1. |
- Northcott, Paul A, et al.
(author)
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Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma.
- 2014
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 511:7510, s. 428-428
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Journal article (peer-reviewed)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.
(author)
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Pressure autoregulation, intracranial pressure, and brain tissue oxygenation in children with severe traumatic brain injury
- 2009
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In: Journal of Neurosurgery: Pediatrics. - 1933-0715. ; 4:5, s. 420-428
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Journal article (peer-reviewed)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.
(author)
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A Patient-Assessed Morbidity to Evaluate Outcome in Surgically Treated Vestibular Schwannomas
- 2016
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In: World Neurosurgery. - : Elsevier BV. - 1878-8750. ; 94, s. 2-550
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Journal article (peer-reviewed)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.
(author)
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Circular rnas in hedgehog signaling activation and hedgehog‐mediated medulloblastoma tumors
- 2021
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In: Cancers. - : MDPI AG. - 2072-6694. ; 13:20
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Journal article (peer-reviewed)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.
(author)
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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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In: Surgical Neurology. - : Elsevier BV. - 0090-3019. ; 72:4, s. 389-394
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Journal article (peer-reviewed)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.
(author)
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Immunizations With IFN gamma Secreting Tumor Cells can Eliminate Fully Established and Invasive Rat Gliomas
- 2009
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In: Journal of Immunotherapy. - 1524-9557. ; 32:6, s. 593-601
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Journal article (peer-reviewed)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.
(author)
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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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In: Pituitary. - : Springer Science and Business Media LLC. - 1386-341X .- 1573-7403. ; 21:5, s. 490-498
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Journal article (peer-reviewed)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.
(author)
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Quality of Life and Work Capacity Are Unrelated to Approach or Complications After Pituitary Surgery
- 2017
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In: World Neurosurgery. - : Elsevier BV. - 1878-8750. ; 108, s. 24-32
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Journal article (peer-reviewed)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.
(author)
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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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In: Scandinavian Journal of Immunology. - : Wiley. - 1365-3083 .- 0300-9475. ; 65:3, s. 289-297
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Journal article (peer-reviewed)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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11. |
- Badn, Wiaam, et al.
(author)
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Postimmunization with IFN-gamma-secreting glioma cells combined with the inducible nitric oxide synthase inhibitor mercaptoethylguanidine prolongs survival of rats with intracerebral tumors
- 2007
-
In: Journal of Immunology. - 1550-6606. ; 179:6, s. 4231-4238
-
Journal article (peer-reviewed)abstract
- High-grade gliomas are one of the most aggressive human tumors with <1% of patients surviving 5 years after surgery. Immunotherapy could offer a possibility to eradicate remnant tumor cells after conventional therapy. Experimental immunotherapy can induce partial cure of established intracerebral tumors in several rodent models. One reason for the limited therapeutic effects could be immunosuppression induced by both the growing tumor and the induced immune reaction. NO has been implicated in tumor-derived immune suppression in tumor-bearing hosts, and unspecific inhibitors of NO synthase have been shown to boost antitumor immunity. In this study, we show that the inducible NO synthase (iNOS)-specific inhibitor mercaptoethylguanidine (MEG) superiorly enhanced lymphocyte reactivity after polyclonal stimulation compared with the iNOS-specific inhibitor L-NIL and the unspecific NO synthase inhibitor L-NAME. Both iNOS inhibitors increased the number and proliferation of T cells but not of B cells. When combined during postimmunization with IFN-gamma-secreting N32 rat glioma cells of rats harboring intracerebral tumors, only MEG increased the cure rate. However, this was only achieved when MEG was administered after immunizations. These findings implicate that NO has both enhancing and suppressive effects after active immunotherapy.
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12. |
- Badn, Wiaam, et al.
(author)
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The Dual Role of Nitric Oxide in Glioma
- 2010
-
In: Current Pharmaceutical Design. - 1381-6128. ; 16:4, s. 428-430
-
Research review (peer-reviewed)abstract
- Malignant gliomas bear the most dismal prognosis of all human cancers despite the progress in therapy of many other tumors. The search for alternative and complementary treatments has therefore a high priority. Emerging knowledge of the dual and diverging role of nitric oxide in glioma biology has focused on possibilities to achieve anti-glioma effects by modulation of nitric oxide (NO) release and function in these tumors. NO has been shown to influence proliferation of glioma cells, vascular function in glioams, invasive capacity of gliomas, effects of chemo and radiotherapy and also immune reactivity against these tumors. The mechanisms behind the reported diverse and dual effects of NO in glioma biology are multiple. Some of the diversity can be explained by different experimental setups as in vitro versus in vivo models but the cellular sources, timing, absolute levels and gradients play a decisive role for the effects of NO on glioma biology. Current research in this field is hampered by the lack of inhibitors and donors approved for clinical use.
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13. |
- Baryawno, Ninib, et al.
(author)
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Detection of human cytomegalovirus in medulloblastomas reveals a potential therapeutic target
- 2011
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In: Journal of Clinical Investigation. - 0021-9738 .- 1558-8238. ; 121:10, s. 4043-4055
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Journal article (peer-reviewed)abstract
- Medulloblastomas are the most common malignant brain tumors in children. They express high levels of COX-2 and produce PGE(2), which stimulates tumor cell proliferation. Human cytomegalovirus (HCMV) is prevalent in the human population and encodes proteins that provide immune evasion strategies and promote oncogenic transformation and oncomodulation. In particular, HCMV induces COX-2 expression; STAT3 phosphorylation; production of PGE2, vascular endothelial growth factor, and IL-6; and tumor formation in vivo. Here, we show that a large proportion of primary medulloblastomas and medulloblastoma cell lines are infected with HCMV and that COX-2 expression, along with PGE2 levels, in tumors is directly modulated by the virus. Our analysis indicated that both HCMV immediate-early proteins and late proteins are expressed in the majority of primary medulloblastomas. Remarkably, all of the human medulloblastoma cell lines that we analyzed contained HCMV DNA and RNA and expressed HCMV proteins at various levels in vitro. When engrafted into immunocompromised mice, human medulloblastoma cells induced expression of HCMV proteins. HCMV and COX-2 expression correlated in primary tumors, cell lines, and medulloblastoma xenografts. The antiviral drug valganciclovir and the specific COX-2 inhibitor celecoxib prevented HCMV replication in vitro and inhibited PGE2 production and reduced medulloblastoma tumor cell growth both in vitro and in vivo. Ganciclovir did riot affect the growth of HCMV-negative tumor cell lines. These findings imply an important role for HCMV in medulloblastoma and suggest HCMV as a novel therapeutic target for this tumor.
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14. |
- Berntsson, Shala Ghaderi, 1964-
(author)
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Towards Novel Biomarkers for Low-grade Glioma
- 2012
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Doctoral thesis (other academic/artistic)abstract
- Gliomas are common primary brain tumours that occur as low-grade (LGG) and high-grade gliomas (HGG). Typically occurring in younger adults, LGG has an indolent course with a median survival of 5-10 years, but carries an inherent potential for transforming into HGG. The thesis focused on LGG in adults, with the aim of identifying prognostic biomarkers for LGG.Paper I. Epileptic seizures are common symptoms in LGG. In a retrospective study, the correlation between 11C-methionine (MET) uptake, measured by Positron Emission Tomography (PET), and seizure activity was assessed in 101 patients with LGG. Although there was no correlation between MET uptake and seizure activity, survival was longer in patients who were seizure-free before surgery.Paper II. This finding prompted the search for common genetic pathways for both tumour and seizure development and a review of genetic polymorphisms in focal epilepsy and glioma risk. Cell cycle and immune response genes affecting both glioma and seizure risk were identified, and genes involved in synaptic transmission presented potential candidates for future studies.Paper III. The transcription factor PROX1 plays a pivotal role in normal development and carcinogenesis of various organs. The prognostic value of PROX1, together with established clinical and molecular prognostic factors for survival, was retrospectively assessed in 116 patients with LGG. High PROX1 expression in the tumour was associated with shorter survival.Paper IV. DNA repair enzymes, such as ERCC6, are crucial for maintaining genomic stability in glioma response to radiotherapy. An association between the polymorphism rs4253079, mapped to ERCC6, and longer survival in patients with LGG and HGG was identified.Paper V. As LGG typically presented as non-contrast enhancing tumours on morphological MRI (magnetic resonance imaging), the value of combined MET PET with physiological MRI for preoperative diagnosis was assessed in a prospective study of 32 patients with suspected LGG. Representative tumour areas were identified through a combination of perfusion-MRI with MET PET, which can be used as a baseline investigation for follow-up over time.Conclusions: The parameters seizure-freedom before surgery, the polymorphism rs4253079 in ERCC6 and low PROX1 expression in the tumor were identified as favorable prognostic biomarkers.
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15. |
- Bexell, Daniel, et al.
(author)
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CD133+ and nestin+ tumor-initiating cells dominate in N29 and N32 experimental gliomas.
- 2009
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In: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 125:1, s. 15-22
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Journal article (peer-reviewed)abstract
- The current study was designed to critically evaluate the notion that cancer stem cell (CSC)-like cells constitute a subpopulation of cells within experimental gliomas. Virtually all cells within the N29 and N32 rat glioma models homogenously expressed CD133, the stem/progenitor marker nestin as well as the neural lineage markers glial fibrillary acidic protein, betaIII-tubulin, and CNPase in vitro. The phenotype was largely retained on exposure to conditions promoting differentiation in vitro and after intracranial implantation of tumor cells into syngeneic hosts. Unsorted adherently grown cells displayed very high clonogenicity in vitro and robust tumorigenicity in vivo. Single N29 and N32 tumor cells invariably formed clones in vitro, and intracerebral inoculation of as few as 10 adherently growing N29 and N32 tumor cells, respectively, gave rise to a tumor. These results provide an alternative view on CSC-like cells in glioma models: sphere-formation is not a prerequisite for accumulation of tumorigenic cells, and CSC-like cells do not reside within a rare subpopulation of cells in these glioma models. N29 and N32 gliomas may accordingly be used for the development of treatment strategies directed specifically against a practically pure population of brain tumor-initiating CSC-like cells. (c) 2009 Wiley-Liss, Inc.
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16. |
- Bexell, Daniel, et al.
(author)
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Rat Multipotent Mesenchymal Stromal Cells Lack Long-Distance Tropism to 3 Different Rat Glioma Models
- 2012
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In: Neurosurgery. - 0148-396X. ; 70:3, s. 731-739
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Journal article (peer-reviewed)abstract
- BACKGROUND: Viral gene therapy of malignant brain tumors has been restricted by the limited vector distribution within the tumors. Multipotent mesenchymal stromal cells (MSCs) and other precursor cells have shown tropism for gliomas, and these cells are currently being explored as potential vehicles for gene delivery in glioma gene therapy. OBJECTIVE: To investigate MSC migration in detail after intratumoral and extratumoral implantation through syngeneic and orthotopic glioma models. METHODS: Adult rat bone marrow-derived MSCs were transduced to express enhanced green fluorescent protein and implanted either directly into or at a distance from rat gliomas. RESULTS: We found no evidence of long-distance MSC migration through the intact striatum toward syngeneic D74(RG2), N32, and N29 gliomas in the ipsilateral hemisphere or across the corpus callosum to gliomas located in the contralateral hemisphere. After intratumoral injection, MSCs migrated extensively, specifically within N32 gliomas. The MSCs did not proliferate within tumors, suggesting a low risk of malignant transformation of in vivo grafted cell vectors. Using a model for surgical glioma resection, we found that intratumorally grafted MSCs migrate efficiently within glioma remnants after partial surgical resection. CONCLUSION: The findings point to limitations for the use of MSCs as vectors in glioma gene therapy, although intratumoral MSC implantation provides a dense and tumor-specific vector distribution.
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17. |
- Borghammar, Camilla, et al.
(author)
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Non-functioning pituitary microadenoma in children and adolescents : Is follow-up with diagnostic imaging necessary?
- 2023
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In: Endocrine. - : Springer Science and Business Media LLC. - 1355-008X .- 1559-0100. ; 79, s. 152-160
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Journal article (peer-reviewed)abstract
- PURPOSE: No consensus exists regarding follow-up recommendations for suspected pituitary microadenoma in children. To address this knowledge gap, we investigated the growth potential of pituitary solid and cystic lesions <10 mm in children and evaluated the accuracy of magnetic resonance imaging (MRI) measurements.METHODS: The children included were <18 years at first pituitary MRI and radiologically diagnosed with a non-functioning microadenoma or cyst <10 mm. Lesion size at first and latest MRI as well as all individual MRI examinations were re-evaluated.RESULTS: In total, 74 children, median age 12 years (range 3-17), had a non-functioning microadenoma, probable microadenoma, or cyst. Of these, 55 underwent repeated MRI (median 3, range 2-7) with a median follow-up of 37 months (range 4-189). None of the pituitary lesions without hormonal disturbances increased significantly during follow-up. Two radiologists agreed that no lesion could be identified in 38/269 (14%) MRI examinations, and in 51/231 (22%) they disagreed about lesion location. In 34/460 (7%) MRI measurements size differed >2 mm, which had been considered significant progression.CONCLUSION: Non-functioning pituitary microadenoma in children has small size variations, often below the spatial resolution of the scanners. We suggest lesions <4 mm only for clinical follow-up, lesions 4-6 mm for MRI after 2 years and ≥7 mm MRI after 1 and 3 years, with clinical follow-up in between. If no progression, further MRI should only be performed after new clinical symptoms or hormonal disturbances.
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18. |
- Cederberg, David, et al.
(author)
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Prolonged and intense neuroinflammation after severe traumatic brain injury assessed by cerebral microdialysis with 300 kDa membranes
- 2023
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In: Journal of Neuroimmunology. - : Elsevier BV. - 0165-5728. ; 377
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Journal article (peer-reviewed)abstract
- Background: A neuroinflammatory response that may lead to edema and secondary brain damage is elicited in severe traumatic brain injury (TBI). Previous studies using microdialysis (MD) membranes with 100 k Dalton (kDa) cut-off found a transient intracerebral release of cytokines and chemokines without significant correlations to clinical course, intracranial pressure (ICP) or metabolites. In this study, a (300 kDa) MD probe was used to measure the levels of cytokines and chemokines in relation to ICP and metabolites. Methods: Seven patients with severe TBI received 2 MD catheters. In four patients sufficient dialysate could be retrieved for analysis from both catheters. MD samples were analyzed bedside, then frozen and analyzed for chemokines and cytokines using a multiplex assay (Mesoscale Discovery). Results: MD sampling was performed from 9 to 350 h. In total, 17 chemokines and cytokines were detected. Of these, IL-6, IL-8, IP-10, MCP-1 and MIP-1β were consistently elevated, and investigated further in relation to metabolites, and ICP. Levels of chemokines and cytokines were higher than previously reported from TBI patients, and partially higher than those reported in patients with cytokine release syndrome. There were no significant differences between the two catheters regarding cytokine/chemokine concentrations, except for IL-6 which was higher in the peri-contusional area. No correlation with metabolites and ICP was observed. No significant increase or decline of chemokine or cytokine secretion was observed during the study period. Conclusion: Our data suggest that cytokine and chemokine levels reflect a perpetual, potent and pan-cerebebral inflammatory response that persists beyond 15 days following TBI.
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19. |
- Cederberg, David, et al.
(author)
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What has inflammation to do with traumatic brain injury?
- 2010
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In: Child's Nervous System. - : Springer Science and Business Media LLC. - 1433-0350 .- 0256-7040. ; 26:2, s. 221-226
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Journal article (peer-reviewed)abstract
- INTRODUCTION: Inflammation is an stereotypical response to tissue damage and has been extensively documented in experimental and clinical traumatic brain injury (TBI), including children. DISCUSSION: The initiation and orchestration of inflammation in TBI, as in other tissues, is complex and multifactorial encompassing pro- and anti-inflammatory cytokines, chemokines, adhesion molecules, complement factors, reactive oxygen and nitrogen species, and other undefined factors. It is evident that inflammation can have both beneficial and detrimental effects in TBI, but the mechanisms underlying this dichotomy are mostly unknown. Modification of the inflammatory response may be neuroprotective. Monitoring inflammation is now possible with techniques such as microdialysis; however, the prognostic value of measuring inflammatory mediators in TBI is still unclear with conflicting reports. Except for corticosteroids, no anti-inflammatory agents have been tested in TBI, and the negative results with these may have been flawed by their multiple side effects. Clinical trials with anti-inflammatory agents that target multiple or central and downstream pathways are warranted in adult and pediatric TBI. This review examines the mechanisms of inflammation after TBI, monitoring, and possible routes of intervention.
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20. |
- de Ståhl, Teresita Diaz, et al.
(author)
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The Swedish childhood tumor biobank : systematic collection and molecular characterization of all pediatric CNS and other solid tumors in Sweden
- 2023
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In: Journal of Translational Medicine. - : BioMed Central (BMC). - 1479-5876. ; 21
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Journal article (peer-reviewed)abstract
- The Swedish Childhood Tumor Biobank (BTB) is a nonprofit national infrastructure for collecting tissue samples and genomic data from pediatric patients diagnosed with central nervous system (CNS) and other solid tumors. The BTB is built on a multidisciplinary network established to provide the scientific community with standardized biospecimens and genomic data, thereby improving knowledge of the biology, treatment and outcome of childhood tumors. As of 2022, over 1100 fresh-frozen tumor samples are available for researchers. We present the workflow of the BTB from sample collection and processing to the generation of genomic data and services offered. To determine the research and clinical utility of the data, we performed bioinformatics analyses on next-generation sequencing (NGS) data obtained from a subset of 82 brain tumors and patient blood-derived DNA combined with methylation profiling to enhance the diagnostic accuracy and identified germline and somatic alterations with potential biological or clinical significance. The BTB procedures for collection, processing, sequencing, and bioinformatics deliver high-quality data. We observed that the findings could impact patient management by confirming or clarifying the diagnosis in 79 of the 82 tumors and detecting known or likely driver mutations in 68 of 79 patients. In addition to revealing known mutations in a broad spectrum of genes implicated in pediatric cancer, we discovered numerous alterations that may represent novel driver events and specific tumor entities. In summary, these examples reveal the power of NGS to identify a wide number of actionable gene alterations. Making the power of NGS available in healthcare is a challenging task requiring the integration of the work of clinical specialists and cancer biologists; this approach requires a dedicated infrastructure, as exemplified here by the BTB.
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21. |
- Eberstål, Sofia, et al.
(author)
-
Immunizations with unmodified tumor cells and simultaneous COX-2 inhibition eradicate malignant rat brain tumors and induce a long-lasting CD8(+) T cell memory.
- 2014
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In: Journal of Neuroimmunology. - : Elsevier BV. - 1872-8421 .- 0165-5728. ; 274:1-2, s. 161-167
-
Journal article (peer-reviewed)abstract
- Malignant brain tumors induce pronounced immunosuppression, which diminishes immune responses generated by immunotherapy. Here we report that peripheral immunotherapy, using irradiated unmodified whole tumor cells, and systemic cyclooxygenase-2 inhibition induce cure in glioma-bearing rats (60% cure rate), whereas neither monotherapy was sufficient to cure any animal. Moreover, the combined therapy protected against secondary tumor challenges (89% cure rate) and the secondary immune response was correlated with increased plasma interferon-gamma levels and CD8(+) T cells systemically and intratumorally. In conclusion, we demonstrate that cyclooxygenase-2 inhibition is sufficient to render unmodified tumor cells immunogenic in immunotherapy of experimental brain tumors.
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22. |
- Eberstål, Sofia, et al.
(author)
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Inhibition of cyclooxygenase-2 enhances immunotherapy against experimental brain tumors.
- 2012
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In: Cancer immunology, immunotherapy. - : Springer Science and Business Media LLC. - 1432-0851 .- 0340-7004. ; 61:8, s. 1191-1199
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Journal article (peer-reviewed)abstract
- Glioblastoma multiforme is the most common and aggressive malignant brain tumor in humans, and the prognosis is very poor despite conventional therapy. Immunotherapy represents a novel treatment approach, but the effect is often weakened by release of immune-suppressive molecules such as prostaglandins. In the current study, we investigated the effect of immunotherapy with irradiated interferon-γ (IFN-γ)-secreting tumor cells and administration of the selective cyclooxygease-2 (COX-2) inhibitor parecoxib as treatment of established rat brain tumors. COX-2 inhibition and immunotherapy significantly enhanced the long-term cure rate (81% survival) compared with immunotherapy alone (19% survival), and there was a significant increase in plasma IFN-γ levels in animals treated with the combined therapy, suggesting a systemic T helper 1 immune response. COX-2 inhibition alone, however, did neither induce cure nor prolonged survival. The tumor cells were identified as the major source of COX-2 both in vivo and in vitro, and unmodified tumor cells produced prostaglandin E(2) in vitro, while the IFN-γ expressing tumor cells secreted significantly lower levels. In conclusion, we show that immunotherapy of experimental brain tumors is greatly potentiated when combined with COX-2 inhibition. Based on our results, the clinically available drug parecoxib may be added to immunotherapy against human brain tumors. Furthermore, the discovery that IFN-γ plasma levels can be used to determine the ongoing in vivo immune response has translational potential.
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23. |
- Eberstål, Sofia, et al.
(author)
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Intratumoral COX-2 inhibition enhances GM-CSF immunotherapy against established mouse GL261 brain tumors.
- 2014
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In: International Journal of Cancer. - : Wiley. - 0020-7136. ; 134:11, s. 2748-2753
-
Journal article (peer-reviewed)abstract
- Immunotherapy has shown effectiveness against experimental malignant brain tumors, but the clinical results have been less convincing most likely due to immunosuppression. Prostaglandin E2 (PGE2 ) is the key immunosuppressive product of cyclooxygenase-2 (COX-2) and increased levels of PGE2 and COX-2 have been shown in several tumor types including brain tumors. In the current study, we report enhanced cure rate of mice with established mouse GL261 brain tumors when immunized with granulocyte macrophage-colony stimulating factor (GM-CSF) secreting tumor cells and simultaneously treated with the selective COX-2 inhibitors parecoxib systemically (5 mg/kg/day; 69% cure rate) or valdecoxib intratumorally (5.3 µg/kg/day; 63% cure rate). Both combined therapies induced a systemic anti-tumor response of proliferating CD4(+) and CD8(+) T cells and further analysis revealed T helper 1 (Th 1) cell supremacy. The GL261 tumor cell line produced very low levels of PGE2 in vitro and co-staining at the tumor site demonstrated that a large fraction of the COX-2(+) cells were derived from CD45(+) immune cells and more specifically macrophages (F4/80(+) ), indicating that tumor-infiltrating immune cells constitute the primary source of COX-2 and PGE2 in this model. We conclude that intratumoral COX-2 inhibition potentiates GM-CSF immunotherapy against established brain tumors at substantially lower doses than systemic administration. These findings underscore the central role of targeting COX-2 during immunotherapy and implicate intratumoral COX-2 as the primary target. © 2013 Wiley Periodicals, Inc.
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24. |
- Ehinger, Erik, et al.
(author)
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Antisecretory factor is safe to use as add-on treatment in newly diagnosed glioblastoma
- 2023
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In: BMC Neurology. - : BioMed Central (BMC). - 1471-2377. ; 23:1
-
Journal article (peer-reviewed)abstract
- PurposeGlioblastoma (GBM) is the most common primary malignant brain tumor in adults. Despite the best available treatment, prognosis remains poor. Current standard therapy consists of surgical removal of the tumor followed by radiotherapy and chemotherapy with the alkylating agent temozolomide (TMZ). Experimental studies suggest that antisecretory factor (AF), an endogenous protein with proposed antisecretory and anti-inflammatory properties, may potentiate the effect of TMZ and alleviate cerebral edema. Salovum is an egg yolk powder enriched for AF and is classified as a medical food in the European Union. In this pilot study, we evaluate the safety and feasibility of add-on Salovum in GBM patients.MethodsEight patients with newly diagnosed, histologically confirmed GBM were prescribed Salovum during concomitant radiochemotherapy. Safety was determined by the number of treatment-related adverse events. Feasibility was determined by the number of patients who completed the full prescribed Salovum treatment.ResultsNo serious treatment-related adverse events were observed. Out of 8 included patients, 2 did not complete the full treatment. Only one of the dropouts was due to issues directly related to Salovum, which were nausea and loss of appetite. Median survival was 23 months.ConclusionsWe conclude that Salovum is safe to use as an add-on treatment for GBM. In terms of feasibility, adherence to the treatment regimen requires a determined and independent patient as the large doses prescribed may cause nausea and loss of appetite.
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25. |
- Enell Smith, Karin, et al.
(author)
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Cure of established GL261 mouse gliomas after combined immunotherapy with GM-CSF and IFNgamma is mediated by both CD8(+) and CD4(+) T-cells.
- 2009
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In: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 124:3, s. 630-637
-
Journal article (peer-reviewed)abstract
- We were the first to demonstrate that combined immunotherapy with GM-CSF producing GL261 cells and recombinant IFNgamma of preestablished GL261 gliomas could cure 90% of immunized mice. To extend these findings and to uncover the underlying mechanisms, the ensuing experiments were undertaken. We hypothesized that immunizations combining both GM-CSF and IFNgamma systemically would increase the number of immature myeloid cells, which then would mature and differentiate into dendritic cells (DCs) and macrophages, thereby augmenting tumor antigen presentation and T-cell activation. Indeed, the combined therapy induced a systemic increase of both immature and mature myeloid cells but also an increase in T regulatory cells (T-regs). Cytotoxic anti-tumor responses, mirrored by an increase in Granzyme B-positive cells as well as IFNgamma-producing T-cells, were augmented after immunizations with GM-CSF and IFNgamma. We also show that the combined therapy induced a long-term memory with rejection of intracerebral (i.c.) rechallenges. Depletion of T-cells showed that both CD4(+) and CD8(+) T-cells were essential for the combined GM-CSF and IFNgamma effect. Finally, when immunizations were delayed until day 5 after tumor inoculation, only mice receiving immunotherapy with both GM-CSF and IFNgamma survived. We conclude that the addition of recombinant IFNgamma to immunizations with GM-CSF producing tumor cells increased the number of activated tumoricidal T-cells, which could eradicate established intracerebral tumors. These results clearly demonstrate that the combination of cytokines in immunotherapy of brain tumors have synergistic effects that have implications for clinical immunotherapy of human malignant brain tumors. (c) 2008 Wiley-Liss, Inc.
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26. |
- Enríquez Pérez, Julio, et al.
(author)
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Convection-enhanced delivery of temozolomide and whole cell tumor immunizations in GL261 and KR158 experimental mouse gliomas
- 2020
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In: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 20
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Glioblastomas (GBM) are therapy-resistant tumors with a profoundly immunosuppressive tumor microenvironment. Chemotherapy has shown limited efficacy against GBM. Systemic delivery of chemotherapeutic drugs is hampered by the difficulty of achieving intratumoral levels as systemic toxicity is a dose-limiting factor. Although some of its effects might be mediated by immune reactivity, systemic chemotherapy can also inhibit induced or spontaneous antitumor immune reactivity. Convection-enhanced delivery of temozolomide (CED-TMZ) can tentatively increase intratumoral drug concentration while reducing systemic side effects. The objective of this study was to evaluate the therapeutic effect of intratumorally delivered temozolomide in combination with immunotherapy and whether such therapy can generate a cellular antitumor immune response. METHODS: Single bolus intratumoral injection and 3-day mini-osmotic pumps (Alzet®) were used to deliver intratumoral TMZ in C57BL6 mice bearing orthotopic gliomas. Immunotherapy consisted of subcutaneous injections of irradiated GL261 or KR158 glioma cells. Tumor size and intratumoral immune cell populations were analyzed by immunohistochemistry. RESULTS: Combined CED-TMZ and immunotherapy had a synergistic antitumor effect in the GL261 model, compared to CED-TMZ or immunotherapy as monotherapies. In the KR158 model, immunization cured a small proportion of the mice whereas addition of CED-TMZ did not have a synergistic effect. However, CED-TMZ as monotherapy prolonged the median survival. Moreover, TMZ bolus injection in the GL261 model induced neurotoxicity and lower cure rate than its equivalent dose delivered by CED. In addition, we found that T-cells were the predominant cells responsible for the TMZ antitumor effect in the GL261 model. Finally, CED-TMZ combined with immunotherapy significantly reduced tumor volume and increased the intratumoral influx of T-cells in both models. CONCLUSIONS: We show that immunotherapy synergized with CED-TMZ in the GL261 model and cured animals in the KR158 model. Single bolus administration of TMZ was effective with a narrower therapeutic window than CED-TMZ. Combined CED-TMZ and immunotherapy led to an increase in the intratumoral influx of T-cells. These results form part of the basis for the translation of the therapy to patients with GBM but the dosing and timing of delivery will have to be explored in depth both experimentally and clinically.
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27. |
- Enríquez Pérez, Julio, et al.
(author)
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The effect of locally delivered cisplatin is dependent on an intact immune function in an experimental glioma model
- 2019
-
In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1
-
Journal article (peer-reviewed)abstract
- Several chemotherapeutic drugs are now considered to exert anti-tumour effects, by inducing an immune-promoting inflammatory response. Cisplatin is a potent chemotherapeutic agent used in standard medulloblastoma but not glioblastoma protocols. There is no clear explanation for the differences in clinical efficacy of cisplatin between medulloblastomas and glioblastomas, despite the fact that cisplatin is effective in vitro against the latter. Systemic toxicity is often dose limiting but could tentatively be reduced by intratumoral administration. We found that intratumoral cisplatin can cure GL261 glioma-bearing C57BL/6 mice and this effect was abolished in GL261-bearing NOD-scid IL2rγ null (NSG) mice. Contrary to previous results with intratumoral temozolomide cisplatin had no additive or synergistic effect with whole cell either GL261 wild-type or GM-CSF-transfected GL261 cells whole cell vaccine-based immunotherapy. While whole tumour cell immunizations increased CD8 + T-cells and decreased F4/80 + macrophages intratumorally, cisplatin had no effect on these cell populations. Taken together, our results demonstrate that intratumoral cisplatin treatment was effective with a narrow therapeutic window and may be an efficient approach for glioma or other brain tumour treatment.
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28. |
- Erfurth, Eva Marie, et al.
(author)
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Pituitary disease mortality: is it fiction?
- 2013
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In: Pituitary. - : Springer Science and Business Media LLC. - 1573-7403 .- 1386-341X. ; 16:3, s. 402-412
-
Journal article (peer-reviewed)abstract
- During the last 20 years a tremendous improvement in the care of patients with pituitary tumors and of hypopituitarism has been achieved. If we resolve most of the possible causes of the increased cardiovascular disease and stroke mortality a normal survival is expected in these patients. Recently, a large population based study showed a decline in the risk of non-fatal stroke and of non-fatal cardiac events in GH deficient patients. This improvement was achieved by complete hormone replacement, including long term GH replacement, together with prescription of cardio protective drugs. If we follow the latest achievements in pituitary imaging, surgery techniques, hormone substitutions, cardio protective medications, we would expect a normal longevity in these patients. This review will focus on; (1) pituitary insufficiencies and hormone substitutions, (2) modes of cranial radiotherapy, and (3) new techniques in the surgery of a pituitary adenoma.
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29. |
- Exley, Christopher, et al.
(author)
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The immunobiology of aluminium adjuvants : how do they really work?
- 2010
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In: Trends in immunology. - : Elsevier BV. - 1471-4906 .- 1471-4981. ; 31:3, s. 103-109
-
Journal article (peer-reviewed)abstract
- Aluminium adjuvants potentiate the immune response, thereby ensuring the potency and efficacy of typically sparingly available antigen. Their concomitant critical importance in mass vaccination programmes may have prompted recent intense interest in understanding how they work and their safety. Progress in these areas is stymied, however, by a lack of accessible knowledge pertaining to the bioinorganic chemistry of aluminium adjuvants, and, consequently, the inappropriate application and interpretation of experimental models of their mode of action. The objective herein is, therefore, to identify the many ways that aluminium chemistry contributes to the wide and versatile armoury of its adjuvants, such that future research might be guided towards a fuller understanding of their role in human vaccinations.
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30. |
- Fisher, James L., et al.
(author)
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Loud Noise Exposure and Acoustic Neuroma
- 2014
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In: American Journal of Epidemiology. - : Oxford University Press (OUP). - 0002-9262 .- 1476-6256. ; 180:1, s. 58-67
-
Journal article (peer-reviewed)abstract
- The results from studies of loud noise exposure and acoustic neuroma are conflicting. A population-based case-control study of 451 acoustic neuroma patients and 710 age-, sex-, and region-matched controls was conducted in Sweden between 2002 and 2007. Occupational exposure was based on historical measurements of occupational noise (321 job titles summarized by a job exposure matrix) and compared with self-reported occupational noise exposure. We also evaluated self-reported noise exposure during leisure activity. Conditional logistic regression was used to estimate odds ratios. There was no statistically significant association between acoustic neuroma and persistent occupational noise exposure, either with or without hearing protection. Exposure to loud noise from leisure activity without hearing protection was more common among acoustic neuroma cases (odds ratio = 1.47, 95% confidence interval: 1.06, 2.03). Statistically significant odds ratios were found for specific leisure activities including attending concerts/clubs/sporting events (odds ratio = 1.82, 95% confidence interval: 1.09, 3.04) and participating in workouts accompanied by loud music (odds ratio = 2.84, 95% confidence interval: 1.37, 5.89). Our findings do not support an association between occupational exposure to loud noise and acoustic neuroma. Although we report statistically significant associations between leisure-time exposures to loud noise without hearing protection and acoustic neuroma, especially among women, we cannot rule out recall bias as an alternative explanation.
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31. |
- Fritzell, Sara, et al.
(author)
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IFNγ in combination with IL-7 enhances immunotherapy in two rat glioma models.
- 2013
-
In: Journal of Neuroimmunology. - : Elsevier BV. - 1872-8421 .- 0165-5728. ; 258:1-2, s. 91-95
-
Journal article (peer-reviewed)abstract
- Peripheral immunization, using a combination of interferon-gamma (IFNγ)- and interleukin-7 (IL-7)-producing tumor cells, eradicated 75% of pre-established intracerebral N32 rat glioma tumors, and prolonged survival in the more aggressive RG2 model. Rats immunized with IFNγ- and IL7-transduced N32 cells displayed increases in IFNγ plasma levels and proliferating circulating T cells when compared with rats immunized with N32-wild type cells. Following irradiation, the expression of MHC I and II was high on N32-IFNγ cells, but low on RG2-IFNγ cells. In conclusion, IFNγ and IL-7 immunizations prolong survival in two rat glioma models.
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32. |
- Fritzell, Sara, et al.
(author)
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Intratumoral temozolomide synergizes with immunotherapy in a T cell-dependent fashion.
- 2013
-
In: Cancer Immunology and Immunotherapy. - : Springer Science and Business Media LLC. - 1432-0851 .- 0340-7004. ; 62:9, s. 1463-1474
-
Journal article (peer-reviewed)abstract
- Despite temozolomide (TMZ) treatment, the prognosis for patients with glioblastoma multiforme is still dismal. As dose escalation of TMZ is limited by systemic toxicity, intratumoral delivery emerges as an attractive treatment modality, which may sustain cytotoxic drug concentrations intratumorally and induce immunogenic cell death. Both clinical and experimental gliomas have responded to immunotherapy, but the benefit of simultaneous chemo- and immunotherapy is inadequately studied. Here, we monitored survival of GL261-bearing C57BL/6 mice following a 3-day treatment with either intratumoral TMZ (micro-osmotic pump, 4.2 mg/kg/day) or systemic TMZ (i.p. injections, 50 mg/kg/day) alone, or combined with immunization using GM-CSF secreting GL261 cells. Peripheral and intratumoral leukocytes were analyzed by flow cytometry and immunohistochemistry. Intratumoral TMZ induced higher survival rate than systemic TMZ (45 vs. 8 %). When T cells were depleted following intratumoral TMZ, the therapeutic effect was completely abrogated (0 % survival). Intratumoral TMZ synergistically increased survival rate of immunized mice (from 25 to 83 %), while systemic TMZ failed (0 %). While systemic TMZ induced a transient leukopenia, intratumoral TMZ and immunotherapy sustained the proliferation of CD8(+) T cells and decreased the number of intratumoral immunosuppressive cells. In conclusion, intratumoral TMZ alone or in combination with immunotherapy could cure glioma-bearing mice, due to attenuation of local immunosuppression and increase in potential effector immune cells.
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33. |
- Gesslein, Bodil, et al.
(author)
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Comparison of perimetric 24-2 and 30-2 test patterns in detecting visual field defects in patients with tumours in the pituitary region
- 2024
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In: Acta Ophthalmologica. - 1755-3768. ; 102:3, s. 326-333
-
Journal article (peer-reviewed)abstract
- PURPOSE: Automated perimetry provides a standardized method of measuring the visual field. The Humphrey Field Analyser (HFA) uses the 24-2 test pattern to cover 24 degrees centrally or the 30-2 test pattern to cover a slightly broader region of 30 degrees. The aim of this study was to determine whether the 24-2 test pattern provides comparable information to the 30-2 test pattern in detecting visual field defects in patients with tumours in the pituitary region.METHODS: A retrospective cohort study was carried out on patients with tumours in the pituitary region and radiologically confirmed compression of the visual pathway. Included patients (79 of 133) had been examined using the Humphrey 30-2 visual field test, after which the 30-2 test patterns were reduced into corresponding 24-2 test patterns. The location of visual field defects, visual acuity and the perimetric parameters mean deviation (MD) and visual field index (VFI) were also recorded.RESULTS: No patient was classified differently when evaluated with the 24-2 test pattern, compared to the 30-2 test pattern. Interestingly, although the majority of patients had visual field defects located in the temporal visual field of each eye, a significant minority did not. In addition, it was found that a large proportion of patients had normal visual acuity (≥0.8).CONCLUSIONS: The use of the HFA 24-2 test pattern reliably detected visual field defects in patients with tumours in the pituitary region. The present study indicates that MD and VFI are not reliable parameters for evaluating visual field defects due to compression.
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34. |
- Gunnarsson, Salina, et al.
(author)
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Intratumoral IL-7 delivery by mesenchymal stromal cells potentiates IFNgamma-transduced tumor cell immunotherapy of experimental glioma.
- 2010
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In: Journal of Neuroimmunology. - : Elsevier BV. - 1872-8421 .- 0165-5728. ; 218:1-2, s. 140-144
-
Journal article (peer-reviewed)abstract
- The present study reports regression of pre-established experimental rat gliomas as a result of combining peripheral immunization using interferon gamma (IFNgamma) transduced autologous tumor cells with local intratumoral delivery of interleukin 7 (IL-7) by mesenchymal stromal cells. IL-7 alone significantly decreased the tumor area and this effect was enhanced with IFNgamma immunization. A higher density of intratumoral T-cells was observed in animals receiving combined therapies compared to rats receiving either cytokine alone suggesting that the therapeutic effect is dependent on a T-cell response.
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35. |
- Janelidze, Shorena, et al.
(author)
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Activation of purified allogeneic CD4(+) T cells by rat bone marrow-derived dendritic cells induces concurrent secretion of IFN-gamma, IL-4, and IL-10.
- 2005
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In: Immunology Letters. - : Elsevier BV. - 0165-2478. ; 101:2, s. 193-201
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Journal article (peer-reviewed)abstract
- Dendritic cells (DCs) are highly specialized antigen-presenting cells that play a key role in the initiation and regulation of immune responses. The ability of DCs to process antigens and the outcome of their interaction with T cells are largely dependent on phenotype as well as maturation state of DCs. In this study, we generated DCs from rat bone marrow precursors. Bone marrow cells cultured in the presence of granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-4, and Flt-3 ligand (FL) produced immature DCs that expressed intermediate levels of major histocompatibility complex (MHC) class II, low levels of CD80 and CD86 molecules and displayed a high capacity of endocytosis. Bone marrow-derived DCs (BMDCs) matured in the presence of lipopolysaccharide (LPS) upregulated expression of MHC class II, CD80 and CD86, while their phagocytic capacity was dramatically reduced. Mature BMDCs stimulated vigorous proliferation of purified allogeneic CD4(+) T cells in a primary mixed leukocyte reaction (MLR) and elicited a mixed cytokine profile in allogeneic CD4(+) T cells: DCs activated CD4(+) T cells to produce interferon (IFN)-gamma, IL-4, and IL-10. Thus, rat BMDCs effectively internalize antigens and stimulate T cell proliferation but fail to induce an unidirectional polarization of T helper (T-H) cells and in this respect differ from both human and mouse DCs. (c) 2005 Elsevier B.V. All rights reserved.
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36. |
- Johansson, Anna C, et al.
(author)
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Enhanced expression of iNOS intratumorally and at the immunization site after immunization with IFNgamma-secreting rat glioma cells
- 2002
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In: Journal of Neuroimmunology. - 1872-8421. ; 123:1-2, s. 135-143
-
Journal article (peer-reviewed)abstract
- Nitric oxide (NO) can modulate both tumor growth and antitumor immune responses. In order to elucidate the mechanism of curative therapeutic immunization with IFNgamma-producing glioma cells, we examined the expression of inducible nitric oxide synthase (iNOS) in tissue sections from immunized animals. There was a significantly enhanced iNOS expression both intratumorally and at the immunization site. Although the mechanisms behind this dual expression of iNOS most probably are different, our results suggest a role for NO in both the induction and execution of the antitumor response.
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37. |
- Kopecky, Jan, et al.
(author)
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Intratumoral administration of the antisecretory peptide AF16 cures murine gliomas and modulates macrophage functions
- 2022
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In: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 12:1
-
Journal article (peer-reviewed)abstract
- Glioblastoma has remained the deadliest primary brain tumor while its current therapy offers only modest survival prolongation. Immunotherapy has failed to record notable benefits in routine glioblastoma treatment. Conventionally, immunotherapy relies on T cells as tumor-killing agents; however, T cells are outnumbered by macrophages in glioblastoma microenvironment. In this study, we explore the effect of AF16, a peptide from the endogenous antisecretory factor protein, on the survival of glioma-bearing mice, the tumor size, and characteristics of the tumor microenvironment with specific focus on macrophages. We elucidate the effect of AF16 on the inflammation-related secretome of human and murine macrophages, as well as human glioblastoma cells. In our results, AF16 alone and in combination with temozolomide leads to cure in immunocompetent mice with orthotopic GL261 gliomas, as well as prolonged survival in immunocompromised mice. We recorded decreased tumor size and changes in infiltration of macrophages and T cells in the murine glioma microenvironment. Human and murine macrophages increased expression of proinflammatory markers in response to AF16 treatment and the same effect was seen in human primary glioblastoma cells. In summary, we present AF16 as an immunomodulatory factor stimulating pro-inflammatory macrophages with a potential to be implemented in glioblastoma treatment protocols.
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38. |
- Kurtsdotter, Idha, et al.
(author)
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SOX5/6/21 prevent oncogene-driven transformation of brain stem cells
- 2017
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In: Cancer Research. - 0008-5472 .- 1538-7445. ; 77:18, s. 4985-4997
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Journal article (peer-reviewed)abstract
- Molecular mechanisms preventing self-renewing brain stem cells from oncogenic transformation are poorly defined. We show that the expression levels of SOX5, SOX6, and SOX21 (SOX5/6/21) transcription factors increase in stem cells of the subventricular zone (SVZ) upon oncogenic stress, whereas their expression in human glioma decreases during malignant progression. Elevated levels of SOX5/6/21 promoted SVZ cells to exit the cell cycle, whereas genetic ablation of SOX5/6/21 dramatically increased the capacity of these cells to form glioma-like tumors in an oncogene-driven mouse brain tumor model. Loss-of-function experiments revealed that SOX5/6/21 prevent detrimental hyperproliferation of oncogene expressing SVZ cells by facilitating an antiproliferative expression profile. Consistently, restoring high levels of SOX5/6/21 in human primary glioblastoma cells enabled expression of CDK inhibitors and decreased p53 protein turnover, which blocked their tumorigenic capacity through cellular senescence and apoptosis. Altogether, these results provide evidence that SOX5/6/21 play a central role in driving a tumor suppressor response in brain stem cells upon oncogenic insult.
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39. |
- Liu, Yawei, et al.
(author)
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PD-L1 Expression by Neurons Nearby Tumors Indicates Better Prognosis in Glioblastoma Patients.
- 2013
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In: The Journal of Neuroscience. - 1529-2401. ; 33:35, s. 14231-14245
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Journal article (peer-reviewed)abstract
- Glioblastoma multiforme (GBM) is the most aggressive form of brain tumor. In general, tumor growth requires disruption of the tissue microenvironment, yet how this affects glioma progression is unknown. We studied program death-ligand (PD-L)1 in neurons and gliomas in tumors from GBM patients and associated the findings with clinical outcome. Remarkably, we found that upregulation of PD-L1 by neurons in tumor-adjacent brain tissue (TABT) associated positively with GBM patient survival, whereas lack of neuronal PD-L1 expression was associated with high PD-L1 in tumors and unfavorable prognosis. To understand the molecular mechanism of PD-L1 signaling in neurons, we investigated PD-L1 function in cerebellar and cortical neurons and its impact on gliomas. We discovered that neuronal PD-L1-induced caspase-dependent apoptosis of glioma cells. Because interferon (IFN)-β induces PD-L1 expression, we studied the functional consequences of neuronal Ifnb gene deletion on PD-L1 signaling and function. Ifnb(-/-) neurons lacked PD-L1 and were defective in inducing glioma cell death; this effect was reversed on PD-L1 gene transfection. Ifnb(-/-) mice with intracerebral isografts survived poorly. Similar to the observations in GBM patients, better survival in wild-type mice was associated with high neuronal PD-L1 in TABT and downregulation of PD-L1 in tumors, which was defective in Ifnb(-/-) mice. Our data indicated that neuronal PD-L1 signaling in brain cells was important for GBM patient survival. Reciprocal PD-L1 regulation in TABT and tumor tissue could be a prognostic biomarker for GBM. Understanding the complex interactions between tumor and adjacent stromal tissue is important in designing targeted GBM therapies.
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40. |
- Lundberg, Fredrik, et al.
(author)
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Presence of vitronectin and activated complement factor C9 on ventriculoperitoneal shunts and temporary ventricular drainage catheters
- 1999
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In: Journal of Neurosurgery. - : Journal of Neurosurgery Publishing Group (JNSPG). - 0022-3085. ; 90:1, s. 101-108
-
Journal article (peer-reviewed)abstract
- Object. The pathogenesis of cerebrospinal fluid (CSF) shunt infection is characterized by staphylococcal adhesion to the polymeric surface of the shunt catheter. Proteins from the CSF-fibronectin, vitronectin, and fibrinogen-are adsorbed to the surface of the catheter immediately after insertion. These proteins can interfere with the biological systems of the host and mediate staphylococcal adhesion to the surface of the catheter. In the present study, the presence of fibronectin, vitronectin, and fibrinogen on CSF shunts and temporary ventricular drainage catheters is shown. The presence of fragments of fibrinogen is also examined. Methods. The authors used the following methods: binding radiolabeled antibodies to the catheter surface, immunoblotting of catheter eluates, and scanning force microscopy of immunogold bound to the catheter surface. The immunoblot showed that vitronectin was adsorbed in its native form and that fibronectin was degraded into small fragments. Furthermore, the study demonstrated that the level of vitronectin in CSF increased in patients with an impaired CSF-blood barrier. To study complement activation, an antibody that recognizes the neoepitope of activated complement factor C9 was used. The presence of activated complement factor C9 was shown on both temporary catheters and shunts. Conclusions. Activation of complement close to the surface of an inserted catheter could contribute to the pathogenesis of CSF shunt infection.
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41. |
- Magnusson, Måns, et al.
(author)
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Preoperative vestibular ablation with gentamicin and vestibular 'prehab' enhance postoperative recovery after surgery for pontine angle tumours - first report
- 2007
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In: Acta Oto-Laryngologica. - : Informa UK Limited. - 1651-2251 .- 0001-6489. ; 127:12, s. 1236-1240
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Journal article (peer-reviewed)abstract
- Conclusions. Preoperative gentamicin in combination with vestibular 'prehab' offers a possibility to reduce postoperative malaise and speed up recovery and may be used for patients undergoing such surgery when there is remaining vestibular function. Objectives. Removal of pontine angle tumours in a patient with remaining vestibular function causes symptoms of acute vestibular loss. A simultaneous cerebellar lesion can cause a combined vestibule-cerebellar lesion. Patients and methods. Twelve patients with pontine angle tumours but with near normal vestibular function were treated with intratympanic gentamicin in combination with vestibular 'prehab' to achieve preoperative vestibular ablation and compensation. After work-up patients started with a home-based vestibular training programme for 14 days. They then received a total of 1.2 ml of 30 mg/ml buffered gentamicin in four intratympanic installations over 2 days. They continued training and returned 6-16 weeks later. All patients were tested with calorics, vestibular video-impulse testing of all six canals, VEMP, subjective visual vertical and horizontal, posturography and pure tone and speech audiometry. Results. There was a loss of caloric reactions and loss of impulses. In two patients the hearing deteriorated and in one hearing improved. All subjects were vestibulary compensated before surgery and no patient complained of dizziness or vertigo after surgery.
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42. |
- Magnusson, Måns, et al.
(author)
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Vestibular "PREHAB"
- 2009
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In: Annals of the New York Academy of Sciences. - : Wiley. - 0077-8923. ; 1164, s. 257-262
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Journal article (peer-reviewed)abstract
- A sudden unilateral loss or impairment of vestibular function causes vertigo, dizziness, and impaired postural function. In most occasions, everyday activities supported or not by vestibular rehabilitation programs will promote a compensation and the symptoms subside. As the compensatory process requires sensory input, matching performed motor activity, both motor learning of exercises and matching to sensory input are required. If there is a simultaneous cerebellar lesion caused by the tumor or the surgery of the posterior cranial fossa, there may be a risk of a combined vestibulocerebellar lesion, with reduced compensatory abilities and with prolonged or sometimes permanent disability. On the other hand, a slow gradual loss of unilateral function occurring as the subject continues well-learned everyday activities may go without any prominent symptoms. A pretreatment plan was therefore implemented before planned vestibular lesions, that is, "PREHAB." This was first done in subjects undergoing gentamicin treatment for morbus Meniere. Subjects would perform vestibular exercises for 14 days before the first gentamicin installation, and then continue doing so until free of symptoms. Most subjects would only experience slight dizziness while losing vestibular function. The approach-which is reported here-was then expanded to patients with pontine-angle tumors requiring surgery, but with remaining vestibular function to ease postoperative symptoms and reduce risk of combined cerebellovestibular lesions. Twelve patients were treated with PREHAB and had gentamicin installations transtympanically. In all cases there was a caloric loss, loss of VOR in head impulse tests, and impaired subjective vertical and horizontal. Spontaneous, positional nystagmus, subjective symptoms, and postural function were normalized before surgery and postoperative recovery was swift. Pretreatment training with vestibular exercises continued during the successive loss of vestibular function during gentamicin treatment, and pre-op gentamicin ablation of vestibular function offers a possibility to reduce malaise and speed up recovery.
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43. |
- Mile, Irene, et al.
(author)
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Al adjuvants can be tracked in viable cells by lumogallion staining
- 2015
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In: JIM - Journal of Immunological Methods. - : Elsevier. - 0022-1759 .- 1872-7905. ; 422, s. 87-94
-
Journal article (peer-reviewed)abstract
- The mechanism behind the adjuvant effect of aluminum salts is poorly understood notwithstanding that aluminum salts have been used for decades in clinical vaccines. In an aqueous environment and at a nearly neutral pH, the aluminumsalts form particulate aggregates, and one plausible explanation of the lack of information regarding the mechanisms could be the absence of an efficientmethod of tracking phagocytosed aluminum adjuvants and thereby the intracellular location of the adjuvant. In this paper, we want to report upon the use of lumogallion staining enabling the detection of phagocytosed aluminum adjuvants inside viable cells. Including micromolar concentrations of lumogallion in the culture medium resulted in a strong fluorescence signal from cells that had phagocytosed the aluminum adjuvant. The fluorescence appeared as spots in the cytoplasm and by confocal microscopy and co-staining with probes presenting fluorescence in the far-red region of the spectrum, aluminum adjuvants could to a certain extent be identified as localized in acidic vesicles, i.e., lysosomes. Staining and detection of intracellular aluminum adjuvants was achieved not only by diffusion of lumogallion into the cytoplasm, thereby highlighting the presence of the adjuvant, but also by pre-staining the aluminum adjuvant prior to incubation with cells. Pre-staining of aluminum adjuvants resulted in bright fluorescent particulate aggregates that remained fluorescent for weeks and with only a minor reduction of fluorescence upon extensive washing or incubation with cells. Both aluminum oxyhydroxide and aluminum hydroxyphosphate, two of the most commonly used aluminum adjuvants in clinical vaccines, could be pre-stained with lumogallion and were easily tracked intracellularly after incubation with phagocytosing cells. Staining of viable cells using lumogallion will be a useful method in investigations of the mechanisms behind aluminum adjuvants' differentiation of antigen-presenting cells into inflammatory cells. Information will be gained regarding the phagosomal pathways and the events inside the phagosomes, and thereby the ultimate fate of phagocytosed aluminum adjuvants could be resolved.
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44. |
- Mold, Matthew, et al.
(author)
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Unequivocal identification of intracellular aluminium adjuvant in a monocytic THP-1 cell line.
- 2014
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 4
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Journal article (peer-reviewed)abstract
- Aluminium-based adjuvants (ABA) are the predominant adjuvants used in human vaccinations. While a consensus is yet to be reached on the aetiology of the biological activities of ABA several studies have identified shape, crystallinity and size as critical factors affecting their adjuvanticity. In spite of recent advances, the fate of ABA following their administration remains unclear. Few if any studies have demonstrated the unequivocal presence of intracellular ABA. Herein we demonstrate for the first time the unequivocal identification of ABA within a monocytic T helper 1 (THP-1) cell line, using lumogallion as a fluorescent molecular probe for aluminium. Use of these new methods revealed that particulate ABA was only found in the cell cytoplasm. Transmission electron microscopy revealed that ABA were contained within vesicle-like structures of approximately 0.5-1 μm in diameter.
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45. |
- Offer, Svenja, et al.
(author)
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Extracellular lipid loading augments hypoxic paracrine signaling and promotes glioma angiogenesis and macrophage infiltration
- 2019
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In: Journal of Experimental & Clinical Cancer Research. - : Springer Science and Business Media LLC. - 1756-9966. ; 38
-
Journal article (peer-reviewed)abstract
- BackgroundPrimary brain tumors, in particular glioblastoma (GBM), remain among the most challenging cancers. Like most malignant tumors, GBM is characterized by hypoxic stress that triggers paracrine, adaptive responses, such as angiogenesis and macrophage recruitment, rescuing cancer cells from metabolic catastrophe and conventional oncological treatments. The unmet need of strategies to efficiently target tumor “stressness” represents a strong clinical motivation to better understand the underlying mechanisms of stress adaptation. Here, we have investigated how lipid loading may be involved in the paracrine crosstalk between cancer cells and the stromal compartment of the hypoxic tumor microenvironment.MethodsRegions from patient GBM tumors with or without the lipid loaded phenotype were isolated by laser capture microdissection and subjected to comparative gene expression analysis in parallel with cultured GBM cells with or without lipid loading. The potential involvement of extracellular lipids in the paracrine crosstalk with stromal cells was studied by immunoprofiling of the secretome and functional studies in vitro as well as in various orthotopic GBM mouse models, including hyperlipidemic ApoE−/− mice. Statistical analyses of quantitative experimental methodologies were performed using unpaired Student’s T test. For survival analyses of mouse experiments, log-rank test was used, whereas Kaplan-Meier was performed to analyze patient survival.ResultsWe show that the lipid loaded niche of GBM patient tumors exhibits an amplified hypoxic response and that the acquisition of extracellular lipids by GBM cells can reinforce paracrine activation of stromal cells and immune cells. At the functional level, we show that lipid loading augments the secretion of e.g. VEGF and HGF, and may potentiate the cross-activation of endothelial cells and macrophages. In line with these data, in vivo studies suggest that combined local tumor lipid loading and systemic hyperlipidemia of ApoE−/− mice receiving a high fat diet induces tumor vascularization and macrophage recruitment, and was shown to significantly decrease animal survival.ConclusionsTogether, these data identify extracellular lipid loading as a potentially targetable modulator of the paracrine adaptive response in the hypoxic tumor niche and suggest the contribution of the distinct lipid loaded phenotype in shaping the glioma microenvironment.
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46. |
- Ohlsson, Lars, et al.
(author)
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Aluminium based adjuvants and their effects on mitochondria and lysosomes of phagocytosing cells
- 2013
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In: Journal of Inorganic Biochemistry. - : Elsevier. - 0162-0134 .- 1873-3344. ; 128, s. 229-236
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Journal article (peer-reviewed)abstract
- Aluminium oxyhydroxide, Al(OH)3 is one of few compounds approved as an adjuvant in human vaccines. However, the mechanism behind its immune stimulating properties is still poorly understood. In vitro co- culture of an aluminium adjuvant and the human monocytic cell line THP-1 resulted in reduced cell proliferation. Inhibition occurred at concentrations of adjuvant several times lower than would be found at the injection site using a vaccine formulation containing an aluminium adjuvant. Based on evaluation of the mitochondrial membrane potential, THP-1 cells showed no mitochondrial rupture after co-culture with the aluminium adju- vant, instead an increase in mitochondrial activity was seen. The THP-1 cells are phagocytosing cells and after co-culture with the aluminium adjuvant the phagosomal pathway was obstructed. Primary or early phagosomes mature into phagolysosomes with an internal pH of 4.5 – 5 and carry a wide variety of hydrolysing enzymes. Co-culture with the aluminium adjuvant yielded a reduced level of acidic vesicles and cathepsin L activity, a proteolytic enzyme of the phagolysosomes, was almost completely inhibited. THP-1 cells are an appropriate in vitro model in order to investigate the mechanism behind the induction of a phagocytosing antigen presenting cell into an inflammatory cell by aluminium adjuvants. Much information will be gained by investigating the phagosomal pathway and what occurs inside the phagosomes and to elucidate the ultimate fate of phagocytosed aluminium particles.
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47. |
- Palmisano, Sadie, et al.
(author)
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Role of tobacco use in the etiology of acoustic neuroma.
- 2012
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In: American journal of epidemiology. - : Oxford University Press (OUP). - 1476-6256 .- 0002-9262. ; 175:12, s. 1243-51
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Journal article (peer-reviewed)abstract
- Two previous studies suggest that cigarette smoking reduces acoustic neuroma risk; however, an association between use of snuff tobacco and acoustic neuroma has not been investigated previously. The authors conducted a case-control study in Sweden from 2002 to 2007, in which 451 cases and 710 population-based controls completed questionnaires. Cases and controls were matched on gender, region, and age within 5 years. The authors estimated odds ratios using conditional logistic regression analyses, adjusted for education and tobacco use (snuff use in the smoking analysis and smoking in the snuff analysis). The risk of acoustic neuroma was greatly reduced in male current smokers (odds ratio (OR) = 0.41, 95% confidence interval (CI): 0.23, 0.74) and moderately reduced in female current smokers (OR = 0.70, 95% CI: 0.40, 1.23). In contrast, current snuff use among males was not associated with risk of acoustic neuroma (OR = 0.94, 95% CI: 0.57, 1.55). The authors' findings are consistent with previous reports of lower acoustic neuroma risk among current cigarette smokers than among never smokers. The absence of an association between snuff use and acoustic neuroma suggests that some constituent of tobacco smoke other than nicotine may confer protection against acoustic neuroma.
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48. |
- Petersson, M., et al.
(author)
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Natural history and surgical outcome of Rathke's cleft cysts-A study from the Swedish Pituitary Registry
- 2022
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In: Clinical Endocrinology. - : Wiley. - 0300-0664 .- 1365-2265. ; 96:1, s. 54-61
-
Journal article (peer-reviewed)abstract
- Objective Rathke's cleft cysts are benign, embryological remnants in the pituitary gland. The majority of them are small and asymptomatic but a few may become large, and cause mass effects, pituitary hormone deficiencies and visual impairment. Recommendations for the follow-up of Rathke's cleft cysts vary since data on the natural history are sparse. Patients and Design Data at diagnosis and at 1, 5 and 10 years for patients with a Rathke's cleft cyst (434 at diagnosis, 317 females) were retrieved from the Swedish Pituitary Registry. Cysts <= 3 mm in diameter were excluded from the study. Measurements Data included demographics, cyst size, pituitary function, visual defects and surgery. Results The mean age at diagnosis was 45 years. In patients with cysts <10 mm in diameter (n = 204) 2.9% had pituitary hormone deficiencies and 2% had visual field impairments. Cyst size did not progress during the 5 years. Cysts with a diameter of >= 10 mm that were not operated (n = 174) decreased in size over the years (p < .01). Pituitary hormone deficiencies and visual impairments were more frequent (18% and 5.7%, respectively) but were stable over time. Transphenoidal surgery was performed in 56 patients of whom 51 underwent surgery before the 1-year follow-up. The mean cyst diameter at diagnosis was 18 mm (range: 930 mm), 36% had pituitary hormone deficiency, 45% had visual field defects and 20% had impaired visual acuity. One year after surgery 60% had no cyst remnants, 50% had a pituitary deficiency, 26% had visual field defects and 12% had impaired visual acuity. No major changes were observed after 5 years. Twelve of the operated patients had a follow-up at 10 years, in eight the cyst remnants or recurrences increased in size over time (p < .05). Conclusions Rathke's cleft cysts with a size less than 10 mm rarely grow and our results indicate that radiological follow-up can be restricted to 5 years. In contrast, progression of postoperative remnants or recurrent cysts is more likely and require long-term follow-up.
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49. |
- Pettersson, David, et al.
(author)
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Long-term Mobile Phone Use and Acoustic Neuroma Risk
- 2014
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In: Epidemiology. - : Lippincott, Williams andamp; Wilkins. - 1044-3983 .- 1531-5487. ; 25:2, s. 233-241
-
Journal article (peer-reviewed)abstract
- Background: There is concern about potential effects of radiofrequency fields generated by mobile phones on cancer risk. Most previous studies have found no association between mobile phone use and acoustic neuroma, although information about long-term use is limited. Methods: We conducted a population-based, nation-wide, case-control study of acoustic neuroma in Sweden. Eligible cases were persons aged 20 to 69 years, who were diagnosed between 2002 and 2007. Controls were randomly selected from the population registry, matched on age, sex, and residential area. Postal questionnaires were completed by 451 cases (83%) and 710 controls (65%). Results: Ever having used mobile phones regularly (defined as weekly use for at least 6 months) was associated with an odds ratio (OR) of 1.18 (95% confidence interval = 0.88 to 1.59). The association was weaker for the longest induction time (10 years) (1.11 [0.76 to 1.61]) and for regular use on the tumor side (0.98 [0.68 to 1.43]). The OR for the highest quartile of cumulative calling time (680 hours) was 1.46 (0.98 to 2.17). Restricting analyses to histologically confirmed cases reduced all ORs; the OR for 680 hours was 1.14 (0.63 to 2.07). A similar pattern was seen for cordless land-line phones, although with slightly higher ORs. Analyses of the complete history of laterality of mobile phone revealed considerable bias in laterality analyses. Conclusions: The findings do not support the hypothesis that long-term mobile phone use increases the risk of acoustic neuroma. The study suggests that phone use might increase the likelihood that an acoustic neuroma case is detected and that there could be bias in the laterality analyses performed in previous studies.
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50. |
- Réen, Linus, et al.
(author)
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Low Morbidity and Mortality in Children with Severe Traumatic Brain Injury Treated According to the Lund Concept : A Population-Based Study
- 2023
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In: Journal of Neurotrauma. - : Mary Ann Liebert Inc. - 0897-7151 .- 1557-9042. ; 40:7-8, s. 720-729
-
Journal article (peer-reviewed)abstract
- Previous reports of mortality and morbidity in pediatric severe traumatic brain injury (TBI) vary considerably, with few population-based studies. Mortality rates from 3-33 % and varying morbidity have been reported, most commonly using the Extended Glasgow Outcome Scale (eGOS). The Lund concept is a treatment algorithm for severe TBI aiming at controlling intracranial pressure (ICP) by reducing cerebral perfusion pressure (CPP). The aim of the present study was to retrospectively assess mortality and morbidity in a population of pediatric TBI treated according to the Lund concept. All cases of severe pediatric TBI (age <18 years) in the southern region of Sweden during 19 years were identified. Patients were treated according to the Lund concept. Mortality, eGOS, ICP, CPP, time in the neurosurgical intensive care unit (NICU), drugs delivered and surgical procedures were recorded. Data were analyzed both by dichotomized outcomes and by ordinal statistics. A total of 135 cases of severe TBI <18 years of age were recorded (incidence 2.0/100000) and 86 patients were admitted to the tertiary NICU. Mortality including all cases was 43% (mortality rate 0.7/100,000) and in NICU 10%. Outcome was good in 60%, moderate in 25%, unfavorable in 15%, with none in a vegetative status. In both dichotomized and ordinal analyses, CPP <40 mm Hg and ICP >15 were associated with poor outcome, supporting current guidelines. However, high CPP also was associated with increased mortality and morbidity, supporting that elevated CPP might increase cerebral edema. In this study, the Lund concept resulted in low mortality and a favorable outcome in a majority of severe pediatric TBI patients; however, randomized controlled trials are warranted to verify this.
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