[C-11]Methionine ([C-11]MET) PET provides high sensitivity to localize corticotroph pituitary neuroendocrine tumors (PitNETs) in de novo Cushing's disease but remains inconclusive in up to 20% of cases. Current PET protocols rely on late acquisitions (20-40 min post-injection). Since other endocrine tumors present earlier peak tracer uptake, corticotroph PitNETs might also exhibit early differential amino acid uptake, compared to the normal pituitary gland. This exploratory study based on data derived from a previously registered prospective multicenter cohort study (ClinicalTrials.gov identifier: NCT03346954) included 15 patients with pathologically confirmed corticotroph PitNETs accurately localized using MRI. Kinetic analysis showed rapid early uptake in PitNETs and normal pituitary gland, followed by a significant decline over time, with consistently higher uptake in PitNETs (p < 0.05), but no statistically significant difference in temporal uptake pattern (p = 0.09). Early uptake slope and peak uptake were significantly higher in PitNETs compared to normal gland (p < 0.01), with moderate-to-high discriminative performance (area under the curve 0.78; 95%CI 0.60-0.94 and 0.86; 95%CI 0.69-0.98, respectively). Time-to-peak showed no statistically significant discriminative value. These findings suggest that kinetic parameters of [& sup1;& sup1;C]MET PET, particularly early slope and peak uptake, may provide complementary information to static PET for PitNET characterization.

INTRODUCTION:Acromegaly results from different histological subtypes of pituitary adenomas, mainly pure GH-secreting adenomas (densely or sparsely granulated) and GH-PRL adenomas. Data on the impact of histological subtype on surgical outcomes in acromegaly remain limited. OBJECTIVES:This study aimed to assess the impact of pituitary adenoma histological subtype on acromegaly remission at 3 months and last follow-up, as well as on disease control. METHODS:We conducted a retrospective, single-center study of 128 patients who underwent surgery for GH or GH-PRL adenomas, without prior medical therapy, between 2012 and 2022. RESULTS:Among the adenomas, 61% were pure GH (39% DG, 22% SG) and 39% were GH-PRL. Compared to DG adenomas, SG adenomas were diagnosed at a younger age (p = 0.006), were larger (p = 0.022), expressed more SST5 (p = 0.032) and less SST2 (p < 0.001). GH-PRL adenomas were more frequently p53-positive (p = 0.024), had a higher mitotic count (p = 0.017) than DG adenomas and expressed more SST2 than SG adenomas (p < 0.001). The remission rates for DG, GH-PRL and SG adenomas were not significantly different at 3 months (60%, 58% and 43%, p = 0.337), or at last follow-up (80%, 74% and 57%, p = 0.091), nor was disease control at last follow-up (94%, 96% and 82%, p = 0.115) after 42 months. CONCLUSION:Histological subtype was not significantly associated with remission or control of acromegaly. Although a trend toward lower remission rates was observed in SG adenomas, its clinical impact appears limited.

[11C]Methionine ([11C]MET) PET provides high sensitivity to localize corticotroph pituitary neuroendocrine tumors (PitNETs) in de novo Cushing’s disease but remains inconclusive in up to 20% of cases. Current PET protocols rely on late acquisitions (20–40 min post-injection). Since other endocrine tumors present earlier peak tracer uptake, corticotroph PitNETs might also exhibit early differential amino acid uptake, compared to the normal pituitary gland. This exploratory study based on data derived from a previously registered prospective multicenter cohort study (ClinicalTrials.gov identifier: NCT03346954) included 15 patients with pathologically confirmed corticotroph PitNETs accurately localized using MRI. Kinetic analysis showed rapid early uptake in PitNETs and normal pituitary gland, followed by a significant decline over time, with consistently higher uptake in PitNETs (p < 0.05), but no statistically significant difference in temporal uptake pattern (p = 0.09). Early uptake slope and peak uptake were significantly higher in PitNETs compared to normal gland (p < 0.01), with moderate-to-high discriminative performance (area under the curve 0.78; 95%CI 0.60–0.94 and 0.86; 95%CI 0.69–0.98, respectively). Time-to-peak showed no statistically significant discriminative value. These findings suggest that kinetic parameters of [¹¹C]MET PET, particularly early slope and peak uptake, may provide complementary information to static PET for PitNET characterization.

Tumors of the pineal region are rare neoplasms accounting for only about 1% of all central nervous system tumors. This chapter details the histopathological features and molecular alterations of these tumors. The two most common types are germ cell tumors (GCTs) and pineal parenchymal tumors (PPTs). PPTs are a group of neoplasms that exhibit varying degrees of pinealocytic differentiation and diverse prognoses. They comprise well-differentiated low-grade pineocytomas, pineal parenchymal tumors of intermediate differentiation (PPTIDs), and poorly differentiated high-grade pineoblastomas (PBs). The molecular pathogenesis of PBs notably involves alterations in the microRNA biogenesis and retinoblastoma pathway. PPTIDs are characterized by small in-frame insertions in the KBTBD4 gene. Pineal GCTs are thought to originate from primordial germ cells that have overmigrated along the midline. They exhibit the same histopathological spectrum as their gonadal counterparts. Germinomas are the most frequent GCTs in the pineal region and frequently present mutations in the MAPK pathway. Papillary tumor of the pineal region is a specific type of ependymal tumor that primarily affects the pineal region and exhibits a loss of chromosome 10 in most cases.

Supernumerary breasts (polymastia) and supernumerary nipples (polythelia) are congenital anomalies resulting from incomplete regression of the embryonic mammary ridge. They most frequently occur along the embryologic milk line extending from the axilla to the groin. Ectopic localization outside this line is rare, and dorsal presentations are exceptional. In such cases, an association with underlying spinal dysraphism has occasionally been reported. We report the case of an 11-year-old girl presenting with a congenital dorsal midline swelling initially diagnosed as a lipoma. Progressive enlargement and the appearance of a central pigmented structure prompted further evaluation. Clinical examination confirmed a dorsal midline areola-nipple complex with underlying tumefaction. Spinal MRI demonstrated an intradural lipoma at the T4 level associated with a fibrous tract extending toward the cutaneous lesion, resulting in a tethered cord configuration. The patient underwent combined resection of the ectopic mammary tissue and neurosurgical detethering with partial lipoma resection. Postoperative recovery was uneventful with no neurological deficit. Dorsal midline ectopic mammary tissue is extremely rare and may represent a cutaneous marker underlying spinal dysraphism. Careful clinical examination and spinal imaging should therefore be considered in such atypical presentations.

Two new cases of low-grade diffusely infiltrative tumour (LGDIT), SMARCB1 mutant, are described in an 18-year-old and a 50-year-old male, both with supratentorial lesions, characteristic rhabdoid histology on a myxoid-collagenous background, and complete INI1 loss. Both tumours showed homozygous SMARCB1 deletion and clustered with previously reported LGDIT on t-SNE analysis, in proximity to ATRT-MYC. These observations reinforce the distinct clinicopathological profile of LGDIT and support its consideration as a provisional CNS tumour type.

Background The tumor microenvironment (TME) represents a promising avenue to understand gonadotroph tumors and develop therapeutic tools. Here, we aimed to gain insight into the tumorigenesis mechanisms driven by the gonadotroph TME.Methods Single-cell and spatial-omics were combined with histological analysis. Mice engrafted with tumor cells were used for functional validation.Results Using single-cell and spatial transcriptomic data from gonadotroph tumors and normal tissues, we identified mast cells in the microenvironment of gonadotroph tumors and confirmed their physical and functional interaction with endothelial cells. Quantification of mast cells in 40 patients suggested their pro-tumoral role as tumors relapsing after surgery harbored more mast cells. More interestingly, the distribution of mast cells was associated with the presence of a higher number of blood vessels, with an increased microvessel density (MVD), and with blood vessels with thicker walls. Ligand-receptor network analysis highlighted VEGFA as a modulator of mast/endothelial cell communication, a result confirmed by the identification of intratumoral mast cells expressing VEGFA in mouse and human gonadotroph tumors. Finally, using mice engrafted with gonadotroph tumor cells, we demonstrated that the depletion of mast cells reduces tumor volume through increased apoptosis. These observations were associated with increased hemorrhagic areas and a significant reduction of the number of blood vessels and MVD as evidenced in human gonadotroph tumors.Conclusion We demonstrate that mast cells represent a new actor of the gonadotroph TME, and highlight their pro-angiogenic and pro-tumorigenic roles as potential targets for the therapeutic treatment of gonadotroph tumors.

INTRODUCTION:We report a case of primary pyruvate dehydrogenase complex deficiency (PPDCD) presenting with prenatal neuroimaging features highly suggestive of cytomegalovirus (CMV) fetopathy, highlighting an important alternative diagnosis when infectious investigations are negative. CASE PRESENTATION:A 32-year-old patient was referred at 29 weeks' gestation for fetal microcephaly, borderline ventriculomegaly, and a short corpus callosum. Detailed neurosonography and fetal MRI demonstrated a clastic pattern including a periventricular echogenic halo, germinolysis pseudocysts, delayed sylvian operculation, and reduced transverse cerebellar diameter - findings classically associated with congenital CMV infection. Despite this highly suggestive imaging phenotype, extensive infectious work-up was negative. Given the severity of cerebral lesions, pregnancy termination was elected. Neuropathological examination confirmed clastic lesions and showed inferior olivary nuclei heterotopia, dentato-olivary dysplasia, thalamic microcalcifications, and hypoplastic pyramidal tracts. This distinctive combination raised suspicion of a metabolic disorder affecting cerebral energy metabolism. Subsequent exome sequencing identified a de novo pathogenic duplication in the PDHA1 gene, confirming the diagnosis of PPDCD. CONCLUSION:This case demonstrates that PPDCD can closely mimic CMV fetopathy on prenatal brain imaging that one should evocate in case of such an imaging pattern and negative infectious testing. Its recognition has major implications for counseling and recurrence risk assessment.

INTRODUCTION:In IDH-mutant gliomas, the accumulation of 2-hydroxyglutarate (2-HG) induces widespread epigenetic disruption and drives gliomagenesis. L-2-hydroxyglutaric aciduria (L-2-HGA) is a metabolic disorder causing L-2-HG accumulation, resulting in myelin toxicity, and increased brain tumor risk. Gliomas arising in L-2-HGA remain poorly characterized. We report a new case of high-grade glioma in a L-2-HGA patient, including methylome profiling, and review previously published cases to clarify glioma characteristics and provide hypothesis regarding 2-HG-driven gliomagenesis. MATERIAL AND METHODS:A new case of high-grade glioma in a L-2-HGA patient was locally identified. A literature review was conducted following PRISMA guidelines. RESULTS:A 45-year-old L-2-HGA woman developed a diffuse anaplastic glioma harboring a TERTp C228T mutation, revealed by progressive neurological decline. Methylation profiling assigned the tumor to the "Diffuse pediatric-type high-grade gliomas" superfamily (score ≥0.9). Despite chemotherapy, the patient died 5 months post-diagnosis. Literature review yielded 20 documented cases of glioma in L-2-HGA patients, with a mean age at diagnosis of 18 ± 9.5 years. Tumor location was relatively stereotyped, with 75% in the temporal lobe or thalamus/basal ganglia. Molecular alterations typical of glioblastoma were observed (EGFR amplification, partial 10q loss) and the epigenetic profile was similar. Although some tumors misleadingly harbored the microscopic features of low-grade gliomas, the median overall survival was 6 months. CONCLUSION:Although gliomas associated with L-2HGA predominantly affect young patients, their characteristics differ from those of IDH-mutant gliomas. These tumors may possibly be related to diffuse pediatric-type high-grade glioma H3-wildtype and IDH-wildtype, which is consistent with their highly aggressive clinical course.

Acromegaly caused by ectopic growth hormone-releasing hormone (GHRH)-secreting neuroendocrine tumor (NET) is extremely rare, with cosecreting NETs even more seldom. We report a case of a female patient who presented with primary hyperparathyroidism (pHPT) and a GHRH- and insulin cosecreting pancreatic NET (pNET) and genetically confirmed multiple endocrine neoplasia type 1 (MEN1), within an undiagnosed family with various MEN1-related NETs. Due to the diagnosis of MEN1, screening for pituitary tumor was performed with biochemical evidence of acromegaly. Sellar magnetic resonance imaging revealed a sellar lesion, which was excised and compatible with somatotroph hyperplasia. Postoperatively, the patient developed severe hypoglycemia requiring hospitalization and the pNET was removed. Histopathology confirmed GHRH and insulin secreting pNET. Ectopic acromegaly in MEN1 is exceedingly rare. Patients with MEN1 often present with multiple pNETs, which may exhibit multihormonal secretion and frequently cosecrete GHRH and insulin in MEN1, while hypoglycemia may not be manifested possibly due to GH and insulin's counteractive effects on glucose metabolism.

Background Aggressive pituitary tumors and pituitary Carcinomas (PCs) represent very uncommon entities within the field of pituitary diseases. Unfortunately, treatment options after progression on temozolomide are limited. However, advances in the understanding of pituitary tumor genetics and their immunological landscape are paving the way for new targeted molecular therapies. Methods In this article, we present an overview of the most recent literature, focusing on the specificities and role of current treatments and future perspectives in the management of these lesions. Results and Conclusions Aggressive pituitary tumors and PCs remain very challenging conditions requiring a specific multidisciplinary approach in Pituitary Tumor Centers of excellence. If standard therapy fails, Temozolomide represents the first-line treatment option. Peptide Receptor Radionuclide Therapy may be also considered, especially in tumors expressing specific Somatostatin receptors. When tumors progress after Temozolomide treatment, the prognosis is typically poor, and among the various second-line treatment options immune checkpoint inhibitors have proven to be the most effective. Further studies exploring new potential targeted therapies and predictive factors for pituitary tumor aggressiveness are now essential to improve the management and outcomes for these patients.

BACKGROUND AND PURPOSE:CNS embryonal tumor with pleomorphic adenoma gene-like 1 (PLAGL1)/pleomorphic adenoma gene-like 2 (PLAGL2) amplification (ET, PLAGL) is a newly identified, highly malignant pediatric tumor. Systematic MRI descriptions of ET, PLAGL are currently lacking. MATERIALS AND METHODS:MRI data from 19 treatment-naïve patients with confirmed ET, PLAGL were analyzed. Evaluation focused on anatomic involvement, tumor localization, MRI signal characteristics, DWI behavior, and the presence of necrosis and hemorrhage. Descriptive statistics (median, interquartile range, percentage) were assessed. RESULTS:Ten patients had PLAGL1 and nine had PLAGL2 amplifications. The solid components of the tumors were often multinodular with heterogeneous enhancement (mild to intermediate in 47% and intermediate to strong in 47% of cases). Nonsolid components included cysts in 47% and necrosis in 84% of the cases. The tumors showed heterogeneous T2WI hyper- and isointensity (74%), relatively little diffusion restriction (ADC values less than contralateral normal-appearing WM in 36% of cases with available DWI), and tendencies toward hemorrhage/calcification (42%). No reliable distinction was found between PLAGL1- and PLAGL2-amplified tumors or compared with other embryonal CNS tumors. CONCLUSIONS:The study contributes to understanding the imaging characteristics of ET, PLAGL. It underscores the need for collaboration in studying rare pediatric tumors and advocates the use of harmonized imaging protocols for better characterization.

Background Medulloblastoma (MB) is one of the most prevalent embryonal malignant brain tumors. Current classification organizes these tumors into 4 molecular subgroups (WNT, SHH, Group 3, and Group 4 MB). Recently, a comprehensive classification has been established, identifying numerous subtypes, some of which exhibit a poor prognosis. It is critical to establish effective subtyping methods for accurate diagnosis and patient's management that strikes a delicate balance between improving outcomes and minimizing the risk of comorbidities.Methods We evaluated the ability of Nanopore sequencing to provide clinically relevant methylation and copy number profiles of MB. Nanopore sequencing was applied to an EPIC cohort of 44 frozen MB, benchmarked against the gold standard EPIC array, and further evaluated on an integrated diagnosis cohort of 116 MB.Results Most MB of both cohorts (42/44; 95.5% and 106/116; 91.4%, respectively) were accurately subgrouped by Nanopore sequencing. Employing Flongle flow cells for 18 MB allowed a more rapid and cost-effective analysis, with 94.4% (17/18) being correctly classified. Nanopore sequencing enabled us to accurately subtype 28/30 (93.3%) MB.Conclusion This study, conducted on the largest cohort of MB analyzed with Nanopore sequencing to date, establishes the proof of concept that this modern and innovative technology is well-suited for MB classification. Nanopore sequencing demonstrates a robust capacity for precise subtyping of MB, a critical advancement that holds significant potential for enhancing patient stratification in future clinical trials. Its ability to deliver quick and cost-effective results firmly establishes it as a game-changer in the field of MB classification.

BACKGROUND:Brain tumors are the deadliest solid tumors in children and adolescents. Most of these tumors are glial in origin and exhibit strong heterogeneity, hampering the development of effective therapeutic strategies. In the past decades, patient-derived tumor organoids (PDT-O) have emerged as powerful tools for modeling tumoral cell diversity and dynamics, and they could then help define new therapeutic options for pediatric brain tumors. METHODS:Through an integrative approach based on our expertise and a careful review of the literature about glioblastoma 3D primary cultures, we set up a standardized methodological pipeline for the establishment, characterization, and biobanking of PDT-O through direct 3D in vitro culture of the deadliest pediatric glial brain tumors. To assess PDT-O fidelity and validate their preclinical relevance, we performed comprehensive histological, molecular, and drug-response analyses. RESULTS:Our methodological pipeline allowed the rapid and efficient generation of PDT-O recapitulating their parental tumor features, including intratumoral heterogeneity, even after several passages and cryopreservation/revival as 3D cultures. Moreover, we successfully performed preclinical test responses on these PDT-O to standard-of-care therapies and new therapeutic options. Finally, we identified ONC201 as a selective drug for pediatric glial tumor types not restricted to H3K27-altered glial tumors, as well as combination strategies to increase the therapeutic response to ONC201. CONCLUSIONS:Hence, we describe a fast and robust process to biobank PDT-O for pediatric glial brain tumors. These PDT-O models have the potential for patient-specific modeling even after long-term expansion in vitro, and we established the proof-of-concept of their usefulness to support powerful preclinical studies.

Paediatric tumours of the pineal region are rare CNS tumours accounting for 3% of brain tumours in children and adolescents; the majority of which are germ cell tumours. This review focuses on pineal parenchymal tumours (pineoblastoma, pineal parenchymal tumour of intermediate differentiation, pineocytoma) and those specifically arising in the pineal region (papillary tumours of the pineal region, desmoplastic myxoid tumour of the pineal region, SMARCB1-mutant and pineal cyst), which together account for up to a third of pineal tumours. In recent years, the diagnostic classification of these specific tumour-types has been refined by the integration of molecular pathology. Given the differences in grade, tumour biology and clinical behaviour, an accurate integrated neuropathological diagnosis is essential in deciding an appropriate treatment strategy which can range from surgery only to intensive multi-modal therapies. The most common of these tumours in children is WHO Grade 4 pineoblastoma, where specific molecular subgroups occurring in very young patients are difficult to treat successfully. Further challenges include the anatomical position and associated surgical risk together with a lack of molecularly annotated clinical data and consequent limited evidence to guide the therapeutic approach due to their rarity. These guidelines aim to provide a framework for diagnosis, prognostication and management based on current literature and expert opinion.

CNS embryonal tumors with PLAGL amplification (ET, PLAGL) are a recently described tumor type marked by amplification of one of the PLAG family genes, PLAGL1 or PLAGL2. Separately, a supratentorial, ependymoma-like CNS tumor type with PLAG family alteration, namely PLAGL1 fusion, was also reported (NET_PLAGL1). Here, we use DNA methylation profiling in combination with copy number, RNA-seq, and histological analysis to characterize and classify a novel group of CNS embryonal tumors harboring PLAG1 gene fusions (n=12). Through our screening, we identified a subset of CNS tumors (n=12) epigenetically distinct from other known CNS tumor types, but clustering close to the PLAGL1- and PLAGL2-amplified ET, PLAGL subtypes in our t-SNE analysis. Copy number profiles indicated putative PLAG1 fusions, which were confirmed in 9/12 tumors (not determined in 3/12). Different 5’ fusion partners (ASAP1, ADGRG1, TMEM68, TCF4, CHD7, NCALD, HNRNPK, LOC105378102) were identified that upregulate wild-type PLAG1 through promoter hijacking. Expression analysis shows upregulation of PLAG1 as well as IGF2, DLK1, Desmin, CYP2W1, and RET, which are also robustly expressed in PLAGL1/2-amplified tumors. Patient characteristics, survival data, and clinical/imaging analysis show additional similarities to PLAGL1/2-amplified tumors. Median age at diagnosis was 5 years, tumors were located throughout the neuroaxis, and original histological diagnoses were heterogeneous. The tumors demonstrated morphologic heterogeneity, with most composed of densely cellular areas of primitive small blue cells, alongside focal regions showing clear cell morphology, microcystic changes, and ependymoma-like perivascular pseudorosettes. Applied treatment regimens were also heterogeneous, but some favorable responses to therapy were observed. In summary, we describe a third subtype of PLAG family-altered pediatric CNS embryonal tumor characterized by PLAG1 gene fusion, which leads to upregulation of PLAG1 and downstream genes. We therefore propose to rename ET, PLAGL to ET, PLAG (CNS embryonal tumor with PLAG family gene alteration) together with a specification of the respective subtype.

Although gonadotroph tumor regrowth is frequent after pituitary surgery, the systematic use of adjuvant radiotherapy is limited by its long-term complications. In this context, it is important to predict which tumors are most likely to regrow after surgery, and especially, which tumors are most likely to regrow rapidly. Clinicopathological characteristics associated with the prognosis of radiotherapy-naïve, recurrent pituitary tumors are currently unknown. In this longitudinal, observational, retrospective, monocentric cohort study, we analyzed the clinicopathological characteristics associated with the prognosis of recurrent, radiotherapy-naïve gonadotroph tumors, specifically with the progression-free survival after a second pituitary surgery. We found that the Ki67 index of radiotherapy-naïve, recurrent gonadotroph tumors was the only parameter statistically associated with the progression-free survival after a second pituitary surgery, P = 0.02. Specifically, radiotherapy-naïve gonadotroph tumors with a positive Ki67 index had shorter progression-free survival after the second surgery (median 31 months) compared to radiotherapy-naïve gonadotroph tumors with a negative Ki67 index (median 75 months). Thus, our study pinpoints that the Ki67 index could be used to guide the management strategy for recurrent gonadotroph tumors that are still radiotherapy-naïve by the time of the second pituitary surgery.

Functional small pituitary neuroendocrine tumors (PitNETs) of the corticotroph type lead to Cushing disease (CD), a condition associated with significant morbidity and increased mortality. Pituitary MRI is the primary imaging modality used to localize the tumor, but it is inconclusive in up to 30% of cases. Accumulating retrospective evidence suggests that [11C]methionine ([11C]MET) PET could address this diagnostic gap. This prospective study evaluates the sensitivity of [11C]MET PET/MRI compared with MRI for small PitNET localization in CD. Methods: This prospective multicenter study (ClinicalTrials.gov NCT03346954) included consecutive patients with biochemically confirmed de novo CD who underwent [11C]MET PET/MRI before surgery. Images were evaluated by experienced radiologists and nuclear medicine physicians. Their sensitivity to correctly localized PitNETs was calculated, with pathologic analysis of the surgical specimen used as a reference. Results: Thirty patients (73% women; mean age, 39.4 ± 12.7 y) underwent PET/MRI, and pathology confirmed PitNET in 22 patients (73%). [11C]MET PET/MRI correctly localized the tumor in 18 patients (82%; 95% CI, 0.60-0.95), whereas MRI correctly localized the tumor in 19 patients (86%; 95% CI, 0.65-0.97; P = 1.0). [11C]MET PET/MRI and MRI were concordant in 18 patients (82%), with the tumor correctly localized in 17 of 18 patients (94%). Among the 4 patients with discordant findings, MRI correctly localized the tumor in 2 cases for which PET was inaccurate; in 1 case, PET accurately identified the lesion, which was not visualized on MRI, and in the final case, both modalities failed to localize the tumor. Conclusion: This prospective study shows that [11C]MET PET/MRI has high sensitivity but does not differ significantly from 3-T MRI for the accurate localization of small PitNETs of the corticotroph type in patients with de novo CD. Future research could benefit from emerging imaging technologies and should focus on optimizing PET imaging protocols and exploring alternative radiotracers.