Isolated IgG4-related Infundibulo-hypophysitis.

A 72-year-old man presented with several months of weakness, poor appetite, and depressed moods. Laboratory tests indicated central hypocortisolism, hypothyroidism and hypogonadism, and mild hyperprolactinemia. Imaging indicated a homogenously enhancing solid suprasellar mass inseparable from the hypothalamus and contiguous with a thickened proximal infundibulum. Neuro-ophthalmological evaluation was normal. Symptoms improved with hydrocortisone, levothyroxine, and testosterone replacement. After 6 months, transsphenoidal biopsy was performed due to mass enlargement and revealed fibrosis, lymphoplasmacytic infiltration, and CD138 and IgG4 staining. The levels of serum IgG4, complement, inflammatory markers, protein electrophoresis, amylase, and lipase and imaging of the chest, abdomen, and thyroid were unremarkable. After 1 month of prednisone therapy (starting dose 40 mg/day), the mass significantly involuted and remained stable afterward. Prednisone was gradually tapered to 5 mg daily over 10 weeks. During 22 months of follow-up, no systemic IgG4 disease was detected. Glucocorticoid, thyroid, and testosterone replacement was continued. This case of isolated IgG4-related hypophysitis illustrates the variable presentation that may not entail vasopressin deficiency or clinical mass effect. This entity should be considered in the differential diagnosis of suprasellar masses even in the absence of IgG4 systemic disease or characteristic serology. Management entails multidisciplinary collaboration and long-term follow-up.

The diverging role of O-GlcNAc transferase in corticotroph and somatotroph adenomas.

PURPOSE: Molecular mechanisms involved in the pathogenesis and tumor progression of pituitary adenomas (PA) remain incompletely understood. Corticotroph and somatotroph PA are associated with a high clinical burden, and despite improved surgical outcomes and medical treatment options, they sometimes require multiple surgeries and radiation. Preliminary data suggested a role for O-GlcNAc Transferase (OGT), the enzyme responsible for the O-GlcNAcylation of proteins. O-GlcNAcylation and OGT have been found elevated in other types of tumors. METHODS: We evaluated 60 functioning and nonfunctioning PA (NFPA) from operated patients and postmortem normal and tumoral pituitary tissue by immunohistochemistry. We performed transcriptomic analyses to explore the relevance of the O-GlcNAc Transferase (OGT) in PAs. We detected OGT in immunobiological analysis and define its level in PA tissue in patients. RESULTS: OGT was strongly associated with PA hormone secretory capacity in functioning PA and with tumor growth in NFPAs. In NFPAs, OGT was positively associated with tumor size but not with cavernous sinus invasion (Knosp grading). In GH-secreting PA, OGT expression was negatively correlated with circulating Insulin-like Growth Factor 1 level. In adrenocorticotropic hormone (ACTH)-secreting PA, OGT expression was positively associated with circulating ACTH levels. OGT did not correlate with tumor size in secreting PAs. OGT levels were higher in gonadotroph PA compared to normal glands. CONCLUSION: O-GlcNAcylation can be downregulated in non-cancerous tumors such as GH-secreting adenomas. Future studies are warranted to elucidate the role of OGT in the pathogenesis of PAs.

Spinal Cord Stimulation Trial Electrodes Rapidly Produce Epidural Scarring, Impeding Surgical Paddle Lead Placement.

OBJECTIVES: After a successful percutaneous cylindrical electrode five-to-seven-day trial of spinal cord stimulation, subsequent permanent surgical paddle lead (SPL) placement can be impeded by epidural scar induced by the trial leads (TLs). Our goal was to determine whether a delay between TL and subsequent SPL placement provokes enhanced epidural scarring with an increased need for laminotomy extension required for scar removal for optimal SPL placement. MATERIALS AND METHODS: Using a prospectively maintained data base, a single-facility/surgeon retrospective study identified 261 patients with newly placed thoracolumbar SPLs from June 2013 to November 2023. Data were obtained from the patients' charts, including, but not limited to, timing between TL and SPL, operative time, and need for extension of laminotomy. RESULTS: We found that the need for laminotomy extension due to TL epidural scarring and longer operative times was not required in our patients if the SPL was placed within ten days of placement of the TL (0/26), leading to shorter operative times in those with SPL placed after ten days (122.42 ± 10.72 minutes vs 140.75 ± 4.72 minutes; p = 0.005). We found no association with other medical comorbidities that may be confounding factors leading to epidural scarring/extension of laminotomy or association with level of SPL placement, size of the spinal canal, or indication for SPL placement. CONCLUSIONS: TL placement leads to scarring in the epidural space that appears to mature after ten days of its placement. In approximately 34% of patients, this leads to prolonged operative time owing to the need for extension of laminotomy and subsequent clearing of epidural scar for optimal SPL placement.

Noninvasive Autopsy-Validated Tumor Probability Maps Identify Glioma Invasion Beyond Contrast Enhancement.

BACKGROUND AND OBJECTIVES: This study identified a clinically significant subset of patients with glioma with tumor outside of contrast enhancement present at autopsy and subsequently developed a method for detecting nonenhancing tumor using radio-pathomic mapping. We tested the hypothesis that autopsy-based radio-pathomic tumor probability maps would be able to noninvasively identify areas of infiltrative tumor beyond traditional imaging signatures. METHODS: A total of 159 tissue samples from 65 subjects were aligned to MRI acquired nearest to death for this retrospective study. Demographic and survival characteristics for patients with and without tumor beyond the contrast-enhancing margin were computed. An ensemble algorithm was used to predict pixelwise tumor presence from pathological annotations using segmented cellularity (Cell), extracellular fluid, and cytoplasm density as input (6 train/3 test subjects). A second level of ensemble algorithms was used to predict voxelwise Cell, extracellular fluid, and cytoplasm on the full data set (43 train/22 test subjects) using 5-by-5 voxel tiles from T1, T1 + C, fluid-attenuated inversion recovery, and apparent diffusion coefficient as input. The models were then combined to generate noninvasive whole brain maps of tumor probability. RESULTS: Tumor outside of contrast was identified in 41.5% of patients, who showed worse survival outcomes (hazard ratio = 3.90, P < .001). Tumor probability maps reliably tracked nonenhancing tumor on a range of local and external unseen data, identifying tumor outside of contrast in 69% of presurgical cases that also showed reduced survival outcomes (hazard ratio = 1.67, P = .027). CONCLUSION: This study developed a multistage model for mapping gliomas using autopsy tissue samples as ground truth, which was able to identify regions of tumor beyond traditional imaging signatures.

Radio-pathomic maps of glioblastoma identify phenotypes of non-enhancing tumor infiltration associated with bevacizumab treatment response.

BACKGROUND: Autopsy-based radio-pathomic maps of glioma pathology have shown substantial promise inidentifying areas of non-enhancing tumor presence, which may be able to differentiate subsets of patients that respond favorably to treatments such as bevacizumab that have shown mixed efficacy evidence. We tested the hypthesis that phenotypes of non-enhancing tumor fronts can distinguish between glioblastoma patients that will respond favorably to bevacizumab and will visually capture treatment response. METHODS: T1, T1C, FLAIR, and ADC images were used to generate radio-pathomic maps of tumor characteristics for 79 pre-treatment patients with a primary GBM or high-grade IDH1-mutant astrocytoma for this study. Novel phenotyping (hypercellular, hypocellular, hybrid, or well-circumscribed front) of the non-enhancing tumor front was performed on each case. Kaplan Meier analyses were then used to assess differences in survival and bevacizumab efficacy between phenotypes. Phenotype compartment segmentations generated longitudinally for a subset of 26 patients over the course of bevacizumab treatment, where a mixed effect model was used to detect longitudinal changes. RESULTS: Well-Circumscribed patients showed significant/trending increases in survival compared to Hypercellular Front (HR = 2.0, p = 0.05), Hypocellular Front (HR = 2.02, p = 0.03), and Hybrid Front tumors (HR = 1.75, p = 0.09). Only patients with hypocellular or hybrid fronts showed significant survival benefits from bevacizumab treatment (HR = 2.35, p = 0.02; and HR = 2.45, p = 0.03, respectively). Hypocellular volumes decreased by an average 50.52 mm3 per day of bevacizumab treatment (p = 0.002). CONCLUSION: Patients with a hypocellular tumor front identified by radio-pathomic maps showed improved treatment efficacy when treated with bevacizumab, and reducing hypocellular volumes over the course of treatment may indicate treatment response.

Radio-pathomic maps of glioblastoma identify phenotypes of non-enhancing tumor infiltration associated with bevacizumab treatment response.

Background: Autopsy-based radio-pathomic maps of glioma pathology have shown substantial promise inidentifying areas of non-enhancing tumor presence, which may be able to differentiate subsets of patients that respond favorably to treatments such as bevacizumab that have shown mixed efficacy evidence. We tested the hypthesis that phenotypes of non-enhancing tumor fronts can distinguish between glioblastoma patients that will respond favorably to bevacizumab and will visually capture treatment response. Methods: T1, T1C, FLAIR, and ADC images were used to generate radio-pathomic maps of tumor characteristics for 79 pre-treatment patients with a primary GBM or high-grade IDH1-mutant astrocytoma for this study. Novel phenotyping (hypercellular, hypocellular, hybrid, or well-circumscribed front) of the non-enhancing tumor front was performed on each case. Kaplan Meier analyses were then used to assess differences in survival and bevacizumab efficacy between phenotypes. Phenotype compartment segmentations generated longitudinally for a subset of 26 patients over the course of bevacizumab treatment, where a mixed effect model was used to detect longitudinal changes. Results: Well-Circumscribed patients showed significant/trending increases in survival compared to Hypercellular Front (HR = 2.0, p = 0.05), Hypocellular Front (HR = 2.02, p = 0.03), and Hybrid Front tumors (HR = 1.75, p = 0.09). Only patients with hypocellular or hybrid fronts showed significant survival benefits from bevacizumab treatment (HR = 2.35, p = 0.02; and HR = 2.45, p = 0.03, respectively). Hypocellular volumes decreased by an average 50.52 mm3 per day of bevacizumab treatment (p = 0.002). Conclusion: Patients with a hypocellular tumor front identified by radio-pathomic maps showed improved treatment efficacy when treated with bevacizumab, and reducing hypocellular volumes over the course of treatment may indicate treatment response.

Consecutive resections of double pituitary adenoma for resolution of Cushing disease: illustrative case.

BACKGROUND: Double pituitary adenomas are rare presentations of two distinct adenohypophyseal lesions seen in <1% of surgical cases. Increased rates of recurrence or persistence are reported in the resection of Cushing microadenomas and are attributed to the small tumor size and localization difficulties. The authors report a case of surgical treatment failure of Cushing disease because of the presence of a secondary pituitary adenoma. OBSERVATIONS: A 32-year-old woman with a history of prolactin excess and pituitary lesion presented with oligomenorrhea, weight gain, facial fullness, and hirsutism. Urinary and nighttime salivary cortisol elevation were elevated. Magnetic resonance imaging confirmed a 4-mm3 pituitary lesion. Inferior petrosal sinus sampling was diagnostic for Cushing disease. Primary endoscopic endonasal transsphenoidal resection was performed to remove what was determined to be a lactotroph-secreting tumor on immunohistochemistry with persistent hypercortisolism. Repeat resection yielded a corticotroph-secreting tumor and postoperative hypoadrenalism followed by long-term normalization of the hypothalamic-pituitary-adrenal axis. LESSONS: This case demonstrates the importance of multidisciplinary management and postoperative hormonal follow-up in patients with Cushing disease. Improved strategies for localization of the active tumor in double pituitary adenomas are essential for primary surgical success and resolution of endocrinopathies.

Case report: Two unique cases of co-existing primary brain tumors of glial origin in opposite hemispheres.

Background: Primary CNS tumors are rare. Coexistence of two glial tumors of different histological origins in the same patient is even rarer. Here we describe two unique cases of coexisting distinct glial tumors in opposite hemispheres. Cases: Patient 1 is a 38-year-old male who presented with a seizure in February/2016. MRI showed a left parietal and a right frontal infiltrating nonenhancing lesions. Both lesions were resected revealing an oligodendroglioma WHO grade-2 and an astrocytoma WHO grade-2. Patient 2 is a 34-year-old male who presented with a seizure in November/2021. MRI showed a left frontal and a right mesial temporal lobe infiltrating nonenhancing lesions. Both lesions were resected revealing an oligodendroglioma WHO grade-2 and a diffuse low-grade glioma, MAPK pathway-altered (BRAF V600E-mutant). Patient 1 underwent adjuvant treatment. Both patients are without recurrence to date. Discussion: Two histologically distinct glial tumors may coexist, especially when they are non-contiguous. Pathological confirmation of each lesion is imperative for appropriate management. We highlight the different management of gliomas based on the new CNS WHO 2021 classification compared to its 2016 version, based on NCCN guidelines. Although more molecular markers are being incorporated into glioma classification, their clinical impact of it is yet to be determined.

Case report: Fractional brain tumor burden magnetic resonance mapping to assess response to pulsed low-dose-rate radiotherapy in newly-diagnosed glioblastoma.

Background: Pulsed low-dose-rate radiotherapy (pLDR) is a commonly used reirradiation technique for recurrent glioma, but its upfront use with temozolomide (TMZ) following primary resection of glioblastoma is currently under investigation. Because standard magnetic resonance imaging (MRI) has limitations in differentiating treatment effect from tumor progression in such applications, perfusion-weighted MRI (PWI) can be used to create fractional tumor burden (FTB) maps to spatially distinguish active tumor from treatment-related effect. Methods: We performed PWI prior to re-resection in four patients with glioblastoma who had undergone upfront pLDR concurrent with TMZ who had radiographic suspicion for tumor progression at a median of 3 months (0-5 months or 0-143 days) post-pLDR. The pathologic diagnosis was compared to retrospectively-generated FTB maps. Results: The median patient age was 55.5 years (50-60 years). All were male with IDH-wild type (n=4) and O6-methylguanine-DNA methyltransferase (MGMT) hypermethylated (n=1) molecular markers. Pathologic diagnosis revealed treatment effect (n=2), a mixture of viable tumor and treatment effect (n=1), or viable tumor (n=1). In 3 of 4 cases, FTB maps were indicative of lesion volumes being comprised predominantly of treatment effect with enhancing tumor volumes comprised of a median of 6.8% vascular tumor (6.4-16.4%). Conclusion: This case series provides insight into the radiographic response to upfront pLDR and TMZ and the role for FTB mapping to distinguish tumor progression from treatment effect prior to redo-surgery and within 20 weeks post-radiation.

Intracranial mesenchymal tumors with FET-CREB fusion are composed of at least two epigenetic subgroups distinct from meningioma and extracranial sarcomas.

'Intracranial mesenchymal tumor, FET-CREB fusion-positive' occurs primarily in children and young adults and has previously been termed intracranial angiomatoid fibrous histiocytoma (AFH) or intracranial myxoid mesenchymal tumor (IMMT). Here we performed genome-wide DNA methylation array profiling of 20 primary intracranial mesenchymal tumors with FET-CREB fusion to further study their ontology. These tumors resolved into two distinct epigenetic subgroups that were both divergent from all other analyzed intracranial neoplasms and soft tissue sarcomas, including meningioma, clear cell sarcoma of soft tissue (CCS), and AFH of extracranial soft tissue. The first subgroup (Group A, 16 tumors) clustered nearest to but independent of solitary fibrous tumor and AFH of extracranial soft tissue, whereas the second epigenetic subgroup (Group B, 4 tumors) clustered nearest to but independent of CCS and also lacked expression of melanocytic markers (HMB45, Melan A, or MITF) characteristic of CCS. Group A tumors most often occurred in adolescence or early adulthood, arose throughout the neuroaxis, and contained mostly EWSR1-ATF1 and EWSR1-CREB1 fusions. Group B tumors arose most often in early childhood, were located along the cerebral convexities or spinal cord, and demonstrated an enrichment for tumors with CREM as the fusion partner (either EWSR1-CREM or FUS-CREM). Group A tumors more often demonstrated stellate/spindle cell morphology and hemangioma-like vasculature, whereas Group B tumors more often demonstrated round cell or epithelioid/rhabdoid morphology without hemangioma-like vasculature, although robust comparison of these clinical and histologic features requires future study. Patients with Group B tumors had inferior progression-free survival relative to Group A tumors (median 4.5 vs. 49 months, p = 0.001). Together, these findings confirm that intracranial AFH-like neoplasms and IMMT represent histologic variants of a single tumor type ('intracranial mesenchymal tumor, FET-CREB fusion-positive') that is distinct from meningioma and extracranial sarcomas. Additionally, epigenomic evaluation may provide important prognostic subtyping for this unique tumor entity.

Intraosseous Meningioma Along the Left Petrous Bone: A Rare Cause of Trigeminal Neuralgia.

Trigeminal neuralgia (TN) presents with symptoms of intense recurrent shock-like brief pain localized to specific areas of the face innervated by the fifth cranial nerve. The pathology of trigeminal neuralgia is attributed to the fifth cranial nerve compression or demyelination. Most cases of this diagnosis are not due to bony structures, making this case an uncommon presentation of trigeminal neuralgia. Herein, we present a case of trigeminal neuralgia due to an intraosseous meningioma that formed along the left petrous bone, resulting in trigeminal nerve compression. On head computed tomography (CT), osteomatous growths along the left petrous bone were noticed compressing the trigeminal nerve. After trigeminal nerve decompression and drilling out the protruding part of the petrous bone through middle cranial fossa craniotomy, the patient's symptoms were completely improved postoperatively and at the two-month follow-up. To our knowledge, there are only four reported cases of trigeminal neuralgia caused by petrous bone compression in the literature. We emphasize the significance of considering petrous bone lesions as a cause of trigeminal neuralgia.

Giant pituitary macroadenoma of stem cell origin: illustrative case.

BACKGROUND: Giant pituitary macroadenomas with a diameter >4 cm are rare tumors, accounting for only about 5% of pituitary adenomas. They are more difficult to maximally resect safely owing to limited access as well as encasement of adjacent structures. Acidophil stem cell adenomas are rare immature neoplasms proposed to derive from common progenitor cells of somatotroph and lactotroph cells. These adenomas comprise about 4.3% of surgically removed pituitary adenomas. No previous reports have described acidophil stem cell adenomas that grow to the size of giant macroadenomas. This rare entity poses special challenges given the need for maximal safe resection in an immature neoplasm. OBSERVATIONS: The authors report a 21-year-old female who presented with 3 years of progressive visual decline and a giant macroadenoma. She underwent endoscopic transsphenoidal surgery for decompression. Given the tumor size and involvement of adjacent critical structures, gross-total resection was not achieved. The authors review the literature on giant pituitary adenomas and provide a discussion on clinical management for this rare entity. LESSONS: The authors present a very rare case of a giant pituitary adenoma of acidophil stem cell origin and discuss the technical and management challenges in this rare entity.

Two Cases of Cerebral Infarcts Caused by Topical Hemostatic Agent Embolism.

ABSTRACT: Resorbable topical hemostatic agents are widely used in surgical procedures to control intraoperative bleeding. There have been multiple reports of complications from use of these agents, including pulmonary vasculature thromboembolism, cerebral venous sinus occlusion, and postoperative inflammatory mass lesions each containing the hemostatic agent. We report 2 cases of inadvertent intra-arterial embolization of hemostatic agent. Both cases followed elective surgical cervical spinal procedures, during which gelatin-based local hemostatic agents were used to control unanticipated bleeding. Postoperatively, both patients exhibited neurologic defects and were found to have infarcts of the brain. At autopsy, vertebrobasilar thromboemboli containing foreign material grossly and microscopically consistent with hemostatic matrix material were found in both cases. These are the first reports of hemostatic agent embolization resulting in cerebral infarcts and leading to death.

Intracranial mesenchymal tumor with FET-CREB fusion-A unifying diagnosis for the spectrum of intracranial myxoid mesenchymal tumors and angiomatoid fibrous histiocytoma-like neoplasms.

Intracranial mesenchymal tumors with FET-CREB fusions are a recently described group of neoplasms in children and young adults characterized by fusion of a FET family gene (usually EWSR1, but rarely FUS) to a CREB family transcription factor (ATF1, CREB1, or CREM), and have been variously termed intracranial angiomatoid fibrous histiocytoma or intracranial myxoid mesenchymal tumor. The clinical outcomes, histologic features, and genomic landscape are not well defined. Here, we studied 20 patients with intracranial mesenchymal tumors proven to harbor FET-CREB fusion by next-generation sequencing (NGS). The 16 female and four male patients had a median age of 14 years (range 4-70). Tumors were uniformly extra-axial or intraventricular and located at the cerebral convexities (n = 7), falx (2), lateral ventricles (4), tentorium (2), cerebellopontine angle (4), and spinal cord (1). NGS demonstrated that eight tumors harbored EWSR1-ATF1 fusion, seven had EWSR1-CREB1, four had EWSR1-CREM, and one had FUS-CREM. Tumors were uniformly well circumscribed and typically contrast enhancing with solid and cystic growth. Tumors with EWSR1-CREB1 fusions more often featured stellate/spindle cell morphology, mucin-rich stroma, and hemangioma-like vasculature compared to tumors with EWSR1-ATF1 fusions that most often featured sheets of epithelioid cells with mucin-poor collagenous stroma. These tumors demonstrated polyphenotypic immunoprofiles with frequent positivity for desmin, EMA, CD99, MUC4, and synaptophysin, but absence of SSTR2A, myogenin, and HMB45 expression. There was a propensity for local recurrence with a median progression-free survival of 12 months and a median overall survival of greater than 60 months, with three patients succumbing to disease (all with EWSR1-ATF1 fusions). In combination with prior case series, this study provides further insight into intracranial mesenchymal tumors with FET-CREB fusion, which represent a distinct group of CNS tumors encompassing both intracranial myxoid mesenchymal tumor and angiomatoid fibrous histiocytoma-like neoplasms.

Epigenetic control of vasopressin expression is maintained by steroid hormones in the adult male rat brain.

Although some DNA methylation patterns are altered by steroid hormone exposure in the developing brain, less is known about how changes in steroid hormone levels influence DNA methylation patterns in the adult brain. Steroid hormones act in the adult brain to regulate gene expression. Specifically, the expression of the socially relevant peptide vasopressin (AVP) within the bed nucleus of the stria terminalis (BST) of adult brain is dependent upon testosterone exposure. Castration dramatically reduces and testosterone replacement restores AVP expression within the BST. As decreases in mRNA expression are associated with increases in DNA promoter methylation, we explored the hypothesis that AVP expression in the adult brain is maintained through sustained epigenetic modifications of the AVP gene promoter. We find that castration of adult male rats resulted in decreased AVP mRNA expression and increased methylation of specific CpG sites within the AVP promoter in the BST. Similarly, castration significantly increased estrogen receptor α (ERα) mRNA expression and decreased ERα promoter methylation within the BST. These changes were prevented by testosterone replacement. This suggests that the DNA promoter methylation status of some steroid responsive genes in the adult brain is actively maintained by the presence of circulating steroid hormones. The maintenance of methylated or demethylated states of some genes in the adult brain by the presence of steroid hormones may play a role in the homeostatic regulation of behaviorally relevant systems.

Winning territorial disputes selectively enhances androgen sensitivity in neural pathways related to motivation and social aggression.

Winning aggressive disputes can enhance future fighting ability and the desire to seek out additional contests. In some instances, these effects are long lasting and vary in response to the physical location of a fight. Thus, in principle, winning aggressive encounters may cause long-term and context-dependent changes to brain areas that control the output of antagonistic behavior or the motivation to fight (or both). We examined this issue in the territorial California mouse (Peromyscus californicus) because males of this species are more likely to win fights after accruing victories in their home territory but not after accruing victories in unfamiliar locations. Using immunocytochemistry and real-time quantitative PCR, we found that winning fights either at home or away increases the expression of androgen receptors (AR) in the medial anterior bed nucleus of the stria terminalis, a key brain area that controls social aggression. We also found that AR expression in brain regions that mediate motivation and reward, nucleus accumbens (NAcc) and ventral tegmental area (VTA), increases only in response to fights in the home territory. These effects of winning were likely exclusive to the neural androgenic system because they have no detectible impact on the expression of progestin receptors. Finally, we demonstrated that the observed changes in androgen sensitivity in the NAcc and VTA are positively associated with the ability to win aggressive contests. Thus, winning fights can change brain phenotype in a manner that likely promotes future victory and possibly primes neural circuits that motivate individuals to fight.