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Purpose/Objective Multiple tumorous lesions in one pituitary gland are rare and mostly described in case reports. Their incidences and combinations are defined in larger collectives. Therefore, we analyzed our large collection for double tumors and combinations of tumors, cysts, and inflammation. Methods The German Registry of Pituitary Tumors, including cases from 1990 to 2018, served as the database. Our collection comprises a total of 16,283 cases up until the end of 2018. Of these cases, 12,673 originated from surgical and 3,610 from autopsy material. All specimens were fixed in formalin and embedded in paraffin. The sections were stained with hematoxylin–eosin and PAS. Monoclonal (prolactin, TSH, FSH, LH, and α subunit) or polyclonal (GH and ACTH) antibodies were used to detect pituitary hormones in the lesions. Since 2017, antibodies against the transcription factors Pit-1, T-Pit, and SF-1 have been used in difficult cases. The criteria of the 2017 WHO classification have been basic principles for classification since 2018 (Osamura et al. 2017). For differentiation of other sellar tumors, such as meningiomas, chordomas, or metastases, the use of additional antibodies was necessary. For these cases, it was possible to use a broad antibody spectrum. Autopsy pituitaries were generally studied by H&E and PAS sections. If any lesions were demonstrated in these specimens, additional immunostaining was performed. Results Multiple tumorous lesions with more than one pituitary neuroendocrine tumor (PitNET) respectively adenoma make up 1.4% (232 cases) in our collection. Within the selected cases, synchronous multiple pituitary neuroendocrine tumors (PitNETs) account for 17.3%, PANCH cases (pituitary adenoma with neuronal choristoma) for 14.7%, PitNETs and posterior lobe tumors for 2.2%, PitNETs and metastases for 5.2%, PitNETs and mesenchymal tumors for 2.6%, PitNETs and cysts for 52.2%, and PitNETs and primary inflammation for 6.0%. The mean patient age was 53.8 years, with a standard deviation of 18.5 years. A total of 55.3% of the patients were female and 44.7% were male. From 1990 to 2018, there was a continuous increase in the number of multiple tumorous lesions. Conclusion From our studies, we conclude that considering possible tumorous double lesions during surgeries and in preoperative X-ray analyses is recommended.

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.

Although non-functioning pituitary tumors are frequent, diagnostic and therapeutic concepts are not well standardized. We here present the first German multidisciplinary guideline on this topic. The single most important message is to manage the patients by a multidisciplinary team (consisting at least of an endocrinologist, a neurosurgeon, and a (neuro-) radiologist). The initial diagnostic work-up comprises a detailed characterization of both biochemical (focusing on hormonal excess or deficiency states) and morphological aspects (with magnetic resonance imaging of the sellar region). An ophthalmological examination is only needed in presence of symptoms or large tumors affecting the visual system. Asymptomatic, hormonally inactive tumors allow for a 'wait and scan' strategy. In contrast, surgical treatment by an experienced pituitary surgeon is standard of care in case of (impending) visual impairment. Therapeutic options for incompletely resected or recurrent tumors include re-operation, radiotherapy, and observation; the individual treatment plan should be developed multidisciplinary. Irrespective of the therapeutic approach applied, patients require long-term follow-up. Patient with larger pituitary tumors or former surgery/radiotherapy should be regularly counseled regarding potential symptoms of hormonal deficiency states.

Background The long-term outcome of facet joint replacement (FJR) still is to be proven. Methods We present a prospective case series of 26 (male-to-female ratio of 1:1; mean age: 61 years) patients undergoing FJR with a follow-up of at least 1 year (range: 12–112; mean: 67 months). Visual analog scale (VAS) for back and leg pain, Oswestry Disability Index (ODI), and the 12-Item Short Form Health Survey (SF-12) were applied pre- and postoperatively (after 3, 6, and 12 months) as well as at the last follow-up (N = 24). Using X-rays of the lumbar spine (N = 20), the range of motion (ROM) and disk height in the indicator and adjacent levels were assessed. Results FJR was performed at L3/L4 (N = 7), L4/L5 (N = 17), and L5/S1 (N = 2). Mean VAS (mm) for back pain decreased from 71 to 18, mean VAS for right leg pain from 61 to 7, and from 51 to 3 for the left leg. Mean ODI dropped from 51 to 22% (for all p Conclusions In selected cases, long-term results of FJR show good outcome concerning pain, quality of life, preservation of lumbar spine motion, and protection of adjacent level.

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.

Brucellosis is a frequent zoonosis in some regions of the world and may cause various symptoms. Neurobrucellosis is a rare but serious complication of the infection. Our case report describes the course of neurobrucellosis in a patient who had received a ventriculoperitoneal shunt in his native country 13 years prior to diagnosis of brucellosis. He initially presented to us with symptoms of peritonitis, which misled us to perform abdominal surgery first. After the diagnosis of neurobrucellosis was confirmed and appropriate antibiotics were initiated, the symptoms soon disappeared. Although the ventriculoperitoneal shunt was subsequently removed, the patient did not develop a symptomatic hydrocephalus further on. This case displays the challenges in diagnosing an infection that occurred sporadically in Europe and may be missed by currently applied routine microbiological workup. Considering the political context, with increasing relocation from endemic areas to European countries, it is to be expected that the cases of brucellosis and neurobrucellosis will rise. Brucellosis should be considered and adequate investigations should be performed.

Context Craniopharyngioma is a rare neoplastic entity of the central nervous system. Childhood-onset craniopharyngioma is the subject of frequent research whereas the information on adult-onset craniopharyngioma is scarce. Objective The objective of this study was to examine the level of daily impairment in adult patients suffering from craniopharyngioma. Design Noninterventional patient registry indexed as PV4842 with the local ethics committee. Setting The study is set in a hospitalized and ambulatory setting. Patients 148 patients with adult-onset craniopharyngioma were recruited from 8 centers, 22 prospectively and 126 retrospectively. Mean follow-up was 31 months. Interventions No interventions performed. Main Outcome Measures Complications, symptoms, body mass index (BMI), and quality of life (QoL; EORTC QLQ C30 and BN20) were recorded preoperatively and at follow-up. The hypotheses tested were generated after data collection. Results Complications were more frequent after transcranial than transsphenoidal approaches (31 % vs. 11%; P < 0.01). Preoperative obesity was present in 0% papillary and in 38% of all adamantinomatous craniopharyngiomas (P = 0.05), and diabetes insipidus was more frequent for papillary craniopharyngioma (36.8% vs. 16,7%; P < 0.05). Hormone deficits at follow-up were reduced in 16.9%, equal in 31.4%, and increased in 63.6% (P < 0.001). BMI increased from 28.7 ± 7.4 kg/m2 before surgery to 30.2 ± 7.4 kg/m2 at follow-up (P < 0.001). In QoL, a decrease of future uncertainty (62.5 vs. 36.8; P = 0.02) and visual disorders (38.9 vs. 12.0; P = 0.01) were observed in the prospective collective after surgery. Conclusions Adult craniopharyngioma is associated with a complex sociological and psychological burden and hypothalamic dysfunction, warranting further investigation and emphasizing the need for a wider treatment approach.

ObjectiveTo determine the occurrence of intracranial haemorrhagic complications (IHC) on heparin prophylaxis (low-dose subcutaneous heparin, LDSH) in primary spontaneous intracerebral haemorrhage (ICH) (not oral anticoagulation-associated ICH, non-OAC-ICH), vitamin K antagonist (VKA)-associated ICH and non-vitamin K antagonist oral anticoagulant (NOAC)-associated ICH.MethodsRetrospective cohort study (RETRACE) of 22 participating centres and prospective single-centre study with 1702 patients with VKA-associated or NOAC-associated ICH and 1022 patients with non-OAC-ICH with heparin prophylaxis between 2006 and 2015. Outcomes were defined as rates of IHC during hospital stay among patients with non-OAC-ICH, VKA-ICH and NOAC-ICH, mortality and functional outcome at 3 months between patients with ICH with and without IHC.ResultsIHC occurred in 1.7% (42/2416) of patients with ICH. There were no differences in crude incidence rates among patients with VKA-ICH, NOAC-ICH and non-OAC-ICH (log-rank p=0.645; VKA-ICH: 27/1406 (1.9%), NOAC-ICH 1/130 (0.8%), non-OAC-ICH 14/880 (1.6%); p=0.577). Detailed analysis according to treatment exposure (days with and without LDSH) revealed no differences in incidence rates of IHC per 1000 patient-days (LDSH: 1.43 (1.04–1.93) vs non-LDSH: 1.32 (0.33–3.58), conditional maximum likelihood incidence rate ratio: 1.09 (0.38–4.43); p=0.953). Secondary outcomes showed differences in functional outcome (modified Rankin Scale=4–6: IHC: 29/37 (78.4%) vs non-IHC: 1213/2048 (59.2%); p=0.019) and mortality (IHC: 14/37 (37.8%) vs non-IHC: 485/2048 (23.7%); p=0.045) in disfavour of patients with IHC. Small ICH volume (OR: volume ConclusionsHeparin administration for venous thromboembolism (VTE) prophylaxis in patients with ICH appears to be safe regarding IHC among non-OAC-ICH, VKA-ICH and NOAC-ICH in this observational cohort analysis. Randomised controlled trials are needed to verify the safety and efficacy of heparin compared with other methods for VTE prevention.

Inflammatory pituitary lesions account for 1.8% of all specimens from the German Pituitary Tumor Registry. They occure in 0.5% of the autoptical specimens and in 2.2% of the surgical cases. Women are significantly more often affected than men and are often younger when first diagnosed. In general, primary and secondary inflammation can be distinguished, with secondary types occurring more frequently (75.1%) than idiopathic inflammatory lesions (15.4%). In primary inflammation, the lymphocytic type is more common (88.5%) than the granulomatous type of hypophysitis (11.5%). The most common causes of secondary inflammation are Rathke’s cleft cysts (48.6%), followed by tumors (17.4%) such as the craniopharyngioma (9.1%), adenoma (5.5%) or germinoma (2.0%). More causes are tumor-like lesions (7.1%) such as xanthogranuloma (3.5%) or Langerhans histiocytosis (3.5%), abscesses (5.5%), generalized infections (5.1%), spreaded inflammations (4.7%) and previous surgeries (4.0%). In 1.6% of all specimens the reason for the inflammation remains unclear. The described classification of hypophysitis is important for specific treatment planning after surgery.

Background The 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. Methods This 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. Results The 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. Conclusion The 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.

Between 1996 and 2020, 12,565 cases were enrolled in the German Registry of Pituitary Tumors including 10,084 PitNETs (10,067 adenomas and 19 carcinomas obtained surgically and 193 adenomas diagnosed at autopsy) as well as 69 spindle cell tumors of the neurohypophysis (64 surgical specimens and 5 autopsies). In six patients (1 post mortem and 5 surgical specimens), PitNETs as well as posterior lobe tumors were found in the specimens. Two of the PitNETs were sparsely granulated prolactin-producing tumors, combined in one case with a granular cell tumor and in one case with a pituicytoma. One of the PitNETs revealed that autopsy was a sparsely granulated GH tumor combined with a neurohypophyseal granular cell tumor. Two PitNETs were null cell adenomas combined with a pituicytoma and a spindle cell oncocytoma, respectively. Further, one Crooke cell tumor was combined with a spindle cell oncocytoma. In five cases, the PitNETs were larger than the posterior lobe tumors and accounted for the clinical symptoms. Previously, four cases of co-existing pituitary anterior and posterior lobe tumors were described in the literature, comprising two ACTH PitNETs, one gonadotrophic PitNET and one null cell PitNET, each in combination with a pituicytoma. PitNETs and concomitant granular cell tumor or spindle cell oncocytoma, as observed in our cohort, have not been reported before.

Context Acromegaly is a rare disease caused by excessive growth hormone (GH) secretion from pituitary adenomas in most cases. If neurosurgical therapy is contraindicated or not sufficient, medical therapy is the second line therapy. Objective To describe current medical therapy in acromegaly. Design & Methods Retrospective data analysis from 2732 patients treated in 69 centers of the German Acromegaly Registry. 749 patients were seen within the recent 18 months, of which 420 were on medical therapy (56.1%). Results 73% of medically treated acromegalic patients had normal/low IGF-1 levels. 57% of patients with non-normalized IGF-1 levels had an IGF-1 value between 1- and 1.25-fold above the upper limit of normal. Most patients (55%) received somatostatin analogs as monotherapy, 12% GH receptor monotherapy, and 9% dopamine agonist therapy. Doses of each medical therapy varied widely, with 120 mg lanreotide LAR every 4 weeks, 30 mg octreotide LAR every 4 weeks, 140 mg pegvisomant per week and 1mg cabergoline per week being the most frequent used regimens. A combination of different medical regimens was used in almost 25% of the patients. Conclusion The majority of German acromegalic patients receiving medical therapy are controlled according to normal IGF-1 levels.

Background Transsphenoidal surgery for sellar lesions may affect patency and function of the nasal airways, smell and sinonasal quality of life. Below is our report on otorhinolaryngological data garnered from patients undergoing endonasal transsphenoidal pituitary microsurgery. Methods In a prospective study, 68 patients scheduled for transsphenoidal operations (32 female, 36 male, age 17–72 years) underwent otorhinolaryngological evaluation of their nasal morphology, a standardized smell test (sniffin’ sticks) and rhinomanometry to analyse nasal breathing function preoperatively, 3–5 days postoperatively (without rhinomanometry), after 3–4 months and after 9 months. Results Immediately after surgery, a reduction in smell sensation was detected in almost all patients. Within 3 months, this impairment resolved in all cases except one. In 2 patients (3%) with preoperative anosmia, improvement of smell function to>6 out of 12 sniffin’ sticks was observed. At final visit no patient was noted to have new anosmia. Within 3 months, the results of the rhinomanometry revealed that all patients except one, regained their preoperative nasal breathing function. In 6 patients (8.8%) an improvement in their nose breathing abilities compared to the preoperative state was found. Three patients (4.4%) underwent a LASER transection of mucosal synechiae. In one case with persistent nasal obstruction (1.5%), secondary septoplasty had to be performed. There was no case in which perforation of the nasal septum, nasal tip deflection, or saddle nose deformity was observed. Conclusion Microsurgical resection of pituitary tumors via the endonasal transsphenoidal approach poses an acceptable risk with regards to sinonasal complications. The incidence of secondary rhinosurgical interventions is low. Standardized comparative studies between endoscopic and microsurgical transsphenoidal operations should be undertaken.

Background Guidelines for patient behavior following transsphenoidal surgery do not exist. To gain generally recommendations, the German pituitary working group conducted a study among pituitary surgeons to elucidate their opinions and customs of patients’ counselling. Methods Questions concerning daily activities, exertion of sports and work life were addressed. It was asked to provide the postoperative time interval after which specific activities can be resumed both after a routine or an extended approach. Results Fourteen pituitary surgeons returned the completed questionnaire. Following routine operations, washing the hair was allowed within one week, blowing the nose after 3, flying on an airplane and driving a car after one, lifting heavy weights after 4, playing wind instruments after 6, use of CPAP (continuous positive airway pressure) device after 3, permit leisure sports after 2 to 4 weeks (except for scuba diving). Competitive sports can be resumed after 6 weeks. Occupation with mental demands was considered feasible after 2 weeks, with physical labor after 4 weeks. After extended transsphenoidal surgery, the recommended time interval was roughly twice as long compared to the routine approach. Driving a car was allowed within the first 4 weeks after surgery by some pituitary surgeons, while others allow driving only after 3 months analogous to the regulations after craniotomy. The risk of scuba diving was considered high. Conclusions The data of our study and the literature, and expert opinions from related scientific fields resulted in a consensus on recommendations for patients’ conduct to minimize risks after transsphenoidal surgery.

Gain-of-function somatic mutations in the ubiquitin specific protease 8 (USP8) gene have recently been reported as a cause of pituitary adenomas in Cushing disease. Molecular diagnostic testing of tumor tissue may aid in the diagnosis of specimens obtained through therapeutic transsphenoidal surgery; however, for small tumors, availability of fresh tissue is limited, and contamination with normal tissue is frequent. We performed molecular testing of DNA isolated from single formalin-fixed and paraffin-embedded (FFPE) tissue sections of 42 pituitary adenomas from patients with Cushing disease (27 female patients and 15 male patients; mean age at surgery, 42.5 years; mean tumor size, 12.2 mm). By Sanger sequencing, we identified previously reported USP8 missense mutations in six tumors. Targeted next-generation sequencing (NGS) revealed known or previously undescribed missense mutations in three additional tumors (two with two different mutations each), with mutant allele frequencies as low as 3%. Of the nine tumors with USP8 mutations (mutation frequency, 21.4%), seven were from female patients (mutation frequency, 25.9%), and two were from male patients (mutation frequency, 13.3%). Mutant tumors were on average 11.4 mm in size, and patients with mutations were on average 43.9 years of age. The overall USP8 mutation frequency in our cohort was lower than in previously described cohorts, and we did not observe USP8 deletions that were frequent in other cohorts. We demonstrate that testing for USP8 variants can be performed from small amounts of FFPE tissue. NGS showed higher sensitivity for USP8 mutation detection than did Sanger sequencing. Assessment for USP8 mutations may complement histopathological diagnosis., Sanger and targeted NGS of FFPE tissue from 42 corticotroph adenomas identified USP8 missense mutations in nine tumors; such tests may complement histopathological diagnosis.

Primary leptomeningeal melanocytic tumors (PLMTs) are rare. They usually arise along the spinal cord and at the skull base. Here we report on a patient with a very rare intraventricular melanocytoma. Histologically, a melanocytic tumor was clearly diagnosed. However, to make the uncommon diagnosis of an intraventricular melanocytoma, metastatic melanoma needed to be excluded. Next generation sequencing covering gene mutations that may occur in PLMTs and cutaneous melanoma was performed. The unique gene mutation profile detected, consisting of an activating CYSLTR2 L129Q mutation and EIF1AX G9R mutation and a lack of mutations in genes known to occur in metastatic melanoma (i.e. BRAF or NRAS) confirmed the diagnosis of an intraventricular melanocytoma. This case report is the second intraventricular melanocytoma published to date and demonstrates the value of applying novel genetic assays to make this diagnosis.

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 (

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.

BACKGROUND The diagnosis of Cushing disease is based on endocrinological pa-rameters, with no single test being specific. In some patients, dynamic thin-slice sellar magnetic resonance imaging fails to detect a pituitary tumor. OBJECTIVE The purpose of this study is to investigate the role of ectopic pituitary adenoma in this situation. METHODS In a retrospective chart review, 5 patients (6%) with ectopic adenomas were identified in 83 consecutive patients undergoing transsphenoidal surgery for adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas by 1 surgeon. RESULTS In all 5 patients (all female, 32-41 years of age), an exclusively extrasellar ACTH-secreting adenoma was excised. Three adenomas were located in the cavernous sinus, 1 in the sphenoid sinus, and 1 in the ethmoidal cells. Histologically, none of the tumors showed signs of aggressiveness. Three of the 5 adenomas specifically expressed somatostatin receptor 5. In 4 patients with Cushing disease, postoperative remission was obtained, with 1 recurrence after 14 months. In the patient with Nelson syndrome, ACTH decreased from >800 to

Background and Purpose— Given inconclusive studies, it is debated whether clinical and imaging characteristics, as well as functional outcome, differ among patients with intracerebral hemorrhage (ICH) related to vitamin K antagonists (VKA) versus non–vitamin K antagonist (NOAC)-related ICH. Notably, clinical characteristics according to different NOAC agents and dosages are not established. Methods— Multicenter observational cohort study integrating individual patient data of 1328 patients with oral anticoagulation–associated ICH, including 190 NOAC-related ICH patients, recruited from 2011 to 2015 at 19 tertiary centers across Germany. Imaging, clinical characteristics, and 3-months modified Rankin Scale (mRS) outcomes were compared in NOAC- versus VKA-related ICH patients. Propensity score matching was conducted to adjust for clinically relevant differences in baseline parameters. Subgroup analyses were performed regarding NOAC agent, dosing and present clinically relevant anticoagulatory activity (last intake 30 ng/mL). Results— Despite older age in NOAC patients, there were no relevant differences in clinical and hematoma characteristics between NOAC- and VKA-related ICH regarding baseline hematoma volume (median [interquartile range]: NOAC, 14.7 [5.1–42.3] mL versus VKA, 16.4 [5.8–40.6] mL; P =0.33), rate of hematoma expansion (NOAC, 49/146 [33.6%] versus VKA, 235/688 [34.2%]; P =0.89), and the proportion of patients with unfavorable outcome at 3 months (mRS, 4–6: NOAC 126/179 [70.4%] versus VKA 473/682 [69.4%]; P =0.79). Subgroup analyses revealed that NOAC patients with clinically relevant anticoagulatory effect had higher rates of intraventricular hemorrhage (n/N [%]: present 52/109 [47.7%] versus absent 9/35 [25.7%]; P =0.022) and hematoma expansion (present 35/90 [38.9%] versus absent 5/30 [16.7%]; P =0.040), whereas type of NOAC agent or different NOAC-dosing regimens did not result in relevant differences in imaging characteristics or outcome. Conclusions— If effectively anticoagulated, there are no differences in hematoma characteristics and functional outcome among patients with NOAC- or VKA-related ICH. Clinical Trial Registration— URL: https://www.clinicaltrials.gov . Unique identifier: NCT03093233.

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 cm(3) vs 18.8 cm(3)). 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 cm(3) was identified; below this level, surgical hematoma evacuation was associated with lower likelihood of favorable functional outcome (volume ≤12 cm(3), 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 cm(3), 74.5% vs 45.1% [P

Perisellar infiltration may be responsible for incomplete removal of pituitary tumors. Since intraoperative visualization of parasellar structures is difficult during transsphenoidal surgery, we are describing the use of intraoperative direct contact ultrasound (IOUS). Within 5 years, in 113 transsphenoidal operations (58 male, 55 female, age 14–81 years, 110 pituitary adenomas (mean diameter 26.6 mm, 69 non-secreting adenomas, 41 secreting adenomas), and 1 of each Rathke’s cleft cyst, craniopharyngioma, and xanthogranuloma), IOUS was applied. After wide opening of the sellar floor and removal of the intrasellar tumor portions, a commercially available side fire ultrasound probe is introduced, and in direct contact to the sellar envelope, the perisellar space is scanned perpendicular to the axis of the working channel. We compared the results of IOUS to postoperative MRI after 3–6 months. Identification of the intracavernous ICA, the anterior optic pathway, and the ACA, was possible, it was safe to operate close to them. In 65 operations (58%), further resection of tumor remnants was performed after IOUS. In this selected series, complete resection of tumors (stated by postoperative MRI after 3–6 months) was achieved in 75 operations (66%) and remission was achieved in 18 operations of secreting adenomas (44%). Compared to MRI after 3 to 6 months, the sensitivity of IOUS was 0.568 and the specificity was 0.907. No complications related to IOUS were seen. Visualization of the perisellar compartments by IOUS is easy and fast to perform. It allows the surgeon to identify resectable tumor remnants intraoperatively, which otherwise could be missed.

Guidelines for patient behavior following transsphenoidal surgery do not exist. To gain generally recommendations, the German pituitary working group conducted a study among pituitary surgeons to elucidate their opinions and customs of patients' counselling.Questions concerning daily activities, exertion of sports and work life were addressed. It was asked to provide the postoperative time interval after which specific activities can be resumed both after a routine or an extended approach.Fourteen pituitary surgeons returned the completed questionnaire. Following routine operations, washing the hair was allowed within one week, blowing the nose after 3, flying on an airplane and driving a car after one, lifting heavy weights after 4, playing wind instruments after 6, use of CPAP (continuous positive airway pressure) device after 3, permit leisure sports after 2 to 4 weeks (except for scuba diving). Competitive sports can be resumed after 6 weeks. Occupation with mental demands was considered feasible after 2 weeks, with physical labor after 4 weeks. After extended transsphenoidal surgery, the recommended time interval was roughly twice as long compared to the routine approach. Driving a car was allowed within the first 4 weeks after surgery by some pituitary surgeons, while others allow driving only after 3 months analogous to the regulations after craniotomy. The risk of scuba diving was considered high.The data of our study and the literature, and expert opinions from related scientific fields resulted in a consensus on recommendations for patients' conduct to minimize risks after transsphenoidal surgery.

BackgroundTransnasal surgery (TNS) is the first choice in the treatment of pediatric Cushing’s disease. The question is how can high remission rates be achieved with minimally invasive investigations and TNS whilst avoiding radiotherapy or bilateral adrenalectomy in children.MethodsData from a published series 1 (n=55) of surgeon DKL will be compared with his recent series 2 (n=45) until 2009. All patients were operated by direct transnasal microsurgery. Over time, inferior petrosal sinus sampling (IPSS) was replaced by cavernous sinus sampling (CSS), restricted to unclear cases without increase of salivary cortisol in corticotropin-releasing hormone-test, difficult sellar anatomy or negative magnetic resonance imaging (MRI). Multiple direct intra-operative micro-cytology, micro-doppler and adequate visualization techniques are described.ResultsIn series 1, IPSS was performed in 13 (24%) of whom 46% had false adenoma lateralization. All adenomas could be removed with extensive pituitary exploration. Three patients had early successful re-surgery. In series 2, with more refined MRI and endocrinology, CSS was used in only seven patients (15%) and all micro-adenomas were correctly localized. In three of four patients with persistent cortisol excess, repeat-TNS was necessary and successful. Side effects of TNS were minimal. Recurrence rates were 16% and 11% in series 1 and 2, respectively. Only four of 100 children with invasive adenomas were irradiated, significantly less than in other experienced pediatric centers.ConclusionsThus, 98% remission rate could be achieved with fewer invasive pre-surgical investigations, such as central catheter studies, refined TNS and early repeat-TNS. Repeat-TNS in recurrences minimized the need for irradiation.

Background Recurrences of pituitary adenomas are not so rare. Methods In the German Registry of Pituitary Tumors, more than 12,000 surgical specimens were collected between 1967 and 2012, of which 312 patients with altogether 334 recurrences (n = 646 specimens) were included in our study. Results The histopathology of 162 recurrent adenomas could be compared with the original tumor and 37 second recurrences could be compared with the first recurrence. Comparing the proliferation index (Ki-67) of the original and the first recurrent tumor (n = 162), we found an unchanged index in 43 cases (26%), whereas in 69 cases (43%) the index increased and in 50 cases (31%) it decreased. Comparing the first with the second recurrence (n = 37), we found an unchanged index in 8 cases (22%), an increased index in 15 cases (40%), and a decreased index in 14 cases (38%). The third recurrence showed an unchanged index in 1 case (20%), an increased index in 2 cases (40%), and a decreased index in 2 cases (40%). p53 was unchanged in recurrences in 44% of cases, increased in 33%, and decreased in 22%. In 4 cases, adenomas developed into adenomas with strongly increased proliferation (formerly atypical adenomas, now aggressive adenomas) for the first recurrence, and 9 recurrences became aggressive adenomas. A change of tumor type without change of the common transcription factor occurred in 82 cases. Conclusions A second independent de novo adenoma was present in 10 cases, probably due to changes of transcription factors.

Aims Evidence is lacking regarding acute anticoagulation management in patients after intracerebral haemorrhage (ICH) with implanted mechanical heart valves (MHVs). Our objective was to investigate anticoagulation reversal and resumption strategies by evaluating incidences of haemorrhagic and thromboembolic complications, thereby defining an optimal time-window when to restart therapeutic anticoagulation (TA) in patients with MHV and ICH. Methods and results We pooled individual patient-data (n = 2504) from a nationwide multicentre cohort-study (RETRACE, conducted at 22 German centres) and eventually identified MHV-patients (n = 137) with anticoagulation-associated ICH for outcome analyses. The primary outcome consisted of major haemorrhagic complications analysed during hospital stay according to treatment exposure (restarted TA vs. no-TA). Secondary outcomes comprised thromboembolic complications, the composite outcome (haemorrhagic and thromboembolic complications), timing of TA, and mortality. Adjusted analyses involved propensity-score matching and multivariable cox-regressions to identify optimal timing of TA. In 66/137 (48%) of patients TA was restarted, being associated with increased haemorrhagic (TA = 17/66 (26%) vs. no-TA = 4/71 (6%); P

The review assesses immunohistochemical findings of somatostatin receptors and of metalloproteinases in different pituitary adenoma types and the significance of molecular genetic data. Current evidence does not support routine immunohistochemical assessment of somatostatin or dopamine receptor subtype expression on hormone-secreting or nonfunctioning pituitary adenomas. Further prospective studies are needed to define its role for clinical decision making. Until then we suggest to restrict membrane receptor profiling to individual cases or for study purposes. The problems of adenoma expansion and invasion are discussed. Despite partially contradictory publications, proteases clearly play a major role in permission of infiltrative growth of pituitary adenomas. Therefore, detection of at least MMP-2, MMP-9, TIMP-2, and uPA seems to be justified. Molecular characterization is important for familial adenomas, adenomas in MEN, Carney complex, and McCune-Albright syndrome and can gain insight into pathogenesis of sporadic adenomas.

WHO classifications should be used for comparing the results from different groups of pathologist and clinicians by standardized histopathological methods. Our present report describes the important parameters of pituitary adenoma pathology as demand of the WHO classification for correlation to endocrine data and prognosis. The combination of HE stain based structures with immunostainings for pituitary hormones allows subclassification of adenomas as the best method not only for correlations to clinical hyperfunctions but also for statements to the sensitivity of drug therapies (somatostatin analogs, dopamine agonists). GH-, PRL- and ACTH-secreting pituitary adenomas are further classified based on the size and number of their secretory granules by electron microscopy, or as is mostly the case nowadays by cytokeratin staining pattern, into densely and sparsely granulated. Granulation pattern may be considered for the prediction of treatment response in patients with GH-secreting adenomas, since the sparsely granulated subtype was shown to be less responsive to somatostatin analog treatment. For prognosis, it is important to identify aggressive adenomas by measurements of the Ki-67 index, of the number of mitoses, and of nuclear expression of p53. Among the criteria for atypical adenomas, high Ki-67 labeling index and invasive character are the most important adverse prognostic factors. Promising molecular markers have been identified that might supplement the currently used proliferation parameters. For defining atypical adenomas in a future histopathological classification system, we propose to provide the proliferative potential and the invasive character separately.

Data on the dural invasiveness of pituitary adenomas have been correlated to the expression of matrix metalloproteinases (e.g. MMP-9). Serine proteases have not yet been investigated in human pituitary adenomas. In this study, paraffin-embedded material from 84 human pituitary adenomas (acromegaly n=18, Cushing's disease n=21, prolactinoma n=18, thyroid-stimulating hormone-secreting adenoma n=1, nonsecreting adenoma n=26) and 9 nontumourous anterior pituitary lobes (obtained from patients with prostate cancer) was immunohistochemically analysed for expression of MMP-2, MMP-9, tissue inhibitor of metalloproteinases-2 (TIMP-2), urokinase-type plasminogen activator (uPA), uPA receptor (uPAR), tissue-type plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), and interleukin-6 (IL-6). Cavernous sinus invasion was determined by assessment of preoperative magnetic resonance imaging and intraoperative inspection (invasive n=50, noninvasive n=34). In pituitary adenomas, reactions were positive (diffuse expression) to MMP-2 (74% of cases), MMP-9 (49%), TIMP-2 (88%), uPA (89%), uPAR (90%), tPA (69%), and PAI-1 (87%). A weak expression of IL-6 was found in 12% of the adenomas. All reactions were positive (focal expression) in every sample of anterior lobe tissue, except for uPA (negative in 3 out of 9 cases), and IL-6 (faintly positive in 5 out of 8 cases). Adenomas showed remarkably greater expression of uPA than anterior lobe tissue (Chi-square P

OBJECTIVES The declines of ACTH and other POMC metabolites immediately after tumor extirpation do not predict the complete tumor removal of an ACTH-secreting pituitary adenoma in Cushing's disease. However, the pituitary surgeon should be in a position to evaluate the surgical result as soon as possible for the eventual planning of early repeat surgery. So far, subnormal serum cortisol levels after surgery are widely accepted as the criterion for cure. We investigated whether the early postoperative ACTH concentration is a reliable marker for the initial surgical outcome as well as the long-term remission. METHODS In a prospective study, 147 patients undergoing primary transsphenoidal microsurgery for Cushing's disease between 1990 and 1996 were investigated. The early postoperative ACTH courses were reviewed and compared with the long-term outcome. ACTH measurements were performed immediately after tumor excision, 1, 2, 4, 8, and 12 hours later, and the following morning. Further ACTH levels were determined on various days of the hospital stay. Glucocorticoids were not given until hypocortisolism was proven. RESULTS Ninety-five patients (65 %) presented with subnormal ACTH levels (< 10 ng/l) during their postoperative stay, of whom two patients (2 %) experienced recurrence of disease after 66 and 100 months. Of 29 procedures with early postoperative ACTH levels ranging from 10-20 ng/l (20 %), one patient received further treatment for persistent (3.5 %) and one patient for recurrent Cushing's disease (3.5 %). Of 12 patients (8 %) with early postoperative ACTH levels in between 20 to 30 ng/l, one patient received further treatment for persistent (8 %) and four patients for recurrent disease (33 %). ACTH levels of more than 30 ng/l, found in 11 patients (7 %), were accompanied by persistent (8 patients, 73 %) or recurrent (2 patients, 18 %) Cushing's disease. CONCLUSION Subnormal (< 10 ng/l) or low normal (< 20 ng/l) postoperative ACTH levels within the first 7 days after surgery can be regarded as early markers for complete removal of an ACTH adenoma as well as indicators for long-term outcome in Cushing's disease. The risks of persistence or recurrence of Cushing's disease rise with the level of early postoperative ACTH values. Normal ACTH levels should result into further evaluation of the ACTH-cortisol secretion, for example by stimulation- or suppression tests.

The management of adrenocorticotropic hormone (ACTH)-dependent Cushing's disease implies difficulties in the differential diagnosis, in the detection of minute pituitary adenomas, as well as in the radical removal of invasive adenomas. Magnetic resonance imaging (MRI) is unspecific and often negative in minute adenomas of three or less millimeters diameter. The trias of detectable ACTH, suppression of cortisol in the high-dose dexamethasone test, and stimulation in the corticotropin-releasing-hormone (CRH)-test has a high accuracy to prove pituitary dependency. In unclear cases, the use of inferior petrosal sinus sampling (IPSS) or cavernous sinus sampling (CSS) for the exclusion of ectopic ACTH-syndrome is currently advised especially in cases where cranial MRI is negative. The reliability of these methods to localize the mostly lateralized microadenomas is still discussed. Transsphenoidal microsurgical adenomectomy, the accepted primary therapy of Cushing's disease, has been published from experienced pituitary centers with remission rates ranging from 70% to 98% in the last decade. False diagnosis (pseudo-Cushing, ectopic ACTH-syndrome), incorrect adenoma localization by IPSS or CSS, and the rate of minute or non-resectable invasive tumors influence the results. The handling of minute specimen implies problems for surgeon and pathologist. Intraoperative tumor localization was improved by ACTH measurement from the cavernous sinus and the adenoma itself, by cytology, and frozen sections. The histology of the anterior lobe (rate of Crooke's cells) bears information of clinical relevance. Invasive macroadenomas may deserve repeat microsurgery, medical treatment, and radiosurgery.

BACKGROUND During transsphenoidal surgery (TSS) for Cushing’s disease, the surgeon depends on experience to find minute adenomas. Cytological slide preparations or frozen sections, even when successful, are not specific concerning the hormone activity. In an attempt to improve accurate localization of minute ACTH adenomas, we evaluated a new intraoperative method of ACTH measurements in adenoma and anterior lobe microsamples. As most ACTH adenomas are monohormonal, the possible benefit of a GH measurement was investigated. METHODS We included pituitary tissue of 32 patients, 22 with Cushing’s disease and 10 endocrine inactive pituitary adenomas as control. All patients underwent TSS by one surgeon. Preoperative data, intraoperative and perioperative hormone measurements of homogenized, weighed pituitary tissue samples, and histological findings are presented. RESULTS In ACTH adenomas, the median ACTH content was found to be 1,688 ng/mg, minimum 345 ng/mg. The median GH was measured at 36 ng/mg. Anterior lobe tissue contained median 80 ng ACTH/mg, maximum 279 ng/mg. Median GH was 2,200 ng/mg. In hormonally inactive adenomas ACTH was less than 0.1 ng/mg, median GH was 5.5 ng/mg. There was no overlap of ACTH content in the tissues investigated. Therefore, by adopting 300 ng ACTH/mg as a cutoff level, a clear discrimination is given. Additional GH measurements are not necessary. CONCLUSION This new intraoperative method permits a clear differentiation between adenoma and pituitary tissue. In addition to intraoperative cytology and histology, this method can serve as a specific proof that the ACTH adenoma has been identified during surgery. This may be valuable in difficult cases with unclear intraoperative findings, especially after previously negative exploration.

In 1994 we reported on a small series of 3 children with malignant, marker-positive pineal nongerminomatous germ cell tumors treated with a ‘sandwich’ protocol. Here, we report on the long-term survival of these children. Preoperative chemotherapy consisted of two courses of bleomycin, etoposide, and cisplatin. En bloc resection of the tumors via the supracerebellar, infratentorial route was performed immediately after decline of tumor marker levels. Postoperatively, two courses of vinblastine, ifosfamide, and cisplatin were applied, followed by craniospinal irradiation. The patients showed no major neurological deficits and no evidence (neuroradiologically or with regard to tumor marker levels) of recurrence of disease after 66, 71, and 78 months, respectively. We propose this regimen for children with tumors of the pineal region in whom the tumor markers are positive. It should be started without histological classification of the tumor to avoid possible spillage of malignant tumor cells to the cerebrospinal fluid.

OBJECTIVE : Transnasal adenomectomy is the treatment of choice for Cushing's disease. We review the diagnostic peculiarities, specific surgical problems, and outcome of children and adolescents with Cushing's disease. METHODS : We report on our series of 55 consecutive children and adolescents (range, 4.2-18.9 yr [mean age, 14.4 yr] ; female :male = 1.1 :1.0 ; mean follow-up, 54.5 ± 38.6 mo [standard deviation]) with Cushing's disease on whom we performed surgery since 1980. The indication for transsphenoidal surgery is based on endocrinological parameters and not on neuroradiological findings. RESULTS : Detection rate of the tumor site was 22% using computed tomography and 33% using magnetic resonance imaging. Only 7 of 13 interpetrosal adrenocorticotropic hormone gradients obtained during inferior petrosal sinus sampling correctly lateralized the tumor site preoperatively (53.8%). In cases of incomplete sphenoid pneumatization, adequate exposure is achieved by drilling. The tumor finding rate is 98%. The remission rate is 100% when two early subsequent operations are included. The recurrence rate for 45 primary operations with follow-up of at least 1 year is 15.5%. Seven of nine subsequent operations for recurrent hypercortisolism were successful. One patient needed three more operations until hypercortisolism subsided ; one patient achieved remission after additional pituitary irradiation. The surgical morbidity was low in this series, which consisted of two cerebrospinal fluid fistulas. The incidence of hypopituitarism after primary operations (10.3%) is significantly lower than after subsequent operations (45.5%). CONCLUSION : Direct transnasal submucosal surgery for Cushing's disease is successful, and pituitary function can be preserved in most of these young patients.

Objective Localization of microadenomas in Cushing's disease may be difficult as in up to 45% of patients sellar MRI fails to detect a pituitary tumor. Intraoperative transsphenoidal ultrasound may identify microadenomas as hyperechoic structures. We report on the first 18 consecutive cases with intraoperative use of a new device for direct contact high-frequency-ultrasound in patients with Cushing's disease. Patients and technique 18 patients (14 female, 4 male, age 24-71 years) with typical endocrinological findings for Cushing's disease were included in the study. One macroadenoma and 13 microadenomas were suspected or identified preoperatively by MRI. In 4 cases, two of them with recurrent disease, sellar MRIs were negative. During transsphenoidal microsurgery an end fire ultrasound-probe (B-mode frequency range 7.5-13 Mhz, field of view 5 mm, penetration 20 mm) was introduced after opening of sellar floor. The pituitary gland was scanned in direct contact to the capsule. Results In 13 out of 17 cases (77%) with later on proven microadenomas high-frequency-ultrasound identified the tumors as hyperechoic masses, including 3 of the 4 cases with negative preoperative MRI. In 2 cases ultrasound correctly localized the tumor at a site different from MRI finding (MRI false positive). In the macroadenoma, identification of the border between tumor and anterior pituitary gland was not possible. In all 18 patients postoperative early decline of serum cortisol to subnormal levels confirmed remission of hypercortisolism (100%). Other pituitary functions were unaltered in 17 cases (94%). Conclusions Intraoperative scanning of the pituitary gland with high-frequency-ultrasound probes may identify intrapituitary anatomy and pathologies even in MRI-negative cases. This may prevent extensive exploration of the gland with the risk of subsequent hypopituitarism.

Objective: The study aimed to evaluate the anatomical relations of sellar and perisellar structures with T2-weighted MRI and to apply criteria for cavernous sinus (CS) invasion by pituitary adenomas to normal sellar anatomy. Methods: Thin slice (3 mm) coronal T2-weighted MR-images (1.5 Tesla) were obtained in 117 individuals (234 CS) without pituitary disorders (58 females, 59 males; age 17 months to 87 years). In 99 cases data indicating the presence of arterial hypertension (AH) were available, 25 with AH, 74 without AH. Results: The medial wall of the cavernous sinus was detectable in 33% of cases. The inferior rim of the horizontal part of the ICA was located at the level of the sellar floor in 33%, below in 47%, and above in 20%. The mean distance between the both ICAs was 17.8 mm (range, 7–38 mm). The mean distance between the pituitary and the ICA in AH was significantly shorter than in patients without AH (Chi-square, p=0.01). There was contact between the gland and the ICA in 41.5% of the cases. In 16.7% (39 sides) of all 234 SCs investigated, the area of contact between the ICA and the gland was at least 25% of the vessel's circumference. The medial intercarotid line (ICL) was crossed by the pituitary gland in 9% (21 of 234 CS), the central ICL was touched in another 5% (11 of 234 CS), lateral ICL was never reached. There was a weak correlation with age: a more extensive lateral extension of the gland was seen in individuals older than 40 years compared to younger individuals (Chi-square, p=0.03). There was a marked difference in the anatomical findings between both sides in 41.9% of cases. Conclusion: Inter- and intra-individual variations of the perisellar anatomy and its relation to the pituitary gland exist, which are partly related to age and AH. This must be remembered when the invasiveness of pituitary adenomas is assessed in MRI. Einleitung: Ziel der Studie ist die Beschreibung der perisellaren Anatomie im T2-gewichteten MRT und die Anwendung der zur Beurteilung der Invasivitat humaner Hypophysenadsenome verwendeten MRT-Kriterien auf die normalen perisellaren anatomischen Verhaltnisse. Methoden: Dunnschicht-MRTs (3 mm) in coronarer Schnittfuhrung und T2-Wichtung (1,5 T) von 117 Probanden (234 untersuchte Sinus cavernosi) ohne bekannte Hypophysenerkrankung (58 weiblich, 59 mannlich, Alter 17 Monate bis 87 Jahre) wurden untersucht. In 99 Fallen lagen Daten bezuglich einer moglichen arteriellen Hypertonie (AH) vor (25 Probanden mit AH, 74 ohne AH). Ergebnisse: Die mediale Wand des Sinus cavernosus (CS) war in 33% der Falle sichtbar. Der Unterrand der intracavernosen Arteria carotis interna (ICA) war in 33% auf dem Niveau des Sellabodens, in 47% darunter und in 20% daruber lokalisiert. Die mittlere Entfernung zwischen den intracavernosen Abschnitten der ICAs war 17,8 mm (von 7 bis 38 mm). Die mittlere Distanz zwischen Hypophyse und ICA war bei Hypertonikern signifikant kurzer als bei Normotonikern (Chi-Quadrat-Test, p=0,01). Ein Kontakt zwischen Hypophysengewebe und ICA wurde in 41,5% der Falle gesehen. In 16,7% (39 von 234 CS) betrug das Ausmas des Kontaktes zwischen Druse und ICA mindestens 25% des Arterienumfanges. Die Anwendung der Knosp-Kriterien auf die normale Anatomie zeigte ein Uberschreiten nur der medialen intercarotidalen Linie (ICL) in 9% der Falle (21 der 234 CS), in weiteren 5% (11 von 234 CS) wurde die zentrale ICL erreicht. Die laterale ICL wurde nie tangiert. Es bestand lediglich eine schwache Korrelation mit dem Alter, wenn man die Probanden ab 40 Jahre mit den Jungeren verglich (Chi-Quadrat-Test, p=0,03). Relevante intraindividuelle Unterschiede zwischen den Seiten wurden in 41,9% der Probanden gefunden. Schlussfolgerung: Es existieren inter- und intraindividuelle Variationen der perisellaren Anatomie und ihrer Beziehung zur Hypophyse, teilweise abhangig von Alter und Blutdruck. Dies sollte bei der Interpretation praoperativer MRTs moglicherweise parasellar infitrativ wachsender Hypophysenadenome berucksichtigt werden.

To elucidate the question whether expansion of pituitary adenomas into the cavernous sinus (CS) has to be regarded as focal penetration rather than invasion, a microanatomical study of the medial wall (MW) of the CS was performed. Fourteen sellar hemiblocks underwent microsurgical dissection from lateral and medial approach. The thickness of the MW of the CS was examined by diaphanoscopy. The internal carotid artery (ICA) was adherent to the MW in five cases. In five specimens the lateral wall of the sella turcica consisted of a single layer without perforations. In nine cases this wall had two layers. There was no perforation of both layers in any case. Diaphanoscopy revealed thin MW in the lateral border of the sella (n = 13), below the horizontal segment of the ICA (n = 10), and antero-inferiorly to the carotid syphon (n = 9). Expansion into the CS may be facilitated by low anatomical resistance against chronic tumor growth.

Background. Microsurgical selective adenomectomy is the best established method available for the treatment of Cushing's disease. However, this surgical method warrants still more efforts to improve the results in minute microadenomas. In this paper the authors evaluate a method of intraoperative cytological investigations during transsphenoidal surgery. Method. Between January 1997 and September 1999, transsphenoidal surgery was performed in 75 patients with the diagnosis of Cushing's disease. Fifty-one cases of proven microadenomas were reviewed. Findings. Of 51 cases, 33 tumors were 3 mm or less in diameter, here after called minute adenomas. In 49 of 51 (96.1%) microadenomas, adenoma tissue was identified by intraoperative cytological techniques. Postoperatively, only 35 of 51 ACTH-secreting microadenomas (68.6%) were confirmed by immunostaining methods. This lower percentage was most probably due to the small amount of tissue obtained. Therefore, in 14 cases (including 12 minute adenomas) the presence of the adenoma was only proven by cytological preparation and clinical outcome. The sensitivity of cytological preparations in cases of confirmed Cushing's disease was 100%. Interpretation. The method described here was particularly well suited for the intraoperative discrimination and documentation of minute adenomas. Cytological preparation appears to be effective in improving the adenoma finding rate and the surgical outcome in cases of Cushing's disease.

In Cushing's disease, selective total removal of a corticotroph tumor of the pituitary regularly results in subnormal ACTH- and cortisol plasma levels. The duration of secondary adrenocortical insufficiency varies widely, with an average of 17 months in our patients. The goal of this study is to elucidate the underlying causes for the variation in duration of postoperative hypocortisolism. In this retrospective study, we evaluated 35 patients with postoperative hypocortisolism lasting more than 36 months, and compared them to 51 patients with a duration of less than 36 months. Preoperative data, intraoperative findings, and postoperative results with follow-up evaluations are presented. Extensive pituitary exploration, medial localization of the tumor, and a higher age were associated with increased risk for isolated secondary long-term hypocortisolism. The histological examination of paraadenomateous tissue identified a significantly larger amount of Crooke's cells in long-term cortisol insufficient patients. Previous pituitary surgery increased the risk for hypopituitarism. In some of our patients, the long-term adrenocortical insufficiency resolved after a period of over five years.

After transnasal operations in Cushing’s syndrome persisting hypercortisolism either due to negative pituitary exploration or due to subtotal tumor removal, and recurrence of the disease after successful surgery still are challenging. We report on the therapeutic failures among 310 consecutive patients who underwent primary transsphenoidal microsurgery for Cushing’s disease. In 287 patients an ACTH-producing pituitary adenoma could be detected (finding rate: 92.6%). In 264 cases remission of hypercortisolism could be attained (remission rate with adenoma 92.0%, for the whole series of primary operations 85.2%). In 23 patients no adenoma could be found despite extensive pituitary exploration (7.4%). Here, we will focus on the management of the 23/287 patients with persistent hypercortisolism after transnasal tumor operation (8.0%) and those 29 cases of the 264 patients with a remission who developed a recurrence of hypercortisolism (11.0%). In recurrent hypercortisolism we recommend transsphenoidal reoperation even when no tumor is visible in MRI. Seventeen of 24 reoperations in recurrent Cushing’s disease were successful (70.8%). In persistent hypercortisolism we perform a reoperation during the same hospital stay. Nine of 16 early reoperations led to remission of hypercortisolism (56.3%). If transsphenoidal reoperation fails we indicate radiation therapy of different modalities depending on the extension and location of the tumor remnants. Bilateral adrenalectomy is proposed by us only if all other therapeutic measures failed.