Automated segmentation of ablated lesions using deep convolutional neural networks: A basis for response assessment following laser interstitial thermal therapy.

BACKGROUND: Laser interstitial thermal therapy (LITT) of intracranial tumors or radiation necrosis enables tissue diagnosis, cytoreduction, and rapid return to systemic therapies. Ablated tissue remains in situ, resulting in characteristic post-LITT edema associated with transient clinical worsening and complicating post-LITT response assessment. METHODS: All patients receiving LITT at a single center for tumors or radiation necrosis from 2015 to 2023 with ≥9 months of MRI follow-up were included. An nnU-Net segmentation model was trained to automatically segment contrast-enhancing lesion volume (CeLV) of LITT-treated lesions on T1-weighted images. Response assessment was performed using volumetric measurements. RESULTS: Three hundred and eighty four unique MRI exams of 61 LITT-treated lesions and 6 control cases of medically managed radiation necrosis were analyzed. Automated segmentation was accurate in 367/384 (95.6%) images. CeLV increased to a median of 68.3% (IQR 35.1-109.2%) from baseline at 1-3 months from LITT (P = 0.0012) and returned to baseline thereafter. Overall survival (OS) for LITT-treated patients was 39.1 (9.2-93.4) months. Lesion expansion above 40% from volumetric nadir or baseline was considered volumetric progression. Twenty-one of 56 (37.5%) patients experienced progression for a volumetric progression-free survival of 21.4 (6.0-93.4) months. Patients with volumetric progression had worse OS (17.3 vs 62.1 months, P = 0.0015). CONCLUSIONS: Post-LITT CeLV expansion is quantifiable and resolves within 6 months of LITT. Development of response assessment criteria for LITT-treated lesions is feasible and should be considered for clinical trials. Automated lesion segmentation could speed the adoption of volumetric response criteria in clinical practice.

Surgical Management and Advances in the Treatment of Glioma.

The care of patients with both high-grade glioma and low-grade glioma necessitates an interdisciplinary collaboration between neurosurgeons, neuro-oncologists, neurologists and other practitioners. In this review, we aim to detail the considerations, approaches and advances in the neurosurgical care of gliomas. We describe the impact of extent-of-resection in high-grade and low-grade glioma, with particular focus on primary and recurrent glioblastoma. We address advances in surgical methods and adjunct technologies such as intraoperative imaging and fluorescence guided surgery that maximize extent-of-resection while minimizing the potential for iatrogenic neurological deficits. Finally, we review surgically-mediated therapies other than resection and discuss the role of neurosurgery in emerging paradigm-shifts in inter-disciplinary glioma management such as serial tissue sampling and "window of opportunity trials".

Utility of Routine Preoperative Urinalysis in the Prevention of Surgical Site Infections.

OBJECTIVE: Preoperative assessment is important for neurosurgical risk stratification, but the level of evidence for individual screening tests is low. In preoperative urinalysis (UA), testing may significantly increase costs and lead to inappropriate antibiotic treatment. We prospectively evaluated whether eliminating preoperative UA was noninferior to routine preoperative UA as measured by 30-day readmission for surgical site infection in adult elective neurosurgical procedures. METHODS: A single-institution prospective, pragmatic study of patients receiving elective neurosurgical procedures from 2018 to 2020 was conducted. Patients were allocated based on same-day versus preoperative admission status. Rates of preoperative UA and subsequent wound infection were measured along with detailed demographic, surgical, and laboratory data. RESULTS: The study included 879 patients. The most common types of surgery were cranial (54.7%), spine (17.4%), and stereotactic/functional (19.5%). No preoperative UA was performed in 315 patients, while 564 underwent UA. Of tested patients, 103 (18.3%) met criteria for suspected urinary tract infection, and 69 (12.2%) received subsequent antibiotic treatment. There were 14 patients readmitted within 30 days (7 without UA [2.2%] vs. 7 with UA [1.2%]) for subsequent wound infection with a risk difference of 0.98% (95% confidence interval -0.89% to 2.85%). The upper limit of the confidence interval exceeded the preselected noninferiority margin of 1%. CONCLUSIONS: In this prospective study of preoperative UA for elective neurosurgical procedures using a pragmatic, real-world design, risk of readmission due to surgical site infection was very low across the study cohort, suggesting a limited role of preoperative UA for elective neurosurgical procedures.

CD8+ T cells maintain killing of MHC-I-negative tumor cells through the NKG2D-NKG2DL axis.

The accepted paradigm for both cellular and anti-tumor immunity relies upon tumor cell killing by CD8+ T cells recognizing cognate antigens presented in the context of target cell major histocompatibility complex (MHC) class I (MHC-I) molecules. Likewise, a classically described mechanism of tumor immune escape is tumor MHC-I downregulation. Here, we report that CD8+ T cells maintain the capacity to kill tumor cells that are entirely devoid of MHC-I expression. This capacity proves to be dependent instead on interactions between T cell natural killer group 2D (NKG2D) and tumor NKG2D ligands (NKG2DLs), the latter of which are highly expressed on MHC-loss variants. Necessarily, tumor cell killing in these instances is antigen independent, although prior T cell antigen-specific activation is required and can be furnished by myeloid cells or even neighboring MHC-replete tumor cells. In this manner, adaptive priming can beget innate killing. These mechanisms are active in vivo in mice as well as in vitro in human tumor systems and are obviated by NKG2D knockout or blockade. These studies challenge the long-advanced notion that downregulation of MHC-I is a viable means of tumor immune escape and instead identify the NKG2D-NKG2DL axis as a therapeutic target for enhancing T cell-dependent anti-tumor immunity against MHC-loss variants.

Risk of Tract Seeding Following Laser Interstitial Thermal Therapy for Brain Tumors.

BACKGROUND: The management of intracranial oncological disease remains a significant challenge despite advances in systemic cancer therapy. Laser interstitial thermal therapy (LITT) represents a novel treatment for local control of brain tumors through photocoagulation with a stereotactically implanted laser fiber. Because the use of laser interstitial thermal therapy continues to increase within neurosurgery, characterization of LITT is necessary to improve outcomes. OBJECTIVE: To quantify the risk of tumor seeding along the laser fiber tract in patients receiving LITT for primary or metastatic brain tumors at a high-volume treatment center. METHODS: We retrospectively reviewed all patients receiving LITT from 2015 to 2021 at our medical center. Patients with biopsy-confirmed tumors were included in this study. Tract seeding was identified as discontinuous, newly enhancing tumor along the LITT tract. RESULTS: Fifty-six patients received LITT for biopsy-confirmed tumors from 2015 to 2021, with tract seeding identified in 3 (5.4%). Twenty-nine (51.8%) patients had gliomas, while the remainder had metastases, of which lung was the most common histology (20 patients, 74%). Tract seeding was associated with ablation proceeding inward from superficial tumor margin closest to the cranial entry point ( P = .03). Patients with tract seeding had a shorter median time to progression of 1.1 (0.1-1.3) months vs 4.2 (2.2-8.6) months ( P = .03). CONCLUSION: Although the risk of tract seeding after LITT is reassuringly low, it is associated with decreased progression-free survival. This risk may be related to surgical technique or experience. Follow-up radiosurgery to the LITT tract has the potential to prevent this complication.

CD4 T-Cell Exhaustion: Does It Exist and What Are Its Roles in Cancer?

In chronic infections and in cancer, persistent antigen stimulation under suboptimal conditions can lead to the induction of T-cell exhaustion. Exhausted T cells are characterized by an increased expression of inhibitory markers and a progressive and hierarchical loss of function. Although cancer-induced exhaustion in CD8 T cells has been well-characterized and identified as a therapeutic target (i.e., via checkpoint inhibition), in-depth analyses of exhaustion in other immune cell types, including CD4 T cells, is wanting. While perhaps attributable to the contextual discovery of exhaustion amidst chronic viral infection, the lack of thorough inquiry into CD4 T-cell exhaustion is particularly surprising given their important role in orchestrating immune responses through T-helper and direct cytotoxic functions. Current work suggests that CD4 T-cell exhaustion may indeed be prevalent, and as CD4 T cells have been implicated in various disease pathologies, such exhaustion is likely to be clinically relevant. Defining phenotypic exhaustion in the various CD4 T-cell subsets and how it influences immune responses and disease severity will be crucial to understanding collective immune dysfunction in a variety of pathologies. In this review, we will discuss mechanistic and clinical evidence for CD4 T-cell exhaustion in cancer. Further insight into the derivation and manifestation of exhaustive processes in CD4 T cells could reveal novel therapeutic targets to abrogate CD4 T-cell exhaustion in cancer and induce a robust antitumor immune response.

Large and Small Dendritic Spines Serve Different Interacting Functions in Hippocampal Synaptic Plasticity and Homeostasis.

The laying down of memory requires strong stimulation resulting in specific changes in synaptic strength and corresponding changes in size of dendritic spines. Strong stimuli can also be pathological, causing a homeostatic response, depressing and shrinking the synapse to prevent damage from too much Ca(2+) influx. But do all types of dendritic spines serve both of these apparently opposite functions? Using confocal microscopy in organotypic slices from mice expressing green fluorescent protein in hippocampal neurones, the size of individual spines along sections of dendrite has been tracked in response to application of tetraethylammonium. This strong stimulus would be expected to cause both a protective homeostatic response and long-term potentiation. We report separation of these functions, with spines of different sizes reacting differently to the same strong stimulus. The immediate shrinkage of large spines suggests a homeostatic protective response during the period of potential danger. In CA1, long-lasting growth of small spines subsequently occurs consolidating long-term potentiation but only after the large spines return to their original size. In contrast, small spines do not change in dentate gyrus where potentiation does not occur. The separation in time of these changes allows clear functional differentiation of spines of different sizes.

STAT1 and NF-κB Inhibitors Diminish Basal Interferon-Stimulated Gene Expression and Improve the Productive Infection of Oncolytic HSV in MPNST Cells.

UNLABELLED: Interferon-stimulated genes (ISG) encode diverse proteins that mediate intrinsic antiviral resistance in infected cells. Here it was hypothesized that malignant peripheral nerve sheath tumor (MPNST) cells resist the productive infection of oncolytic herpes simplex virus (oHSV) through activation of the JAK/STAT1 pathway and resultant upregulation of ISGs. Multiple human and mouse MPNST cells were used to explore the relationship between STAT1 activation and the productive infection of Δγ134.5 oHSVs. STAT1 activation in response to oHSV infection was found to associate with diminished Δγ134.5 oHSVs replication and spread. Multiday pretreatment, but not cotreatment, with a JAK inhibitor significantly improved viral titer and spread. ISG expression was found to be elevated prior to infection and downregulated when treated with the inhibitor, suggesting that the JAK/STAT1 pathway is active prior to infection. Conversely, upregulation of ISG expression in normally permissive cells significantly decreased oHSV productivity. Finally, a possible link between NF-κB pathway activation and ISG expression was established through the expression of inhibitor of kB (IκB) which decreased basal STAT1 transcription and ISG expression. These results demonstrate that basal ISG expression prior to infection contributes to the resistance of Δγ134.5 oHSVs in MPNST cells. IMPLICATIONS: Although cancer-associated ISG expression has been previously reported to impart resistance to chemotherapy and radiotherapy, these data show that basal ISG expression also contributes to oncolytic HSV resistance. Mol Cancer Res; 14(5); 482-92. ©2016 AACR.

Potential glucocorticoid receptor ligands with pulmonary selectivity using I-QSAR with the signature molecular descriptor.

We intend in this research to establish a rational method for the development of novel glucocorticoid receptor ligands to more effectively prevent respiratory inflammation. Corticosteroids, a class of steroid hormones, are naturally inclined to bind to the glucocorticoid receptor and, in this research, are the basis for exploring other novel and non-intuitive structures. To be more effective than currently available medications, novel compounds must be highly selective toward the lungs and must be inactivated when exposed to the main circulation, thus preventing the participation of the ligand in other systems and consequently reducing systemic side-effects. We look to use the inverse-quantitative structure-activity relationship algorithm with the Signature molecular descriptor to generate new ligands based upon the structures and activities of 65 experimentally studied corticosteroids. Inverse-quantitative structure-activity relationship explore many possible combinations of atom connectivity while structural filters and other scoring approaches are used to predict and identify the most promising candidates for further study. Properties explored include high receptor binding affinity, high systemic clearance, high plasma protein binding and low oral bioavailability. Among more than 300 million potential candidates generated, 84 high priority compounds with properties predicted to be at least as or more effective than currently available corticosteroids have been identified with this procedure.