) died because of intratumoral bleedings after SRS. Stereotactic radiosurgery alone achieves excellent local tumor control rates for patients with small brain metastases from renal cell carcinoma.

Clinical quality standards for gamma knife radiosurgery--the Munich protocol.

The clinical quality standards for outpatient gamma knife radiosurgery as developed in the German Gamma Knife Center Munich during the last ten years are described. The following aspects have been taken into account: appropriate patient selection, standardised treatment cycle, acquisition of high-quality stereotactic MR images, the integrated therapeutic concept, dose conformity and dose level, patient follow-up, quality control and scientific data analysis. Particular emphasis has been put on the importance of the interdisciplinary treatment concept by subspecialised experts. The results of the Munich concept in consideration of the described quality standards verifies that gamma knife radiosurgery is a safe and effective treatment option for well selected indications.

Gamma knife radiosurgery for nonfunctioning pituitary adenomas.

The efficacy of gamma knife radiosurgery (GKS) for non-functioning pituitary adenomas (NPAs) has been assessed. Sixty patients with NPA were treated by GKS. Complete neurological and endocrinological follow-up information was available for 51 patients. Follow-up examinations included stereotactic magnetic resonance imaging for sequential measurements of the NPA volume. The median dose to the tumor margin was 16.5 Gy (range 11-20 Gy). The mean prescription isodose was 50% (range 45-75%). All patients underwent surgery for NPA before GKS. Fractionated radiotherapy was not applied. Median follow up after GKS was 21,7 months. Actuarial recurrence-free survival was 95% after three years with respect to a single GKS and 100% for patients who underwent repeated GKS. No neurological side effects were detected. Two patients developed new partial pituitary insufficiency after radiosurgery. Postoperative GKS for residual or recurrent small fragments of NPAs is an effective and safe treatment option. The follow-up examination for NPAs should include tumor volumetric analysis.

Results of outpatient gamma knife radiosurgery for primary therapy of acoustic neuromas.

Stereotactic radiosurgery (SRS) has been recognized as a non-invasive alternative to surgery for the treatment of acoustic neuromas. Purpose of the current study was to define the impact of outpatient gamma knife radiosurgery (GKS) for patients with unilateral sporadic acoustic neuromas treated within ten years. Follow-up images were analyzed using tumor volume measurements. 219 patients with sporadic acoustic neuromas were treated by GKS as primary therapy. Patients with NF-2 tumors were excluded. Patients were eligible for GKS up to a size limit of 12.5 cm3. The median follow up time was 6 years after radiosurgery. The local tumor control rate was high (97%). Cranial nerve morbidities were comparably low. 10% of the patients developed hearing loss after radiosurgery and one patient experienced a transient facial neuropathy (0.5%). Transient trigeminal neuropathy developed in 12 patients (5%) and was found to be dependent on the tumor size before treatment. Outpatient gamma knife radiosurgery is a safe and effective treatment method for selected patients with sporadic vestibular schwannomas.

Special indications in gamma knife surgery.

Pilocytic astrocytoma (PA) represent a rare indication for Gamma Knife Surgery. Mostly small remnants after surgical debulking are treated. The prognosis depends on specific variants of biological and clinical criteria. In this regard we differentiated two groups of tumors; the so-called 'typical' tumors with a histological grading of WHO Grade I, no prior fractionated radiotherapy and no cystic component and the so called 'atypical' tumors with either a malignant transformation, previous fractionated radiotherapy and/or cystic components. The outcome after GKS was much more favourable for typical PA than for atypical. In typical cases a high tumor control with a very low risk of side effects can be achieved.

Quality assurance in stereotactic radiosurgery/radiotherapy according to DIN 6875-1.

The new DIN ('Deutsche Industrie-Norm') 6875-1, which is currently being finalised, deals with quality assurance (QA) criteria and tests methods for linear accelerator and Gamma Knife stereotactic radiosurgery/radiotherapy including treatment planning, stereotactic frame and stereotactic imaging and a system test to check the whole chain of uncertainties. Our existing QA program, based on dedicated phantoms and test procedures, has been refined to fulfill the demands of this new DIN. The radiological and mechanical isocentre corresponded within 0.2 mm and the measured 50% isodose lines were in agreement with the calculated ones within less than 0.5 mm. The measured absorbed dose was within 3%. The resultant output factors measured for the 14-, 8- and 4-mm collimator helmet were 0.9870 +/- 0.0086, 0.9578 +/- 0.0057 and 0.8741 +/- 0.0202, respectively. For 170 consecutive tests, the mean geometrical accuracy was 0.48 +/- 0.23 mm. Besides QA phantoms and analysis software developed in-house, the use of commercially available tools facilitated the QA according to the DIN 6875-1 with which our results complied.

[Stereotactic radiosurgery using the Gamma Knife for large uveal melanomas]. / Stereotaktische Konvergenzbestrahlung grosser uvealer Melanome mit dem Gamma-Knife. Vorläufige Ergebnisse bei 100 Patienten.

BACKGROUND: We report the results over 3 years with stereotactic radiosurgery using the Gamma Knife for large and unsuitably located uveal melanomas. PATIENTS AND METHODS: A total of 100 patients (51 male, 49 female) have been treated since 1997 following a standardised treatment protocol (outpatient single-shot treatment, maximum dose 50 Gy, tumour margin dose min.25 Gy, retrobulbar anaesthesia alone for globe fixation). The localisation and/or dimension of the tumours did not allow radiation brachytherapy with Ru106 plaques. Of the tumours 18 were located in the ciliary body, 61 were located at the posterior pole, and 21 were located in the mid-periphery. All patients were followed and tested ophthalmologically and neuroradiologically at regular intervals. The 1-year follow-up data were available for 73 patients, 2-year follow-up data for 33 patients and 3-year follow-up-data for 17 patients. RESULTS: Before therapy the maximum apical tumour height (MAH) was median 7.8 mm (95% CI 2.9-12.5 mm): 1 year after treatment (73 patients) the MAH was median 5.7 mm (95% KI 2.4-10.2 mm),2 years after treatment (33 patients) the MAH was median 4.3 mm (95% KI 2.2-8.8 mm),and 3 years after treatment (17 patients) the MAH was median 4.6 mm (95% KI 2.4-8.5 mm). All differences to the MAH of the corresponding patients before treatment were statistically significant (paired t-test). Within the first year after treatment seven patients were enucleated due to a painful secondary glaucoma,within the second year after radiation two patients (one tumour recurrence, and one secondary glaucoma) and within the third year one more patient (tumour recurrence) was enucleated. CONCLUSIONS: Our 3-year results demonstrate that radiosurgery using the Gamma Knife is beneficial in achieving a local tumour control in 98% of eyes with large and unsuitably located uveal melanomas. The risk for a secondary enucleation is highest in the first year after treatment with a favourable overall rate of 10%. Due to the excellent local tumour control rate we decreased the maximum dose to 40 Gy (min.tumour margin dose 20 Gy) in the subsequently treated patients.

[Ambulatory radiosurgery in cerebral metastatic renal cell carcinoma. 5-year outcome in 58 patients]. / Ambulante Radiochirurgie bei zerebral metastasiertem Nierenzellkarzinom. Fünfjahresergebnisse von 58 Patienten.

Brain metastases (BM) indicate an advanced stage of renal cell cancer (RCC). They pose an increasing challenge to urologists as a result of improved survival due to modern therapy. Median survival of untreated patients with BM who often suffer from neurological deficits is 3 months. Radiosurgery with the Gamma Knife (GK) has increased in use as an alternative to whole brain radiation therapy (WBRT) and/or surgery. This study reports the results of a consecutive series of RCC patients treated for BM by GK radiosurgery during a 5-year period. Between 1994 and 1999, 58 patients with a total of 277 BM and 3.0 (1-19) BM/patient were treated. Because of recurrent BM, 23 (40%) patients received repeated (multiple) GK sessions. The median tumor volume was 3.4 cm3 (0.1-19.1). The median interval between diagnosis of RCC and GK treatment was 2.2 years (0.1-17.2). Symptomatic side effects were detected in 9 (16%) of 58 patients. The median actuarial survival time was 9.9 months. Local tumor control could be achieved in 95% of patients. The GK therapy induced a significant tumor remission accompanied by rapid neurological improvement in 70% of patients. Compared to standard radiotherapy, GK radiosurgery is more effective, less time consuming, and can be repeated. Compared to surgery, radiosurgery is less invasive and better suited to treat multiple metastases in one single session. Surgery and radiosurgery, however, are supplementary methods that are highly effective to control intracerebral metastasizing RCC.

[Stereotaxic precision irradiation of large uveal melanomas with the gamma knife]. / Die stereotaktische Präzisionsbestrahlung grosser uvealer Melanome mit dem Gamma-Knife.

BACKGROUND: We report our experience with stereotactic radiosurgery using the Gamma-knife in large uveal melanoma unsuitable for brachytherapy (Ru106). PATIENTS AND METHODS: We treated 35 patients (16 male, 19 female; age: median 59 years (95% Confidence interval (CI): 31-84 years; 18 right eyes, 17 left eyes). 7 tumors were located juxtapapillary, 16 tumors were located in the mid-periphery and 12 tumors were located in the ciliary body, The localization and/or the dimension of the tumors did not allow for radiation brachytherapy (Ru106). All patients underwent regular clinical, echographical and neuroradiological follow-up examinations. RESULTS: The follow-up time was median 12 months (95% CI: 4-20 months). A local tumor control defined as either continuous tumor regression or stopping of tumor progression was achieved in 34 (97%) of the 35 treated patients within the observation period. The eye of one patient was enucleated due to tumor regrowth. Maximum apical tumor height according to standardized A-scan before treatment was median 9.1 mm (95% CI: 3.2-13.9 mm) and after treatment median 6.4 mm (95% CI: 2.1 bis 11.9 mm). The difference was statistically highly significant (p < 0.001, one-tailed paired t-test). CONCLUSIONS: Our results in 35 patients indicate that radiosurgery using the Gamma-knife is beneficial in retaining the eyes of patients with large uveal melanomas that are not suitable for brachytherapy (Ru106).

Stereotactic radiosurgery of large uveal melanomas with the gamma-knife.

OBJECTIVE: To present our experience with the Gamma-knife in treating large uveal melanomas with stereotactic radiosurgery. DESIGN: Prospective, noncomparative, interventional case series. PARTICIPANTS: Fifty-eight patients with unilateral uveal melanomas were treated from 1996 through 1999 with stereotactic radiosurgery using the Gamma-knife. From these we report the results of 35 patients who had a follow-up of more than 1 year after irradiation. INTERVENTION: Stereotactic radiosurgery with the Gamma-knife. MAIN OUTCOME MEASURES: Tumor control, maximum apical tumor height, eye retention rate, and visual acuity. RESULTS: In 34 eyes (97%), local tumor control was achieved. The maximum apical tumor height decreased from a median of 9.1 mm (95% confidence interval [CI], 3.2-13.9 mm) before treatment to 6.2 mm (95% CI, 2.1-11.9 mm) at 1 year after treatment (P<0.001, paired t test). The tumor volume decreased from a median of 0.8 cm(3) before treatment to 0.5 cm(3) 1 year after treatment (P<0.001, paired t test). Two eyes required enucleation (one radiation failure, one secondary glaucoma). The median visual acuity decreased from 20/60 (95% CI, hand movement [HM] to 20/20) before treatment to 20/200 (95% CI, HM to 20/30) at 1 year after treatment (P = 0.001, paired t test). CONCLUSIONS: Stereotactic radiosurgery using the Gamma-knife is an alternative to enucleation in treating large uveal melanomas. The visual function may be preserved in selected cases.