Notch signaling regulates metabolic heterogeneity in glioblastoma stem cells.

Glioblastoma (GBM) stem cells (GSCs) reside in both hypoxic and vascular microenvironments within tumors. The molecular mechanisms that allow GSCs to occupy such contrasting niches are not understood. We used patient-derived GBM cultures to identify GSC subtypes with differential activation of Notch signaling, which co-exist in tumors but occupy distinct niches and match their metabolism accordingly. Multipotent GSCs with Notch pathway activation reside in perivascular niches, and are unable to entrain anaerobic glycolysis during hypoxia. In contrast, most CD133-expressing GSCs do not depend on canonical Notch signaling, populate tumors regardless of local vascularity and selectively utilize anaerobic glycolysis to expand in hypoxia. Ectopic activation of Notch signaling in CD133-expressing GSCs is sufficient to suppress anaerobic glycolysis and resistance to hypoxia. These findings demonstrate a novel role for Notch signaling in regulating GSC metabolism and suggest intratumoral GSC heterogeneity ensures metabolic adaptations to support tumor growth in diverse tumor microenvironments

Artificial-intelligence-based molecular classification of diffuse gliomas using rapid, label-free optical imaging

Molecular classification has transformed the management of brain tumors by enabling more accurate prognostication and personalized treatment. However, timely molecular diagnostic testing for patients with brain tumors is limited, complicating surgical and adjuvant treatment and obstructing clinical trial enrollment. In this study, we developed DeepGlioma, a rapid ($< 90$ seconds), artificial-intelligence-based diagnostic screening system to streamline the molecular diagnosis of diffuse gliomas. DeepGlioma is trained using a multimodal dataset that includes stimulated Raman histology (SRH); a rapid, label-free, non-consumptive, optical imaging method; and large-scale, public genomic data. In a prospective, multicenter, international testing cohort of patients with diffuse glioma ($n=153$) who underwent real-time SRH imaging, we demonstrate that DeepGlioma can predict the molecular alterations used by the World Health Organization to define the adult-type diffuse glioma taxonomy (IDH mutation, 1p19q co-deletion and ATRX mutation), achieving a mean molecular classification accuracy of $93.3\pm 1.6\%$. Our results represent how artificial intelligence and optical histology can be used to provide a rapid and scalable adjunct to wet lab methods for the molecular screening of patients with diffuse glioma.Comment: Paper published in Nature Medicin

The Contralateral Transcallosal Approach: Experience With 32 Patients

OBJECTIVE: To demonstrate the usefulness of the contralateral transcallosal approach for resecting lesions located laterally in or adjacent to the lateral ventricle. METHODS: Modifications to the standard ipsilateral transcallosal technique include positioning the head with the midline oriented horizontally, placing the side with the lesion up, and performing the craniotomy and interhemispheric dissection on the contralateral side. This approach avoids a transcortical incision, allows gravity to hold open the interhemispheric fissure, and increases the lateral exposure of the lesion. This approach was used in 32 patients with a variety of lesions, including 6 cavernous malformations, 7 arteriovenous malformations, and 19 tumors of various types. All but three lesions were located on the left side. RESULTS: All six cavernous malformations, all four benign tumors, and four of the seven arteriovenous malformations were resected completely. Malignant tumors were resected subtotally, and three arteriovenous malformations required stereotactic radiosurgery to treat residual deep nidus. There was no surgical mortality. Two patients experienced neurological deterioration. CONCLUSION: The contralateral transcallosal approach can be used to treat a variety of lesions safely and successfully

Treatment of sellar metastases with gamma knife radiosurgery in patients with advanced cancer

Purpose Metastases should be considered in a patient with a cancer history and a sellar/suprasellar lesion, as this diagnosis can change the management strategy in such patients. Once the diagnosis is established, stereotactic radiosurgery (SRS) can be a safe and effective approach for these patients. Methods This case series describes five patients with pituitary metastases managed with GKRS at a single institution, taken from our prospective registry. All patients had SRS using the Gamma Knife Perfexion or Icon (Elekta), according to our standard institutional protocol. The optic nerves and chiasm were contoured, and the plan was adjusted to restrict dose to the optic apparatus as necessary. The tumor margin doses delivered were 11 Gy, 12 Gy, 14 Gy, 18 Gy (3 sessions of 6 Gy), and 12 Gy at the 50% isodose line. Results In this series, all sellar metastases were treated successfully with good radiographic and clinical response. The histology of the tumors included endometrial, gastrointestinal, and lung adenocarcinomas. Typically, histology is taken into consideration when choosing the treatment dose, along with size and location. In these patients, however, the dose used for the sellar metastases was chosen primarily for visual safety. This was typically lower than the dose for brain metastases in other locations. Conclusion SRS provides an alternative treatment approach for sellar/suprasellar metastases with excellent local control, symptom improvement and maintenance of systemic therapy as desired. As such, CNS failure is rarely the proximate cause of demise in pituitary metastases provided that endocrinopathies are recognized and managed appropriately

Simultaneous Treatment of Petroclival Meningiomas and the Trigeminal Nerve with Gamma Knife Radiosurgery for Tumor-Related Trigeminal Neuralgia

Some petroclival meningiomas cause trigeminal nerve compression, leading to disabling trigeminal neuralgia (TN). Tumor resection and nerve decompression can offer pain relief but might not be feasible in all patients. Simultaneous stereotactic radiosurgery (SRS) to the tumor and nerve is another option. SRS is an effective means of treating meningiomas and TN separately, but data on the efficacy and outcomes of their concomitant treatment are limited. We report a series of 4 patients who presented with TN secondary to a petroclival mass causing compression of the trigeminal nerve. All patients underwent SRS to both the petroclival mass and trigeminal nerve in a single session. The average margin tumor dose was 12.25 Gy (range, 12-12.5 Gy), and the average maximum trigeminal nerve dose was 80 Gy (range, 75-85 Gy). In all patients, before intervention, the Barrow Neurologic Institute (BNI) pain intensity score was grade IV or V. At last follow-up (average, 29.8 months), all patients were pain-free (BNI I or IIIA). Two patients experienced reduced facial sensation in 1 or all 3 distributions. No brainstem edema was seen. This series highlights the benefits and safety of simultaneous treatment of petroclival tumors and the trigeminal nerve in a single session for patients affected by tumor-related TN

Delayed Wound Infection Associated with Bone Wax in Lateral Skull Base Surgery

Background: Bone wax (Ethicon, Somerville, NJ) is a commonly used agent in neurotologic and skull base procedures. Its pliable nature makes it well suited for both hemostasis, especially for marrow-related bleeding, and obliteration of bony air cell tracts. The objective of this study was to review the first series to our knowledge of delayed wound infections associated with bone wax in lateral skull base surgery. We review the clinical presentations, imaging findings, microbiology, and outcomes. Design: Retrospective case series. Setting: Two tertiary academic referral hospitals. Participants: Five patients underwent lateral skull base surgery for vestibular schwannoma or meningioma and presented with delayed wound infections. All patients underwent operative wound exploration as a part of their treatment. Results: All patients presented with significantly delayed wound complications, from 4 months to 8 years after their original procedure. Purulence and inflammatory tissue surrounding bone wax was noted in each case, and fistula formation in some. Bacterial species cultured included pseudomonas aeruginosa, Proteus mirabilis, staphylococcus epidermidis, and Acremonium species (a fungus). Three of the four cases underwent some form of wound debridement or removal of hardware that was insufficient to clear the infection until a deeper nidus of bone wax was removed. Conclusion: Although a valuable tool in lateral skull base surgery, bone wax should be used sparingly, and perhaps not to obstruct air cells. Residual accumulation of this material can be associated with foreign body reaction, fistula formation, and significantly delayed wound infections