Biologically informed deep neural networks provide quantitative assessment of intratumoral heterogeneity in post treatment glioblastoma.

Intratumoral heterogeneity poses a significant challenge to the diagnosis and treatment of recurrent glioblastoma. This study addresses the need for non-invasive approaches to map heterogeneous landscape of histopathological alterations throughout the entire lesion for each patient. We developed BioNet, a biologically-informed neural network, to predict regional distributions of two primary tissue-specific gene modules: proliferating tumor (Pro) and reactive/inflammatory cells (Inf). BioNet significantly outperforms existing methods (p < 2e-26). In cross-validation, BioNet achieved AUCs of 0.80 (Pro) and 0.81 (Inf), with accuracies of 80% and 75%, respectively. In blind tests, BioNet achieved AUCs of 0.80 (Pro) and 0.76 (Inf), with accuracies of 81% and 74%. Competing methods had AUCs lower or around 0.6 and accuracies lower or around 70%. BioNet's voxel-level prediction maps reveal intratumoral heterogeneity, potentially improving biopsy targeting and treatment evaluation. This non-invasive approach facilitates regular monitoring and timely therapeutic adjustments, highlighting the role of ML in precision medicine.

Biologically-informed deep neural networks provide quantitative assessment of intratumoral heterogeneity in post-treatment glioblastoma.

Intratumoral heterogeneity poses a significant challenge to the diagnosis and treatment of glioblastoma (GBM). This heterogeneity is further exacerbated during GBM recurrence, as treatment-induced reactive changes produce additional intratumoral heterogeneity that is ambiguous to differentiate on clinical imaging. There is an urgent need to develop non-invasive approaches to map the heterogeneous landscape of histopathological alterations throughout the entire lesion for each patient. We propose to predictively fuse Magnetic Resonance Imaging (MRI) with the underlying intratumoral heterogeneity in recurrent GBM using machine learning (ML) by leveraging image-localized biopsies with their associated locoregional MRI features. To this end, we develop BioNet, a biologically-informed neural network model, to predict regional distributions of three tissue-specific gene modules: proliferating tumor, reactive/inflammatory cells, and infiltrated brain tissue. BioNet offers valuable insights into the integration of multiple implicit and qualitative biological domain knowledge, which are challenging to describe in mathematical formulations. BioNet performs significantly better than a range of existing methods on cross-validation and blind test datasets. Voxel-level prediction maps of the gene modules by BioNet help reveal intratumoral heterogeneity, which can improve surgical targeting of confirmatory biopsies and evaluation of neuro-oncological treatment effectiveness. The non-invasive nature of the approach can potentially facilitate regular monitoring of the gene modules over time, and making timely therapeutic adjustment. These results also highlight the emerging role of ML in precision medicine.

Development and implementation of an Enhanced Recovery After Cranial Surgery pathway following supratentorial tumor resection at a tertiary care center.

OBJECTIVE: Controlling length of stay (LOS) reduces rates of nosocomial infections and falls, facilitates earlier return to daily activities, and decreases strain on the healthcare system. Complications following supratentorial tumor resection present early in the postoperative period, thereby enhancing the prospect of safe, early discharge. Here, the authors describe their initial experience with the development and implementation of an Enhanced Recovery After Cranial Surgery (ERACS) pathway following resection of supratentorial tumors in select patients. METHODS: This was a nonrandomized, ambispective quality improvement study of patients undergoing elective craniotomy for supratentorial tumor resection at New York University Langone Health between November 17, 2020, and May 19, 2022. Eligible patients were prospectively enrolled in either the ERACS pathway or the standard pathway. These prospective cohorts were compared to a retrospective cohort of patients who met eligibility criteria for the pathway. Patients in the ERACS pathway cohort were targeted for discharge on postoperative day 2. The primary outcome metric was hospital LOS. Secondary outcome metrics included duration of intensive care unit (ICU) care and rates of 30-day emergency department visits, readmissions, and complications. RESULTS: Over the study period, 188 of 317 patients (59.3%) who underwent supratentorial tumor resection met inclusion criteria for ERACS pathway enrollment. Sixty-three patients were enrolled in the ERACS pathway, and 125 patients completed the standard pathway. The historical cohort consisted of 332 patients who would have been eligible for ERACS enrollment. Patients in the ERACS pathway cohort had a median LOS of 1.93 days compared with 2.92 and 2.88 days for patients in the standard pathway and historical cohort, respectively (p < 0.001). There was a significant reduction in ICU utilization in ERACS pathway patients (16.0 ± 6.53 vs 29.5 ± 53.0 vs 21.8 ± 18.2 hours, p = 0.005). There were no differences in the rates of 30-day emergency department visits (12.7% vs 9.6% vs 10.9%, p = 0.809) and readmissions (4.8% vs 4.0% vs 7.8%, p = 0.279) between groups. CONCLUSIONS: Patients in the ERACS pathway cohort experienced reduced LOS and ICU utilization, with similar rates of adverse outcomes compared to standard pathway patients. The authors' initial experience suggests that an accelerated recovery pathway can be safely implemented following supratentorial tumor resection in select patients.

Re-convolving the compositional landscape of primary and recurrent glioblastoma reveals prognostic and targetable tissue states.

Glioblastoma (GBM) diffusely infiltrates the brain and intermingles with non-neoplastic brain cells, including astrocytes, neurons and microglia/myeloid cells. This complex mixture of cell types forms the biological context for therapeutic response and tumor recurrence. We used single-nucleus RNA sequencing and spatial transcriptomics to determine the cellular composition and transcriptional states in primary and recurrent glioma and identified three compositional 'tissue-states' defined by cohabitation patterns between specific subpopulations of neoplastic and non-neoplastic brain cells. These tissue-states correlated with radiographic, histopathologic, and prognostic features and were enriched in distinct metabolic pathways. Fatty acid biosynthesis was enriched in the tissue-state defined by the cohabitation of astrocyte-like/mesenchymal glioma cells, reactive astrocytes, and macrophages, and was associated with recurrent GBM and shorter survival. Treating acute slices of GBM with a fatty acid synthesis inhibitor depleted the transcriptional signature of this pernicious tissue-state. These findings point to therapies that target interdependencies in the GBM microenvironment.

Chronic convection-enhanced delivery of topotecan for patients with recurrent glioblastoma: a first-in-patient, single-centre, single-arm, phase 1b trial.

BACKGROUND: Topotecan is cytotoxic to glioma cells but is clinically ineffective because of drug delivery limitations. Systemic delivery is limited by toxicity and insufficient brain penetrance, and, to date, convection-enhanced delivery (CED) has been restricted to a single treatment of restricted duration. To address this problem, we engineered a subcutaneously implanted catheter-pump system capable of repeated, chronic (prolonged, pulsatile) CED of topotecan into the brain and tested its safety and biological effects in patients with recurrent glioblastoma. METHODS: We did a single-centre, open-label, single-arm, phase 1b clinical trial at Columbia University Irving Medical Center (New York, NY, USA). Eligible patients were at least 18 years of age with solitary, histologically confirmed recurrent glioblastoma showing radiographic progression after surgery, radiotherapy, and chemotherapy, and a Karnofsky Performance Status of at least 70. Five patients had catheters stereotactically implanted into the glioma-infiltrated peritumoural brain and connected to subcutaneously implanted pumps that infused 146 µM topotecan 200 µL/h for 48 h, followed by a 5-7-day washout period before the next infusion, with four total infusions. After the fourth infusion, the pump was removed and the tumour was resected. The primary endpoint of the study was safety of the treatment regimen as defined by presence of serious adverse events. Analyses were done in all treated patients. The trial is closed, and is registered with ClinicalTrials.gov, NCT03154996. FINDINGS: Between Jan 22, 2018, and July 8, 2019, chronic CED of topotecan was successfully completed safely in all five patients, and was well tolerated without substantial complications. The only grade 3 adverse event related to treatment was intraoperative supplemental motor area syndrome (one [20%] of five patients in the treatment group), and there were no grade 4 adverse events. Other serious adverse events were related to surgical resection and not the study treatment. Median follow-up was 12 months (IQR 10-17) from pump explant. Post-treatment tissue analysis showed that topotecan significantly reduced proliferating tumour cells in all five patients. INTERPRETATION: In this small patient cohort, we showed that chronic CED of topotecan is a potentially safe and active therapy for recurrent glioblastoma. Our analysis provided a unique tissue-based assessment of treatment response without the need for large patient numbers. This novel delivery of topotecan overcomes limitations in delivery and treatment response assessment for patients with glioblastoma and could be applicable for other anti-glioma drugs or other CNS diseases. Further studies are warranted to determine the effect of this drug delivery approach on clinical outcomes. FUNDING: US National Institutes of Health, The William Rhodes and Louise Tilzer Rhodes Center for Glioblastoma, the Michael Weiner Glioblastoma Research Into Treatment Fund, the Gary and Yael Fegel Foundation, and The Khatib Foundation.

Rapid, label-free detection of diffuse glioma recurrence using intraoperative stimulated Raman histology and deep neural networks.

BACKGROUND: Detection of glioma recurrence remains a challenge in modern neuro-oncology. Noninvasive radiographic imaging is unable to definitively differentiate true recurrence versus pseudoprogression. Even in biopsied tissue, it can be challenging to differentiate recurrent tumor and treatment effect. We hypothesized that intraoperative stimulated Raman histology (SRH) and deep neural networks can be used to improve the intraoperative detection of glioma recurrence. METHODS: We used fiber laser-based SRH, a label-free, nonconsumptive, high-resolution microscopy method (<60 sec per 1 × 1 mm2) to image a cohort of patients (n = 35) with suspected recurrent gliomas who underwent biopsy or resection. The SRH images were then used to train a convolutional neural network (CNN) and develop an inference algorithm to detect viable recurrent glioma. Following network training, the performance of the CNN was tested for diagnostic accuracy in a retrospective cohort (n = 48). RESULTS: Using patch-level CNN predictions, the inference algorithm returns a single Bernoulli distribution for the probability of tumor recurrence for each surgical specimen or patient. The external SRH validation dataset consisted of 48 patients (recurrent, 30; pseudoprogression, 18), and we achieved a diagnostic accuracy of 95.8%. CONCLUSION: SRH with CNN-based diagnosis can be used to improve the intraoperative detection of glioma recurrence in near-real time. Our results provide insight into how optical imaging and computer vision can be combined to augment conventional diagnostic methods and improve the quality of specimen sampling at glioma recurrence.

Near real-time intraoperative brain tumor diagnosis using stimulated Raman histology and deep neural networks.

Intraoperative diagnosis is essential for providing safe and effective care during cancer surgery1. The existing workflow for intraoperative diagnosis based on hematoxylin and eosin staining of processed tissue is time, resource and labor intensive2,3. Moreover, interpretation of intraoperative histologic images is dependent on a contracting, unevenly distributed, pathology workforce4. In the present study, we report a parallel workflow that combines stimulated Raman histology (SRH)5-7, a label-free optical imaging method and deep convolutional neural networks (CNNs) to predict diagnosis at the bedside in near real-time in an automated fashion. Specifically, our CNNs, trained on over 2.5 million SRH images, predict brain tumor diagnosis in the operating room in under 150 s, an order of magnitude faster than conventional techniques (for example, 20-30 min)2. In a multicenter, prospective clinical trial (n = 278), we demonstrated that CNN-based diagnosis of SRH images was noninferior to pathologist-based interpretation of conventional histologic images (overall accuracy, 94.6% versus 93.9%). Our CNNs learned a hierarchy of recognizable histologic feature representations to classify the major histopathologic classes of brain tumors. In addition, we implemented a semantic segmentation method to identify tumor-infiltrated diagnostic regions within SRH images. These results demonstrate how intraoperative cancer diagnosis can be streamlined, creating a complementary pathway for tissue diagnosis that is independent of a traditional pathology laboratory.

Magnetic Resonance Imaging-Guided Laser Interstitial Thermal Therapy for Epilepsy: Systematic Review of Technique, Indications, and Outcomes.

BACKGROUND: For patients with focal drug-resistant epilepsy (DRE), surgical resection of the epileptogenic zone (EZ) may offer seizure freedom and benefits for quality of life. Yet, concerns remain regarding invasiveness, morbidity, and neurocognitive side effects. Magnetic resonance-guided laser interstitial thermal therapy (MRgLITT) has emerged as a less invasive option for stereotactic ablation rather than resection of the EZ. OBJECTIVE: To provide an introduction to MRgLITT for epilepsy, including historical development, surgical technique, and role in therapy. METHODS: The development of MRgLITT is briefly recounted. A systematic review identified reported techniques and indication-specific outcomes of MRgLITT for DRE in human studies regardless of sample size or follow-up duration. Potential advantages and disadvantages compared to available alternatives for each indication are assessed in an unstructured review. RESULTS: Techniques and outcomes are reported for mesial temporal lobe epilepsy, hypothalamic hamartoma, focal cortical dysplasia, nonlesional epilepsy, tuberous sclerosis, periventricular nodular heterotopia, cerebral cavernous malformations, poststroke epilepsy, temporal encephalocele, and corpus callosotomy. CONCLUSION: MRgLITT offers access to foci virtually anywhere in the brain with minimal disruption of the overlying cortex and white matter, promising fewer neurological side effects and less surgical morbidity and pain. Compared to other ablative techniques, MRgLITT offers immediate, discrete lesions with real-time monitoring of temperature beyond the fiber tip for damage estimates and off-target injury prevention. Applications of MRgLITT for epilepsy are growing rapidly and, although more evidence of safety and efficacy is needed, there are potential advantages for some patients.

Frameless Stereotactic Radiosurgery on the Gamma Knife Icon: Early Experience From 100 Patients.

BACKGROUND: The Gamma Knife (GK) Icon (Elekta AB) uses a cone-beam computed tomography (CBCT) scanner and an infrared camera system to support the delivery of frameless stereotactic radiosurgery (SRS). There are limited data on patients treated with frameless GK radiosurgery (GKRS). OBJECTIVE: To describe the early experience, process, technical details, and short-term outcomes with frameless GKRS at our institution. METHODS: We reviewed our patient selection and described the workflow in detail, including image acquisition, treatment planning, mask-based immobilization, stereotactic CBCT localization, registration, treatment, and intrafraction monitoring. Because of the short interval of follow-up, we provide crude rates of local control. RESULTS: Data from 100 patients are reported. Median age is 67 yr old. 56 patients were treated definitively, 21 postoperatively, and 23 had salvage GKRS for recurrence after surgery. Forty-two patients had brain metastases, 26 meningiomas, 16 vestibular schwannomas, 9 high-grade gliomas, and 7 other histologies. Median doses to metastases were 20 Gy in 1 fraction (range: 14-21), 24 Gy in 3 fractions (range: 19.5-27), and 25 Gy in 5 fractions (range: 25-30 Gy). Thirteen patients underwent repeat SRS to the same area. Median treatment time was 17.7 min (range: 5.8-61.7). We found an improvement in our workflow and a greater number of patients eligible for GKRS because of the ability to fractionate treatments. CONCLUSION: We report a large cohort of consecutive patients treated with frameless GKRS. We look forward to studies with longer follow-up to provide valuable data on clinical outcomes and to further our understanding of the radiobiology of hypofractionation in the brain.

Utilization and Economic Impact of Posterolateral Fusion and Posterior/Transforaminal Lumbar Interbody Fusion Surgeries in the United States.

STUDY DESIGN: Retrospective database study. OBJECTIVE: To analyze the economic and age data concerning primary and revision posterolateral fusion (PLF) and posterior/transforaminal lumbar interbody fusion (PLIF/TLIF) throughout the United States to improve value-based care and health care utilization. METHODS: The National Inpatient Sample (NIS) database was queried by the International Classification of Diseases, Ninth Revision, Clinical Modification codes for patients who underwent primary or revision PLF and PLIF/TLIF between 2011 and 2014. Age and economic data included number of procedures, costs, and revision burden. The National Inpatient Sample database represents a 20% sample of discharges from US hospitals weighted to provide national estimates. RESULTS: From 2011 to 2014, the annual number of PLF and PLIF/TLIF procedures decreased 18% and increased 23%, respectively, in the Unites States. During the same period, the number of revision PLF decreased 19%, while revision PLIF/TLIF remained relatively unchanged. The average cost of PLF was lower than the average cost of PLIF/TLIF. The aggregate national cost for PLF was more than $3 billion, while PLIF/TLIF totaled less than $2 billion. Revision burden (ratio of revision surgeries to the sum of both revision and primary surgeries) remained constant at 8.0% for PLF while it declined from 3.2% to 2.9% for PLIF/TLIF. CONCLUSION: This study demonstrated a steady increase in PLIF/TLIF, while PLF alone decreased. The increasing number of PLIF/TLIF procedures may account for the apparent decline of PLF procedures. There was a higher average cost for PLIF/TLIF as compared with PLF. Revision burden remained unchanged for PLF but declined for PLIF/TLIF, implying a decreased need for revision procedures following the initial PLIF/TLIF surgery.

Fluorescein-guided resection of gliomas.

Standard of care in the management of high-grade gliomas includes gross total resection (GTR) followed by treatment with radiation and temozolomide. GTR remains one of the few independent prognostic factors for improved survival in this disease. Sodium fluorescein is an organic fluorophore that has been studied as a surgical adjunct to improve the likelihood of achieving GTR in gliomas. Though sodium fluorescein does not selectively accumulate in glioma cells, it allows for real-time identification of regions of blood brain barrier breakdown, corresponding to the contrast-enhancing cores of high-grade gliomas. In addition to its high predictive value for identifying pathologic tissue, use of fluorescein has been shown to improve rates of GTR. In stereotactic needle biopsies, it helps reduce procedure time by rapidly confirming the presence of diagnostic tissue. Furthermore, in non-enhancing, low-grade gliomas, it labels focal regions of vascular dysregulation that have been correlated with high-grade features. Fluorescein has also been shown to be significantly less expensive than other contemporary surgical adjuncts such as intraoperative ultrasound, intraoperative MRI, and the recently FDA approved fluorophore, 5-aminolevulinic acid (5-ALA). Here, we review the current literature on the effectiveness of fluorescein as a surgical tool in the resection of gliomas.

Bisphenol A activates EGFR and ERK promoting proliferation, tumor spheroid formation and resistance to EGFR pathway inhibition in estrogen receptor-negative inflammatory breast cancer cells.

Emerging evidence from epidemiological studies suggests a link between environmental chemical exposure and progression of aggressive breast cancer subtypes. Of all clinically distinct types of breast cancers, the most lethal phenotypic variant is inflammatory breast cancer (IBC). Overexpression of epidermal growth factor receptors (EGFR/HER2) along with estrogen receptor (ER) negativity is common in IBC tumor cells, which instead of a solid mass present as rapidly proliferating diffuse tumor cell clusters. Our previous studies have demonstrated a role of an adaptive response of increased antioxidants in acquired resistance to EGFR-targeting drugs in IBC. Environmental chemicals are known to induce oxidative stress resulting in perturbations in signal transduction pathways. It is therefore of interest to identify chemicals that can potentiate EGFR mitogenic effects in IBC. Herein, we assessed in ER-negative IBC cells a subset of chemicals from the EPA ToxCast set for their effect on EGFR activation and in multiple cancer phenotypic assays. We demonstrated that endocrine-disrupting chemicals such as bisphenol A (BPA) and 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane can increase EGFR/ERK signaling. BPA also caused a corresponding increase in expression of SOD1 and anti-apoptotic Bcl-2, key markers of antioxidant and anti-apoptotic processes. BPA potentiated clonogenic growth and tumor spheroid formation in vitro, reflecting IBC-specific pathological characteristics. Furthermore, we identified that BPA was able to attenuate the inhibitory effect of an EGFR targeted drug in a longer-term anchorage-independent growth assay. These findings provide a potential mechanistic basis for environmental chemicals such as BPA in potentiating a hyperproliferative and death-resistant phenotype in cancer cells by activating mitogenic pathways to which the tumor cells are addicted for survival.