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Contains fulltext : 291966.pdf (Publisher’s version ) (Open Access) OBJECTIVE: Vestibular schwannoma (VS) growth of ≥2 mm during serial MRI observation, irrespective of size, is the benchmark for treatment initiation in almost all centers. Although the probability of less optimal outcomes significantly increases in VS closer to the brainstem, early intervention does not improve long-term quality of life. Moving beyond the recommendation of definitive treatment for all VS after detected growth, we subclassified Koos 2 tumors based on extrameatal extension and relation to the brainstem. The aim of the current study was to evaluate the Koos 2 subclassification's validity and the inter-and intra-rater reliability of the entire Koos classification. METHODS: Six experts, including neurosurgeons, otorhinolaryngologists and radiologists from two tertiary referral centers, classified 43 VS MRI scans. Validity of the Koos 2 subclassification was evaluated by the percentage agreement against the multidisciplinary skull base tumor board management advice. Inter- and intra-rater reliability were calculated using the intraclass correlation coefficient (ICC). RESULTS: Validity was almost perfect in Koos 2a VSs with a 100% agreement and 87.5% agreement for Koos 2b. Inter-rater reliability for all Koos grades was significantly excellent (ICC 0.91; 95%CI 0.866 to 0.944, p= 0.90; p=

Supplementary Figure 1 Examples of 1H NMR spectra for different genotypes A. Example of NMR spectrum of a sporadic tumor depicting the peak positions of lactic acid, acetic acid and catecholamines. B. Example of NMR spectrum of a SDHB tumor depicting peak position of succinic acid. C. Example of NMR spectrum of a RET tumor depicting ATP/ADP/AMP and adrenaline specific peaks. Supplementary Figure 2 Comparison of epinephrine and norepinephrine content in tumor tissues as determined by HPLC and 1H-NMR spectroscopy. Passing - Bablok regression plot to compare measurement of epinephrine and norepinephrine content in PGL tumor tissues by HPLC and 1HNMR spectroscopy expressed as μg per mg tissue in Log10 scale. Supplementary Figure 3: Activities of respiratory chain complex II and tumor tissue succinate content in SDH related tumors. Black bars represent complex II activity expressed in mU/mg protein and grey bars represent tumor tissue succinate content in mmol/mg tissue for each individual tumor. Represented on X axis is the hereditary mutation in the patient from whom the tumor was resected.

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Purpose: Pheochromocytomas and paragangliomas (PGL) are neuroendocrine tumors of sympathetic and parasympathetic paraganglia. This study investigated the relationships between genotype-specific differences in mitochondrial function and catecholamine content in PGL tumors.Experimental Design: Respiratory chain enzyme assays and 1H-nuclear magnetic resonance (NMR) spectroscopy at 500 MHz were conducted on homogenates of 35 sporadic PGLs and 59 PGLs from patients with hereditary mutations in succinate dehydrogenase subunits B and D (SDHB, SDHD), succinate dehydrogenase assembly factor 2, von Hippel-Lindau (VHL), rearranged during transfection (RET), neurofibromatosis type 1 (NF1), and myc-associated factor X.Results: In SDHx-related PGLs, a significant decrease in complex II activity (P < 0.0001) and a significant increase in complex I, III, and IV enzyme activities were observed when compared to sporadic, RET, and NF1 tumors. Also, a significant increase in citrate synthase (P < 0.0001) enzyme activity was observed in SDHx-related PGLs when compared to sporadic-, VHL-, RET-, and NF1-related tumors. An increase in succinate accumulation (P < 0.001) and decrease in ATP/ADP/AMP accumulation (P < 0.001) was observed when compared to sporadic PGLs and PGLs of other genotypes. Positive correlations (P < 0.01) were observed between respiratory chain complex II activity and total catecholamine content and ATP/ADP/AMP and total catecholamine contents in tumor tissues.Conclusions: This study for the first time establishes a relationship between determinants of energy metabolism, like activity of respiratory chain enzyme complex II, ATP/ADP/AMP content, and catecholamine content in PGL tumors. Also, this study for the first time successfully uses NMR spectroscopy to detect catecholamines in PGL tumors and provides ex vivo evidence for the accumulation of succinate in PGL tumors with an SDHx mutation. Clin Cancer Res; 19(14); 3787–95. ©2013 AACR.

Contains fulltext : 251746.pdf (Publisher’s version ) (Open Access)

OBJECTIVES: Otomastoiditis caused by the anaerobic Fusobacterium necrophorum (F. necrophorum) often induces severe complications, such as meningitis and sinus thrombosis. Early diagnosis is difficult, partly because little is known about specific early signs. Comprehensive research about clinically chosen antimicrobial therapy has not been done yet and prognostic information about otomastoiditis caused by F. necrophorum is scarce. More knowledge about this subject is required.METHODS: In this retrospective cohort study, we included all cases of otomastoiditis caused by F. necrophorum treated in two university medical centres in the Netherlands during the past 10 years. Data was gathered from patient records and analysed using independent sample T-tests and Chi2-tests.RESULTS: This study reveals that otomastoiditis caused by F. necrophorum potentially induces neurological sequelae. Thereby, 80% of all included patients (n = 16) needed readmission within six months due to recurrence or complications of otomastoiditis caused by F. necrophorum. Mean (range) of age, CRP and temperature were 4.5 years (0.9-29.3), 243 mg/L (113-423) and 40 °C (37-41). All patients were hospitalized and treated with antibiotics, mostly metronidazole (n = 13/16) and a β -lactam (n = 15/16). Additional treatment contained low molecular weight heparin (83%, n = 10/12), dexamethasone (78%, n = 7/9) and/or surgery (80%, n = 12/16, whereof 9/12 mastoidectomy).CONCLUSIONS: Patients and/or their parents need to be informed about this potential unfortunate prognosis when otomastoiditis caused by F. necrophorum is diagnosed. To improve early diagnosis, otomastoiditis caused by F. necrophorum should be suspected and therefore immediately cultured when a) young children present with otomastoiditis, with b) high CRP values, and/or c) vomiting and decreased consciousness.

Purpose: Pheochromocytomas and paragangliomas (PGL) are neuroendocrine tumors of sympathetic and parasympathetic paraganglia. This study investigated the relationships between genotype-specific differences in mitochondrial function and catecholamine content in PGL tumors. Experimental Design: Respiratory chain enzyme assays and 1H-nuclear magnetic resonance (NMR) spectroscopy at 500 MHz were conducted on homogenates of 35 sporadic PGLs and 59 PGLs from patients with hereditary mutations in succinate dehydrogenase subunits B and D (SDHB, SDHD), succinate dehydrogenase assembly factor 2, von Hippel-Lindau (VHL), rearranged during transfection (RET), neurofibromatosis type 1 (NF1), and myc-associated factor X. Results: In SDHx-related PGLs, a significant decrease in complex II activity (P < 0.0001) and a significant increase in complex I, III, and IV enzyme activities were observed when compared to sporadic, RET, and NF1 tumors. Also, a significant increase in citrate synthase (P < 0.0001) enzyme activity was observed in SDHx-related PGLs when compared to sporadic-, VHL-, RET-, and NF1-related tumors. An increase in succinate accumulation (P < 0.001) and decrease in ATP/ADP/AMP accumulation (P < 0.001) was observed when compared to sporadic PGLs and PGLs of other genotypes. Positive correlations (P < 0.01) were observed between respiratory chain complex II activity and total catecholamine content and ATP/ADP/AMP and total catecholamine contents in tumor tissues. Conclusions: This study for the first time establishes a relationship between determinants of energy metabolism, like activity of respiratory chain enzyme complex II, ATP/ADP/AMP content, and catecholamine content in PGL tumors. Also, this study for the first time successfully uses NMR spectroscopy to detect catecholamines in PGL tumors and provides ex vivo evidence for the accumulation of succinate in PGL tumors with an SDHx mutation. Clin Cancer Res; 19(14); 3787–95. ©2013 AACR.