BRAF and MEK inhibitor targeted therapy in papillary craniopharyngiomas: a cohort study.

OBJECTIVE: Targeted therapy (TT) with BRAF/MEK inhibitors has emerged as a potential treatment in papillary craniopharyngiomas (PCPs). However, standardized data on large cohorts are lacking. Our study aimed to assess real-life efficacy and safety of BRAF/MEK inhibition in patients with PCPs. DESIGN: Retrospective French multicenter study involving BRAF V600E-mutated PCP patients, treated with BRAF/MEK inhibitor combination dabrafenib and trametinib, from April 2019 to July 2023. METHODS: Objective response and clinical and safety outcomes were assessed after 3 months and at the last available follow-up during TT. RESULTS: Sixteen patients (8 females, mean age 50.5 ± 15.75 years), receiving either neoadjuvant therapy (NEO) for non-resectable tumors (n = 6), post-surgical adjuvant therapy (ADJ; n = 8), or palliative therapy (PAL) following failure of multimodal treatment (n = 2), were included.At the last follow-up (mean 7.6 ± 5.3 months), 12 patients showed subtotal response, 3 exhibited partial response, and 1 maintained stable disease. Mean volume reduction was 88.9 ± 4.4%, 73.3 ± 23.4%, and 91.8 ± 4.3% in the NEO, ADJ, and PAL groups, respectively.Targeted therapy resolved headaches in 5/5 patients and visual impairment in 6/9; 2/3 patients had improved neurological symptoms, 1/4 presented weight loss, and 2/14 recovered endocrine function.Targeted therapy was well-tolerated in 62.5% of cases; adverse events led to treatment discontinuation in 5 patients and definitive discontinuation in 3 cases. CONCLUSIONS: In this study, 94% of patients showed partial response or better to TT. Adverse events were acceptable. Further research is needed to establish standardized protocols; however, these results advocate for a NEO approach in invasive PCPs.

"Evaluating surgical approaches for Rathke's cleft cysts and sellar meningiomas: factors influencing treatment of choice".

This study reviews recent progress in the surgical treatment of Rathke's cleft cysts (RCCs) and Sellar region meningiomas, based on findings from three key studies. RCCs are benign, fluid-filled remnants from pituitary gland development that are usually asymptomatic and found by chance. However, surgical intervention is needed when they become symptomatic or increase in size. Research by Stefan Linsler et al. and others examines various surgical methods, including transcranial keyhole and transsphenoidal techniques for RCCs, and endoscopic endonasal and supraorbital keyhole approaches for Sellar meningiomas. The results show that both transcranial keyhole and transsphenoidal surgeries for RCCs have high success rates with no recurrences over 5.7 years, although the keyhole approach has fewer complications. For Sellar meningiomas, the choice between endoscopic endonasal and supraorbital keyhole techniques should be based on tumor characteristics, highlighting the importance of surgeon proficiency in both methods. These studies emphasize the need for personalized treatment strategies tailored to patient and tumor characteristics and highlight the importance of ongoing surgical skill development and further research to refine minimally invasive techniques. This study highlights the crucial role of personalized surgical approaches in improving outcomes for patients with RCCs and Sellar region meningiomas.

Cutis verticis gyrata in a patient with acromegaly: an unusual case and review of literature.

Acromegaly is a rare systemic syndrome induced by the overproduction of growth hormone (GH) and insulin-like growth factor type one (IGF1). It is responsible for changes in the skeletal and soft tissue systems and it almost always occurs because of a pituitary adenoma. Amongst the skin complications related to acromegaly, cutis verticis gyrate (CVG) is occasionally found. It is a skin condition characterized by excessive growth of the skin of the scalp, resulting in furrows and folds. Only a few cases of this uncommon association have been reported in the literature. The present clinical case illustrates typical CVG associated with acromegaly. Imaging revealed a pituitary macroadenoma lesion and hormonal evaluation revealed elevated IGF1 and hypopituitarism. The patient underwent a transsphenoidal resection of the pituitary adenoma and the histopathological examination confirmed the diagnosis. The diagnosis of CVG is clinical, so radiologic assessments are generally not necessary. The management of acromegaly associated with CVG depends on controlling the serum levels of GH and IGF1. In some cases, specific injections or surgery can be used to minimize CVG.

A rare association of pheochromocytoma, paraganglioma, and pituitary adenoma (3PA): A case report and literature review.

RATIONALE: 3P association (3PA) is a rare condition with co-occurrence of pituitary adenoma and pheochromocytoma/paraganglioma. There have been less than a hundred documented cases of 3PA, which can be sporadic or related to genetic mutations. The present case report describes the first Iranian patient with 3PA and a 90th case of 3PA in the available literature. PATIENT CONCERNS AND INTERVENTIONS: A 36-year-old Caucasian male was admitted with headache and sudden increase in blood pressure. An abdominal CT scan revealed a retroperitoneal mass posterior to the inferior vena cava, later removed and diagnosed as a pheochromocytoma. Four years later, he noticed occasional mild headaches and a painless mass on the right side of his neck. The ultrasonography evaluations suggested a carotid body tumor, which was surgically removed. About a month after his second surgery, the severity of the patient's headaches worsened, and he developed right homonymous hemianopia. A brain MRI showed a mass in favor of macroadenoma, craniopharyngioma, or meningioma, and elevated prolactin level led to the diagnosis of macroprolactinoma. DIAGNOSES: Based on the provided history, this patient was diagnosed with 3PA, and a genetic study identified a positive succinate-dehydrogenase-complex subunit b mutation, possibly linked to his family history of carotid body tumor. OUTCOMES: He has remained symptom-free during his visits every 3 months. LESSONS: The number of cases diagnosed with 3PA worldwide is increasing. Using clinical and genetic assessments, we can timely diagnose and adequately monitor individuals with or at risk of 3PA.

Hypopituitarism after gamma knife radiosurgery for pituitary adenomas: long-term results from a single-center experience.

OBJECTIVE: The aim of this study was to investigate the incidence and risk factors of new-onset hypopituitarism after gamma knife radiosurgery (GKRS) for pituitary adenomas in a single center. METHODS: In this retrospective study, 241 pituitary adenoma patients who underwent GKRS from 1993 to 2016 were enrolled. These patients had complete endocrine, imaging, and clinical data before and after GKRS. The median follow-up time was 56.0 (range, 12.7-297.6) months. RESULTS: Fifty patients (20.7%) developed new-onset hypopituitarism after GKRS, including hypogonadism (n = 22), hypothyroidism (n = 29), hypocortisolism (n = 20), and growth hormone deficiency (n = 4). The median time to new-onset hypopituitarism was 44.1 (range, 13.5-141.4) months. The rates of new-onset hypopituitarism were 7%, 16%, 20%, 39%, and 45% at 1, 3, 5, 10, and 15 years, respectively. For those patients treated with a single GKRS, sex (p = 0.012), suprasellar extension (p = 0.048), tumor volume (≥ 5 cm3) (p < 0.001), tumor progression (p = 0.001), pre-existing hypopituitarism (p = 0.011), and previous surgery (p = 0.009) were significantly associated with new-onset hypopituitarism in univariate analysis. In the multivariate analysis, tumor volume (≥ 5 cm3) and tumor progression were associated with new-onset hypopituitarism (hazard ratio [HR] = 3.401, 95% confidence interval [CI] = 1.708-6.773, p < 0.001 and HR = 3.594, 95% CI = 1.032-12.516, p = 0.045, respectively). For patients who received 2 or more times GKRS, no risk factors associated with new-onset hypopituitarism were found. CONCLUSION: New-onset hypopituitarism was not uncommon after GKRS for pituitary adenomas. In this study, large tumor volume (≥ 5 cm3) and tumor progression were associated with new-onset hypopituitarism after a single GKRS.

scRNA sequencing technology for PitNET studies.

Pituitary neuroendocrine tumors (PitNETs) are common, most likely benign tumors with complex clinical characteristics related to hormone hypersecretion and/or growing sellar tumor mass. PitNET types are classified according to their expression of specific transcriptional factors (TFs) and hormone secretion levels. Some types show aggressive, invasive, and reoccurrence behavior. Current research is being conducted to understand the molecular mechanisms regulating these high-heterogeneous neoplasms originating from adenohypophysis, and single-cell RNA sequencing (scRNA-seq) technology is now playing an essential role in these studies due to its remarkable resolution at the single-cell level. This review describes recent studies on human PitNETs performed with scRNA-seq technology, highlighting the potential of this approach in revealing these tumor pathologies, behavior, and regulatory mechanisms.

Application of the semidiving technique in fully endoscopic microvascular decompression.

Microvascular decompression (MVD) is the preferred treatment for hemifacial spasm (HFS) and trigeminal neuralgia (TN), and fully endoscopic microvascular decompression (E-MVD) has been widely discussed in recent years. Considering the endoscopic diving technique used in endoscopic transsphenoidal pituitary adenoma resection, we developed the endoscopic semidiving technique. This technique involves preserving some cerebrospinal fluid (CSF) and positioning the endoscope at an appropriate distance from it; the potential advantages include reducing cerebellar retraction, accurately identifying the responsible vessels and minimizing mechanical damage. This study aimed to preliminarily evaluate the safety and feasibility of the semidiving technique in E-MVD. A total of 359 patients with HFS and TN scheduled to undergo E-MVD were included in the study. Patients with each disease were divided into a nonsemidiving technique group and a semidiving technique group. Surgical data, postoperative outcomes, complications, and recurrence rates were compared between the groups. In patients with HFS, the effective rate was 95.6% (nonsemidiving)and 92.9% (semidiving) respectively, with no statistically significant difference. The semidiving technique group had a lower incidence of postoperative permanent hearing loss compared with the nonsemidiving technique group (0% vs. 5.9%). In TN patients, no significant differences in effectiveness or postoperative complications were observed. The application of the semidiving technique in E-MVD for HFS not only ensures surgical quality and postoperative efficacy but also reduces the incidence of postoperative hearing loss, shortens the surgical duration and reduces the number of postoperative hospitalization days, aligning with the concept of enhanced recovery after surgery (ERAS).

Solitary isolated disseminations of glioblastoma to sellar and suprasellar regions: two case reports.

Herein, we present two cases of isolated suprasellar dissemination of glioblastoma in patients with well-controlled primary lesions. A 22-year-old woman and a 56-year-old woman developed rapid growth of suprasellar glioblastoma dissemination 26 and 17 months after initial surgery, respectively. Both patients presented with acute visual impairment (decreased acuity and visual field disturbances) but lacked severe pituitary dysfunction. During surgery for the disseminated tumors, gross total tumor resection was difficult due to intraoperative findings suggesting optic pathway invasion. Both patients developed further intracranial dissemination within several months post-surgery. The presence of solitary sellar and suprasellar dissemination may indicate a terminal stage.

Induction of apoptosis by oridonin in nonfunctioning pituitary adenoma cells.

Nonfunctioning pituitary adenoma (NFPA) is one of the major subtypes of pituitary adenomas (PA) and its primary treatment is surgical resection. However, normal surgery fails to remove lesions completely and there remains in lack of frontline treatment, so the development of new drugs for NFPA is no doubt urgent. Oridonin (ORI) has been reported to have antitumor effects on a variety of tumors, but whether it could exhibit the same effect on NFPA requires to be further investigated. The effects of ORI on pituitary-derived folliculostellate cell line (PDFS) cell viability, colony formation, proliferation ability, migration, and invasion were examined by Cell Counting Kit-8, colony formation assay, 5­Ethynyl­2'­deoxyuridine proliferation assay, wound-healing assay, and Transwell assay. The differentially expressed genes in the control and ORI-treated groups were screened by transcriptome sequencing analysis and analyzed by Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment. Cell cycle analysis was performed to detect changes in cell cycle. Annexin V-fluorescein isothiocyanate/propidium iodide staining was performed to detect apoptosis in ORI-treated cells. Western blot assay was performed to detect Bax, Bcl-2, and cleaved Caspase-3 protein expression. ORI inhibited PDFS cell viability and significantly suppressed cell proliferation, migration, and invasion. GO and KEGG results showed that ORI was associated with signaling pathways such as cell cycle and apoptosis in PDFS cells. In addition, ORI blocked cells in G2/M phase and induced apoptosis in PDFS cells. ORI can trigger cell cycle disruption and apoptosis collaboratively in PDFS cells, making it a promising and effective agent for NFPA therapy.

Recurrent adamantinomatous craniopharyngiomas show MAPK pathway activation, clonal evolution and rare TP53-loss-mediated malignant progression.

The two types of craniopharyngioma, adamantinomatous (ACP) and papillary (PCP), are clinically relevant tumours in children and adults. Although the biology of primary craniopharyngioma is starting to be unravelled, little is known about the biology of recurrence. To fill this gap in knowledge, we have analysed through methylation array, RNA sequencing and pERK1/2 immunohistochemistry a cohort of paired primary and recurrent samples (32 samples from 14 cases of ACP and 4 cases of PCP). We show the presence of copy number alterations and clonal evolution across recurrence in 6 cases of ACP, and analysis of additional whole genome sequencing data from the Children's Brain Tumour Network confirms chromosomal arm copy number changes in at least 7/67 ACP cases. The activation of the MAPK/ERK pathway, a feature previously shown in primary ACP, is observed in all but one recurrent cases of ACP. The only ACP without MAPK activation is an aggressive case of recurrent malignant human craniopharyngioma harbouring a CTNNB1 mutation and loss of TP53. Providing support for a functional role of this TP53 mutation, we show that Trp53 loss in a murine model of ACP results in aggressive tumours and reduced mouse survival. Finally, we characterise the tumour immune infiltrate showing differences in the cellular composition and spatial distribution between ACP and PCP. Together, these analyses have revealed novel insights into recurrent craniopharyngioma and provided preclinical evidence supporting the evaluation of MAPK pathway inhibitors and immunomodulatory approaches in clinical trials in against recurrent ACP.

Pituitary pseudo-adenoma from cerebrospinal fluid leak in patient with Marfan syndrome.

Intracranial hypotension may result in pituitary gland enlargement due to compensatory hyperaemia and venous engorgement. Spontaneous intracranial hypotension (SIH) is frequently associated with connective tissue disorders predisposing patients to dural weakening including dural ectasia and meningeal diverticula. Symptoms of SIH typically include postural headache, dizziness and tinnitus. We present a case of a female in her 20s with Marfan syndrome and a history of pituitary adenoma, who reported intractable postural headaches. Hormonal workup revealed no abnormalities, whereas brain MRI showed sequelae of intracranial hypotension. Further MRI studies revealed thoracic and lumbar meningeal diverticula with significant dural sac ectasia at the L4-S2 level. Myelogram confirmed numerous lumbar spine diverticula with cerebrospinal fluid leak at the L5 and S1 right nerve roots. The patient underwent blood patch administrations at the level of the leak with improvement of symptoms.

Extraconal orbital craniopharyngioma.

A female, in her 60s, presented with pain and swelling of the right eye for 3 years. The radiological work-up revealed an extraconal solid-cystic orbital tumour suggestive of an epidermoid cyst. The patient underwent supraorbital craniotomy with a gross total excision of the tumour. An intraoperative diagnosis was sought, which on both squash smear and frozen section showed features of craniopharyngioma (CP), later confirmed on paraffin sections and immunohistochemistry. The orbit is a very rare site for ectopic CP, with only two cases reported in the literature. Many theories have been proposed to explain the occurrence of CP at ectopic sites. This report aims to provide insight into the different hypotheses of the pathogenesis of ectopic CP through a review of the literature.

[Clinical observation of 7 cases of functional pituitary neuroendocrine tumor treated by endoscopic transnasal selective resection of the cavernous sinus medial wall].

The clinical data of 7 patients (3 males and 4 females) with functional pituitary neuroendocrine tumor treated by endoscopic transnasal resection of the cavernous sinus medial wall from May to October 2023 in the Department of Neurosurgery of the First Affiliated Hospital of University of Science and Technology of China were retrospectively analyzed. They ranged in age from 29 to 60, with an average age of 45. The clinical diagnosis was acromegaly in 5 cases and Cushing's disease in 2 cases. There were 1 cases of microadenoma and 6 cases of macroadenoma. Knosp grade: Grade 1 adenoma in 3 cases, grade 2 adenoma in 3 cases and grade 3A adenoma in 1 case. Intraoperative resection of cavernous sinus medial wall was performed on the side of tumor. Five cases were determined to be invaded by tumor, and 2 cases were uncertain. No internal carotid artery injury occurred in all patients. The average intraoperative blood loss was 156 ml, and no patient was transfused. Postoperative endocrine remission was found in 6 cases, and tumor cells were found in 6 cases by pathological examination of the medial wall of cavernous sinus. No serious complications occurred in all patients. For Knosp grade 1-3 functional pituitary neuroendocrine tumor surgery, if there is no clear false envelope or normal pituitary between the tumor and the cavernous sinus medial wall during the operation, the cavernous sinus medial wall should be actively removed to improve the postoperative endocrine remission rate.

Endoscopic Supraorbital Translaminar Approach.

Surgical selection for third ventricle tumors demands meticulous planning, given the complex anatomic milieu. Traditional open microsurgical approaches may be limited in their access to certain tumors, prompting the exploration of alternative techniques. The endoscopic supraorbital translaminar approach (ESOTLA) has emerged as a promising alternative for managing these tumors. By combining a minimally invasive keyhole approach with endoscopic visualization, the ESOTLA provides enhanced illumination and a wider angle of view within the third ventricle. This unique advantage allows for improved access to retrochiasmatic tumors and reduces the need for frontal lobe and optic chiasm retraction required of microscopic techniques, decreasing the risk of neurocognitive and visual deficits. Complications related to the ESOTLA are rare and primarily pertain to cosmetic issues and potential compromise of the hypothalamus or optic apparatus, which can be minimized through careful subarachnoid dissection. This chapter offers a comprehensive description of the technical aspects of the ESOTLA, providing insights into its application, advantages, and potential limitations. Additionally, a case description highlights the successful surgical extirpation of an intraventricular papillary craniopharyngioma via the ESOTLA followed by targeted therapy. To better illustrate the stepwise dissection through this novel approach, a series of cadaveric and intraoperative photographs are included.

Aortic root dilation in acromegaly.

Previous studies have linked persistent elevations in growth hormone (GH) and insulin-like growth factor-1 (IGF-1) to cardiac abnormalities including aortic root dilation. Guidelines in the management of this dilation below the size recommended for surgery have not been well defined but follow-up and intervention when appropriate could be life-saving. We report the case of a man in his 60s who had been living with undiagnosed acromegaly for many years. His initial assessment through point-of-care ultrasound raised concerns about potential cardiac enlargement, prompting further investigation with a formal echocardiogram, which revealed a significant aortic root dilation measuring 4.5 cm. Subsequent blood tests confirmed elevated levels of IGF-1. Brain MRI showed a focal lesion in the pituitary gland, which was surgically resected, confirming the diagnosis of a GH-secreting pituitary adenoma. One year after surgery, a repeat CT angiogram of the chest demonstrated a stable size of the aortic root aneurysm.

Natural history and surgical outcomes of Rathke's cleft cysts: a Spanish multicenter study.

Rathke's cleft cysts (RCC) are a common type of lesion found in the sellar or suprasellar area. They are usually monitored clinically, but in some cases, surgery may be required. However, their natural progression is not yet well understood, and the outcomes of surgery are uncertain. The objective of this study is to evaluate the natural history of Rathke's cleft cysts in patients who are clinically monitored without treatment, and to determine the outcomes of surgery and the incidence of recurrences over time. Design and patients: National multicentric study of patients diagnosed of Rathke's cleft cyst (RCC- Spain) from 2000 onwards and followed in 15 tertiary centers of Spain. A total of 177 patients diagnosed of RCC followed for 67.3 months (6-215) and 88 patients who underwent surgery, (81 patients underwent immediate surgery after diagnosis and 7 later for subsequent growth) followed for 68.8 months (3-235). Results: The cyst size remained stable or decreased in 73.5% (133) of the patients. Only 44 patients (24.3%) experienced a cyst increase and 9 of them (5.1%) experienced an increase greater than 3 mm. In most of the patients who underwent surgery headaches and visual alterations improved, recurrence was observed in 8 (9.1%) after a median time of 96 months, and no predictors of recurrence were discovered. Conclusions: Rathke's cleft cysts without initial compressive symptoms have a low probability of growth, so conservative management is recommended. Patients who undergo transsphenoidal surgery experience rapid clinical improvement, and recurrences are infrequent. However, they can occur after a long period of time, although no predictors of recurrence have been identified.

Correlation of pre-operative and post-operative retinal nerve fibre layer thickness with visual outcome following decompression of pituitary macroadenoma.

OBJECTIVE: To (i) correlate preoperative retinal nerve fibre layer (RNFL) thickness with visual parameters in patients with pituitary macroadenomas. (ii) study the predictive role of preoperative RNFL in visual outcome following surgery for pituitary macroadenomas (iii) correlate change in postoperative RNFL thickness (RNFLT) with visual outcome. METHODS: Preoperative and post-operative RNFL thickness of thirty-three consecutive patients operated for pituitary macro adenoma between June 2022 and May 2023 were measured using Optical Coherence Tomography (OCT) and compared with standard visual examination findings and Magnetic Resonance Imaging (MRI) measurements. RESULTS: A total of 66 eyes of 33 patients who underwent surgical excision of pituitary macro adenoma between June 2022 and May 2023 were studied. The mean age in years of the study group was 44.36 ± 13.77 and both sexes were equally represented (Male: Female = 16:17). RNFL thinning predominantly involved the temporal (51.21+/-15.19 µm) followed by nasal quadrants (62.67+/- 17.03 µm) and correlated well with the visual field (VF) deficit (p <0.001). Patients with severe disc pallor had extremely thin RNFL (less than 67 +/- 8.68 µm). Patients with moderate to severe visual acuity (VA) deficits had significantly thinner RNFLs (65.08±7.09) compared to patients with normal to mild impairment in vision. (83.185±1.2) (p<0.05). RNFL values were significantly thinner for patients with Wilson Grade C, D and E tumours (66.13 ±12.19 µm) compared to those in Grade A and B (77.67±22.12 µm). The mean preop RNFL of patients who showed post-operative improvement in vision was 87.025± 15.02 µm, of patients in whom vision remained static was 74.58 ±18.31 µm. The mean VA (Decimal) increased from a minimum of 0.60 at the pre-operative timepoint to a maximum of 0.68 at the post-operative timepoint. (Wilcoxon Test: V = 42.5, p = <0.001). The mean RNFLT (µm) increased from 77.14 µm at the pre-operative timepoint to 83.77 µm at the post-operative timepoint. (Wilcoxon Test: V = 218.0, p = <0.001). The mean change of RNFL in patients in whom vision improved was 3.6 µm and the mean change of RNFL in patients in whom vision remained static was 9.51 µm. Absence of postoperative visual improvement was noted despite postoperative RNFL thickness improvement in eyes which showed significant preoperative thinning of the nasal (<65 µm) and temporal (<52µm) quadrants. CONCLUSION: RNFL thinning corelates directly with visual acuity, visual field, and optic disc pallor. Patients with pituitary adenoma have preferential thinning of temporal and nasal quadrants. Visual outcome is better in patients with preserved RNFLT of values more than 82 +/- 5 µm. Reversal of RNFL thinning postoperatively need not necessarily correlate with visual improvement especially in patients who showed significant preoperative thinning of nasal and temporal quadrants.

Neuro-ophthalmic evaluation and management of pituitary disease.

Neuro-ophthalmic evaluation is a crucial component of the diagnostic and prognostic assessment of pituitary disease and compressive chiasmopathy, and can inform the timing of vision-restoring tumour resection surgery. The most common disease affecting the pituitary with neuro-ophthalmic implications are pituitary adenomas. Neuro-ophthalmic manifestations include decreased vision, abnormal colour vision and impaired visual field or diplopia. The recognition of these syndromes is critical to achieve early diagnosis and treatment and to improve prognosis. The pattern of vision loss in chiasmal compression is determined by the anatomical relationship between the pituitary lesion and optic chiasm, and potential visual field defects include bitemporal deficits, junctional scotomas, monocular cecocentral defects, and incongruous homonymous hemianopias. Rarer neuro-ophthalmic manifestations of pituitary disease include ophthalmoplegia, nystagmus, and obstructive hydrocephalus. There is growing evidence that demonstrates the strong diagnostic utility of optical coherence tomography (OCT) parameters in detecting the presence of compressive chiasmopathy, as well as the prognostic ability to predict the rate and degree of visual recovery following decompression surgery. Long-term neuro-ophthalmic monitoring is critical for detecting delayed vision loss following resection surgery, which may represent tumour recurrence or secondary complications.