Medulloblastomas in Pediatric and Adults.

Medulloblastoma is the primary malignant embryonic tumor of the cerebellum and the most common malignant tumor of childhood, accounting up to 25% of all CNS tumors in children, but is extremely rare in adults. Despite the fact that medulloblastomas are one of the most malignant human tumors, it is worthy to note that a great breakthrough has been achieved in our understanding of oncogenesis and the development of real methods of treatment. The main objective of surgical treatment is a maximum resection of tumor with minimal impairment of neurological functions, in order to reduce the volume, remove tumor tissue, get the biopsy, and restore the cerebrospinal fluid flow. The progress of surgical techniques (using a microscope, ultrasound suction), anesthesiology, and intensive care has significantly decreased surgical mortality and increased radicality of tumor removal. Postoperative mortality is less than one percent in most studies, while neurological complications have been reported between 5-10%. Radiotherapy is the main method of treatment in patients older than 3 years, which dramatically improved the recurrence-free survival. Nevertheless, the radiation therapy without systemic chemotherapy leads to a high risk of systemic metastases. After the role of chemotherapy was statistically proven, investigations of the optimal combination of different chemotherapy regimens continued around the world. Currently, 80% of patients can already be cured, however, the quality of life of patients in the long-term period remains quite low, which depends on many factors including endocrinological, cognitive, neurological, and otoneurologic aspects. Thus, the main strategic goal of the development of neuro-oncology is to reduce the doses of radiation therapy to the CNS and the main task of international research is to optimize existing protocols and develop fundamentally new ones based on molecular genetic research in order to improve the quality of life.

Stereotactic Gamma Knife® Radiosurgery of Intraocular Retinoblastoma: Six-Year Experience.

Background External beam radiotherapy for resistant retinoblastoma is now seen as a last resort to saving the eye because of the risk of severe side effects: secondary cancers and cosmetic problems of orbital bone growth retardation. To reduce such complications, treatment modalities have shifted towards new radiation therapy techniques. No information on single fraction Gamma Knife® radiosurgery (GKRS) for intraocular retinoblastoma exists. Materials and methods Eighteen children (19 eyes) with retinoblastoma were treated with GKRS. The mean age at the time of treatment was 35 months (from 12 to 114 months). Before GKRS, all routes of chemotherapy delivery were held in all cases. The eligibility criteria for GKRS were retinoblastomas not amenable either to systemic or local chemotherapy and local ophthalmological treatment, retinoblastomas too large for conventional local methods, and inability to perform intraarterial chemotherapy. Conventional external beam radiotherapy was excluded in the presented cases, given the possible complications mentioned above. In every case, eye removal was suggested to the child's parents, but they flatly refused. GKRS was proposed as the last chance to save the eye (in four cases, it was performed on the only eye). The median prescribed dose was 22 Gy (interquartile range [IQR]: 18-35 Gy), and the median prescribed isodose was 50% (IQR: 36-90%). Results Local control was achieved in 79% of cases (complete tumor regression in 69%, incomplete regression in 10%). Two eyes (10.5%) could not be preserved and had to be enucleated due to the tumor recurrence. Two eyes (10.5%) developed secondary complications (total vitreous hemorrhage, retinal detachment, and iris neovascularization), making adequate tumor control nearly impossible. Overall, 15 eyes (79%) were preserved, and four eyes (21%) were enucleated after GKRS with no signs of tumor recurrence and metastasis in the mean follow-up of 41 months. No acute radiation side effects occurred in any patient after GKRS. Ten children (10 eyes, 53%) were diagnosed with vitreous hemorrhage from mild to severe. Three eyes presented with optic neuropathy one year after GKRS, and four eyes developed retinopathy. Radiation-induced cataract occurred in two eyes. There were no cases of secondary glaucoma or keratopathy in our study. All patients and eyes treated by GKRS were stable within 41 months (from seven to 74 months). Conclusions Single fraction Gamma Knife® radiosurgery may be a reasonable salvage treatment for resistant and recurrent retinoblastoma as an alternative approach to enucleation in selected cases. GKRS should be considered in retinoblastoma management.

Reparative properties of human glioblastoma cells after single exposure to a wide range of X-ray doses.

Radiation therapy induces double-stranded DNA breaks in tumor cells, which leads to their death. A fraction of glioblastoma cells repair such breaks and reinitiate tumor growth. It was necessary to identify the relationship between high radiation doses and the proliferative activity of glioblastoma cells, and to evaluate the contribution of DNA repair pathways, homologous recombination (HR), and nonhomologous end joining (NHEJ) to tumor-cell recovery. We demonstrated that the GO1 culture derived from glioblastoma cells from Patient G, who had previously been irradiated, proved to be less sensitive to radiation than the Sus\fP2 glioblastoma culture was from Patient S, who had not been exposed to radiation before. GO1 cell proliferation decreased with radiation dose, and MTT decreased to 35% after a single exposure to 125 Gγ. The proliferative potential of glioblastoma culture Sus\fP2 decreased to 35% after exposure to 5 Gγ. At low radiation doses, cell proliferation and the expression of RAD51 were decreased; at high doses, cell proliferation was correlated with Ku70 protein expression. Therefore, HR and NHEJ are involved in DNA break repair after exposure to different radiation doses. Low doses induce HR, while higher doses induce the faster but less accurate NHEJ pathway of double-stranded DNA break repair.

Gamma Knife capsulotomy for correction of obsessive-compulsive symptoms in a patient with schizophrenia: Case report.

The treatment of mental illnesses that are resistant to conservative therapy poses a serious problem. Surgical methods with proven efficacy have been proposed for only a small group of psychiatric diseases, while in practice non-classical clinical situations are seen rather often. A 36-year-old man with a 18-year history of "schizophrenia with a predominant obsessive-compulsive syndrome" was referred to the Burdenko National Medical Research Center of Neurosurgery for consideration of neurosurgical treatment. Based on results of longitudinal independent evaluations of the patient in several specialized clinical centers the disease was considered resistant to medical therapy. Radiosurgical procedure was performed by means of Leksell Gamma Knife Perfexion™ (Elekta AB; Stockholm, Sweden). Ventral portion of the anterior limb of internal capsule was targeted with two 4-mm isocenters on each side, with prescription dose at 50% isodose line of 80 Gy and a maximal dose of 160 Gy. No obvious complications or side effects were noted during 13-month follow-up after radiosurgery. Gradual clinical improvement was observed with 25% reduction of the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score at 13 months after treatment. Similarly, the Hospital Anxiety and Depression Scale (HADS) anxiety and depression scores decreased by 24% and 58%, respectively. This is the first published case of radiosurgical treatment of a psychiatric disorder in Russia. It demonstrates the potential efficacy of Gamma Knife capsulotomy for non-classical forms of obsessive-compulsive disorder comorbid with schizophrenia. Nevertheless, definitive conclusions about the reliability of this radiosurgical indication can only be made based on the results of larger studies.

Discrepancies between frame- and CBCT-based stereotactic space definition on the Gamma Knife Icon.

PURPOSE: To assess differences between frame-based and cone beam computed tomography (CBCT)-defined stereotactic space and to identify predictors of the observed findings. METHODS AND MATERIALS: Differences between frame-based and CBCT-defined stereotactic space after image co-registration were reviewed for 529 patients. Treatment planning system reported the information about the shifts in X, Y, and Z coordinates of the center of the stereotactic space (i.e., coordinate X = 100 mm, Y = 100 mm, and Z = 100 mm) defined by the frame, and the maximum shot displacement (MSD) in mm. We collected the potential predictors of the differences. In total, 19 factors were investigated. We used multiple linear regression to evaluate associations with the increased differences. RESULTS: Rotational and translational shifts greater than 1° and 1 mm, respectively, were observed in 2.6% of patients. At the same time, a decrease in tumor coverage of more than 5% was detected in 8.3% of cases. It was revealed that the higher fiducial errors (both mean and maximum), the greater weight of the patient, and the lower Karnofsky Performance Scale were predictors of increased rotational, translational shifts, and the MSD.

LINAC-based radiosurgery for functional and psychiatric disorders: Problems and their solutions.

Stereotactic radiosurgery (SRS) is practically non-invasive treatment option, and its application for ablative procedures in functional and psychiatric brain disorders seems rather promising. In such cases, gamma knife surgery (GKS) is considered a standard option due to its proved accuracy in targeting and dosimetry. However, modern linear accelerators (LINAC), which are the most commonly used radiosurgical device, provide comparable treatment preciseness. Although at present experience with LINAC-based SRS of functional brain disorders is rather limited, from the technological viewpoint it definitely seems possible and theoretically may be of the similar efficacy as established with GKS for the same indications. However, widespread introduction of such practice requires resolution of several important methodological issues, particularly related to establishment of specific treatment standards, development of dedicated training for involved medical professionals, and creation of the data accumulation and outcome analysis systems.

Systematic Clinical Evaluation of a Deep Learning Method for Medical Image Segmentation: Radiosurgery Application.

We systematically evaluate a Deep Learning model in a 3D medical image segmentation task. With our model, we address the flaws of manual segmentation: high inter-rater contouring variability and time consumption of the contouring process. The main extension over the existing evaluations is the careful and detailed analysis that could be further generalized on other medical image segmentation tasks. Firstly, we analyze the changes in the inter-rater detection agreement. We show that the model reduces the number of detection disagreements by [Formula: see text] [Formula: see text]. Secondly, we show that the model improves the inter-rater contouring agreement from [Formula: see text] to [Formula: see text] surface Dice Score [Formula: see text]. Thirdly, we show that the model accelerates the delineation process between [Formula: see text] and [Formula: see text] times [Formula: see text]. Finally, we design the setup of the clinical experiment to either exclude or estimate the evaluation biases; thus, preserving the significance of the results. Besides the clinical evaluation, we also share intuitions and practical ideas for building an efficient DL-based model for 3D medical image segmentation.

Clinically Tractable Outcome Prediction of Non-WNT/Non-SHH Medulloblastoma Based on TPD52 IHC in a Multicohort Study.

PURPOSE: International consensus and the 2021 WHO classification recognize eight molecular subgroups among non-WNT/non-SHH (Group 3/4) medulloblastoma, representing approximately 60% of tumors. However, very few clinical centers worldwide possess the technical capabilities to determine DNA methylation profiles or other molecular parameters of high risk for group 3/4 tumors. As a result, biomarker-driven risk stratification and therapy assignment constitutes a major challenge in medulloblastoma research. Here, we identify an IHC marker as a clinically tractable method for improved medulloblastoma risk stratification. EXPERIMENTAL DESIGN: We bioinformatically analyzed published medulloblastoma transcriptomes and proteomes identifying as a potential biomarker TPD52, whose IHC prognostic value was validated across three group 3/4 medulloblastoma clinical cohorts (n = 387) treated with conventional therapies. RESULTS: TPD52 IHC positivity represented a significant independent predictor of early relapse and death for group 3/4 medulloblastoma [HRs between 3.67 and 26.7; 95% confidence interval (CI) between 1.00 and 706.23; P = 0.05, 0.017, and 0.0058]. Cross-validated survival models incorporating TPD52 IHC with clinical features outperformed existing state-of-the-art risk stratification schemes, and reclassified approximately 50% of patients into more appropriate risk categories. Finally, TPD52 immunopositivity was a predictive indicator of poor response to chemotherapy [HR, 12.66; 95% CI, 3.53-45.40; P < 0.0001], suggesting important implication for therapeutic choices. CONCLUSIONS: This study redefines the approach to risk stratification in group 3/4 medulloblastoma in global practice. Because integration of TPD52 IHC in classification algorithms significantly improved outcome prediction, this test could be rapidly adopted for risk stratification on a global scale, independently of advanced but technically challenging molecular profiling techniques.

Radiation-induced gliomas represent H3-/IDH-wild type pediatric gliomas with recurrent PDGFRA amplification and loss of CDKN2A/B.

Long-term complications such as radiation-induced second malignancies occur in a subset of patients following radiation-therapy, particularly relevant in pediatric patients due to the long follow-up period in case of survival. Radiation-induced gliomas (RIGs) have been reported in patients after treatment with cranial irradiation for various primary malignancies such as acute lymphoblastic leukemia (ALL) and medulloblastoma (MB). We perform comprehensive (epi-) genetic and expression profiling of RIGs arising after cranial irradiation for MB (n = 23) and ALL (n = 9). Our study reveals a unifying molecular signature for the majority of RIGs, with recurrent PDGFRA amplification and loss of CDKN2A/B and an absence of somatic hotspot mutations in genes encoding histone 3 variants or IDH1/2, uncovering diagnostic markers and potentially actionable targets.

Subgroup and subtype-specific outcomes in adult medulloblastoma.

Medulloblastoma, a common pediatric malignant central nervous system tumour, represent a small proportion of brain tumours in adults. Previously it has been shown that in adults, Sonic Hedgehog (SHH)-activated tumours predominate, with Wingless-type (WNT) and Group 4 being less common, but molecular risk stratification remains a challenge. We performed an integrated analysis consisting of genome-wide methylation profiling, copy number profiling, somatic nucleotide variants and correlation of clinical variables across a cohort of 191 adult medulloblastoma cases identified through the Medulloblastoma Advanced Genomics International Consortium. We identified 30 WNT, 112 SHH, 6 Group 3, and 41 Group 4 tumours. Patients with SHH tumours were significantly older at diagnosis compared to other subgroups (p < 0.0001). Five-year progression-free survival (PFS) for WNT, SHH, Group 3, and Group 4 tumours was 64.4 (48.0-86.5), 61.9% (51.6-74.2), 80.0% (95% CI 51.6-100.0), and 44.9% (95% CI 28.6-70.7), respectively (p = 0.06). None of the clinical variables (age, sex, metastatic status, extent of resection, chemotherapy, radiotherapy) were associated with subgroup-specific PFS. Survival among patients with SHH tumours was significantly worse for cases with chromosome 3p loss (HR 2.9, 95% CI 1.1-7.6; p = 0.02), chromosome 10q loss (HR 4.6, 95% CI 2.3-9.4; p < 0.0001), chromosome 17p loss (HR 2.3, 95% CI 1.1-4.8; p = 0.02), and PTCH1 mutations (HR 2.6, 95% CI 1.1-6.2; p = 0.04). The prognostic significance of 3p loss and 10q loss persisted in multivariable regression models. For Group 4 tumours, chromosome 8 loss was strongly associated with improved survival, which was validated in a non-overlapping cohort (combined cohort HR 0.2, 95% CI 0.1-0.7; p = 0.007). Unlike in pediatric medulloblastoma, whole chromosome 11 loss in Group 4 and chromosome 14q loss in SHH was not associated with improved survival, where MYCN, GLI2 and MYC amplification were rare. In sum, we report unique subgroup-specific cytogenetic features of adult medulloblastoma, which are distinct from those in younger patients, and correlate with survival disparities. Our findings suggest that clinical trials that incorporate new strategies tailored to high-risk adult medulloblastoma patients are urgently needed.

The last decade's experience of management of central neurocytomas: Treatment strategies and new options.

BACKGROUND: The purpose of the presented work is to evaluate the last decade's experience in surgical management of central neurocytoma (CN) and elucidate on the treatment strategies and new options. METHODS: The current series consists of the remaining 125 patients (70 females and 55 males) operated on during the past decade from 2008 to 2018. Most tumors were resected through transcortical (n = 76, 61%), or transcallosal (n = 40, 32%) approaches. In 5 (4%) patients with predominantly posterior location of the tumor, non-dominant superior parietal lobule approach was utilized. Both approaches (transcortical + transcallosal) were used in 4 (3%) of cases. Seven consecutive patients with large CN underwent prophylactic intraventricular stenting to prevent hydrocephalus. RESULTS: Gross total resection was achieved in 45 patients (36%), subtotal resection (STR) in 40 (32%) cases. After surgery, 63 (50%) patients had neurocognitive problems, including disorientation, attention deficit, global amnesia, short-term memory deficits, and perceptual motor and social cognition problems. A total of 26 patients (21%) had postoperative hemorrhage in the resection bed. Obstructive hydrocephalus was noted in 25 (20%) patients. The entrapment of the occipital and/or temporal horns was observed in seven cases. None of the seven patients with prophylactic intraventricular stents required shunting. CONCLUSION: Although high rates of gross total or STR can be expected, the mortality and morbidity remain significant even in the modern neurosurgical era. Prophylactic intraventricular stenting in patients with large posteriorly located tumors with hydrocephalus may prevent ventricular entrapment and shunting. The main risk factors for recurrence are presence of residual disease and Ki-67 index over 5%. Recurrent symptomatic tumors should be treated surgically, whereas asymptomatic progression can be managed with stereotactic radiosurgery. Both treatment modalities are associated with low risk of complications and high tumor control rates.

Accelerating 3D Medical Image Segmentation by Adaptive Small-Scale Target Localization.

The prevailing approach for three-dimensional (3D) medical image segmentation is to use convolutional networks. Recently, deep learning methods have achieved human-level performance in several important applied problems, such as volumetry for lung-cancer diagnosis or delineation for radiation therapy planning. However, state-of-the-art architectures, such as U-Net and DeepMedic, are computationally heavy and require workstations accelerated with graphics processing units for fast inference. However, scarce research has been conducted concerning enabling fast central processing unit computations for such networks. Our paper fills this gap. We propose a new segmentation method with a human-like technique to segment a 3D study. First, we analyze the image at a small scale to identify areas of interest and then process only relevant feature-map patches. Our method not only reduces the inference time from 10 min to 15 s but also preserves state-of-the-art segmentation quality, as we illustrate in the set of experiments with two large datasets.

Therapeutic implications of improved molecular diagnostics for rare CNS embryonal tumor entities: results of an international, retrospective study.

BACKGROUND: Only few data are available on treatment-associated behavior of distinct rare CNS embryonal tumor entities previously treated as "CNS-primitive neuroectodermal tumors" (CNS-PNET). Respective data on specific entities, including CNS neuroblastoma, FOXR2 activated (CNS NB-FOXR2), and embryonal tumors with multilayered rosettes (ETMR) are needed for development of differentiated treatment strategies. METHODS: Within this retrospective, international study, tumor samples of clinically well-annotated patients with the original diagnosis of CNS-PNET were analyzed using DNA methylation arrays (n = 307). Additional cases (n = 66) with DNA methylation pattern of CNS NB-FOXR2 were included irrespective of initial histological diagnosis. Pooled clinical data (n = 292) were descriptively analyzed. RESULTS: DNA methylation profiling of "CNS-PNET" classified 58 (19%) cases as ETMR, 57 (19%) as high-grade glioma (HGG), 36 (12%) as CNS NB-FOXR2, and 89(29%) cases were classified into 18 other entities. Sixty-seven (22%) cases did not show DNA methylation patterns similar to established CNS tumor reference classes. Best treatment results were achieved for CNS NB-FOXR2 patients (5-year PFS: 63% ± 7%, OS: 85% ± 5%, n = 63), with 35/42 progression-free survivors after upfront craniospinal irradiation (CSI) and chemotherapy. The worst outcome was seen for ETMR and HGG patients with 5-year PFS of 18% ± 6% and 22% ± 7%, and 5-year OS of 24% ± 6% and 25% ± 7%, respectively. CONCLUSION: The historically reported poor outcome of CNS-PNET patients becomes highly variable when tumors are molecularly classified based on DNA methylation profiling. Patients with CNS NB-FOXR2 responded well to current treatments and a standard-risk CSI-based regimen may be prospectively evaluated. The poor outcome of ETMR across applied treatment strategies substantiates the necessity for evaluation of novel treatments.

Challenges in Building of Deep Learning Models for Glioblastoma Segmentation: Evidence from Clinical Data.

In this article, we compare the performance of a state-of-the-art segmentation network (UNet) on two different glioblastoma (GB) segmentation datasets. Our experiments show that the same training procedure yields almost twice as bad results on the retrospective clinical data compared to the BraTS challenge data (in terms of Dice score). We discuss possible reasons for such an outcome, including inter-rater variability and high variability in magnetic resonance imaging (MRI) scanners and scanner settings. The high performance of segmentation models, demonstrated on preselected imaging data, does not bring the community closer to using these algorithms in clinical settings. We believe that a clinically applicable deep learning architecture requires a shift from unified datasets to heterogeneous data.

CyberKnife for the management of Cushing's disease: our institutional experience and review of literature.

INTRODUCTION: Surgery is the primary treatment for Cushing's disease(CD). In cases with no biochemical remission after surgical resection or when recurrence occurs after a period of remission stereotactic radiosurgery (SRS) is used as alternative/adjuvant treatment. The aim of this study is to demonstrate the effectiveness of SRS and FSRS(Fractionated stereotactic radiosurgery) for the treatment of CD in a long term follow up. METHODS: This is a retrospective study in which 41 patient (36 females and 5 males) who underwent surgery for CD from 2009 to 2019 were included. Out of 41 cases, 34 cases had microadenomas while 7 had macroadenomas. These patients had recurrence or persistence of hypercortisolism post-operatively. After multidisciplinary evaluation, these patients were treated by CyberKnife (SRS & FSRS). RESULTS: Remission rate in our study was 60.97% with a median follow up period of 79.03 months. The median time to biochemical remission was 14 months. Tumour growth control was achieved in 95.12%. Hypopituitarism of different axes was seen in 34.14% patients. Secondary hypothyroidism was the most common pituitary insufficiency (34%) followed by secondary hypogonadism in 17%. CONCLUSION: CyberKnife radiosurgery and hypofractionated radiosurgery can be used as an adjuvant treatment in patient with active disease and no biochemical remission after one or multiple surgical resections. Risk of radiation induced hypopituitarism and other complication is relatively low 34.14% and tumour growth control is significantly higher.

Integrated molecular analysis of adult sonic hedgehog (SHH)-activated medulloblastomas reveals two clinically relevant tumor subsets with VEGFA as potent prognostic indicator.

BACKGROUND: Up to now, adult medulloblastoma (MB) patients are treated according to the protocols elaborated for pediatric MB although these tumors are different in terms of clinical outcomes and biology. Approximately 70% of adult MB disclose a sonic hedgehog (SHH) molecular signature in contrast to about 30% in pediatric cohorts. In addition, adult SHH-MB (aSHH-MB) are clinically heterogeneous but there is consensus neither on their optimal treatment nor on risk stratification. Thus, the identification of clinically relevant molecular subsets of aSHH-MB and identification of potential treatment targets remains inconclusive. METHODS: We analyzed 96 samples of institutionally diagnosed aSHH-MB through genome-wide DNA methylation profiling, targeted DNA sequencing, and RNA sequencing to identify molecular subcategories of these tumors and assess their prognostic significance. RESULTS: We defined two aSHH-MB numerically comparable epigenetic subsets with clinical and molecular variability. The subset "aSHH-MBI" (46%/48%) was associated with PTCH1/SMO (54%/46%) mutations, "neuronal" transcriptional signatures, and favorable outcomes after combined radio-chemotherapy (5-year PFS = 80% and OS = 92%). The clinically unfavorable "aSHH-MBII" subset (50%/52%; 5-year PFS = 24% and OS = 45%) disclosed GLI2 amplifications (8%), loss of 10q (22%), and gene expression signatures associated with angiogenesis and embryonal development. aSHH-MBII tumors revealed strong and ubiquitous expression of VEGFA both at transcript and protein levels that was correlated with unfavorable outcome. CONCLUSIONS: (1) The histologically uniform aSHH-MB cohort exhibits clear molecular heterogeneity separating these tumors into two molecular subsets (aSHH-MBI and aSHH-MBII), which are associated with different cytogenetics, mutational landscapes, gene expression signatures, and clinical course. (2) VEGFA appears to be a promising biomarker to predict clinical course, which needs further prospective validation as its potential role in the pathogenesis of this subset.

Molecular analysis of pediatric CNS-PNET revealed nosologic heterogeneity and potent diagnostic markers for CNS neuroblastoma with FOXR2-activation.

Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly malignant neoplasms posing diagnostic challenge due to a lack of defining molecular markers. CNS neuroblastoma with forkhead box R2 (FOXR2) activation (CNS_NBL) emerged as a distinct pediatric brain tumor entity from a pool previously diagnosed as primitive neuroectodermal tumors of the central nervous system (CNS-PNETs). Current standard of identifying CNS_NBL relies on molecular analysis. We set out to establish immunohistochemical markers allowing safely distinguishing CNS_NBL from morphological mimics. To this aim we analyzed a series of 84 brain tumors institutionally diagnosed as CNS-PNET. As expected, epigenetic analysis revealed different methylation groups corresponding to the (1) CNS-NBL (24%), (2) glioblastoma IDH wild-type subclass H3.3 G34 (26%), (3) glioblastoma IDH wild-type subclass MYCN (21%) and (4) ependymoma with RELA_C11orf95 fusion (29%) entities. Transcriptome analysis of this series revealed a set of differentially expressed genes distinguishing CNS_NBL from its mimics. Based on RNA-sequencing data we established SOX10 and ANKRD55 expression as genes discriminating CNS_NBL from other tumors exhibiting CNS-PNET. Immunohistochemical detection of combined expression of SOX10 and ANKRD55 clearly identifies CNS_NBL discriminating them to other hemispheric CNS neoplasms harboring "PNET-like" microscopic appearance. Owing the rarity of CNS_NBL, a confirmation of the elaborated diagnostic IHC algorithm will be necessary in prospective patient series.

Clinical Outcomes and Patient-Matched Molecular Composition of Relapsed Medulloblastoma.

PURPOSE: We sought to investigate clinical outcomes of relapsed medulloblastoma and to compare molecular features between patient-matched diagnostic and relapsed tumors. METHODS: Children and infants enrolled on either SJMB03 (NCT00085202) or SJYC07 (NCT00602667) trials who experienced medulloblastoma relapse were analyzed for clinical outcomes, including anatomic and temporal patterns of relapse and postrelapse survival. A largely independent, paired molecular cohort was analyzed by DNA methylation array and next-generation sequencing. RESULTS: A total of 72 of 329 (22%) SJMB03 and 52 of 79 (66%) SJYC07 patients experienced relapse with significant representation of Group 3 and wingless tumors. Although most patients exhibited some distal disease (79%), 38% of patients with sonic hedgehog tumors experienced isolated local relapse. Time to relapse and postrelapse survival varied by molecular subgroup with longer latencies for patients with Group 4 tumors. Postrelapse radiation therapy among previously nonirradiated SJYC07 patients was associated with long-term survival. Reirradiation was only temporizing for SJMB03 patients. Among 127 patients with patient-matched tumor pairs, 9 (7%) experienced subsequent nonmedulloblastoma CNS malignancies. Subgroup (96%) and subtype (80%) stabilities were largely maintained among the remainder. Rare subgroup divergence was observed from Group 4 to Group 3 tumors, which is coincident with genetic alterations involving MYC, MYCN, and FBXW7. Subgroup-specific patterns of alteration were identified for driver genes and chromosome arms. CONCLUSION: Clinical behavior of relapsed medulloblastoma must be contextualized in terms of up-front therapies and molecular classifications. Group 4 tumors exhibit slower biological progression. Utility of radiation at relapse is dependent on patient age and prior treatments. Degree and patterns of molecular conservation at relapse vary by subgroup. Relapse tissue enables verification of molecular targets and identification of occult secondary malignancies.

Modern Methods of Stereotactic Radiosurgery and Radiotherapy for the Treatment of Cushing Disease.

Cushing's disease is caused by a pituitary tumor causing increased production of adrenocorticotropic hormone, which leads to chronic hypersecretion of cortisol through adrenal cortices. Endoscopic trans-sphenoidal adenomectomy is the first choice of treatment with greatest efficiency for the treatment of the disease. However, in the absence of remission or recurrence of hypercortisolism after neurosurgical resection (adenomectomy), as well as in cases when surgical intervention cannot be carried due to medical contraindications to surgical intervention, radiation treatment is used as an alternative or adjoining therapy. In this literature review the efficiency of different radiation techniques (the conventional and the modern techniques), as well as possible complications of modern methods of radiosurgery and radiotherapy have been looked for.

Nonmetastatic Medulloblastoma of Early Childhood: Results From the Prospective Clinical Trial HIT-2000 and An Extended Validation Cohort.

PURPOSE: The HIT-2000-BIS4 trial aimed to avoid highly detrimental craniospinal irradiation (CSI) in children < 4 years of age with nonmetastatic medulloblastoma by systemic chemotherapy, intraventricular methotrexate, and risk-adapted local radiotherapy. PATIENTS AND METHODS: From 2001-2011, 87 patients received systemic chemotherapy and intraventricular methotrexate. Until 2006, CSI was reserved for nonresponse or progression. After 2006, local radiotherapy was introduced for nonresponders or patients with classic medulloblastoma (CMB) or large-cell/anaplastic medulloblastoma (LCA). DNA methylation profiles of infantile sonic hedgehog-activated medulloblastoma (SHH-INF) were subdivided into iSHH-I and iSHH-II subtypes in the HIT-2000-BIS4 cohort and a validation cohort (n = 71) from the HIT group and Russia. RESULTS: Five years after diagnosis, patients with desmoplastic medulloblastoma (DMB) or medulloblastoma with extensive nodularity (MBEN; n = 42) had 93% progression-free survival (5y-PFS), 100% overall survival (5y-OS), and 93% CSI-free (5y-CSI-free) survival. Patients with CMB/LCA (n = 45) had 37% 5y-PFS, 62% 5y-OS, and 39% 5y-CSI-free survival. Local radiotherapy did not improve survival in patients with CMB/LCA. All DMB/MBEN assessed by DNA methylation profiling belonged to the SHH-INF subgroup. Group 3 patients (5y-PFS, 36%; n = 14) relapsed more frequently than the SHH-INF group (5y-PFS, 93%; n = 28) or group 4 patients (5y-PFS, 83%; n = 6; P < .001). SHH-INF split into iSHH-I and iSHH-II subtypes in HIT-2000-BIS4 and the validation cohort, without prognostic impact (5y-PFS: iSHH-I, 73%, v iSHH-II, 83%; P = .25; n = 99). Intelligence quotient (IQ) was significantly lower in patients after CSI (mean IQ, 90 [no radiotherapy], v 74 [CSI]; P = .012). CONCLUSION: Systemic chemotherapy and intraventricular methotrexate led to favorable survival in both iSHH subtypes of SHH-activated DMB/MBEN with acceptable neurotoxicity. Survival in patients with non-wingless (WNT)/non-SHH disease with CMB/LCA was not improved by local radiotherapy. Patients with group 4 disease had more favorable survival rates than those with group 3 medulloblastoma.