The case is reported according to the Case Report (CARE) guidelines (9) and the patient provided written informed consent for this publication. The two tissue samples referenced in this report were obtained from the same patient in March 2024 during a single surgical procedure. One sample was collected from the lesion within the preexisting resection cavity, while the other was taken from a distant site at the planum sphenoidale. Following the surgery, the samples were fixed in formalin and subsequently transferred to the local biobank. The tissues were then made available for scientific research and subjected to detailed neuropathological analysis. This process included embedding the tissues in paraffin and preparing thin sections on microscope slides. Histological staining was conducted using hematoxylin and eosin (H&E) or hematoxylin alone, alongside immunohistochemical staining for SSTR2 and glial fibrillary acidic protein (GFAP), following standardized protocols.

All tissue samples were fixed in 4% buffered formalin at room temperature, embedded in paraffin, and sectioned to a thickness of 1 µm. H&E and hematoxylin staining was performed using the VENTANA^© HE 600 System (Roche Diagnostics GmbH). Immunohistochemical staining was carried out on the BenchMark ULTRA Slide Staining System (Roche Diagnostics GmbH) using an anti-GFAP polyclonal rabbit antibody (cat. no. Z0334; Dako; Agilent Technologies, Inc.) at a 1:4,000 dilution, with an incubation time of 16 min at 36°C. Staining for SSTR2 was performed using a polyclonal rabbit antibody (cat. no. RBK046-05; Zytomed Systems GmbH) at a 1:50 dilution, with antigen retrieval for 64 min at 90°C in CC1 buffer (Roche Diagnostics GmbH), followed by antibody incubation for 24 min at 36°C. All stained slides were examined under a light microscope (Eclipse 80i; Nikon Corporation).

In September 2021, a 56-year-old male patient attended University Hospital Essen (Essen, Germany) and was diagnosed with an intracerebral, right temporal, ring-like contrast-enhancing lesion. The patient underwent microsurgical tumor removal, and a neuropathological assessment revealed the diagnosis of a glioblastoma of Central Nervous System World Health Organization (WHO) grade 4 (10). The prior medical history included a posterior fossa neurinoma, which was previously treated with stereotactic irradiation. Postoperatively, concomitant radiochemotherapy according to Stupp et al (11) was initiated, followed by six cycles of adjuvant temozolomide, administered at 200 mg/m² daily for the first 5 days of a 4-week cycle, and tumor-treating fields.

In January 2024, at the age of 58 years, the patient experienced a new extra-axial lesion at the planum sphenoidale with homogeneous contrast-enhancement, radiographically consistent with meningioma but suspicious for a distant glioblastoma manifestation due to its de novo appearance. The case was discussed, and a [⁶⁸Ga]-DOTA-octreotide (DOTATOC) PET/MRI was recommended. The imaging was performed 2 weeks later (dosage, 85 MBq; uptake time, 30 min after injection). MRI confirmed the extra-axial lesion and additionally showed local tumor recurrence in the right temporal lobe. [⁶⁸Ga]-DOTATOC PET demonstrated pronounced tracer accumulation in the pituitary gland and doubled maximum standardized uptake (SUV_max) values in the extra-axial lesion compared to the glioblastoma recurrence [SUV_max extra-axial lesion of the planum sphenoidale (lesion_1), 2.91; SUV_max local glioblastoma recurrence (lesion_2), 1.35; SUV_max pituitary gland, 8.23]. The [⁶⁸Ga]-DOTATOC PET/MRI investigation is illustrated in Fig. 1A-C. Due to the uncertainty of the diagnosis of the extra-axial lesion, the patient underwent tumor removal, involving both the right temporal lesion and the extra-axial lesion. The neuropathological assessment revealed a glioblastoma diagnosis in both lesions. The right temporal lesion demonstrated a diffusely infiltrative glioma, composed of astrocytic, differentiated tumor cells with marked pleomorphism, while the extra-axial lesion revealed a highly cellular glioma with a small cell-like appearance. Representative neuropathological slices are presented in Fig. 2. Retrospectively, SSTR2 expression was assessed, and consistent with [⁶⁸Ga]-DOTATOC PET imaging, the right temporal lesion showed weak positivity for SSTR2, while the extra-axial lesion demonstrated increased SSTR2 expression. Representative staining is presented in Fig. 1D. Post-surgery, systemic treatment with lomustine, administered at 110 mg/m² on the first day of a 6-week cycle, combined with tumor-treating fields was initiated. Following the second recurrence, the treatment strategy was adjusted to systemic therapy with trofosfamide and etoposide, administered at 100 and 25 mg/m², respectively, following a ‘1 week on - 1 week off’ schedule within a 4-week cycle, while continuing the use of tumor-treating fields. At the most recent follow-up in May 2024, the patient remains alive and under clinical observation, with a survival period of 2 years and 8 months since the initial diagnosis.

To provide a comprehensive review of all reports on [⁶⁸Ga]-DOTA-conjugated SSTR-targeting peptide PET and glioma, a broad search strategy was implemented. To avoid database bias, research was conducted using PubMed/MEDLINE (https://pubmed.ncbi.nlm.nih.gov/), Scopus (https://www.elsevier.com/en-gb/products/scopus), Embase (https://embase.com) and Web of Science (https://webofscience.com), utilizing the search string: [(‘68-Ga-DOTA*’ OR ‘68Ga-DOTA*’ OR ‘Gallium-68 DOTA*’) AND (‘glioma*’ OR ‘glioblastoma*’ OR ‘astrocytoma*’ OR ‘ependymoma*’]. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (12), a computerized literature search was performed on May 25, 2024. All duplicates were excluded. The titles and abstracts of the remaining publications were reviewed, and suitable articles were extracted. All articles were independently screened by two investigators for their suitability. The references of eligible publications were reviewed, and additional citations were extracted. Research studies were considered eligible for inclusion if they addressed the use of [⁶⁸Ga]-DOTA-conjugated SSTR-targeting peptide PET in glioma, including preclinical and clinical research. Review articles or conference abstracts were not included. The resulting publication list was used to prepare this review, and all included studies were subsequently analyzed in detail. The final publication list was reviewed by two investigators, and relevant data points were extracted.

The systematic literature search and subsequent analysis identified six publications investigating the use of [⁶⁸Ga]-DOTA-conjugated SSTR-targeting peptide PET in glioma patients or preclinical glioma models (8,13–17). Five publications were clinically oriented and examined patients with either primary or recurrent tumor entities. Results are presented in Table SI. One publication referred to the preclinical examination of PET imaging on chemically induced glioma in animal models. Details are provided in Table SII. In total, 44 patients with glioma underwent PET imaging. Extensive heterogeneity was observed among the studied entities, as the inclusion extended beyond high-grade tumors, with individual tumor grading occasionally unspecified. Additionally, the study protocols often differed regarding the administered tracer dose and uptake time, with some details occasionally missing. Absolute tumor-to-brain ratio or SUV values were rarely reported; however, a common finding was tracer uptake in malignant gliomas of WHO grades III and IV, corresponding to contrast enhancement in MRI according to the 2016 WHO classification (10).