Treating Trigeminal Schwannoma through a Transorbital Approach: A Systematic Review.

Background: Trigeminal schwannomas (TSs) are uncommon tumors found along any segment of the fifth cranial nerve (CN V). Typically located at the skull base, these benign tumors carry substantial morbidity due to the extent of traditional surgical methods. Minimally invasive endoscopic surgery such as the endoscopic transorbital approach (ETOA) presents promising new avenues for treatment, with the transorbital approach emerging as a potentially successful alternative. Methods: This review systematically assesses the application of the ETOA in treating TSs. PubMed, Ovid MEDLINE, and Embase were thoroughly searched for articles detailing the use of the ETOA in clinical case studies. The outcomes of interest encompassed epidemiological profiling, surgical results, and complication rates. Results: This study included 70 patients with TSs (from six studies), with 22 males (31.4%) and 58 females (68.6%). Patients averaged 55 years and were monitored for around 16.4 months (on average). In most tumors, the middle cranial fossa was involved to some degree. The majority (87.2%) were large (3-6 cm) and underwent gross total resection (GTR) or near-total resection in 87.2% of patients. Preoperatively, sensory alterations were common, along with proptosis, neuropathic pain, and diplopia. Postoperatively, complications included ptosis, diplopia, sensory impairment, corneal keratopathy, masticatory difficulty, and neuralgia. The pure ETOA was the primary surgical technique used in 90% of cases, with no recurrence observed during the follow-up period. Conclusions: Using the ETOA to treat TSs demonstrated an oncologic control rate of 87.2%. Postoperative complications including ptosis, diplopia, and sensory disturbances have been observed, but careful monitoring and management can mitigate these problems. The ETOA emerges as a viable surgical option, especially for tumors involving the middle cranial fossa, capable of adapting to individual patient needs and demonstrating efficacy in TS management.

Nomogram for radiation-induced lymphopenia in patients receiving intensity-modulated radiotherapy based-chemoradiation therapy for newly diagnosed glioblastoma: A multi-institutional study.

Purpose: Severe lymphopenia (SLP) has emerged as a significant prognostic factor in glioblastoma. Intensity-modulated radiation therapy (IMRT)-based radiation therapy (RT) is suggested to minimize the risk of SLP. This study aimed to evaluate SLP incidence based on multi-institutional database in patients with GBM treated with IMRT and develop a predictive nomogram. Patients and methods: This retrospective study reviewed data from 348 patients treated with IMRT-based concurrent chemoradiation therapy (CCRT) at two major hospitals from 2016 to 2021. After multivariate regression analysis, a nomogram was developed and internally validated to predict SLP risk. Results: During treatment course, 21.0% of patients developed SLP and SLP was associated with poor overall survival outcomes in patients with GBM. A newly developed nomogram, incorporating gender, pre-CCRT absolute lymphocyte count, and brain mean dose, demonstrated fair predictive accuracy (AUC 0.723). Conclusions: This study provides the first nomogram for predicting SLP in patients with GBM treated with IMRT-based CCRT, with acceptable predictive accuracy. The findings underscore the need for dose optimization and radiation planning to minimize SLP risk. Further external validation is crucial for adopting this nomogram in clinical practice.

Endoscopic transorbital approach to the petrous apex: is orbital rim removal worthwhile for the exposure? An anatomical study with illustrative case.

OBJECTIVE: The endoscopic transorbital approach (ETOA) has been demonstrated to be a feasible ventral route to the petrous apex. Yet, it has been pointed to as a deep and narrow corridor for anterior petrosectomy; particularly, medialization of the instruments can become an issue when targeting the petroclival area. To overcome this limitation, an ETOA with orbital rim removal (ETOA-OR) has been suggested, but not de facto compared, with a transorbital approach without removal of the rim. This addition could augment the surgical exposure and freedom of movement when accessing the petrous apex area. METHODS: Five human cadaveric heads (10 sides) were dissected. First, anterior petrosectomy was performed via a conventional ETOA (without orbital rim removal). Second, en bloc removal of the orbital rim was performed, with enlargement of the orbital craniectomy and, subsequently, further drilling of the medial petrous apex. Qualitative and quantitative comparisons are provided. An illustrative surgical case is also shown. RESULTS: The transorbital route allowed the authors to perform an anterior petrosectomy in all specimens. The landmarks of bone removal are superposed onto those in the transcranial route. The ETOA-OR increased the volume of craniectomy (from 4.0 mL to 5.5 mL), the lateromedial angulation, and superoinferior angulation of the instruments within the petrous area. Thus, this approach improved the exposure of the medial petroclival area, allowing for an augmented petrosectomy (from 1.4 mL to 2.0 mL, 39.5% increase) and for increased maneuverability, both in the petrous area (from 44.1 cm2 to 76.5 cm2, 73.3% increase) and in the posterior fossa (from 20.2 cm2 to 52.0 cm2, 158% increase). The ETOA-OR was also pragmatically applied to treat a recurrent petroclival meningioma. Complete removal was achieved, the abducens nerve palsy improved, and the trigeminal neuralgia decreased in severity, yet still required medication. CONCLUSIONS: The authors provide the first formal anatomical comparison between the transorbital approach with preservation of the orbital rim and a transorbital approach with removal of the rim to access the petrous apex. In addition, an illustrative case is used as a proof of concept and feasibility. According to the authors' data, the ETOA-OR significantly improves surgical exposure and the surgeon's comfort in this deep region. The bony defect can be reconstructed to avoid cosmetic deformities, maintaining the minimally disruptive concept of transorbital surgery.

Lateral Rectus Muscle Entrapment in Complex Orbital Fracture in a Child.

A 6-year-old boy presented with a lateral rectus muscle entrapment in a complex orbital fracture sustained during bicycle riding. He was diagnosed with a skull-base fracture with pneumocephalus and zygomatic and inferior orbital wall fractures at another hospital. The zygomatic fracture and pneumocephalus were treated conservatively. Although a detailed ocular motility examination could not be performed due to pain and inability to open the eyelid, the inferior wall fracture was surgically repaired. Postoperatively, persistent extraocular movement limitation prompted a referral to our clinic. Orbital CT imaging demonstrated a fracture at the greater wing of the sphenoid with a hypoattenuated area in the adjacent middle cranial fossa. Orbital MRI taken thereafter revealed lateral rectus and orbital fat prolapse into the middle cranial fossa, indicating entrapment of these structures through the lateral wall fracture. The incarcerated lateral rectus was released using an endoscopic transorbital approach via an upper lid crease, resulting in the recovery of extraocular movement.

The Transorbital Approach: A Comprehensive Review of Targets, Surgical Techniques, and Multiportal Variants.

The transorbital approach (TOA) is gaining popularity in skull base surgery scenarios. This approach represents a valuable surgical corridor to access various compartments and safely address several intracranial pathologies, both intradurally and extradurally, including tumors of the olfactory groove in the anterior cranial fossa (ACF), cavernous sinus in the middle cranial fossa (MCF), and the cerebellopontine angle in the posterior cranial fossa (PCF). The TOA exists in many variants, both from the point of view of invasiveness and from that of the entry point to the orbit, corresponding to the four orbital quadrants: the superior eyelid crease (SLC), the precaruncular (PC), the lateral retrocanthal (LRC), and the preseptal lower eyelid (PS). Moreover, multiportal variants, consisting of the combination of the transorbital approach with others, exist and are relevant to reach peculiar surgical territories. The significance of the TOA in neurosurgery, coupled with the dearth of thorough studies assessing its various applications and adaptations, underscores the necessity for this research. This extensive review delineates the multitude of target lesions reachable through the transorbital route, categorizing them based on surgical complexity. Furthermore, it provides an overview of the different transorbital variations, both standalone and in conjunction with other techniques. By offering a comprehensive understanding, this study aims to enhance awareness and knowledge regarding the current utility of the transorbital approach in neurosurgery. Additionally, it aims to steer future investigations toward deeper exploration, refinement, and exploration of additional perspectives concerning this surgical method.

Endoscopic transorbital approach in children: surgical technique and early results.

OBJECTIVE: In this study, the authors aimed to describe the endoscopic transorbital approach (ETOA) in children. METHODS: Six pediatric patients (2 girls and 4 boys) underwent the ETOA for paramedian skull base lesions at a single institution between September 2016 and February 2023. RESULTS: The median age at the time of surgery was 7.5 (range 4-18) years. The median follow-up period was 33 (range 9-60) months. In this series, the ETOA level of difficulty included stage 1 (n = 2, 33.3%), stage 3 (n = 3, 50%), and stage 5 (n = 1, 16.7%). The ETOA was performed for tumor resection in 4 cases; the final pathology consisted of fibrous dysplasia, pilocytic astrocytoma, metastatic neuroblastoma, and choroid plexus papilloma. The procedure was also performed for repair of a petrous apex meningocele and for lateral orbital wall decompression of traumatic lateral rectus muscle entrapment. One patient experienced a transient cranial nerve III palsy after the procedure. There were no operative deaths in this series. CONCLUSIONS: In select cases, the ETOA can be considered a minimally invasive alternative for conventional skull base approaches in the armamentarium of pediatric skull base surgery. Further investigation and the accumulation of experience are warranted in the future to enhance the efficacy and applicability of the ETOA in pediatric patients.

Longitudinal changes in optic disc cupping from the baseline in chiasmal lesion optic neuropathy and glaucoma.

We aimed to investigate the changes in cupping in chiasmal lesion optic neuropathy (chON) compared to baseline optic disc and glaucoma. We used a novel study design to enroll patients who had fundus photographs incidentally taken during routine health check-ups prior to the onset of optic neuropathy. In 31 eyes (21 patients) with chON and 33 eyes (30 patients) with glaucoma, we investigated the change in cup-to-disc (C/D) area from the baseline to overt cupping using flicker analysis. Compared to the baseline, 23 eyes (74.2%) had increased cup size and 3 (9.7%) had vascular configuration changes in the chONgroup; in contrast, all glaucoma eyes exhibited changes in cup size and vascular configuration. The increase in C/D area ratio was significantly smaller in chON (0.04 ± 0.04) compared to glaucoma (0.10 ± 0.04, P < 0.001); the minimum residual neuroretinal rim width showed a more pronounced difference (29.7 ± 8.2% vs 7.1 ± 3.9%, P < 0.001). The changes distributed predominantly towards the nasal direction in chON, contrasting the changes to the arcuate fibers in glaucoma. In conclusion, our results provide the first longitudinal evidence of true pathological cupping in chONcompared to photographically disease-free baseline. The marked difference in the residual minimum rim width reaffirms the importance of rim obliteration in the differential diagnosis between the two diseases.

A prospective multicenter assessor blinded pilot study using confocal laser endomicroscopy for intraoperative brain tumor diagnosis.

In this multi-center, assessor-blinded pilot study, the diagnostic efficacy of cCeLL-Ex vivo, a second-generation confocal laser endomicroscopy (CLE), was compared against the gold standard frozen section analysis for intraoperative brain tumor diagnosis. The study was conducted across three tertiary medical institutions in the Republic of Korea. Biopsy samples from newly diagnosed brain tumor patients were categorized based on location and divided for permanent section analysis, frozen section analysis, and cCeLL-Ex vivo imaging. Of the 74 samples from 55 patients, the majority were from the tumor core (74.3%). cCeLL-Ex vivo exhibited a relatively higher diagnostic accuracy (89.2%) than frozen section analysis (86.5%), with both methods showing a sensitivity of 92.2%. cCeLL-Ex vivo also demonstrated higher specificity (70% vs. 50%), positive predictive value (PPV) (95.2% vs. 92.2%), and negative predictive value (NPV) (58.3% vs. 50%). Furthermore, the time from sample preparation to diagnosis was notably shorter with cCeLL-Ex vivo (13 min 17 s) compared to frozen section analysis (28 min 28 s) (p-value < 0.005). These findings underscore cCeLL-Ex vivo's potential as a supplementary tool for intraoperative brain tumor diagnosis, with future studies anticipated to further validate its clinical utility.

Clinical Characteristics, Diagnosis, and Treatment of Thyroid Stimulating Hormone-Secreting Pituitary Neuroendocrine Tumor (TSH PitNET): A Single-Center Experience.

BACKGRUOUND: Thyroid-stimulating hormone (TSH)-secreting pituitary neuroendocrine tumor (TSH PitNET) is a rare subtype of PitNET. We investigated the comprehensive characteristics and outcomes of TSH PitNET cases from a single medical center. Also, we compared diagnostic methods to determine which showed superior sensitivity. METHODS: A total of 17 patients diagnosed with TSH PitNET after surgery between 2002 and 2022 in Samsung Medical Center was retrospectively reviewed. Data on comprehensive characteristics and treatment outcomes were collected. The sensitivities of diagnostic methods were compared. RESULTS: Seven were male (41%), and the median age at diagnosis was 42 years (range, 21 to 65); the median follow-up duration was 37.4 months. The most common (59%) initial presentation was hyperthyroidism-related symptoms. Hormonal co-secretion was present in four (23%) patients. Elevated serum alpha-subunit (α-SU) showed the greatest diagnostic sensitivity (91%), followed by blunted response at thyrotropin-releasing hormone (TRH) stimulation (80%) and elevated sex hormone binding globulin (63%). Fourteen (82%) patients had macroadenoma, and a specimen of one patient with heavy calcification was negative for TSH. Among 15 patients who were followed up for more than 6 months, 10 (67%) achieved hormonal and structural remission within 6 months postoperatively. A case of growth hormone (GH)/TSH/prolactin (PRL) co-secreting mixed gangliocytoma-pituitary adenoma (MGPA) was discovered. CONCLUSION: The majority of the TSH PitNET cases was macroadenoma, and 23% showed hormone co-secretion. A rare case of GH/TSH/PRL co-secreting MGPA was discovered. Serum α-SU and TRH stimulation tests showed great diagnostic sensitivity. Careful consideration is needed in diagnosing TSH PitNET. Achieving remission requires complete tumor resection. In case of nonremission, radiotherapy or medical therapy can improve the long-term remission rate.

Endoscopic Transorbital Surgery for Trigeminal Schwannoma: Introduction of a Novel Approach: 2-Dimensional Operative Video.

INDICATIONS CORRIDOR AND LIMITS OF EXPOSURE: The major indications of endoscopic transorbital approach include spheno-orbital meningiomas, cavernous sinus lesions, and Meckel cave lesion such as trigeminal schwannomas. It can avoid excessive brain retraction and allows for a fast recovery to the normal daily living activity. ANATOMIC ESSENTIALS NEED FOR PREOPERATIVE PLANNING AND ASSESSMENT: To access the cavernous sinus, the sagittal crest and meningo-orbital band should be identified and cut. ESSENTIAL STEPS OF THE PROCEDURE: 1. Skin incision along the superior eyelid is performed. 2. Careful dissection of the soft tissue under the orbicularis is required not to injure the orbital septum. 3. After the lateral orbital rim is exposed, the periosteum and periorbita are elevated from the lateral orbital wall. 4. Drilling of the zygomatic bone within the orbit exposes the temporalis muscle first followed by the exposure of the temporal dura. It is essential to obtain adequate working room when the base of the greater sphenoidal wing is drilled. The sagittal crest should be removed, and the meningo-orbital band should be cut to expose the lateral cavernous sinus wall. PITFALLS/AVOIDANCE OF COMPLICATIONS: For successful access through the orbit, endoscopic transorbital approach needs to minimize the retraction of the orbit. To achieve this goal, retraction of the orbit should be limited to a maximum of 10 minutes. VARIANTS AND INDICATIONS OF THEIR USE: This approach can be combined with lateral orbitotomy. It provides a wider working room and makes surgery easier to access the lateral temporal lobe.The patient consented to the procedure, and the participants and any identifiable individuals consented to publication of his/her image. Images at 1:29 reproduced from Corrivetti F, de Notaris M, Di Somma A, et al, "Sagittal crest": definition, stepwise dissection, and clinical implications from a transorbital perspective, Operative Neurosurgery , 22(5), p e206-e212, ©2022, by permission from the Congress of Neurological Surgeons. Video screen capture from The Neurosurgical Atlas at 1:06 used with permission from Aaron Cohen-Gadol; ©The Neurosurgical Atlas, all rights reserved.

Feasibility and efficacy of endoscopic transorbital optic canal decompression for meningiomas causing compressive optic neuropathy.

OBJECTIVE: The endoscopic transorbital approach (ETOA) and transorbital anterior clinoidectomy have been suggested as novel procedures through which to reach the superolateral compartments of the orbit, allowing optic canal decompression. However, there is limited literature describing the technical details and surgical outcomes of these procedures. In this study, the authors aimed to analyze the feasibility and efficacy of endoscopic transorbital decompression of the optic canal through anterior clinoidectomy for compressive optic neuropathic lesions. METHODS: Between 2016 and 2022, the authors performed ETOA for compressive optic neuropathic lesions in 14 patients. All these patients underwent transorbital anterior clinoidectomy through the surgically defined "intraorbital clinoidal triangle," which is composed of the roof of the superior orbital fissure, the medial margin of the optic canal, the medial border of the superior orbital fissure, and the optic strut. Demographic data, tumor characteristics, pre- and postoperative imaging, pre- and postoperative visual examinations, and surgical outcomes were retrospectively reviewed. RESULTS: The mean age at the time of ETOA was 53.3 years (range 41-64 years), and the mean follow-up was 16.8 months (range 6.7-51.4 months). The inclusion criterion in this study was having a meningioma (14 patients). In the preoperative visual function examination, 7 patients with a meningioma showed progressive visual impairment. After endoscopic transorbital optic canal decompression, visual function improved in 5 patients, remained unchanged in 8 patients, and worsened in 1 patient. No new-onset neurological deficit was associated with ETOA and anterior clinoidectomy in any patients. CONCLUSIONS: Endoscopic transorbital decompression of the optic canal with extradural anterior clinoidectomy is a safe and feasible technique that avoids significant injury to the clinoidal internal carotid artery and surrounding neurovascular structures.

The Transorbital Approach, A Game-Changer in Neurosurgery: A Guide to Safe and Reliable Surgery Based on Anatomical Principles.

During the last few years, the superior eyelid endoscopic transorbital approach has been proposed as a new minimally invasive pathway to access skull base lesions, mostly in ophthalmologic, otolaryngologic, and maxillofacial surgeries. However, most neurosurgeons performing minimally invasive endoscopic neurosurgery do not usually employ the orbit as a surgical corridor. The authors undertook this technical and anatomical study to contribute a neurosurgical perspective, exploring the different possibilities of this novel route. Ten dissections were performed on ten formalin-fixed specimens to further refine the transorbital technique. As part of the study, the authors also report an illustrative transorbital surgery case to further detail key surgical landmarks. Herein, we would like to discuss equipment, key anatomical landmarks, and surgical skills and stress the steps and details to ensure a safe and successful procedure. We believe it could be critical to promote and encourage the neurosurgical community to overcome difficulties and ensure a successful surgery by following these key recommendations.

Outcomes after Microvascular Decompression for Hemifacial Spasm without Definite Radiological Neurovascular Compression at the Root Exit Zone.

The purpose of this study was to investigate the outcome of microvascular decompression (MVD) in patients with hemifacial spasm (HFS) who have no definite radiological neurovascular compression (NVC). Sixteen HFS patients without radiological NVC on preoperative MRI underwent MVD surgery. The symptoms were left-sided in fourteen (87.5%) and right-sided in two patients (12.5%). Intraoperatively, the most common vessel compressing the facial nerve was the AICA (8, 44.4%), followed by arterioles (5, 27.8%), veins (4, 22.2%), and the PICA (1, 5.6%). The most common compression site was the cisternal portion (13, 76.5%) of the facial nerve, followed by the REZ (4, 23.5%). One patient (6.3%) was found to have multiple NVC sites. Arachnoid type (7, 50%) was the most common compressive pattern, followed by perforator type (4, 28.6%), sandwich type (2, 14.3%), and loop type (1, 7.1%). A pure venous compression was seen in two patients, while a combined venous-arterial "sandwich" compression was detected in two patients. Symptom improvement was observed in all of the patients. Only one patient experienced recurrence after improvement. Based on our experience, MVD surgery can be effective for primary HFS patients with no definite radiological NVC. MVD can be considered if the patient shows typical HFS features, although NVC is not evident on MRI.

Impact of boost sequence in concurrent chemo-radiotherapy on newly diagnosed IDH-wildtype glioblastoma multiforme.

BACKGROUND: The standard of care for glioblastoma multiforme (GBM) is maximal surgical resection followed by conventional fractionated concurrent chemoradiotherapy (CCRT) with a total dose of 60 Gy. However, there is currently no consensus on the optimal boost technique for CCRT in GBM. METHODS: We conducted a retrospective review of 398 patients treated with CCRT between 2016 and 2021, using data from two institutional databases. Patients were divided into two groups: those receiving sequential boost (SEB, N = 119) and those receiving simultaneous integrated boost (SIB, N = 279). The primary endpoint was overall survival (OS). To minimize differences between the SIB and SEB groups, we conducted propensity score matching (PSM) analysis. RESULTS: The median follow-up period was 18.6 months. Before PSM, SEB showed better OS compared to SIB (2-year, 55.6% vs. 44.5%, p = 0.014). However, after PSM, there was no significant difference between two groups (2-year, 55.6% vs. 51.5%, p = 0.300). The boost sequence was not associated with inferior OS before and after PSM (all p-values > 0.05). Additionally, the rates of symptomatic pseudo-progression were similar between the two groups (odds ratio: 1.75, p = 0.055). CONCLUSIONS: This study found no significant difference in OS between SEB and SIB for GBM patients treated with CCRT. Further research is needed to validate these findings and to determine the optimal boost techniques for this patient population.

Peripapillary Vascular Density in Compressive Optic Neuropathy and Normal-Tension Glaucoma: A Severity-Controlled Comparison.

Purpose: To investigate the differences in peripapillary vessel density (VD) between compressive optic neuropathy (CON) and normal-tension glaucoma (NTG). Methods: We compared patients with chronic CON and NTG, particularly after strictly controlling the mean extent of macular damage by the area of the ganglion cell-inner plexiform layer (GCIPL) loss in optical coherence tomography (OCT). We compared retinal nerve fiber layer (RNFL) and GCIPL thickness from OCT and peripapillary and macular VD from OCT angiography (OCTA) between the CON and NTG groups. Results: From the initial 184 patients with CON and 443 patients with OAG, we included 41 patients with CON (57 eyes) and 64 patients with NTG (75 eyes) with a comparable extent of macular GCIPL thinning. Under similar mean macular involvement, the peripapillary VD was significantly lower in the CON group than in the NTG group after considering the effects of age, spherical equivalent, visual field sensitivity, peripapillary RNFL (pRNFL) thickness, GCIPL thickness, and image quality scores (P < 0.001). Marked loss of VD in the temporal and nasal sectors in CON was notable, attributing to the significantly lower peripapillary VD compared to NTG. Conclusions: Patients with CON had a significantly lower peripapillary VD than those with NTG under similar mean degrees of pRNFL thickness and GCIPL damage. Our results reveal the potential utility of OCTA VD besides OCT pRNFL thickness, in relation to different topographic patterns of pRNFL loss, and possible differences in the pathogenesis of microvascular compromise between CON and NTG.

Time taken to resume activities of daily living after transsphenoidal surgery for pituitary tumors.

Postoperative management after transsphenoidal surgery (TSS) is important; however, the guidelines for resuming daily activities after TSS are insufficient. This study aimed to examine the time to return to activities of daily living (ADL) after TSS for pituitary tumors. A 4-month prospective data collection was completed for 114 of 117 patients who underwent TSS for pituitary tumors from April to July 2021. The time when the patient returned to ADL after surgery was measured using the self-recording sheet. More than 97% and 92% of the patients returned within 1 month (median: within 7 days) for the elements of basic ADL and within 2 months (median: within 15 days) for the elements of instrumental ADL, excluding a few. Notably, 73.3% of patients returned to work within 4 months. The median time for the activities included 64 days for washing hair head down, 44 days for blowing nose, 59 days for lifting heavy objects, and 102 days for sexual activity. For patients who received extended-TSS or had postoperative problems, the time to return was delayed. Based on these results, it will be possible to provide practical information and guidelines on the time to return to ADL after TSS in pituitary tumor patients.

Pharmacogenomic profiling reveals molecular features of chemotherapy resistance in IDH wild-type primary glioblastoma.

BACKGROUND: Although temozolomide (TMZ) has been used as a standard adjuvant chemotherapeutic agent for primary glioblastoma (GBM), treating isocitrate dehydrogenase wild-type (IDH-wt) cases remains challenging due to intrinsic and acquired drug resistance. Therefore, elucidation of the molecular mechanisms of TMZ resistance is critical for its precision application. METHODS: We stratified 69 primary IDH-wt GBM patients into TMZ-resistant (n = 29) and sensitive (n = 40) groups, using TMZ screening of the corresponding patient-derived glioma stem-like cells (GSCs). Genomic and transcriptomic features were then examined to identify TMZ-associated molecular alterations. Subsequently, we developed a machine learning (ML) model to predict TMZ response from combined signatures. Moreover, TMZ response in multisector samples (52 tumor sectors from 18 cases) was evaluated to validate findings and investigate the impact of intra-tumoral heterogeneity on TMZ efficacy. RESULTS: In vitro TMZ sensitivity of patient-derived GSCs classified patients into groups with different survival outcomes (P = 1.12e-4 for progression-free survival (PFS) and 3.63e-4 for overall survival (OS)). Moreover, we found that elevated gene expression of EGR4, PAPPA, LRRC3, and ANXA3 was associated to intrinsic TMZ resistance. In addition, other features such as 5-aminolevulinic acid negative, mesenchymal/proneural expression subtypes, and hypermutation phenomena were prone to promote TMZ resistance. In contrast, concurrent copy-number-alteration in PTEN, EGFR, and CDKN2A/B was more frequent in TMZ-sensitive samples (Fisher's exact P = 0.0102), subsequently consolidated by multi-sector sequencing analyses. Integrating all features, we trained a ML tool to segregate TMZ-resistant and sensitive groups. Notably, our method segregated IDH-wt GBM patients from The Cancer Genome Atlas (TCGA) into two groups with divergent survival outcomes (P = 4.58e-4 for PFS and 3.66e-4 for OS). Furthermore, we showed a highly heterogeneous TMZ-response pattern within each GBM patient using in vitro TMZ screening and genomic characterization of multisector GSCs. Lastly, the prediction model that evaluates the TMZ efficacy for primary IDH-wt GBMs was developed into a webserver for public usage ( http://www.wang-lab-hkust.com:3838/TMZEP ). CONCLUSIONS: We identified molecular characteristics associated to TMZ sensitivity, and illustrate the potential clinical value of a ML model trained from pharmacogenomic profiling of patient-derived GSC against IDH-wt GBMs.