Novel Combination Treatment for Melanoma: FLASH Radiotherapy and Immunotherapy Delivered by a Radiopaque and Radiation Responsive Hydrogel.

Immunotherapies have become the standard treatment for melanoma. To further improve patient responses, combinations of immunotherapies and radiotherapy (RT) are being studied, since radiotherapies can potentially provide additional immune stimulation, in addition to direct antitumor effects. FLASH-RT is a novel, ultrahigh dose rate, radiation delivery approach, with the potential of at least equivalent tumor control efficacy and reduced damage to healthy tissue.

A Prospective Phase I/II Clinical Trial of High-Dose Proton Therapy for Chordomas and Chondrosarcomas.

Purpose: The purpose of this study was to evaluate the feasibility and safety of dose-escalated proton beam therapy for treating chordomas and chondrosarcomas of the skull base and spine. Methods: A prospective cohort of 54 patients (42 with chordomas and 12 with chondrosarcomas) was enrolled between 2010 and 2018. The primary endpoints were feasibility and <20% rate of acute grade ≥3 toxicity, and secondary endpoints included cancer-specific outcomes and toxicities.

An immunosuppressive vascular niche drives macrophage polarization and immunotherapy resistance in glioblastoma.

Cancer immunity is subjected to spatiotemporal regulation by leukocyte interaction with neoplastic and stromal cells, contributing to immune evasion and immunotherapy resistance. Here, we identify a distinct mesenchymal-like population of endothelial cells (ECs) that form an immunosuppressive vascular niche in glioblastoma (GBM). We reveal a spatially restricted, Twist1/SATB1-mediated sequential transcriptional activation mechanism, through which tumor ECs produce osteopontin to promote immunosuppressive macrophage (Mφ) phenotypes.

Spatial analysis of tissue immunity and vascularity by light sheet fluorescence microscopy.

The pathogenesis of cancer and cardiovascular diseases is subjected to spatiotemporal regulation by the tissue microenvironment. Multiplex visualization of the microenvironmental components, including immune cells, vasculature and tissue hypoxia, provides critical information underlying the disease progression and therapy resistance, which is often limited by imaging depth and resolution in large-volume tissues. To this end, light sheet fluorescence microscopy, following tissue clarification and immunostaining, may generate three-dimensional high-resolution images at a whole-organ level.

Abundance, distribution, and composition of microplastics in the filter media of nine aged stormwater bioretention systems.

Bioretention systems are designed for quality treatment of stormwater. Particulate contaminants are commonly treated efficiently and accumulate mainly in the surface layer of the bioretention filter material. However, concerns exist that microplastic particles may not show equal accumulation behavior as other sediment particles.

Monitoring the effects of urban and forested land uses on runoff quality: Implications for improved stormwater management.

Urban stormwater is a substantial source of non-point source pollution. Despite considerable monitoring efforts, little is known about stormwater quality in certain geographic regions. These spatial gaps induce uncertainty when extrapolating data and reduce model calibration capabilities, thereby limiting pollutant load reduction strategies.

Gamma Knife radiosurgery for trigeminal neuralgia provides greater pain relief at higher dose rates.

In Gamma Knife (GK) radiosurgery, dose rate decreases during the life cycle of its radiation source, extending treatment times. Prolonged treatments influence the amount of sublethal radiation injury that is repaired during exposure, and is associated with decreased biologically-equivalent dose (BED). We assessed the impact of treatment times on clinical outcomes following GK of the trigeminal nerve - a rare clinical model to isolate the effects of treatment times.

Occurrence, concentration, and distribution of 38 organic micropollutants in the filter material of 12 stormwater bioretention facilities.

The increased use of bioretention facilities as a low impact development measure for treating stormwater runoff underscores the need to further understand their long-term function. Eventually, bioretention filter media must be (partly) replaced and disposed of at the end of its functional lifespan. While there are several studies of metal accumulation and distributions in bioretention media, less is known about organic pollutant pathways and accumulation in these filters.

Targeting PAK4 to reprogram the vascular microenvironment and improve CAR-T immunotherapy for glioblastoma.

Malignant solid tumors are characterized by aberrant vascularity that fuels the formation of an immune-hostile microenvironment and induces resistance to immunotherapy. Vascular abnormalities may be driven by pro-angiogenic pathway activation and genetic reprogramming in tumor endothelial cells (ECs). Here, our kinome-wide screening of mesenchymal-like transcriptional activation in human glioblastoma (GBM)-derived ECs identifies p21-activated kinase 4 (PAK4) as a selective regulator of genetic reprogramming and aberrant vascularization.

Integration of Deep Learning Radiomics and Counts of Circulating Tumor Cells Improves Prediction of Outcomes of Early Stage NSCLC Patients Treated With Stereotactic Body Radiation Therapy.

Purpose: We develop a deep learning (DL) radiomics model and integrate it with circulating tumor cell (CTC) counts as a clinically useful prognostic marker for predicting recurrence outcomes of early-stage (ES) non-small cell lung cancer (NSCLC) patients treated with stereotactic body radiation therapy (SBRT).

Methods And Materials: A cohort of 421 NSCLC patients was used to train a DL model for gleaning informative imaging features from computed tomography (CT) data. The learned imaging features were optimized on a cohort of 98 ES-NSCLC patients treated with SBRT for predicting individual patient recurrence risks by building DL models on CT data and clinical measures.

Cell plasticity, senescence, and quiescence in cancer stem cells: Biological and therapeutic implications.

Cancer stem cells (CSCs) are a distinct population of cells within tumors with capabilities of self-renewal and tumorigenicity. CSCs play a pivotal role in cancer progression, metastasis, and relapse and tumor resistance to cytotoxic therapy. Emerging scientific evidence indicates that CSCs adopt several mechanisms, driven by cellular plasticity, senescence and quiescence, to maintain their self-renewal capability and to resist tumor microenvironmental stress and treatments.

Novel Treatment for Glioblastoma Delivered by a Radiation Responsive and Radiopaque Hydrogel.

Successful treatment of glioblastoma (GBM) is hampered by primary tumor recurrence after surgical resection and poor prognosis, despite adjuvant radiotherapy and chemotherapy. In search of improved outcomes for this disease, quisinostat appeared as a lead compound in drug screening. A delivery system was devised for this drug and to exploit current clinical methodology: an injectable hydrogel, loaded with both the quisinostat drug and radiopaque gold nanoparticles (AuNP) as contrast agent, that can release these payloads as a response to radiation.

Synergistic immunotherapy of glioblastoma by dual targeting of IL-6 and CD40.

Immunologically-cold tumors including glioblastoma (GBM) are refractory to checkpoint blockade therapy, largely due to extensive infiltration of immunosuppressive macrophages (Mϕs). Consistent with a pro-tumor role of IL-6 in alternative Mϕs polarization, we here show that targeting IL-6 by genetic ablation or pharmacological inhibition moderately improves T-cell infiltration into GBM and enhances mouse survival; however, IL-6 inhibition does not synergize PD-1 and CTLA-4 checkpoint blockade. Interestingly, anti-IL-6 therapy reduces CD40 expression in GBM-associated Mϕs.

Multiblock Discriminant Analysis of Integrative F-FDG-PET/CT Radiomics for Predicting Circulating Tumor Cells in Early-Stage Non-small Cell Lung Cancer Treated With Stereotactic Body Radiation Therapy.

Purpose: The main objective of the present study was to integrate F-FDG-PET/CT radiomics with multiblock discriminant analysis for predicting circulating tumor cells (CTCs) in early-stage non-small cell lung cancer (ES-NSCLC) treated with stereotactic body radiation therapy (SBRT).

Methods: Fifty-six patients with stage I NSCLC treated with SBRT underwent F-FDG-PET/CT imaging pre-SBRT and post-SBRT (median, 5 months; range, 3-10 months). CTCs were assessed via a telomerase-based assay before and within 3 months after SBRT and dichotomized at 5 and 1.

Personal and Prognostic: Tissue and Liquid Biomarkers of Radiotherapeutic Response in Non-Small Cell Lung Cancer.

Recent treatment advances have improved outcomes for patients with non-small cell lung cancer (NSCLC), often utilizing tumor molecular characterization to identify targetable mutations. This is further enhanced by advancements in "liquid biopsies", using peripheral blood for noninvasive, serial sampling of tumor biology. While tumor genomic alterations have established therapeutic implications in metastatic NSCLC, research is also ongoing to develop applications for tissue and liquid biomarkers in earlier stage disease, such as patients treated with radiation for early stage or locoregional NSCLC.

Combined fluorescence-guided surgery and photodynamic therapy for glioblastoma multiforme using cyanine and chlorin nanocluster.

Introduction: Glioblastoma multiforme (GBM) is the most common primary intracranial malignancy; survival can be improved by maximizing the extent-of-resection.

Methods: A near-infrared fluorophore (Indocyanine-Green, ICG) was combined with a photosensitizer (Chlorin-e6, Ce6) on the surface of superparamagnetic-iron-oxide-nanoparticles (SPIONs), all FDA-approved for clinical use, yielding a nanocluster (ICS) using a microemulsion. The physical-chemical properties of the ICS were systematically evaluated.

Evaluation of Diagnostic Accuracy Following the Coadministration of Delta-Aminolevulinic Acid and Second Window Indocyanine Green in Rodent and Human Glioblastomas.

Purpose: Fluorescence-guided-surgery offers intraoperative visualization of neoplastic tissue. Delta-aminolevulinic acid (5-ALA), which targets enzymatic abnormality in neoplastic cells, is the only approved agent for fluorescence-guided neurosurgery. More recently, we described Second Window Indocyanine Green (SWIG) which targets neoplastic tissue through enhanced vascular permeability.

Stormwater quality performance of permeable interlocking concrete pavement receiving run-on from an asphalt traffic lane in a cold climate.

Cities have turned to permeable pavements as one tool to mitigate the detrimental effects of urban runoff. Permeable pavements permit rainfall to infiltrate through a series of aggregate layers, where pollutants are filtered out before the water discharges via an underdrain or exfiltrates into native soils. This study reports on the water quality performance of a parking area retrofitted with permeable interlocking concrete pavement in Vermilion, OH, USA.

Circulating Tumor Cells Are Associated with Recurrent Disease in Patients with Early-Stage Non-Small Cell Lung Cancer Treated with Stereotactic Body Radiotherapy.

Purpose: Although stereotactic body radiotherapy (SBRT) is effective in early-stage non-small cell lung cancer (NSCLC), approximately 10%-15% of patients will fail regionally and 20%-25% distantly. We evaluate a novel circulating tumor cell (CTC) assay as a prognostic marker for increased risk of recurrence following SBRT.

Experimental Design: Ninety-two subjects (median age, 71 years) with T1a (64%), T1b (23%), or T2a (13%) stage I NSCLC treated with SBRT were prospectively enrolled.

A Patient-Derived Glioblastoma Organoid Model and Biobank Recapitulates Inter- and Intra-tumoral Heterogeneity.

Glioblastomas exhibit vast inter- and intra-tumoral heterogeneity, complicating the development of effective therapeutic strategies. Current in vitro models are limited in preserving the cellular and mutational diversity of parental tumors and require a prolonged generation time. Here, we report methods for generating and biobanking patient-derived glioblastoma organoids (GBOs) that recapitulate the histological features, cellular diversity, gene expression, and mutational profiles of their corresponding parental tumors.

Rapid and ultrasensitive digital PCR (dPCR) profiling of EGFRvIII in tumor cells and tissues.

Background: Amplification of the epidermal growth factor receptor () gene is commonly found in glioblastoma (GBM). About 57% GBM overexpresses EGFR and are associated with tumor progression, poor prognosis, and shorter life expectancy. Molecular profiling of solid tumors usually takes several weeks and may be biased by intrinsic tumor heterogeneity.

Clinical activity of the tyrosine kinase inhibitor osimertinib in -mutant glioblastoma.

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and carries a dismal prognosis. The gene is among the most commonly deranged genes in GBM and thus an important therapeutic target. We report the case of a young female with heavily pretreated -mutated GBM, for whom we initiated osimertinib, an oral, third-generation tyrosine kinase inhibitor that irreversibly inhibits EGFR and has significant brain penetration.

Near-Infrared Imaging with Second-Window Indocyanine Green in Newly Diagnosed High-Grade Gliomas Predicts Gadolinium Enhancement on Postoperative Magnetic Resonance Imaging.

Purpose: Intraoperative molecular imaging with tumor-targeting fluorophores offers real-time detection of neoplastic tissue. The second window indocyanine green (SWIG) technique relies on passive accumulation of indocyanine green (ICG), a near-infrared fluorophore, in neoplastic tissues. In this study, we explore the ability of SWIG to detect neoplastic tissue and to predict postoperative magnetic resonance imaging (MRI) findings intraoperatively.

Early Detection of Recurrence in Patients With Locally Advanced Non-Small-Cell Lung Cancer via Circulating Tumor Cell Analysis.

Background: Assays to identify circulating tumor cells (CTCs) might allow for noninvasive and sequential monitoring of lung cancer. We investigated whether serial CTC analysis could complement conventional imaging for detecting recurrences after treatment in patients with locally advanced non-small-cell lung cancer (LA-NSCLC).

Patients And Methods: Patients with LA-NSCLC (stage II-III) who definitively received concurrent chemoradiation were prospectively enrolled, with CTCs from peripheral blood samples identified using an adenoviral probe that detects elevated telomerase activity present in nearly all lung cancer cells.