Effectiveness and safety of robotic radiosurgery for optic nerve sheath meningiomas: A single institution series

The role of robotic radiosurgery (RRS) in the treatment of optic nerve sheath meningiomas (ONSM) remains controversial and it is only performed in specialized institutions due to tight dose constraints. We evaluated the effectiveness and safety of RRS in the management of ONSM. Twenty-five patients with 27 ONSM lesions who underwent RRS using the Cyberknife (CK) system were retrospectively analyzed (median age, 47.9 years; 84.0% women). Multisession RRS was used with 4–5 fractions with a cumulative dose of 20.0–25.0 Gy in 84.0% of patients and a single fraction at a dose of 14.0–15.0 Gy in 16% of patients. Prior to RRS, seven (28%) patients experienced blindness on the lesion side. In those patients with preserved vision prior to radiosurgery, the visual acuity remained the same in 90.0% and improved in 10.0% of the patients. Overall local tumor control was 96.0% (mean follow-up period; 37.4 ± 27.2 months). Neither patient age, previous surgery, or the period from the initial diagnosis to RRS showed a dependency on visual acuity before or after radiosurgery. RRS is a safe and effective treatment for the management of ONSM. Hypofractionation of radiosurgery in patients with preserved vision before CK treatment results in stable or improved vision

Factors affecting outcome in frameless non-isocentric stereotactic radiosurgery for trigeminal neuralgia: A multicentric cohort study

Background: Stereotactic radiosurgery (SRS) is an effective treatment for trigeminal neuralgia (TN). Nevertheless, a proportion of patients will experience recurrence and treatment-related sensory disturbances. In order to evaluate the predictors of efficacy and safety of image-guided non-isocentric radiosurgery, we analyzed the impact of trigeminal nerve volume and the nerve dose/volume relationship, together with relevant clinical characteristics. Methods: Two-hundred and ninety-six procedures were performed on 262 patients at three centers. In 17 patients the TN was secondary to multiple sclerosis (MS). Trigeminal pain and sensory disturbances were classified according to the Barrow Neurological Institute (BNI) scale. Pain-free-intervals were investigated using Kaplan Meier analyses. Univariate and multivariate Cox regression analyses were performed to identify predictors. Results: The median follow-up period was 38 months, median maximal dose 72.4 Gy, median target nerve volume 25 mm3, and median prescription dose 60 Gy. Pain control rate (BNI I-III) at 6, 12, 24, 36, 48, and 60 months were 96.8, 90.9, 84.2, 81.4, 74.2, and 71.2%, respectively. Overall, 18% of patients developed sensory disturbances. Patients with volume 65 30 mm3 were more likely to maintain pain relief (p = 0.031), and low integral dose (< 1.4 mJ) tended to be associated with more pain recurrence than intermediate (1.4-2.7 mJ) or high integral dose (> 2.7 mJ; low vs. intermediate: log-rank test, \u3c72 = 5.02, p = 0.019; low vs. high: log-rank test, \u3c72 = 6.026, p = 0.014). MS, integral dose, and mean dose were the factors associated with pain recurrence, while re-irradiation and MS were predictors for sensory disturbance in the multivariate analysis. Conclusions: The dose to nerve volume ratio is predictive of pain recurrence in TN, and re-irradiation has a major impact on the development of sensory disturbances after non-isocentric SRS. Interestingly, the integral dose may differ significantly in treatments using apparently similar dose and volume constraints

Efficacy and safety of CyberKnife radiosurgery in elderly patients with brain metastases: A retrospective clinical evaluation

Background: Stereotactic radiosurgery (SRS) has been increasingly applied for up to 10 brain metastases instead of whole brain radiation therapy (WBRT) to achieve local tumor control while reducing neurotoxicity. Furthermore, brain-metastasis incidence is rising due to the increasing survival of patients with cancer. Our aim was to analyze the efficacy and safety of CyberKnife (CK) radiosurgery for elderly patients. Methods: We retrospectively identified all patients with brain metastases 65 65 years old treated with CK-SRS at our institution since 2011 and analyzed data of primary diseases, multimodality treatments, and local therapy effect based on imaging follow-up and treatment safety. Kaplan-Meier analysis for local progression-free interval and overall survival were performed. Results: We identified 97 patients (233 lesions) fulfilling the criteria at the first CK-SRS. The mean age was 73.2 \ub1 5.8 (range: 65.0-87.0) years. Overall, 13.4% of the patients were > 80 years old. The three most frequent primary cancers were lung (40.2%), kidney (22.7%), and malignant melanoma (15.5%). In 38.5% (47/122 treatments) multiple brain metastases were treated with the CK-SRS, with up to eight lesions in one session. The median planning target volume (PTV) was 1.05 (range: 0.01-19.80) cm3. A single fraction was applied in 92.3% of the lesions with a median prescription dose of 19 (range: 12-21) Gy. The estimated overall survivals at 3-, 6-, and 12 months after SRS were 79, 55, and 23%, respectively. The estimated local tumor progression-free intervals at 6-, 12-, 24-, 36-, and 72 months after SRS were 99.2, 89.0, 67.2, 64.6, and 64.6%, respectively. Older age and female sex were predictive factors of local progression. The Karnofsky performance score remained stable in 97.9% of the patients; only one patient developed a neurological deficit after SRS of a cerebellar lesion (ataxia, CTCAE Grade 2). Conclusions: SRS is a safe and efficient option for the treatment of elderly patients with brain metastases with good local control rates without the side effects of WBRT. Older age and female sex seem to be predictive factors of local progression. Prospective studies are warranted to clarify the role of SRS treatment for elderly patients

Establishment and validation of cyberknife irradiation in a syngeneic glioblastoma mouse model

CyberKnife stereotactic radiosurgery (CK-SRS) precisely delivers radiation to intracranial tumors. However, the underlying radiobiological mechanisms at high single doses are not yet fully understood. Here, we established and evaluated the early radiobiological effects of CK-SRS treatment at a single dose of 20 Gy after 15 days of tumor growth in a syngeneic glioblastoma-mouse model. Exact positioning was ensured using a custom-made, non-invasive, and trackable frame. One superimposed target volume for the CK-SRS planning was created from the fused tumor volumes obtained from MRIs prior to irradiation. Dose calculation and delivery were planned using a single-reference CT scan. Six days after irradiation, tumor volumes were measured using MRI scans, and radiobiological effects were assessed using immunofluorescence staining. We found that CK-SRS treatment reduced tumor volume by approximately 75%, impaired cell proliferation, diminished tumor vasculature, and increased immune response. The accuracy of the delivered dose was demonstrated by staining of DNA double-strand breaks in accordance with the planned dose distribution. Overall, we confirmed that our proposed setup enables the precise irradiation of intracranial tumors in mice using only one reference CT and superimposed MRI volumes. Thus, our proposed mouse model for reproducible CK-SRS can be used to investigate radiobiological effects and develop novel therapeutic approaches

Treatment Response Assessment in IDH-Mutant Glioma Patients by Noninvasive 3D Functional Spectroscopic Mapping of 2-Hydroxyglutarate

Purpose: Measurements of objective response rates are critical to evaluate new glioma therapies. The hallmark metabolic alteration in gliomas with mutant isocitrate dehydrogenase (IDH) is the overproduction of oncometabolite 2-hydroxyglutarate (2HG), which plays a key role in malignant transformation. 2HG represents an ideal biomarker to probe treatment response in IDH-mutant glioma patients, and we hypothesized a decrease in 2HG levels would be measureable by in vivo magnetic resonance spectroscopy (MRS) as a result of antitumor therapy. Experimental Design: We report a prospective longitudinal imaging study performed in 25 IDH-mutant glioma patients receiving adjuvant radiation and chemotherapy. A newly developed 3D MRS imaging was used to noninvasively image 2HG. Paired Student t test was used to compare pre- and posttreatment tumor 2HG values. Test-retest measurements were performed to determine the threshold for 2HG functional spectroscopic maps (fSM). Univariate and multivariate regression were performed to correlate 2HG changes with Karnofsky performance score (KPS). Results: We found that mean 2HG (2HG/Cre) levels decreased significantly (median=48.1%; 95% confidence interval=27.3%-56.5%; P=0.007) in the posttreatment scan. The volume of decreased 2HG correlates (R2=0.88, P=0.002) with clinical status evaluated by KPS. Conclusions: We demonstrate that dynamic measurements of 2HG are feasible by 3D fSM, and the decrease of 2HG levels can monitor treatment response in patients with IDH-mutant gliomas. Our results indicate that quantitative in vivo 2HG imaging maybe used for precision medicine and early response assessment in clinical trials of therapies targeting IDH-mutant gliomas

Antipsychotic treatment resistance in first-episode psychosis: prevalence, subtypes and predictors

Background: We examined longitudinally the course and predictors of treatment resistance in a large cohort of first-episode psychosis (FEP) patients from initiation of antipsychotic treatment. We hypothesized that antipsychotic treatment resistance is: (a) present at illness onset; and (b) differentially associated with clinical and demographic factors. Method: The study sample comprised 323 FEP patients who were studied at first contact and at 10-year follow-up. We collated clinical information on severity of symptoms, antipsychotic medication and treatment adherence during the follow-up period to determine the presence, course and predictors of treatment resistance. Results: From the 23% of the patients, who were treatment resistant, 84% were treatment resistant from illness onset. Multivariable regression analysis revealed that diagnosis of schizophrenia, negative symptoms, younger age at onset, and longer duration of untreated psychosis predicted treatment resistance from illness onset. Conclusions: The striking majority of treatment-resistant patients do not respond to first-line antipsychotic treatment even at time of FEP. Clinicians must be alert to this subgroup of patients and consider clozapine treatment as early as possible during the first presentation of psychosis

Targetable Signaling Pathway Mutations Are Associated with Malignant Phenotype in IDH-Mutant Gliomas

Purpose: Isocitrate dehydrogenase (IDH) gene mutations occur in low-grade and high-grade gliomas. We sought to identify the genetic basis of malignant phenotype heterogeneity in IDH-mutant gliomas. Methods: We prospectively implanted tumor specimens from 20 consecutive IDH1-mutant glioma resections into mouse brains and genotyped all resection specimens using a CLIA-certified molecular panel. Gliomas with cancer driver mutations were tested for sensitivity to targeted inhibitors in vitro. Associations between genomic alterations and outcomes were analyzed in patients. Results: By 10 months, 8 of 20 IDH1-mutant gliomas developed intracerebral xenografts. All xenografts maintained mutant IDH1 and high levels of 2-hydroxyglutarate on serial transplantation. All xenograft-producing gliomas harbored “lineage-defining” mutations in CIC (oligodendroglioma) or TP53 (astrocytoma), and 6 of 8 additionally had activating mutations in PIK3CA or amplification of PDGFRA, MET, or N-MYC. Only IDH1 and CIC/TP53 mutations were detected in non–xenograft-forming gliomas (P = 0.0007). Targeted inhibition of the additional alterations decreased proliferation in vitro. Moreover, we detected alterations in known cancer driver genes in 13.4% of IDH-mutant glioma patients, including PIK3CA, KRAS, AKT, or PTEN mutation or PDGFRA, MET, or N-MYC amplification. IDH/CIC mutant tumors were associated with PIK3CA/KRAS mutations whereas IDH/TP53 tumors correlated with PDGFRA/MET amplification. Presence of driver alterations at progression was associated with shorter subsequent progression-free survival (median 9.0 vs. 36.1 months; P = 0.0011). Conclusion: A subset of IDH-mutant gliomas with mutations in driver oncogenes has a more malignant phenotype in patients. Identification of these alterations may provide an opportunity for use of targeted therapies in these patients.Koch Institute Dana Farber/Harvard Cancer Center Bridge Projec

Effect of an education program on improving knowledge of schizophrenia among parents of junior and senior high school students in Japan

<p>Abstract</p> <p>Background</p> <p>Early detection and intervention in schizophrenia are important in improving quality of life after treatment and are major issues in psychiatric care. Therefore, it is necessary to increase knowledge of schizophrenia among the general public. Among parents of junior and senior high school students in Japan, we compared rates of correct answers for items on knowledge of schizophrenia and ability to discriminate this psychosis from other disorders on questionnaires given before and after viewing a web-based education program.</p> <p>Methods</p> <p>Questionnaires were distributed to 2,690 parents. The program was developed to help parents obtain a basic understanding of schizophrenia and to emphasize the necessity of early detection.</p> <p>Results</p> <p>Before the program, the rate of correct answers was 77% for items concerning basic knowledge of schizophrenia, 47% for "discrimination of schizophrenia symptoms," and 30% for "discrimination of prodromal symptoms." The program resulted in an improvement in basic knowledge of schizophrenia, discrimination of schizophrenia symptoms, and discrimination of prodromal symptoms (<it>P </it>< 0.001 for all).</p> <p>Conclusions</p> <p>Our web-based education program was useful in helping parents acquire a basic knowledge of schizophrenia and discriminate correctly the symptoms of schizophrenia.</p

Mechanics Regulates Fate Decisions of Human Embryonic Stem Cells

Research on human embryonic stem cells (hESCs) has attracted much attention given their great potential for tissue regenerative therapy and fundamental developmental biology studies. Yet, there is still limited understanding of how mechanical signals in the local cellular microenvironment of hESCs regulate their fate decisions. Here, we applied a microfabricated micromechanical platform to investigate the mechanoresponsive behaviors of hESCs. We demonstrated that hESCs are mechanosensitive, and they could increase their cytoskeleton contractility with matrix rigidity. Furthermore, rigid substrates supported maintenance of pluripotency of hESCs. Matrix mechanics-mediated cytoskeleton contractility might be functionally correlated with E-cadherin expressions in cell-cell contacts and thus involved in fate decisions of hESCs. Our results highlighted the important functional link between matrix rigidity, cellular mechanics, and pluripotency of hESCs and provided a novel approach to characterize and understand mechanotransduction and its involvement in hESC function

Housing metadata for the common physicist using a relational database

SAM was developed as a data handling system for Run II at Fermilab. SAM is a collection of services, each described by metadata. The metadata are modeled on a relational database, and implemented in ORACLE. SAM, originally deployed in production for the D0 Run II experiment, has now been also deployed at CDF and is being commissioned at MINOS. This illustrates that the metadata decomposition of its services has a broader applicability than just one experiment. A joint working group on metadata with representatives from ATLAS, BaBar, CDF, CMS, D0, and LHCB in cooperation with EGEE has examined this metadata decomposition in the light of general HEP user requirements. Greater understanding of the required services of a performant data handling system has emerged from Run II experience. This experience is being merged with the understanding being developed in the course of LHC experience with data challenges and user case discussions. We describe the SAM schema and the commonalities of function and service support between this schema and proposals for the LHC experiments. We describe the support structure required for SAM schema updates, the use of development, integration, and production instances. We are also looking at the LHC proposals for the evolution of schema using keyword-value pairs that are then transformed into a normalized, performant database schema