Meningiomas are common tumors of the central nervous system that are typically treated with surgeryor radiation, but lack established systemic therapies. Activation of the stimulator of interferon genes pathway with an agonist such as 8803 can trigger anti-tumor immune responses. Using integrated molecular approaches, here we show that this pathway is targetable in both neoplastic and immune populations within themeningiomamicroenvironment. Meningioma tumor cells exhibit promoter hypomethylation and increased chromatin accessibilityof the STING genomiclocus,associated with robust expression of this gene. Treatment of diverse patient meningiomas ex vivo with 8803 induces direct tumor cytotoxicity through inflammatory cell death pathways, includinginduction of gasdermin D membrane pore formation. Release of necrotic tumor debris triggered by 8803 activates macrophages and upregulates matrix metalloproteinase production, facilitating degradation of extra-cellular collagen. Injection of preclinical meningiomas with 8803 induces survival benefits, including in an immunocompetent orthotopic setting, through remodeling of the tumor microenvironment, immune infiltration, and downregulation of tumor-mediated immune suppression, thereby nominating 8803 for treatment consideration in meningiomas.

Tetanus remains a rare but potentially fatal disease, typically associated with traumatic wounds. However, necrotic malignancies such as fungating breast tumors may also serve as an entry point forClostridium tetaniinfection. We report the case of a 58-year-old female with a 3-year history of a fungating left breast mass who presented with trismus. A diagnosis of tetanus was made clinically. The patient received treatment with anti-tetanus globulin, metronidazole, and she was placed in a dark room with sound insulation and shielding. The surgical team was consulted for wound management. However, in accordance with the patient's refusal, surgical debridement was not performed. Instead, local wound cleansing and supportive management were initiated. Tetanus should be considered in patients with necrotic tumors presenting with trismus, especially in low-resource settings where immunization histories are uncertain. Early intervention is crucial to reduce morbidity and prevent complications.

Abstract Glioblastoma multiforme (GBM) is an aggressive cancer with a dismal prognosis despite standard care—maximal safe resection, chemotherapy, and radiation. GBM’s highly immunosuppressive environment has limited immunotherapy approaches. Bacteria with intrinsic tumor-homing behavior and programmability as living therapeutics may overcome these challenges by accessing hypoxic, necrotic tumor cores inaccessible to standard treatments. While bacteria are safe and effective as therapeutics in non-CNS cancer models, their infectiousness and immunogenicity have impeded their use in the brain. Here, we engineered the probiotic E. coli Nissle 1917 (EcN) with a biocontainment circuit dependent on tumor-specific cues (hypoxia and elevated lactate) to restrict bacterial survival and growth to the tumor microenvironment (“iBio” strain). We further attenuated this strain via knockout of a membrane protein and lipopolysaccharide to reduce recognition by toll-like receptors 2 and 4, respectively, minimizing inflammation and intracranial toxicity (“BLL” strain). Healthy and orthotopic GBM-bearing mice were injected intracranially with bacteria; survival, body weight, and end-point bacterial load were measured. The iBio and BLL strains exhibited drastically reduced toxicity in healthy mice, with BLL safety comparable to saline controls. The engineered safety strains showed significantly better survival curves and clinical signs in mice than wild-type EcN. Relative to wild-type EcN, BLL increased the maximum tolerable dose of injected bacteria by 1,000-fold in the brain. In an orthotopic mouse model of GBM (GL261), the BLL strain was as safe as saline and more than doubled median survival from 4 to 9 days (p < 0.0001). These findings indicate that engineered EcN can be safely injected into the brain and impart a survival benefit in a GBM model, supporting further development of bacterial therapeutics for GBM. These results lay the foundation for clinical translation of bacterial-based therapies in GBM. Future studies will evaluate BLL-induced immune activation, inflammation, and tumor cell death.

Abstract INTRODUCTION Differentiating treatment effects (TxE), including cases with radiation necrosis and/or with gliosis and hyalinized vessels on histopathology, from tumor progression in irradiated brain tumors remains a clinical challenge due to overlapping imaging characteristics on conventional MRI. The presence of mixed pathology further complicates diagnosis. Diffusion-Relaxation Correlation Spectroscopic Imaging (DR-CSI) is an emerging technique that characterizes tissue microstructure by measuring the joint variations in T2 relaxation and diffusivity. This study evaluates the feasibility of DR-CSI in distinguishing TxE from viable tumor and benchmarks it against conventional diffusion/perfusion imaging and sodium MRI. METHODS Sixteen patients with suspected brain tumors (glioma or brain metastasis) and/or TxE underwent preoperative MRI, including DR-CSI, sodium, and a standard clinical protocol with diffusion and perfusion sequences, on 3T scanners. DR-CSI was acquired using a 30-point TE-b-value spin-echo EPI sequence. Histopathological diagnosis was: 8 recurrent tumors, 4 pure TxE, and 4 mixed pathology cases. Voxel-wise diffusion-relaxation (D-T2) spectra were calculated from DR-CSI datasets using dictionary-based fitting. Lesion segmentations, including the contrast-enhancing and necrotic tumor tissue, were obtained using an automated AI-based tool. Lesion-averaged D-T2 spectra were compared between tumor and pure TxE groups using a point-by-point Mann-Whitney U-test to identify discriminative spectral regions representing TxE. A “TxE index” for each lesion was calculated by integrating spectral power over these regions. TxE indexes were subsequently compared across groups. RESULTS In TxE, mixed, and tumor groups, the TxE indexes were 0.30±0.04, 0.27±0.05, and 0.14±0.08, respectively. TxE indexes showed significant differences across groups: tumor vs. non-tumor (p=0.02, AUC=0.81), TxE vs. non-TxE (p=0.01, AUC=0.81), and pure TxE vs. pure tumor (p=0.02, AUC=0.90, sensitivity=1.0, specificity=0.83). In contrast, conventional imaging biomarkers (ADC and rCBV) and sodium showed no significant group differences (all p>0.4). CONCLUSION These preliminary results support the potential of DR-CSI as a non-invasive imaging biomarker to resolve microstructural differences and distinguish TxE from tumor, especially in complex or ambiguous cases where conventional imaging is limited.

Brain tumors are life-threatening neurological conditions that develop due to uncontrolled cell growth in the brain. The survival rate of this illness is gradually decreasing due to the lack of early and accurate diagnosis of brain tumors. Multiple classification methods have been developed for the classification of brain tumors, but they have resulted in several limitations, such as complications in segmentation, inconsistency in tumor features, data inequity, low performance, and high error. To overcome the limitations, this research proposed a Producer Scrounger Foraging Optimized Gated Recurrent Unit-Deep Bidirectional Long Short-Term Memory (PSF-GRBM) model for effective brain tumor classification. Additionally, the integration of PSF optimization in the proposed model reduces the high-complexity problems in various dimensions and achieves effective results. The experimental analysis reveals that the proposed method attained 95.74% of accuracy, 95.67% of sensitivity, and 95.81% of specificity, using the MSD dataset, which highlights the improved performance of the PSF-GRBM model in brain tumor classification and grading. The PSF-GRBM model achieves effective classification through an incentive learning mechanism, categorizing brain tumors into four grades: grade 0 for a normal brain, grade 1 for non-enhancing and necrotic tumor core, grade 2 for peritumoral edema, and grade 3 for Gadolinium (GD) enhancing tumors.

While osteomyelitis is not uncommon in veterinary patients, emphysematous osteomyelitis, characterized by the presence of intramedullary gas, is scarcely reported in both veterinary and human literature. This report documents two cases in young, previously healthy dogs that were presented with clinical signs related to infection/inflammation. Multiple imaging modalities were utilized in the workup of one case, while computed tomography (CT) was used as the sole modality in the second. In both cases, peri-femoral abscessation with intramedullary gas was identified, and positive bacterial culture was obtained. One case responded well to treatment and demonstrated expected osseous remodeling consistent with chronic osteomyelitis. The patient in the second case was euthanized secondary to a marked clinical decline. In humans, this condition is often associated with comorbidities, including diabetes mellitus and carries a guarded prognosis, with a 24-32% mortality rate. The presence of multiple, variably sized though small, irregularly marginated foci of gas, without a sclerotic rim within the medullary cavity, without a history of penetrating trauma, necrotic tumor, or recent surgery, should be considered pathognomonic for emphysematous osteomyelitis.

Localized photodynamic therapy (PDT) using a photoactive stent-based catheter involves the direct delivery of reactive oxygen species to the mucosa in esophageal carcinoma; however, the damaged mucosa recovers within 2 to 4 weeks, which considerably limits the clinical application of PDT. Here, we used aluminum(III) phthalocyanine chloride tetrasulfonic acid (AlPcS4) as a photosensitizer due to its excellent photochemical durability, low photobleaching, and high quantum yield and investigated whether repeated and periodic PDT via an AlPcS4-embedded stent-based catheter can provide sustained therapeutic efficacy. AlPcS4 was uniformly embedded in silicone membranes via coordination bonding to form a photoactive stent-based catheter. The membrane demonstrated excellent photostability and consistent singlet oxygen generation under near-infrared irradiation, as evidenced by a 67.2% decrease in 9,10-dimethylanthracene fluorescence intensity, even after 90 J cm−2 irradiation, markedly superior to methylene blue (15.3%) and chlorin e6 (30.9%). Repeated PDT effectively enhanced cell death rates in KYSE-70 cells. In the xenograft model, MRI-based volumetric analysis showed that the tumor volume change in the thrice-PDT group (57.40% ± 9.26%) was significantly lower than those in the control (212.07% ± 38.44%, P < 0.001) and once-PDT groups (130.77% ± 11.25%, P = 0.018), accompanied by apoptotic and necrotic tumor destruction. Repeated PDT at 1-week intervals was technically successful in the porcine esophagus, leading to progressive mucosal injury, luminal narrowing, and apoptosis, while demonstrating sustained therapeutic efficacy. Thus, the minimally invasive repeatable photoactive stent-based catheter may be an effective and safe approach for treating esophageal carcinoma.

Accurate segmentation of brain tumors from multi-modal MRI scans is critical for diagnosis, treatment planning, and disease monitoring. Tumor heterogeneity and inter-image variability across MRI sequences pose challenging problems to state-of-the-art segmentation models. This paper presents a novel Multi-Modal Multi-Scale Contextual Aggregation with Attention Fusion (MM-MSCA-AF) framework that leverages multi-modal MRI images (T1, T2, FLAIR, and T1-CE) to enhance segmentation performance. The model employs multi-scale contextual aggregation to obtain global and fine-grained spatial features, and gated attention fusion for selectively refining effective feature representations and discarding noise. Evaluated on the BRATS 2020 dataset, MM-MSCA-AF achieves a Dice value of 0.8158 for necrotic tumor regions and 0.8589 in total, outperforming state-of-the-art architectures such as U-Net, nnU-Net, and Attention U-Net. These results demonstrate the effectiveness of MM-MSCA-AF in handling complex tumor shapes and improving segmentation accuracy. The proposed approach has significant clinical value, offering a more accurate and automatic brain tumor segmentation solution in medical imaging.

In this case report we describe a Ewing-like high grade small round cell sarcoma of the urinary bladder in which an extremely rare EWSR1::BEND2 fusion was found. A 28-year-old male patient presented with hematuria and in the following examinations a large necrotic bladder tumor with spreading to adjacent prostatic tissue and multiple lung metastases were found. Histology showed a poorly differentiated small round cell tumor with perivascular rosettes and moderate membranous positivity for CD99. The methylation profile of the tumor did not match with any of the tumor entities grouped by the sarcoma classifier. With tumor agnostic methods, mainly next generation sequencing, novel fusions are being found at an accelerating rate. Our case adds to the expanding group of EWSR1 fusion neoplasms, and describes the effects of a Ewing sarcoma treatment protocol on this type of sarcoma. The relevance of traditional methods for detecting Ewing sarcoma with fluorescence in situ hybridization is decreasing as EWSR1 rearrangements are detected in tumors that show different clinical behavior and morphology. The classification of these tumors into WHO defined entities to guide treatment is a challenge.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13000-025-01721-3.

Neoadjuvant immunochemotherapy has shown promising results, with major pathologic response (MPR, ≤10% residual viable tumors [RVT]) as the primary outcome. However, %RVT showed limited predictive power in stratifying outcomes within the MPR and non-MPR groups. To identify a better prognostic marker, this study analyzed 200 non-small-cell lung cancer (NSCLC) samples after neoadjuvant PD-1 blockade combined with chemotherapy across three medical centers. Among these patients, 99 had necrotic regions in their residual lesions. We found that tumor-infiltrating lymphocytes in necrotic areas (nTILs) lose their cellular structure, but retained T-cell-specific antigens, making them detectable by immunohistochemistry. Regardless of PD-L1 status or lymph node metastasis, patients with high CD8+ nTIL density had significantly improved event-free survival (EFS) (hazard ratio [HR]: 0.08; 95% CI: [0.01–0.62]; p = 0.0019). Furthermore, CD8+ nTIL density improved prognostic predictions for patients within the MPR (p = 0.017) and non-MPR groups (p = 0.076). Radiological responses did not correlate with MPR, CD8+ nTIL density or EFS. 41.5% MPR cases were misclassified by radiological assessments. When compared with radiographic response and pathological response, CD8+ nTIL density outperformed these traditional parameters in approximating EFS. These findings demonstrate that the CD8+ nTIL density is a robust predictor of EFS in NSCLC patients treated with neoadjuvant immunochemotherapy and has great potential in guiding treatment decisions.

Background/Objectives: Breast abscesses and necrotic masses often show similar peripheral enhancement and a fluid-containing appearance on breast MRI, leading to diagnostic confusion. Accurate differentiation is critical because biopsies that fail to sample the lesion wall may yield false-negative results, may be misinterpreted as an infectious process, and delay diagnosis. Incorporating SWI into the protocol can provide additional clues to malignancy and, when warranted, prompt a second wall-targeted biopsy, thus reducing the risk of delayed cancer diagnosis. Methods: This single-center prospective diagnostic accuracy study included 42 female patients diagnosed between 2022 and 2025 with either necrotic breast tumors or abscesses, confirmed by histopathology. SWI-based Intralesional Susceptibility Score (ILSS), rim morphology, and mean ADC values were evaluated. Statistical analyses included the Mann–Whitney U test, chi-square test, ROC analysis, DeLong test for comparison of AUCs, and Cohen’s kappa for interobserver agreement. Results: SWI-based ILSS values were significantly higher in necrotic tumors compared to abscesses (mean ILSS: 2.28 vs. 0.85; 95% CI: 1.0–2.0; p < 0.001). Smooth hypointense rims were predominantly observed in abscesses (Sensitivity: 63.1%, 95% CI: 0.38–0.83; Specificity: 88.9%, 95% CI: 0.65–0.98; p = 0.001). Incomplete rim morphology was more frequent in tumors (Sensitivity: 78.9%, 95% CI: 0.54–0.93; Specificity: 77.8%, 95% CI: 0.52–0.93; p < 0.001). The double rim sign was highly specific for abscesses (Specificity: 95.2%, 95% CI: 0.76–0.99 p = 0.002). Conclusions: SWI provides valuable morphological information in differentiating abscesses from necrotic tumors on breast MRI. When used in combination with ADC values, it can enhance diagnostic accuracy.

Tumors evolve to avoid immune destruction and establish an immunosuppressive microenvironment. Syngeneic mouse tumor models are critical for understanding tumor immune evasion and testing cancer immunotherapy. Derived from established mouse tumor cell lines that can already evade the immune system, these models cannot simulate early phases of immunoediting during initial tumorigenesis. We developed a syngeneic mouse teratoma model derived from noncancerous mouse embryonic stem cells and conducted a genome-wide CRISPR screen to identify genes that impact early phases of cancer immunoediting. We found that loss of pro-apoptotic tumor suppressor genes, including Trp53, increased necrosis in teratomas, releasing APOE lipid particles into the extracellular milieu. Infiltrating T cells drawn to tumor necrotic regions accumulated lipids and became dysfunctional. Blocking lipid uptake in T cells or reducing necrosis in teratomas by inactivating the mitochondrial permeability transition pore (mPTP) restored immunosurveillance. Because mouse teratomas were highly enriched for brain tissues, we next examined the tumor-immune interaction in human glioblastoma(GBM). Indeed, infiltrating T cells in TP53-mutated human GBM accumulated APOE and were dysfunctional. Anti-APOE and anti-PDCD1 antibodies synergistically boosted anti-GBM immunity and prolonged survival in mice. Our results link mPTP-mediated tumor necrosis to immune evasion and suggest that targeting the uptake of lipids released by necrotic tumor cells by infiltrating immune cells can enhance cancer immunotherapy.

In this retrospective study, authors aimed to evaluate the glymphatic function alterations associated with glioma and explore the prognostic value of these alterations by calculating the index for diffusivity along the perivascular space (ALPS index). The authors utilized data from the publicly available University of California San Francisco Preoperative Diffuse Glioma MRI (UCSF-PDGM) dataset, which includes 501 adult patients with histopathologically confirmed diffuse glioma, per the 2021 WHO classification, who underwent preoperative MRI, initial tumor resection, and tumor genetic testing at a single medical center from 2015 to 2021.The ALPS index was calculated from diffusivity maps for noninvasive glymphatic system (GS) analysis. The authors extracted 2288 radiomic features across four tumor regions: surrounding FLAIR abnormality, enhancing tumor, central nonenhancing and/or necrotic tumor, and whole tumor (combining necrosis, enhancement, and edema). For normally distributed variables (adjusted for age, enhancing tumor volume, and surrounding FLAIR abnormality volume), ANCOVA was utilized; nonnormally distributed data were analyzed using the Kruskal-Wallis test and Mann-Whitney U-test. Spearman's correlation coefficients were calculated to assess relationships between radiomic features and the ALPS index. Survival analysis included Kaplan-Meier curves, log-rank tests, concordance index (C-index), calibration and decision curves, and Cox regression. Ultimately, 437 patients with grade 2-4 gliomas were included in this study. The mean patient age was 57.46 ± 14.84 years, and 261 patients were male. The ALPS index correlated most strongly with shape features in the surrounding FLAIR abnormality region (MajorAxisLength, which measures elongation of the edema region, r = -0.33, p < 0.001), intensity features in the enhanced region (T2.RootMeanSquared, which quantifies variations in T2-weighted MRI signal intensity, r = 0.25, p < 0.001), and both shape and texture features in the necrotic region (Sphericity, which reflects the roundness of necrosis, r = 0.26, p < 0.001; FLAIR.glszm.GLNU, which reflects the uniformity of MRI signal distribution, r = -0.24, p < 0.001). Patients with higher-grade tumors (p < 0.001), IDH-wildtype glioma (p = 0.01), and 1p19q-intact tumors (p = 0.038) consistently exhibited reduced glymphatic function. Univariate Cox regression analysis demonstrated that a lower ALPS index was related to a shorter survival time (HR 0.297, 95% CI 0.149-0.593, p < 0.001). Subgroup analyses within histological and molecular subtypes (grade 4, IDH wildtype, and 1p19q intact) demonstrated that patients with ALPS values below the median had significantly shorter overall survival. The ALPS index combined with radiomics improved survival prediction, with the C-index increasing from 0.709 to 0.711 in the training cohort and from 0.675 to 0.693 in the validation cohort. Kaplan-Meier analysis further demonstrated more distinguishable survival curves, with the p value decreasing from 0.003 to 0.0001. Worse GS function was associated with more aggressive tumors and shorter survival times.

Gliomas are known to have different sub-regions within the tumor, including the edema, necrotic, and active tumor regions. Segmenting of these regions is very important for glioma treatment decisions and management. This paper aims to demonstrate the application of U-Net and pre-trained U-Net backbone networks in glioma semantic segmentation, utilizing different magnetic resonance imaging (MRI) image weights. The data used in this study for network training, validation, and testing is the Multimodal Brain Tumor Segmentation (BraTS) 2021 challenge. In this study, we applied the U-Net and different pre-trained Backbone U-Net for the semantic segmentation of glioma regions. The ResNet, Inception, and VGG networks, which are pre-trained using the ImageNet dataset, have been used as the Backbone in the U-Net architecture. The Accuracy (ACC) and Intersection over Union (IoU) were employed to assess the performance of the networks. The most prominent finding to emerge from this study is that trained ResNet-U-Net with T1 post-contrast enhancement (T1Gd) has the highest ACC and IoU for the necrotic and active tumor regions semantic segmentation in glioma. It was also demonstrated that a trained ResNet-U-Net with T2 Fluid-Attenuated Inversion Recovery (T2-FLAIR) is a suitable combination for edema segmentation in glioma. Our study further validates that the proposed framework’s architecture and modules are scientifically grounded and practical, enabling the extraction and aggregation of valuable semantic information to enhance glioma semantic segmentation capability. It demonstrates how useful the ResNet-U-Net will be for physicians to extract glioma regions automatically.

Cavernous hemangiomas are relatively uncommon, primarily found in adults, particularly women. These tumors frequently present with unilateral nosebleeds and nasal blockage. Furthermore, there are only a few recorded instances of cavernous hemangiomas originating from the maxillary sinus in medical literature. This case report has been written because of the rare occurrence of cavernous hemangioma in the paranasal sinus. We present a case of a cavernous haemangioma located in the right maxillary sinus of a 30-year-old male. During an anterior rhinoscopy, a large necrotic tumor was observed, which bled upon contact and obstructed the right nasal cavity. A preoperative endoscopic biopsy was conducted on the mass to eliminate the possibility of cancer, but the findings were inconclusive. A CT scan displayed a mass occupying the entire right maxillary sinus and extending into the right nasal cavity, as well as reaching the ethmoid sinuses and choana, without any evidence of bone damage or displacement of the nasal septum. The Intraoperative frozen-section pathology showed that the respiratory epithelium displayed considerable haemorrhage, necrosis, inflammation, and edema, as well as the growth of blood vessels of different sizes. For our patient, the minimally invasive transnasal endoscopic approach was successful with minimal bleeding. The tumor was completely excised, and during the one-year follow-up, the patient has not experienced any recurrence. However, the final biopsy of the lesion confirmed that it was a cavernous hemangioma.

Tumor necrosis facilitates perihilar cholangiocarcinoma metastasis by ANGPTL6-augmented vessel permeability and tumor dissemination

To investigate whether imaging factors can improve the prediction of progression-free survival (PFS) in patients with oligodendroglioma over clinicopathological features. A total of 180 patients diagnosed and treated for oligodendroglioma (IDH-mutant and 1p/19q codeleted) between 2005 and 2021 were included. Clinical data and preoperative MRI images were analyzed for qualitative and quantitative characteristics. Qualitative features included tumor location, calcification, gliomatosis cerebri pattern, cystic change, necrosis, and infiltrative pattern, while quantitative features included total, contrast-enhancing (CE), non-enhancing, and necrotic tumor volumes via automatic segmentation. Significant predictors of PFS were identified using univariable and multivariable Cox analyses. Two prognostic models were developed: model 1 (clinicopathological features) and model 2 (addition of imaging features). The prognostic value of the two models was compared. On univariable analysis, male sex, gliomatosis cerebri pattern, larger total tumor, CE tumor, and non-enhancing tumor volumes, and partial resection or biopsy were unfavorable predictors of PFS. On multivariable analysis, male sex (hazard ratio (HR) = 3.76, p = 0.012), larger CE tumor volume (HR = 1.06, p = 0.003) and partial resection or biopsy (HR = 6.83, p = 0.001) remained as unfavorable predictors for PFS. Compared with the clinicopathological model, the model adding imaging feature demonstrated a higher C-index (0.784 vs. 0.776) and iAUC (0.745 vs. 0.725), with a significantly high time-dependent AUC for PFSat1 year (0.989 vs. 0.943, p = 0.001). The CE tumor volume on preoperative MRI is an independent prognostic factor in oligodendroglioma patients, potentially guiding follow-up and adjuvant treatment decisions. Question This study examines whether imaging factors can improve the prediction of progression-free survival (PFS) in patients with oligodendroglioma over clinicopathological features. Findings Larger contrast-enhancing (CE) tumor volume, male sex, and lesser resection independently predicted shorter PFS. Incorporating CE tumor volume improved model performance over clinicopathological features alone. Clinical relevance The clinicopathological and imaging features were comprehensively investigated in patients with oligodendroglioma to predict PFS. Incorporating CE tumor volume improved the model's predictive performance, providing valuable information for clinical decision-making in identifying high-risk patients.

We present a multi-species partial differential equation (PDE) model for tumor growth and an algorithm for calibrating the model from magnetic resonance imaging (MRI) scans. The model is designed for glioblastoma multiforme (GBM) a fast-growing type of brain cancer. The modeled species correspond to proliferative, infiltrative, and necrotic tumor cells. The model calibration is formulated as an inverse problem and solved by a PDE-constrained optimization method. The data that drives the calibration is derived by a single multi-parametric MRI image. This is a typical clinical scenario for GBMs. The unknown parameters that need to be calibrated from data include 10 scalar parameters and the infinite dimensional initial condition (IC) for proliferative tumor cells. This inverse problem is highly ill-posed as we try to calibrate a nonlinear dynamical system from data taken at a single time. To address this ill-posedness, we split the inversion into two stages. First, we regularize the IC reconstruction by solving a single-species compressed sensing problem. Then, using the IC reconstruction, we invert for model parameters using a weighted regularization term. We construct the regularization term by using auxiliary 1D inverse problems. We apply our proposed scheme to clinical data. We compare our algorithm with single-species reconstruction and unregularized reconstructions. Our scheme enables the stable estimation of non-observable species and quantification of infiltrative tumor cells. Our regularization improves the tumor Dice score by 5%-10% compared to single-species model reconstruction. Also, our regularization reduces model parameter reconstruction errors by 4%-80% in cases with known initial condition and brain anatomy compared to cases without regularization. Importantly, our model can estimate infiltrative tumor cells using observable tumor species.

BackgroundInconsistent responses to anticancer immunotherapies demonstrate the need for non-invasive methods to detect treatment responses earlier than conventional medical imaging methods allow. The chimeric monoclonal antibody, APOMAB®, targets dead tumour cells following DNA-damaging anticancer treatments via binding of the ribonuclear protein, La/SSB, an intracellular protein overexpressed by tumour cells. La/SSB only becomes accessible to APOMAB binding in post-apoptotic necrotic tumour cells.MethodsWe assessed the ability of APOMAB to detect dead tumour cells after immune-mediated cell death. Co-culture of GD2-specific chimeric antigen receptor (CAR) T-cells with GD2-expressing cancer cell lines demonstrated specific and dose-dependent binding of APOMAB to the resulting dead target cells, confirming detection of immune-mediated cell death. Then, using four distinct preclinical tumour models and in a cancer patient, we investigated APOMAB-immunoPET as a technique to detect immune-mediated tumour cell death.ResultsWithin days of treatment, APOMAB-immunoPET showed increased tumour uptake of 89Zirconium-labelled APOMAB (89Zr-APOMAB) after CAR-T cell therapy, immune checkpoint inhibitor (ICI) therapy with and without chemotherapy, and via endogenous T-cell mediated tumour clearance. In a metastatic melanoma patient after ICI therapy, a previously FDG-avid pulmonary tumour reduced in size as tumour 89Zr-APOMAB uptake increased over the 12-day scanning period.ConclusionsThis study demonstrates for the first time that not only does radiolabelled APOMAB provide an initial direct measure of the extent of immune-mediated tumour cell death in vivo but also reveals the heterogeneous nature of tumour responses to T-cell based therapies both within and between individuals.

Necrosis, conventionally thought of as a passive consequence of aggressive tumor growth, is associated with poor prognosis in colorectal cancer (CRC). We recently discovered that necrosis can be caused by neutrophils and neutrophil extracellular traps (NETs) aggregates driving vascular occlusion within the tumor vasculature in models of breast cancer. Here, we evaluated the role of NETs in inducing necrosis and metastasis in CRC. We found that the numbers of neutrophils primed to form NETs were elevated in the circulation of patients with CRC as compared to controls. CD177 Low neutrophils were also elevated, and they showed reduced extravasation capacity with intact ability to form NETs. The extent of necrosis correlated with metastasis (stage IV disease), independent of tumor size, in our human cohort. In both human and murine CRC tumors, necrotic regions were characterized by neutrophil infiltration and NET accumulation, and NET aggregates were observed in the vasculature next to the necrotic regions. Single cell RNA sequencing and spatial transcriptomic analysis of human CRC and liver metastases revealed that necrotic tumors activate pathways associated with increased metastatic potential, including epithelial-to-mesenchymal-transition. Using a mouse model of DNA mismatch repair proficient CRC, we found neutrophil infiltration and NETs increased with tumor progression. Genetic or pharmacological inhibition of NET formation decreased necrosis and metastasis, and importantly enhanced chemotherapy efficacy. Altogether, our findings show that NET formation in human CRC is a key feature of tumor necrosis, that it is associated with metastasis, and further suggest that preventing NET formation may offer clinical benefits to CRC patients.