Unravelling pituitary tumours in medically treated patients with acromegaly: the impact of systematic MRI reassessment.

BACKGROUND: In acromegaly, the primary tumor is usually found during magnetic resonance imaging (MRI) of the pituitary gland. A remnant tumor after surgery is, however, harder to depict. When a tumor is missed, the remaining option is usually lifelong pharmacological treatment. PURPOSE: To identify tumors by reassessment of all available MRI scans in pharmacologically treated patients, operated or not, and to compare our results with the routine MRI reports. MATERIAL AND METHODS: Adult patients diagnosed with acromegaly and managed at a tertiary care center between 2005 and 2021 and currently on pharmacological treatment were included. MRI scans were evaluated in a standardized manner and classified independently by a radiologist and an endocrinologist into "certain," "suspected," or "no tumor." In case of disagreement, consensus was achieved with a senior neuroradiologist. The results were compared using the clinical radiologists' routine MRI reports. RESULTS: We identified certain and suspected tumors in 29/74 and 36/74 patients, respectively. No tumor was identified in nine patients. In five of these, no MRI contrast agent was given. Discrepancy between our results and the routine MRI reports was found in 31/74 patients (P = 0.01). In 22 patients, the routine reports described no tumor while we identified certain tumors in 2/22 patients and suspected tumors in 13/22 patients. CONCLUSION: In most patients with pharmacologically treated acromegaly, we identified a certain or suspected pituitary tumor. These findings were more frequent compared to the routine MRI reports. Based on our results, patients will be considered for a change in long-term treatment modality.

Long-term control of acromegaly after pituitary surgery in South-Eastern Norway.

PURPOSE: Sustained cure of acromegaly can only be achieved by surgery. Most growth hormone (GH) secreting pituitary adenomas are macroadenomas (≥ 10 mm) at diagnosis, with reported surgical cure rates of approximately 50%. Long-term data on disease control rates after surgery are limited. Our aim was to estimate short- and long-term rates of biochemical control after pituitary surgery in acromegaly and identify predictive factors. METHODS: Patients operated for GH-secreting pituitary adenomas between 2005-2020 were included from the local pituitary registry (n = 178). Disease activity and treatment data were recorded at one-year (short-term) and five-year (long-term) postoperative follow-up. Biochemical control was defined as insulin-like growth factor 1 (IGF-1) ≤ 1.2 × upper limit of normal value. Multivariate regression models were used to identify factors potentially predicting biochemical control. RESULTS: A total of 178 patients with acromegaly (median age at diagnosis 49 (IQR: 38-59) years, 46% women) were operated for a pituitary adenoma. Biochemical control was achieved by surgery in 53% at short-term and 41% at long-term follow-up, without additional treatment for acromegaly. Biochemical control rates by surgery were of same magnitude in paired samples (45% vs. 41%, p = 0.213) for short- and long-term follow-up, respectively. At short-term, 62% of patients with microadenomas and 51% with macroadenomas, achieved biochemical control. At long-term, the biochemical control rate was 58% for microadenomas and 37% for macroadenomas (p = 0.058). With adjunctive treatment, 82% achieved biochemical control at long-term. Baseline IGF-1 levels significantly predicted biochemical control by surgery at short-term (OR: 0.98 (95% CI: 0.96-0.99), p = 0.011), but not at long-term (OR: 0.76 (95% CI: 0.57-1.00), p = 0.053). CONCLUSION: In unselected patients with acromegaly, the long-term biochemical control rate remains modest. Our findings indicate a need to identify patients at an earlier stage and improve therapeutic methods and surgical outcomes.

Endoscopic four-hands technique for pituitary tumours. / Endoskopisk firehåndsteknikk ved hypofysesvulster.

Tumours in the pituitary fossa region can be resected by endoscopic transnasal surgery using a four-hands technique. The technique, which is atraumatic, safe and minimally invasive, should be the first-line treatment for pituitary tumours and certain skull-base tumours.

TGFBR3L is associated with gonadotropin production in non-functioning gonadotroph pituitary neuroendocrine tumours.

PURPOSE: Transforming growth factor-beta receptor 3-like (TGFBR3L) is a pituitary enriched membrane protein selectively detected in gonadotroph cells. TGFBR3L is named after transforming growth factor-beta receptor 3 (TGFBR3), an inhibin A co-receptor in mice, due to sequence identity to the C-terminal region. We aimed to characterize TGFBR3L detection in a well-characterized, prospectively collected cohort of non-functioning pituitary neuroendocrine tumours (NF-PitNETs) and correlate it to clinical data. METHODS: 144 patients operated for clinically NF-PitNETs were included. Clinical, radiological and biochemical data were recorded. Immunohistochemical (IHC) staining for FSHß and LHß was scored using the immunoreactive score (IRS), TGFBR3L and TGFBR3 were scored by the percentage of positive stained cells. RESULTS: TGFBR3L staining was selectively present in 52% of gonadotroph tumours. TGFBR3L was associated to IRS of LHß (median 2 [IQR 0-3] in TGFBR3L negative and median 6 [IQR 3-9] in TGFBR3L positive tumours, p < 0.001), but not to the IRS of FSHß (p = 0.32). The presence of TGFBR3L was negatively associated with plasma gonadotropin concentrations in males (P-FSH median 5.5 IU/L [IQR 2.9-9.6] and median 3.0 [IQR 1.8-5.6] in TGFBR3L negative and positive tumours respectively, p = 0.008) and P-LH (median 2.8 IU/L [IQR 1.9-3.7] and median 1.8 [IQR 1.1-3.0] in TGFBR3L negative and positive tumours respectively, p = 0.03). TGFBR3 stained positive in 22% (n = 25) of gonadotroph tumours with no correlation to TGFBR3L. CONCLUSION: TGFBR3L was selectively detected in half (52%) of gonadotroph NF-PitNETs. The association to LHß staining and plasma gonadotropins suggests that TGFBR3L may be involved in hormone production in gonadotroph NF-PitNETs.

Pro-inflammatory cytokines in cystic glioblastoma: A quantitative study with a comparison with bacterial brain abscesses. With an MRI investigation of displacement and destruction of the brain tissue surrounding a glioblastoma.

Cystic glioblastomas are aggressive primary brain tumors that may both destroy and displace the surrounding brain tissue as they grow. The mechanisms underlying these tumors' destructive effect could include exposure of brain tissue to tumor-derived cytokines, but quantitative cytokine data are lacking. Here, we provide quantitative data on leukocyte markers and cytokines in the cyst fluid from 21 cystic glioblastomas, which we compare to values in 13 brain abscess pus samples. The concentration of macrophage/microglia markers sCD163 and MCP-1 was higher in glioblastoma cyst fluid than in brain abscess pus; lymphocyte marker sCD25 was similar in cyst fluid and pus, whereas neutrophil marker myeloperoxidase was higher in pus. Median cytokine levels in glioblastoma cyst fluid were high (pg/mL): TNF-α: 32, IL-6: 1064, IL-8: 23585, tissue factor: 28, the chemokine CXCL1: 639. These values were not significantly different from values in pus, pointing to a highly pro-inflammatory glioblastoma environment. In contrast, levels of IFN-γ, IL-1ß, IL-2, IL-4, IL-10, IL-12, and IL-13 were higher in pus than in glioblastoma cyst fluid. Based on the quantitative data, we show for the first time that the concentrations of cytokines in glioblastoma cyst fluid correlate with blood leukocyte levels, suggesting an important interaction between glioblastomas and the circulation. Preoperative MRI of the cystic glioblastomas confirmed both destruction and displacement of brain tissue, but none of the cytokine levels correlated with degree of brain tissue displacement or peri-tumoral edema, as could be assessed by MRI. We conclude that cystic glioblastomas are highly pro-inflammatory environments that interact with the circulation and that they both displace and destroy brain tissue. These observations point to the need for neuroprotective strategies in glioblastoma therapy, which could include an anti-inflammatory approach.

Glioblastoma microenvironment contains multiple hormonal and non-hormonal growth-stimulating factors.

BACKGROUND: The growth of malignant tumors is influenced by their microenvironment. Glioblastoma, an aggressive primary brain tumor, may have cysts containing fluid that represents the tumor microenvironment. The aim of this study was to investigate whether the cyst fluid of cystic glioblastomas contains growth-stimulating factors. Identification of such growth factors may pave the way for the development of targeted anti-glioblastoma therapies. METHODS: We performed hormone analysis of cyst fluid from 25 cystic glioblastomas and proteomics analysis of cyst fluid from another 12 cystic glioblastomas. RESULTS: Glioblastoma cyst fluid contained hormones within wide concentration ranges: Insulin-like growth factor 1 (0-13.7 nmol/L), insulin (1.4-133 pmol/L), erythropoietin (4.7-402 IU/L), growth hormone (0-0.93 µg/L), testosterone (0.2-10.1 nmol/L), estradiol (0-1.0 nmol/L), triiodothyronine (1.0-11.5). Tumor volume correlated with cyst fluid concentrations of growth hormone and testosterone. Survival correlated inversely with cyst fluid concentration of erythropoietin. Several hormones were present at concentrations that have been shown to stimulate glioblastoma growth in vitro. Concentrations of erythropoietin and estradiol (in men) were higher in cyst fluid than in serum, suggesting formation by tumor or brain tissue. Quantitatively, glioblastoma cyst fluid was dominated by serum proteins, illustrating blood-brain barrier leakage. Proteomics identified several proteins that stimulate tumor cell proliferation and invasiveness, others that inhibit apoptosis or mediate adaption to hypoxia and some that induce neovascularization or blood-brain barrier leakage. CONCLUSION: The microenvironment of glioblastomas is rich in growth-stimulating factors that may originate from the circulation, the tumor, or the brain. The wide variation in cyst fluid hormone concentrations may differentially influence tumor growth.

How I do it: endoscopic endonasal resection of tuberculum sellae meningioma.

BACKGROUND: Tuberculum sellae meningiomas (TSMs) adherent to neurovascular structures are particularly challenging lesions requiring delicate and precise microneurosurgery. There is an ongoing debate about the optimal surgical approach. METHOD: We describe technical nuances and challenges in TSM resection using the endoscopic endonasal approach (EEA) in two cases of fibrous tumors with adherence to neurovascular structures. The cases are illustrated with a video (case 1) and figures (cases 1 and 2). CONCLUSION: A dedicated team approach and precise microsurgical technique facilitate safe resection of complex TSMs through the EEA.

Cut-off values for sufficient cortisol response to low dose Short Synacthen Test after surgery for non-functioning pituitary adenoma.

OBJECTIVE: The aim was to study the prevalence of secondary adrenal insufficiency before and after surgery for non-functioning pituitary adenomas, as well as determine risk factors for developing secondary adrenal insufficiency. A secondary aim was to determine adequate p-cortisol response to a 1-µg Short Synacthen Test after surgery. DESIGN: Longitudinal cohort study. METHODS: One hundred seventeen patients (52/65 females/males, age 59 years) undergoing primary surgery for clinically non-functioning pituitary adenomas were included. P-cortisol was measured in morning blood samples. Three months after surgery, a Short Synacthen Test was performed. RESULTS: All tumours were macroadenomas (mean size 26.9 mm, range 13-61 mm). The surgical indications were visual impairment (93), tumour growth (16), pituitary apoplexy (6) and headache (2). Before surgery, 17% of the patients had secondary adrenal insufficiency (SAI), decreasing to 15% 3 months postoperatively. Risk of SAI was increased in patients operated for pituitary apoplexy (p < 0.001), while age, sex, tumour size and complication rate were not different from the remaining cohort. Three months after surgery, all patients with baseline p-cortisol ≥ 172 nmol/l (6.2 µg/dl) and peak p-cortisol during Short Synacthen Test ≥ 320 nmol/l (11.6 µg/dl) tapered cortisone unproblematically. In patients with intact hypothalamic-pituitary-adrenal axis, p-cortisol peaked < 500 nmol/l (18.1 µg/dl) during Short Synacthen Test in 48% of patient. CONCLUSION: Pituitary surgery is safe and transsphenoidal surgery rarely causes new SAI. Relying solely on morning p-cortisol for diagnosing secondary adrenal insufficiency gives false positives and the Short Synacthen Test remains useful. A peak p-cortisol ≥ 320 during (11.6 µg/dl) Short Synacthen Test indicates a sufficient response, while < 309 nmol/l (11.2 µg/dl) indicates secondary adrenal insufficiency.

Minimally Invasive Microsurgical Resection of Primary, Intradural Spinal Tumors is Feasible and Safe: A Consecutive Series of 83 Patients.

BACKGROUND: To date, the traditional approach to intraspinal tumors has been open laminectomy or laminoplasty followed by microsurgical tumor resection. Recently, however, minimally invasive approaches have been attempted by some. OBJECTIVE: To investigate the feasibility and safety of minimally invasive surgery (MIS) for primary intradural spinal tumors. METHODS: Medical charts of 83 consecutive patients treated with MIS for intradural spinal tumors were reviewed. Patients were followed up during the study year, 2015, by either routine history/physical examination or by telephone consultation, with a focus on tumor status and surgery-related complications. RESULTS: Mean age at surgery was 53.7 yr and 52% were female. There were 49 schwannomas, 18 meningeomas, 10 ependymomas, 2 hemangioblastomas, 1 neurofibroma, 1 paraganglioma, 1 epidermoid cyst, and 1 hemangiopericytoma. The surgical mortality was 0%. In 87% of cases, gross total resection was achieved. The complication rate was 11%, including 2 cerebrospinal fluid leakages, 1 asymptomatic pseudomeningocele, 2 superficial surgical site infections, 1 sinus vein thrombosis, and 4 cases of neurological deterioration. There were no postoperative hematomas, and no cases of deep vein thrombosis or pulmonary embolism. Ninety-three percent of patients were ambulatory and able to work at the time of follow-up. CONCLUSION: This study both demonstrates that it is feasible and safe to remove select, primary intradural spinal tumors using MIS, and augments the previous literature in favor of MIS for these tumors.

The proteome of pus from human brain abscesses: host-derived neurotoxic proteins and the cell-type diversity of CNS pus.

OBJECTIVE What determines the extent of tissue destruction during brain abscess formation is not known. Pyogenic brain infections cause destruction of brain tissue that greatly exceeds the area occupied by microbes, as seen in experimental studies, pointing to cytotoxic factors other than microbes in pus. This study examined whether brain abscess pus contains cytotoxic proteins that might explain the extent of tissue destruction. METHODS Pus proteins from 20 human brain abscesses and, for comparison, 7 subdural empyemas were analyzed by proteomics mass spectrometry. Tissue destruction was determined from brain abscess volumes as measured by MRI. RESULTS Brain abscess volume correlated with extracellular pus levels of antibacterial proteins from neutrophils and macrophages: myeloperoxidase (r = 0.64), azurocidin (r = 0.61), lactotransferrin (r = 0.57), and cathelicidin (r = 0.52) (p values 0.002-0.018), suggesting an association between leukocytic activity and tissue damage. In contrast, perfringolysin O, a cytotoxic protein from Streptococcus intermedius that was detected in 16 patients, did not correlate with abscess volume (r = 0.12, p = 0.66). The median number of proteins identified in each pus sample was 870 (range 643-1094). Antibiotic or steroid treatment prior to pus evacuation did not reduce the number or levels of pus proteins. Some of the identified proteins have well-known neurotoxic effects, e.g., eosinophil cationic protein and nonsecretory ribonuclease (also known as eosinophil-derived neurotoxin). The cellular response to brain infection was highly complex, as reflected by the presence of proteins that were specific for neutrophils, eosinophils, macrophages, platelets, fibroblasts, or mast cells in addition to plasma and erythrocytic proteins. Other proteins (neurofilaments, myelin basic protein, and glial fibrillary acidic protein) were specific for brain cells and reflected damage to neurons, oligodendrocytes, and astrocytes, respectively. Pus from subdural empyemas had significantly higher levels of plasma proteins and lower levels of leukocytic proteins than pus from intracerebral abscesses, suggesting greater turnover of the extracellular fluid of empyemas and washout of pus constituents. CONCLUSIONS Brain abscess pus contains leukocytic proteins that are neurotoxic and likely participate actively in the excessive tissue destruction inherent in brain abscess formation. These findings underscore the importance of rapid evacuation of brain abscess pus.

Cyst Fluid From Cystic, Malignant Brain Tumors: A Reservoir of Nutrients, Including Growth Factor-Like Nutrients, for Tumor Cells.

BACKGROUND: Brain tumors may have cysts, whose content of nutrients could influence tumor cell microenvironment and growth. OBJECTIVE: To measure nutrients in cyst fluid from glioblastoma multiforme (GBM) and metastatic brain tumors. METHODS: Quantification of nutrients in cyst fluid from 12 to 18 GBMs and 4 to 10 metastatic brain tumors. RESULTS: GBM cysts contained glucose at 2.2 mmol/L (median value; range <0.8-3.5) and glutamine at 1.04 mmol/L (0.17-4.2). Lactate was 7.1 mmol/L (2.4-12.5) and correlated inversely with glucose level (r = -0.77; P < .001). Amino acids, including glutamate, varied greatly, but median values were similar to previously published serum values. Ammonia was 75 µmol/L (11-241). B vitamins were present at previously published serum values, and riboflavin, nicotinamide, pyridoxal 5΄-phosphate, and cobalamin were higher in cyst fluid than in cerebrospinal fluid. Inorganic phosphate was 1.25 mmol/L (0.34-3.44), which was >3 times higher than in ventricular cerebrospinal fluid: 0.35 mmol/L (0.22-0.66; P < .001). Tricarboxylic acid cycle intermediates were in the low micromolar range, except for citrate, which was 240 µmol/L (140-590). In cystic metastatic malignant melanomas and lung tumors values were similar to those in GBMs. CONCLUSION: Tumor cysts may be a nutrient reservoir for brain tumors, securing tumor energy metabolism and synthesis of cell constituents. Serum is one likely source of cyst fluid nutrients. Nutrient levels in tumor cyst fluid are highly variable, which could differentially stimulate tumor growth. Cyst fluid glutamate, lactate, and phosphate may act as tumor growth factors; these compounds have previously been shown to stimulate tumor growth at concentrations found in tumor cyst fluid.

High extracellular concentration of excitatory amino acids glutamate and aspartate in human brain abscess.

Brain abscesses often cause symptoms of brain dysfunction, including seizures, suggesting interference with normal neurotransmission. We determined the concentration of extracellular neuroactive amino acids in brain abscesses from 16 human patients. Glutamate was present at 3.6 mmol/L (median value, range 0.5-10.8), aspartate at 1.0 mmol/L (range 0.09-6.8). For comparison, in cerebroventricular fluid glutamate was ∼0.6 µmol/L, and aspartate was not different from zero. The total concentration of amino acids was higher in eight patients with seizures: 66 mmol/L (median value, range 19-109) vs. 21 mmol/L (range 4-52) in eight patients without seizures (p=0.026). The concentration of aspartate and essential amino acids tryptophan, phenylalanine, tyrosine, leucine, and isoleucine was higher in pus from patients with seizures (p⩽0.040), whereas that of glutamate was not (p=0.095). The median concentration of the non-proteinogenic, inhibitory amino acid taurine was similar in the two groups, 0.7-0.8 mmol/L (range 0.1-6.1). GABA could not be detected in pus. The patient groups did not differ with respect to abscess volume, the cerebral lobe affected, age, or time from symptom onset to surgery. Seven patients with extracerebral, intracranial abscesses had significantly lower pus concentration of glutamate (352 µmol/L, range 83-1368) and aspartate (71 µmol/L, range 22-330) than intracerebral abscesses (p<0.001). We conclude that excitatory amino acids glutamate and aspartate may reach very high concentrations in brain abscesses, probably contributing to symptoms through activation of glutamate receptors in the surrounding brain tissue.

Intracranial Non-traumatic Aneurysms in Children and Adolescents.

An intracranial aneurysm in a child or adolescent is a rare, but potentially devastating condition. As little as approximately 1200 cases are reported between 1939 and 2011, with many of the reports presenting diverting results. There is consensus, though, in that pediatric aneurysms represent a pathophysiological entity different from their adult counterparts. In children, there is a male predominance. About two-thirds of pediatric intracranial aneurysms become symptomatic with hemorrhage and the rate of re-hemorrhage is higher than in adults. The rate of hemorrhage from an intracranial aneurysm peaks in girls around menarche. The most common aneurysm site in children is the internal carotid artery, in particular at its terminal ending. Aneurysms in the posterior circulation are more common in children than adults. Children more often develop giant aneurysms, and may become symptomatic from the mass effect of the aneurysm (tumorlike symptoms). The more complex nature of pediatric aneurysms poses a larger challenge to treatment alongside with higher demands to the durability of treatment. Outcome and mortality are similar in children and adults, but long-term outcome in the pediatric population is influenced by the high rate of aneurysm recurrences and de novo formation of intracranial aneurysms. This urges the need for life-long follow-up and screening protocols.

Minimally invasive microsurgical resection of primary, intradural spinal tumours using a tubular retraction system.

STUDY DESIGN: This is a retrospective review of prospectively collected data. BACKGROUND: Primary, intradural spinal tumours have traditionally been microsurgically resected following macrosurgical laminectomy or laminoplasty. We hypothesize that approach-related morbidity can be reduced with less-invasive approaches; we have therefore implemented a minimally invasive approach, with the assistance of a tubular retraction system, for microsurgical resection of primary intradural spinal tumours. METHODS: From January 2007 to December 2009, 54 patients underwent surgery for a spinal intradural tumour. Of these, nine patients who underwent minimally invasive posterior unilateral transmuscular surgery using a tubular retraction system were included in this study. Resection grade and surgery-related complications were retrospectively reviewed. RESULTS: All tumours were totally resected (verified by postoperative magnetic resonance imaging). There were no post-operative complications. Eight of the nine patients were mobilized on the day of surgery or on post-operative day 1. One patient was mobilized on post-operative day 2. CONCLUSIONS: Selected primary, intradural spinal tumours can be safely and successfully resected using a minimally invasive posterior unilateral transmuscular approach with the assistance of a tubular retraction system.