Next-generation sequencing-based evaluation of the actionable landscape of genomic alterations in solid tumors: the "MOZART" prospective observational study.

BACKGROUND: The identification of the most appropriate targeted therapies for advanced cancers is challenging. We performed a molecular profiling of metastatic solid tumors utilizing a comprehensive next-generation sequencing (NGS) assay to determine genomic alterations' type, frequency, actionability, and potential correlations with PD-L1 expression. METHODS: A total of 304 adult patients with heavily pretreated metastatic cancers treated between January 2019 and March 2021 were recruited. The CLIA-/UKAS-accredit Oncofocus assay targeting 505 genes was used on newly obtained or archived biopsies. Chi-square, Kruskal-Wallis, and Wilcoxon rank-sum tests were used where appropriate. Results were significant for P < .05. RESULTS: A total of 237 tumors (78%) harbored potentially actionable genomic alterations. Tumors were positive for PD-L1 in 68.9% of cases. The median number of mutant genes/tumor was 2.0 (IQR: 1.0-3.0). Only 34.5% were actionable ESCAT Tier I-II with different prevalence according to cancer type. The DNA damage repair (14%), the PI3K/AKT/mTOR (14%), and the RAS/RAF/MAPK (12%) pathways were the most frequently altered. No association was found among PD-L1, ESCAT, age, sex, and tumor mutational status. Overall, 62 patients underwent targeted treatment, with 37.1% obtaining objective responses. The same molecular-driven treatment for different cancer types could be associated with opposite clinical outcomes. CONCLUSIONS: We highlight the clinical value of molecular profiling in metastatic solid tumors using comprehensive NGS-based panels to improve treatment algorithms in situations of uncertainty and facilitate clinical trial recruitment. However, interpreting genomic alterations in a tumor type-specific manner is critical.

Anatomical study of the mastoid foramina and mastoid emissary veins: classification and application to localizing the sigmoid sinus.

The mastoid foramen (MF) is located on the mastoid process of the temporal bone, adjacent to the occipitomastoid suture or the parietomastoid suture, and contains the mastoid emissary vein (MEV). In retrosigmoid craniotomy, the MEV has been used to localize the position of the sigmoid sinus and, thus, the placement of the initial burr hole. Therefore, this study aimed to examine the exact location and variants of the MF and MEV to determine if their use in localizing the sigmoid sinus is reasonable. The sample in this study comprised 22 adult dried skulls (44 sides). MF were identified and classified into five types based on location, prevalence, whether they communicated with the sigmoid sinus and exact entrance into the groove of the sigmoid sinus. The diameters and relative locations of the MF in the skull were measured and recorded. Finally, the skulls were drilled to investigate the course of the MEV. Additionally, ten latex-injected sides from human cadavers were also dissected to follow the MEV, especially in cases with more than one vein. We found that type I MFs (single foramen) were the most prevalent (50%). These MFs were mainly located on the occipitomastoid suture; only one case on the right side was adjacent to the parietomastoid suture. Type II (paired foramina) was the second most prevalent (22.73%), followed by type III (13.64%), type 0 (9.09%), and type IV (4.55%). The diameter of the external opening in a connecting MF (2.43 ± 0.79) was twice that of a non-connecting MF (1.14 ± 0.56). Interestingly, on one side, two MFs on the external surface shared a single internal opening; the MEV bifurcated. MFs followed three different courses: ascending, almost horizontal, and descending. Regardless of how many external openings there were for the MF, these all ended at a single opening in the groove for the sigmoid sinus. For cadaveric specimens with multiple MEVs, all terminated in the sigmoid sinus as a single vein, with the more medial veins terminating more medially into the sinus. Based on our study, the MF/MEV can guide the surgeon and help localize the deeper-lying sigmoid sinus. Knowledge of this anatomical relationship could be an adjunct to neuronavigational technologies.

Combined Endoscopic Endonasal Transclival and Contralateral Transmaxillary Approach to the Petrous Apex and the Petroclival Synchondrosis: Working "Around the Corner" of the Internal Carotid Artery-Quantitative Anatomical Study and Clinical Applications.

The endoscopic contralateral transmaxillary (CTM) approach has been proposed as a potential route to widen the corridor posterolateral to the internal carotid artery (ICA). In this study, we first refined the surgical technique of a combined multiportal endoscopic endonasal transclival (EETC) and CTM approach to the petrous apex (PA) and petroclival synchondrosis (PCS) in the dissection laboratory, and then validated its applications in a preliminary surgical series. The combined EETC and CTM approach was performed on three cadaver specimens based on four surgical steps: (1) the nasal, (2) the clival, (3) the maxillary and (4) the petrosal phases. The CTM provided a "head-on trajectory" to the PA and PCS and a short distance to the surgical field considerably furthering surgical maneuverability. The best operative set-up was achieved by introducing angled optics via the endonasal route and operative instruments via the transmaxillary corridor exploiting the advantages of a non-coaxial multiportal surgery. Clinical applications of the combined EETC and CTM approach were reported in three cases, a clival chordoma and two giant pituitary adenomas. The present translational study explores the safety and feasibility of a combined multiportal EETC and CTM approach to access the petroclival region though different corridors.

The Posterior Auricularis Muscle as Superficial Landmark for the Sigmoid Sinus and Transverse-Sigmoid Sinus Junction: An Anatomical Study.

OBJECTIVE: Neuronavigation systems coupled with previously reported external anatomical landmarks assist neurosurgeons during intracranial procedures. We aimed to verify whether the posterior auricularis muscle (PAM) could be used as an external landmark for identifying the sigmoid sinus (SS) and the transverse-sigmoid sinus junction (TSSJ) during posterior cranial fossa surgery. METHODS: The PAM was dissected in 10 adult cadaveric heads and after drilling the underlying bone, the relationships with the underlying SS and TSSJ were noted. The width and length of the PAM, and the distance between the muscle and reference points (asterion, mastoid tip, and midline), were measured. RESULTS: The PAM was identified in 18 sides (9 left, 9 right). The first 20 mm of the muscle length (mean 28.28 mm) consistently overlay the mastoid process anteriorly and the proximal half of the SS slightly posteriorly on all sides. The superior border was a mean of 2.22 mm inferior to the TSSJ and, especially when the muscle length exceeded 20 mm, this border extended closer to the transverse sinus; it was usually found at a mean of 3.11 mm (range 0.0-13.80 mm) inferior to the distal third of the transverse sinus. CONCLUSIONS: Superficial landmarks give surgeons improved surgical access, avoiding overexposure of deep neurovascular structures and reducing brain retraction. On the basis of our cadaveric study, the PAM is a reliable and accurate direct landmark for identifying the SS and TSSJ. The PAM could potentially be used for guiding the retrosigmoid approach.

CD99 Expression and Prognostic Impact in Glioblastoma: A Single-Center Cohort Study.

Glioblastoma is the most frequent and aggressive brain tumor in adults. This study aims to evaluate the expression and prognostic impact of CD99, a membrane glycoprotein involved in cellular migration and invasion. In a cohort of patients with glioblastoma treated with surgery, radiotherapy and temozolomide, we retrospectively analyzed tumor expression of CD99 by immunohistochemistry (IHC) and by quantitative real-time polymerase chain reaction (qRT-PCR) for both the wild type (CD99wt) and the truncated (CD99sh) isoforms. The impact on overall survival (OS) was assessed with the Kaplan-Meier method and log-rank test and by multivariable Cox regression. Forty-six patients with glioblastoma entered this study. Immunohistochemical expression of CD99 was present in 83%. Only the CD99wt isoform was detected by qRT-PCR and was significantly correlated with CD99 expression evaluated by IHC (rho = 0.309, p = 0.037). CD99 expression was not associated with OS, regardless of the assessment methodology used (p = 0.61 for qRT-PCR and p = 0.73 for IHC). In an exploratory analysis of The Cancer Genome Atlas, casuistry of glioblastomas CD99 expression was not associated with OS nor with progression-free survival. This study confirms a high expression of CD99 in glioblastoma but does not show any significant impact on survival. Further preclinical studies are needed to define its role as a therapeutic target in glioblastoma.

Assessing the efficacy of an innovative diagnostic method for identifying 5 % variants in somatic ctDNA.

BACKGROUND: Liquid biopsy is considered a complementary and recently also an alternative method to surgical biopsy. It allows for the acquisition of valuable information regarding the potential presence of tumors, particularly through the analysis of circulating tumor DNA (ctDNA). CtDNA is a fraction of circulating free DNA (cfDNA) that can be extracted from various tissues, with blood being the most readily available. RESULTS: To maximize the yield of plasma separation, specific Streck tubes are recommended for blood collection. The MagPurix CFC DNA Extraction Kit can be used for cfDNA extraction, and the TWIST Library Preparation protocol can be optimized for further analysis. Next-generation sequencing (NGS) can be employed to compare somatic and germline lineages, enabling the identification of somatic variants with a Variant Allele Frequency (VAF) of 5 % or higher, which are absent in the germline lineage. CONCLUSION: This analysis helps in the assessment of recurrence, analysis, and monitoring of cancer tissue.