| 1. |
- Northcott, Paul A, et al.
(författare)
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Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma.
- 2014
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 511:7510, s. 428-428
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Tidskriftsartikel (refereegranskat)abstract
- Medulloblastoma is a highly malignant paediatric brain tumour currently treated with a combination of surgery, radiation and chemotherapy, posing a considerable burden of toxicity to the developing child. Genomics has illuminated the extensive intertumoral heterogeneity of medulloblastoma, identifying four distinct molecular subgroups. Group 3 and group 4 subgroup medulloblastomas account for most paediatric cases; yet, oncogenic drivers for these subtypes remain largely unidentified. Here we describe a series of prevalent, highly disparate genomic structural variants, restricted to groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family proto-oncogenes, GFI1 and GFI1B. Somatic structural variants juxtapose GFI1 or GFI1B coding sequences proximal to active enhancer elements, including super-enhancers, instigating oncogenic activity. Our results, supported by evidence from mouse models, identify GFI1 and GFI1B as prominent medulloblastoma oncogenes and implicate 'enhancer hijacking' as an efficient mechanism driving oncogene activation in a childhood cancer.
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| 2. |
- Figaji, Anthony A., et al.
(författare)
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Pressure autoregulation, intracranial pressure, and brain tissue oxygenation in children with severe traumatic brain injury
- 2009
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Ingår i: Journal of Neurosurgery: Pediatrics. - 1933-0715. ; 4:5, s. 420-428
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Tidskriftsartikel (refereegranskat)abstract
- Object. Cerebral pressure autoregulation is an important neuroprotective mechanism that stabilizes cerebral blood flow when blood pressure (BP) changes In this study the authors examined the association between autoregulation and clinical factors. BR. intracranial pressure (ICP), brain tissue oxygen tension (PbtO(2)), and outcome after pediatric severe traumatic brain injury (TBI). In particular we examined how the Status 01: autoregulation influenced the effect of BP changes on ICP and PbtO(2) Methods In this prospective observational study. 52 autoregulation tests were performed in 24 patients with severe. TBI. The patients had a mean age of 6.3 +/- 3.2 years. and a postresuscitation Glasgow Coma Scale score of 6 (range 3-8). All patients underwent continuous ICP and MID, monitoring. and transcranial Doppler ultrasonography was, used to examine the autoregulatory index (ARI) based on blood flow velocity of the middle cerebral artery after increasing mean arterial pressure by 20% of the baseline value Impaired autoregulation was defined as an ARI < 0 4 and intact autoregulation as an ART >= 0 4 The relationships between autoregulation (measured as both a Continuous and dichotomous variable), outcome, and clinical and physiological variables were examined using Multiple logistic regression analysis Results. Autoregulation was impaired (ART < 0 4) in 29% of patients (7 patients). The initial Glasgow Coma Scale score was significantly associated with the ARI (p = 0.02, r = 0.32) but no other clinical factors were associated with autoregulation Status. Baseline values at the time of testing for ICP, PbtO(2), the ratio PbtO(2)/PaO2, mean arterial pressure, and middle cerebral artery blood flow velocity were similar in the patients with impaired or intact autoregulation. There was an inverse relationship between ART (continuous and dichotomous) with a chancle in ICP (continuous ARI, p 0.005, dichotomous ARI, p = 0 02): that is. ICP increased with the BP increase when ARI was low (weak autoregulation) The ART (continuous and dichotomous) was also inversely associated with a change in PbtO(2). (continuous ART. p 0.002. dichotomous ARI, p = 0 02). The PbtO(2) increased when BP was increased in most patients, even when the ARI was relatively high (stronger autoregulation). but the magnitude of this response was still associated with the ART. There was no relationship between the ART and Outcome Conclusion. These data demonstrate the influence of the strength of autoregulation on the response of ICP and MO. to BP changes and the variability of this response between individuals The findings suggest that autoregulation testing may assist clinical decision-making in pediatric severe TBI and help better define optimal BP or cerebral perfusion pressure targets for individual patients. (DOI: 10.3171/2009.6.PEDS096)
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| 3. |
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| 4. |
- Al-Shudifat, Abdul Rahman Mohummad, et al.
(författare)
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A Patient-Assessed Morbidity to Evaluate Outcome in Surgically Treated Vestibular Schwannomas
- 2016
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Ingår i: World Neurosurgery. - : Elsevier BV. - 1878-8750. ; 94, s. 2-550
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Outcome after treatment of vestibular schwannomas can be evaluated by health providers as mortality, recurrence, performance, and morbidity. Because mortality and recurrence are rare events, evaluation has to focus on performance and morbidity. The latter has mostly been reported by health providers. In the present study, we validate 2 new scales for patient-assessed performance and morbidity in comparison with different outcome tools, such as quality of life (QOL) (European Quality of Life-5 dimensions [EQ-5D]), facial nerve score, and work capacity.METHODS: There were 167 total patients in a retrospective (n = 90) and prospective (n = 50) cohort of surgically treated vestibular schwannomas. A new patient-assessed morbidity score (paMS), a patient-assessed Karnofsky score (paKPS), the patient-assessed QOL (EQ-5D) score, work capacity, and the House-Brackmann facial nerve score were used as outcome measures. Analysis of paMS components and their relation to other outcomes was done as uni- and multivariate analysis.RESULTS: All outcome instruments, except EQ-5D and paKPS, showed a significant decrease postoperatively. Only the facial nerve score (House-Brackmann facial nerve score) differed significantly between the retrospective and prospective cohorts. Out of the 16 components of the paMS, hearing dysfunction, tear dysfunction, balance dysfunction, and eye irritation were most often reported. Both paMS and EQ-5D correlated significantly with work capacity.CONCLUSIONS: Standard QOL and performance instruments may not be sufficiently sensitive or specific to measure outcome at the cohort level after surgical treatment of vestibular schwannomas. A morbidity score may yield more detailed information on symptoms that can be relevant for rehabilitation and occupational training after surgery.
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| 5. |
- Azatyan, Ani, et al.
(författare)
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Circular rnas in hedgehog signaling activation and hedgehog‐mediated medulloblastoma tumors
- 2021
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 13:20
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Tidskriftsartikel (refereegranskat)abstract
- Within the past decade, circular RNAs have largely emerged as novel regulators of human biology, including brain function and cancer development. On the other hand, the Hedgehog pathway has established roles in regulating biological processes, including tumorigenesis. Here, the circular RNA transcriptome, in the context of Hedgehog signaling activation of medulloblastoma Daoy and human embryonic palatal mesenchyme HEPM cells, was determined. In total, 29 out of the 30 selected circular RNAs were validated by Sanger sequencing, with some regulated to a lim-ited extent by Hedgehog signaling. Interestingly, back‐spliced junctions, the marker of exonic RNA circles, were also identified at a low frequency within poly (A) mRNAs, reflecting exon repetition events. Thirteen circular RNAs had reduced expression in human medulloblastoma tumors in comparison to normal cerebellum. For seven out of these thirteen RNA circles, the linear mRNAs origi-nating from the same genes did not exhibit a reduced expression. Depletion and/or overexpression of these seven circular RNAs minimally affected medulloblastoma cell proliferation. These findings highlight that differential expression of a gene product may not necessarily elicit an obvious phenotypic impact. Consequently, further analysis is required to determine the possible subtle contri-butions to the development of this cerebellar tumor.
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| 6. |
- Figaji, Anthony A., et al.
(författare)
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Transcranial Doppler pulsatility index is not a reliable indicator of intracranial pressure in children with severe traumatic brain injury
- 2009
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Ingår i: Surgical Neurology. - : Elsevier BV. - 0090-3019. ; 72:4, s. 389-394
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Tidskriftsartikel (refereegranskat)abstract
- Background: The TCD-derived PI has been associated with ICP in adult studies but has not been well investigated in children. We examined the relationship between PI and ICP and CPP in children with severe TBI. Methods: Data were prospectively collected from consecutive TCD studies in children with severe TBI undergoing ICP monitoring. Ipsilateral ICP and CPP values were examined with Spearman correlation coefficient (mean values and raw observations), with a GEE, and as binary values (1 and 20 mm Hg, respectively). Results: Thirty-four children underwent 275 TCD studies. There was a weak relationship between mean values of ICP and PI (P = .04, r = 0.36), but not when raw observations (P = .54) or GEE (P = .23) were used. Pulsatility index was 0.76 when ICP was lower than 20 mm Hg and 0.86 when ICP was 20 mm Hg or higher. When PI was 1 or higher, ICP was lower than 20 mm Hg in 62.5% (25 of 40 studies), and when ICP was 20 mm Hg or higher, PI was lower than 1 in 75% (46 of 61 studies). The sensitivity and specificity of a PI threshold of 1 for examining the ICP threshold of 20 mm Hg were 25% and 88%, respectively. The relationship between CPP and PI was stronger (P = .001, r -0.41), but there were too few observations below 50 mm Hg to examine PI at this threshold. Conclusion: The absolute value of the PI is not a reliable noninvasive indicator of ICP in children with severe TBI. Further study is required to examine the relationship between PI and a CPP threshold of 50 mm Hg. (C) 2009 Elsevier Inc. All rights reserved.
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| 7. |
- Janelidze, Shorena, et al.
(författare)
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Immunizations With IFN gamma Secreting Tumor Cells can Eliminate Fully Established and Invasive Rat Gliomas
- 2009
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Ingår i: Journal of Immunotherapy. - 1524-9557. ; 32:6, s. 593-601
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Tidskriftsartikel (refereegranskat)abstract
- Immunotherapy of malignant primary brain tumors holds the potential to improve the dismal prognosis after current clinical therapy. Although immunotherapy of experimental gliomas has been demonstrated to have the capacity to cure intracerebral tumors no convincing effects of immunotherapy have been shown in clinical trials. One reason for this could be that some of the models used do not display full features of human glioblastomas. The N29 rat gliomas exhibited all the histologic features of human glioblastoma multiforme including nuclear atypia, mitotic figures, necrosis, and diffuse infiltration into the normal brain tissue. Surprisingly, immunotherapy with autologous interferon gamma producing tumor cells against preestablished intracerebral N29 turners yielded a higher cure rate than immunotherapy against less invasive tumors. Furthermore, when immunizations were postponed until day 5 after tumor establishment 50% of the animals survived. When immunizations were postponed until day 11 after tumor establishment no glioma-bearing animals were cured but survival was significantly prolonged. The superior effect of immunotherapy in the invasive N29 model compared with the less invasive tumors could depend oil combined effects of up-regulation of major histocompatibility complex I and induction of major histocompatibility complex II plus CD80 after transfection and irradiation of the tumor cells used for immunizations. This study demonstrates that immunotherapy against experimental brain tumors indeed is feasible even against highly invasive and established tumors. These results strengthen the translational potential of immunotherapy against malignant brain tumors.
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| 8. |
- Uvelius, Erik, et al.
(författare)
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An early post-operative ACTH suppression test can safely predict short- and long-term remission after surgery of Cushing’s disease
- 2018
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Ingår i: Pituitary. - : Springer Science and Business Media LLC. - 1386-341X .- 1573-7403. ; 21:5, s. 490-498
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The present study evaluates the usefulness of an ACTH suppression test shortly after surgery, and to determine optimal cut-off values of included laboratory analyses, in predicting short- and long-term remission after surgery of Cushing’s disease. Methods: A 48 h suppression test with betamethasone 2 mg/day applied after 45 transphenoidal adenomectomies in 28 patients was evaluated. Receiver operating characteristic (ROC)-curves were created for the included assays: plasma cortisol, plasma adrenocorticotropic hormone (ACTH) and urinary free cortisol (UFC). Plasma levels of cortisol and ACTH were measured both at 24 and 48 h. Youden’s index was used to determine cut-off with the highest sensitivity and specificity in predicting short- (3 months) and long-term (5 years or longer) remission. The area under curve (AUC) illustrated the clinical accuracy of the different assays. Results: Plasma cortisol after 24 h with betamethasone was most accurate in predicting both short- and long-term remission. 3 months remission with cut-off 107 nmol/L: sensitivity 0.85, specificity 0.94, positive predictive value (PPV) 0.96 and AUC 0.92 (95% CI 0.85–1). 5 years remission with cut-off 49 nmol/L: sensitivity: 0.94, specificity 0.93, PPV 0.88, AUC 0.98 (95% CI 0.95–1). Analyses of ACTH or UFC did not improve diagnostic accuracy. Conclusions: A 48 h, 2 mg/day betamethasone suppression test after transphenoidal surgery of Cushing’s disease could predict short- and long-term remission with a high accuracy. Suppression of plasma cortisol after 24 h with betamethasone to values excluding Cushings disease in the diagnostic setting yielded the highest accuracy in predicting long-term remission.
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| 9. |
- Uvelius, Erik, et al.
(författare)
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Quality of Life and Work Capacity Are Unrelated to Approach or Complications After Pituitary Surgery
- 2017
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Ingår i: World Neurosurgery. - : Elsevier BV. - 1878-8750. ; 108, s. 24-32
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Tidskriftsartikel (refereegranskat)abstract
- Objective Endoscopic pituitary surgery has shown favorable clinical outcomes. Less is known about the impact of surgical approaches on health-related quality of life (HRQoL) and work capacity. The present study was undertaken to compare transsphenoidal microscope-assisted surgery with endoscopic transsphenoidal surgery regarding preoperative and surgical factors for the final outcome of HRQoL and work capacity. Methods In a retrospective study of patients operated on for pituitary adenoma, outcome was compared between those operated on before and after transition with endoscopic surgery at our department. Data were gathered via patient questionnaires and patients' files. Results After exclusions, 235 patients were included (99 microsurgical and 136 endoscopic). Frequency of complications was similar but tumor size was significantly larger in the endoscopic group. Complications did not affect HRQoL or work capacity. HRQoL was not affected by surgical technique but showed an overall trend toward lower values compared with the general population. Sick leave, return to work frequency, and permanent sick leave were not affected by surgical technique. Female gender was a factor for lower ratings in all outcome variables. Conclusions Surgical technique does not influence HRQoL or work capacity in this long-term follow-up although both are decreased compared with the general population. We conclude that fully endoscopic pituitary surgery, despite including larger tumors, bears the same risk for complications as microsurgery. In addition, females have a greater risk for decrease in HRQoL and work ability. This factor should be taken into account when informing patients and appreciating expectations of treatment.
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| 10. |
- Badn, Wiaam, et al.
(författare)
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Inhibition of Inducible Nitric Oxide Synthase Enhances Anti-tumour Immune Responses in Rats Immunized with IFN-gamma-Secreting Glioma Cells.
- 2007
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Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 1365-3083 .- 0300-9475. ; 65:3, s. 289-297
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Tidskriftsartikel (refereegranskat)abstract
- Interferon gamma (IFN-gamma) has successfully been used in immunotherapy of different experimental tumours. Mechanistically, IFN-gamma has extensive effects on the immune system including release of nitric oxide (NO) by upregulation of the inducible nitric oxide synthase (iNOS). NO has putative immunosuppressive effects but could also play a role in killing of tumour cells. Therefore, the aim of the present study was to clarify whether inhibition of iNOS in rats immunized with glioma cells (N32) producing IFN-gamma (N32-IFN-gamma), could enhance the anti-tumour immune response. Initially, both a selective iNOS, L-N-6-(I-Iminoethyl)-L-lysine (L-NIL), and non-selective, N-nitro-L-arginine methyl ester (L-NAME), inhibitor of NOS were tested in vitro. After polyclonal stimulation with LPS and SEA, both L-NIL and L-NAME enhanced proliferation and production of IFN-gamma from activated rat splenocytes and this effect was inversely correlated to the production of NO. However, L-NIL had a broader window of efficacy and a lower minimal effective dose. When rats were immunized with N32-IFN-gamma), and administered NOS inhibitors by intraperitoneal (i.p.) mini-osmotic pumps, only splenocytes of rats treated with L-NIL, but not L-NAME, displayed an enhanced proliferation and production of IFN-gamma when re-stimulated with N32 tumour cells. Based on these findings, L-NIL was administered concurrently with N32-IFN-gamma cells to rats with intracerebral (i.c.) tumours resulting in a prolonged survival. These results show that inhibition of iNOS can enhance an IFN-gamma-based immunotherapy of experimental i.c. tumours implying that NO released after immunization has mainly immunosuppressive net effects.
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