Medulloblastomas are malignant embryonal brain tumours that may harbour mutations in histone‐modifying genes, while mutations in histone genes have not been detected to date. We here describe the ...first SHH medulloblastoma with H3 K27M mutation. This may have diagnostic implications as H3 K27M mutations are the hallmark of diffuse midline gliomas, H3 K27M mutant, WHO grade IV. Medulloblastomas arise in midline structures and thus must not be mistaken for DMG when using an antibody detecting the H3 K27M mutation.
Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor. High infiltration rates and poor therapy responses make it the deadliest glioma. The tumor metabolism is known to ...differ from normal one and is influenced through various factors which can lead to longer survival. Metabolites are small molecules (< 1500 Da) that display the metabolic pathways in the tissue. To determine the metabolic alterations between tumor and peritumoral tissue in human GBMs, mass spectrometry imaging (MSI) was performed on thin sections from 25 resected tumors. In addition, the GBMs were compared with six gliomas harboring a mutation in the isocitrate dehydrogenase (IDH1) gene (IDH1). With this technique, a manifold of analytes can be easily visualized on a single tissue section. Metabolites were annotated based on their accurate mass using high resolution MSI. Differences in their mean intensities in the tumor and peritumoral areas were statistically evaluated and abundances were visualized on the tissue. Enhanced levels of the antioxidants ascorbic acid, taurine, and glutathione in tumor areas suggest protective effects on the tumor. Increased levels of purine and pyrimidine metabolism compounds in GBM areas indicate the high energy demand. In accordance with these results, enhanced abundances of lactate and glutamine were detected. Moreover, decreased abundance of N‐acetylaspartate, a marker for neuronal health, was measured in tumor areas. Obtained metabolic information could potentially support and personalize therapeutic approaches, hence emphasizing the suitability of MSI for GBM research.
IMPORTANCE: The association of surgical hematoma evacuation with clinical outcomes in patients with cerebellar intracerebral hemorrhage (ICH) has not been established. OBJECTIVE: To determine the ...association of surgical hematoma evacuation with clinical outcomes in cerebellar ICH. DESIGN, SETTING, AND PARTICIPANTS: Individual participant data (IPD) meta-analysis of 4 observational ICH studies incorporating 6580 patients treated at 64 hospitals across the United States and Germany (2006-2015). EXPOSURE: Surgical hematoma evacuation vs conservative treatment. MAIN OUTCOMES AND MEASURES: The primary outcome was functional disability evaluated by the modified Rankin Scale (mRS score range: 0, no functional deficit to 6, death) at 3 months; favorable (mRS, 0-3) vs unfavorable (mRS, 4-6). Secondary outcomes included survival at 3 months and at 12 months. Analyses included propensity score matching and covariate adjustment, and predicted probabilities were used to identify treatment-related cutoff values for cerebellar ICH. RESULTS: Among 578 patients with cerebellar ICH, propensity score–matched groups included 152 patients with surgical hematoma evacuation vs 152 patients with conservative treatment (age, 68.9 vs 69.2 years; men, 55.9% vs 51.3%; prior anticoagulation, 60.5% vs 63.8%; and median ICH volume, 20.5 cm3 vs 18.8 cm3). After adjustment, surgical hematoma evacuation vs conservative treatment was not significantly associated with likelihood of better functional disability at 3 months (30.9% vs 35.5%; adjusted odds ratio AOR, 0.94 95% CI, 0.81 to 1.09, P = .43; adjusted risk difference ARD, −3.7% 95% CI, −8.7% to 1.2%) but was significantly associated with greater probability of survival at 3 months (78.3% vs 61.2%; AOR, 1.25 95% CI, 1.07 to 1.45, P = .005; ARD, 18.5% 95% CI, 13.8% to 23.2%) and at 12 months (71.7% vs 57.2%; AOR, 1.21 95% CI, 1.03 to 1.42, P = .02; ARD, 17.0% 95% CI, 11.5% to 22.6%). A volume range of 12 to 15 cm3 was identified; below this level, surgical hematoma evacuation was associated with lower likelihood of favorable functional outcome (volume ≤12 cm3, 30.6% vs 62.3% P = .003; ARD, −34.7% −38.8% to −30.6%; P value for interaction, .01), and above, it was associated with greater likelihood of survival (volume ≥15 cm3, 74.5% vs 45.1% P < .001; ARD, 28.2% 95% CI, 24.6% to 31.8%; P value for interaction, .02). CONCLUSIONS AND RELEVANCE: Among patients with cerebellar ICH, surgical hematoma evacuation, compared with conservative treatment, was not associated with improved functional outcome. Given the null primary outcome, investigation is necessary to establish whether there are differing associations based on hematoma volume.
Purpose
Pituitary adenoma (PA) constitutes the third most common intracranial neoplasm. The mostly benign endocrine lesions express no hormone (null cell PA) or the pituitary hormone(s) of the cell ...lineage of origin. In 0.5–1.5% of surgical specimens and in up to 10% of autopsy cases, two or three seemingly separate PA may coincide. These multiple adenomas may express different hormones, but whether or not expression of lineage-restricted transcription factors and molecular features are distinct within multiple lesions remains unknown.
Methods
Searching the data bank of the German Pituitary Tumor Registry 12 double pituitary adenomas with diverse lineage were identified among 3654 adenomas and 6 hypophyseal carcinomas diagnosed between 2012 and 2020. The double adenomas were investigated immunohistochemically for expression of hormones and lineage markers. In addition, chromosomal gains and losses as well as global DNA methylation profiles were assessed, whenever sufficient material was available (n = 8 PA).
Results
In accordance with the literature, combinations of GH/prolactin/TSH–FSH/LH adenoma (4/12), GH/prolactin/TSH–ACTH adenoma (3/12), and ACTH–FSH/LH adenoma (3/12) were observed. Further, two out of 12 cases showed a combination of a GH/prolactin/TSH adenoma with a null-cell adenoma. Different expression pattern of hormones were confirmed by different expression of transcription factors in 11/12 patients. Finally, multiple lesions that were molecularly analysed in 4 patients displayed distinct copy number changes and global methylation pattern.
Conclusion
Our data confirm and extend the knowledge on multiple PA and suggest that such lesions may origin from distinct cell types.
Abstract
Context
Despite growing evidence that temozolomide (TMZ) therapy is effective for the treatment of aggressive pituitary tumors (APTs) or carcinomas (PCs), individual therapy decisions remain ...challenging.
Objective
We therefore aimed to report on clinical characteristics leading to initiation of TMZ therapy and to add evidence on TMZ long-term effectiveness.
Design and subjects
Retrospective survey on TMZ treatment in patients with APTs or PCs. TMZ therapy was initiated in 47 patients (22 females) with APTs (n = 34) or PCs (n = 13). Mean age at diagnosis was 45 ± 15 years. The immunohistochemical subtypes were corticotroph (n = 20), lactotroph (n = 18), and nonfunctioning (n = 9) tumors. TMZ therapy started 8 years after initial diagnosis using a standard regimen (median 6 cycles) for the majority of patients.
Results
Long-term radiological response to TMZ after a median follow-up of 32 months with 4 patients still on TMZ therapy was tumor regression for 9 (20%), stable disease for 8 (17%), and tumor progression for 29 patients (63%) (outcome data available for 46 patients). Progression occurred 16 months after initiation of TMZ. Median estimated progression-free survival was 23 months. Disease stabilization and median progression-free survival did not differ between patients with APTs or PCs. Predictors of tumor response were not identified. Overall, TMZ was well tolerated.
Conclusion
We performed a nationwide survey on TMZ therapy in patients with APTs and PCs. While early response rates to TMZ are promising, long-term outcome is less favorable. Prolonged TMZ administration should be considered. We were not able to confirm previously reported predictors of tumor response to TMZ.
Acromegaly is a rare disease caused by excessive growth hormone (GH) secretion, mostly induced by pituitary adenomas. The care of pregnant women with acromegaly is challenging, in part due to ...existing clinical data being limited and not entirely consistent with regard to potential risks for mother and child.
To retrospectively examine data on pregnancy and maternal as well as neonatal outcomes in patients with acromegaly.
Retrospective data analysis from 47 pregnancies of 31 women treated in centers of the German Acromegaly Registry.
87.1% of the studied women underwent transsphenoidal surgery before pregnancy. In 51.1% a combination of dopamine agonists and somatostatin analogs were used before pregnancy. Three women did not receive any therapy for acromegaly. During pregnancy only 6.4% received either somatostatin analogs or dopamine agonists. In total, 70.2% of all documented pregnancies emerged spontaneously. Gestational diabetes was diagnosed in 10.6% and gravid hypertension in 6.4%. Overall, no preterm birth was detected. Indeed, 87% of acromegalic women experienced a delivery without complications.
Pregnancies in women with acromegaly are possible and the course of pregnancy is in general safe for mother and child both with and without specific treatment for acromegaly. The prevalence of concomitant metabolic diseases such as gestational diabetes is comparable to the prevalence in healthy pregnant women. Nevertheless, larger studies with more data in pregnant patients with acromegaly are needed to provide safe and effective care for pregnant women with this condition.
BACKGROUNDThe increasing use of cranial tomographic imaging has led to the more frequent discovery of pituitary tumors. In this review, we discuss the clinical symptoms that point toward a pituitary ...tumor, the required diagnostic studies, the potential need for follow-up studies, and the indications for neurosurgical treatment. METHODSThis review is based on pertinent publications from the years 2005-2020 that were retrieved by a selective search in PubMed, as well as on the current German S2k guideline, which was created with the present authors playing a coordinating role, and on further guidelines from abroad. Relevant information from older reviews was also considered. RESULTSThe reported prevalence of pituitary tumors varies depending on the method of data acquisition. Autopsy studies yield a figure of 10.7%, while population-based studies reported 77.6-115.6 cases per 100 000 inhabitants. These lesions are nearly always benign, and 85% of them are pituitary adenomas. Pituitary adenomas measuring less than 1 cm in diameter are called microadenomas, while those measuring 1 cm or more are called macroadenomas. According to magnetic resonance imaging (MRI) studies, the prevalence of microadenomas in the general population is in the range of 10-38%, while that of macroadenomas is 0.16-0.3%. Pituitary adenomas can be either hormonally inactive or hormonally active. Half of all patients with hormonally inactive microadenomas display no endocrine abnormality, while 37-85% of patients with hormonally inactive macroadenomas manifest at least partial pituitary insufficiency. The clinical spectrum of pituitary tumors ranges from a fully asymptomatic state to visual disturbances, neurologic deficits, severe hormone excess (e.g., in Cushing disease), and life-threatening pituitary insufficiency. Pituitary adenomas are often diagnosed only after a latency of many years, even when they are symptomatic. If an imaging study shows the tumor to be in contact with the visual pathway, an ophthalmological evaluation should be performed. There are clear indications for surgery, e.g., imminent loss of vision, but most asymptomatic pituitary tumors can be observed only. CONCLUSIONThe manifestations of pituitary tumors are first recognized by primary care physicians. The further diagnostic evaluation of these patients should be carried out in standardized and interdisciplinary fashion.
Abstract
Objective
To identify early available predictors for the long-term outcome
of patients after transsphenoidal surgery (TSS) in the management of
Cushing’s disease.
Methods
This single-center, ...retrospective study included 93 consecutive
patients with Cushing’s disease (follow-up 12–129 months, mean
48, median 38) who underwent TSS (21 had previous operations elsewhere). Six
cases had early re-operation, and the resulting data were evaluated instead of
the respective first operation. During the postoperative course, serum cortisol
levels were assessed every four hours at least until the next morning. An
association of parameters with long-term outcomes was tested using binary
logistic regression. Receiver operating characteristic curves were used to
determine sensitivity, specificity, positive predictive value, and negative
predictive value of different cut-off values of serum cortisol in the
postoperative course in the event of recurrence after remission.
Results
Eighty out of 93 patients (86%) showed postoperative
remission (after primary treatment, 60 out of 72 patients, 90.3%). Of
these, 8 patients (10%) developed recurrence of hypercortisolism.
Compared to patients with persisting long-term remission, those with recurrence
differed in cortisol levels starting from 4 pm on the day of surgery
plus an event of increasing cortisol during the early postoperative course
(“peak”). Binary logistic regression showed the association
between a peak of serum cortisol in the early postoperative course with an
increased probability of recurrence.
Conclusions
Patients with a peak of serum cortisol in the early
postoperative course show an increased recurrence rate. A cut-off value of serum
cortisol for clear identification of patients with later recurrence could not be
determined.
In patients with intracerebral hemorrhage (ICH), the presence of intraventricular hemorrhage constitutes a promising therapeutic target. Intraventricular fibrinolysis (IVF) reduces mortality, yet ...impact on functional disability remains unclear. Thus, we aimed to determine the influence of IVF on functional outcomes.
This individual participant data meta-analysis pooled 1501 patients from 2 randomized trials and 7 observational studies enrolled during 2004 to 2015. We compared IVF versus standard of care (including placebo) in patients treated with external ventricular drainage due to acute hydrocephalus caused by ICH with intraventricular hemorrhage. The primary outcome was functional disability evaluated by the modified Rankin Scale (mRS; range: 0-6, lower scores indicating less disability) at 6 months, dichotomized into mRS score: 0 to 3 versus mRS: 4 to 6. Secondary outcomes included ordinal-shift analysis, all-cause mortality, and intracranial adverse events. Confounding and bias were adjusted by random effects and doubly robust models to calculate odds ratios and absolute treatment effects (ATE).
Comparing treatment of 596 with IVF to 905 with standard of care resulted in an ATE to achieve the primary outcome of 9.3% (95% CI, 4.4-14.1). IVF treatment showed a significant shift towards improved outcome across the entire range of mRS estimates, common odds ratio, 1.75 (95% CI, 1.39-2.17), reduced mortality, odds ratio, 0.47 (95% CI, 0.35-0.64), without increased adverse events, absolute difference, 1.0% (95% CI, -2.7 to 4.8). Exploratory analyses provided that early IVF treatment (≤48 hours) after symptom onset was associated with an ATE, 15.2% (95% CI, 8.6-21.8) to achieve the primary outcome.
As compared to standard of care, the administration of IVF in patients with acute hydrocephalus caused by intracerebral and intraventricular hemorrhage was significantly associated with improved functional outcome at 6 months. The treatment effect was linked to an early time window <48 hours, specifying a target population for future trials.
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