Chaotropic Effect-Induced Sol-Gel Transition and Radical Stabilization for Bacterially Sensitive Near-Infrared Photothermal Therapy.

Deep-seated bacterial infections (DBIs) are stubborn and deeply penetrate tissues. Eliminating deep-seated bacteria and promoting tissue regeneration remain great challenges. Here, a novel radical-containing hydrogel (SFT-B Gel) cross-linked by a chaotropic effect was designed for the sensing of DBIs and near-infrared photothermal therapy (NIR-II PTT). A silk fibroin solution stained with 4,4',4″-(1,3,5-triazine-2,4,6-triyl)tris(1-methylpyridin-1-ium) (TPT3+) was employed as the backbone, which could be cross-linked by a closo-dodecaborate cluster (B12H122-) through a chaotropic effect to form the SFT-B Gel. More interestingly, the SFT-B Gel exhibited the ability to sense DBIs, which could generate a TPT2+• radical with obvious color changes in the presence of bacteria. The radical-containing SFT-B Gel (SFT-B★ Gel) possessed strong NIR-II absorption and a remarkable photothermal effect, thus demonstrating excellent NIR-II PTT antibacterial activity for the treatment of DBIs. This work provides a new approach for the construction of intelligent hydrogels with unique properties using a chaotropic effect.

Alternating magnetic field guiding system for MNP hyperthermia treatment of deep-seated cancers.

OBJECTIVES: Demonstrate the potential application of a novel, endoscope-like device to guide and focus an alternating magnetic field (AMF) for treating deep-seated cancers via magnetic nanoparticle hyperthermia (MNPH). METHODS: AMF delivery, MNP activation, and eddy current distribution characteristics are investigated through experimental studies in phantoms and computational simulations using a full 3-dimensional human model. The 3D simulations compare the novel device to traditional AMF designs, including a MagForce-like, two-coil system (used clinically) and a single surface-coil system. RESULTS: The results demonstrate that this approach can deliver the same magnetic field strength at the prostate's centroid as traditional AMF designs, while reducing eddy current heating by 2 to 6 times. At the same level of normal tissue heating, this method provides 5.0 times, 1.5 times, and 0.92 times the magnetic field strength to the nearest, centroid, and farthest regions of the prostate, respectively. CONCLUSIONS: These results demonstrate proof-of-concept for an endoscopic magnetic field guiding and focusing system capable of delivering clinically relevant AMF from a distance. This innovative approach offers a promising alternative to conventional field delivery methods by directing AMF through the body, concentrating it in the tumor region, reducing eddy currents in surrounding healthy tissue, and avoiding exposure of nearby metallic implants.

Therapeutic drug monitoring of azole antifungal agents.

Deep-seated mycoses are generally opportunistic infections that are difficult to diagnose and treat. They are expected to increase with the spread of advanced medical care and aging populations, thus highlighting the need for safe, effective, and rapid drug-based treatments. Depending on a patient's age, sex, underlying diseases, and immune system status, therapeutic drug monitoring (TDM) may be important for assessing variable pharmacokinetic parameters, as well as preventing drug-drug interactions, adverse events, and breakthrough infections caused by fungal resistance. Azole antifungal agents play an important role in the prevention and treatment of deep-seated fungal infections, with each azoles having its own unique pharmacokinetic properties and specific adverse events. Therefore, it is necessary to use national and international guidelines to build evidence for the expansion of TDM indications. This review focuses on the clinical utility and future perspectives of TDM using azole antifungal agents, in the context of recent evidence in the literature.

Stereotactic radiosurgery for intracranial cavernous malformations of the deep-seated locations: systematic review and meta-analysis.

OBJECTIVE: To determine the outcomes of stereotactic radiosurgery (SRS) for deep-seated (brainstem, basal ganglia, thalamus, cerebellar peduncle) intracranial cavernous malformations (ICMs). METHODS: A systematic review and meta-analysis was performed according to PRISMA and MOOSE guidelines. The main outcomes were comparing pre- and post-SRS hemorrhage rates, using the pooled risk ratios (RR) as the measure of effect. Additionally, the study assessed lesion volume changes and radiation-injury incidence. RESULTS: Data of 850 patients across 14 studies were included in the meta-analysis. The pooled RR of all deep-seated ICMs show a decrease in hemorrhage rate after SRS compared to pre-SRS over the total follow-up period (RR =0.13), initial 2 years (RR =0.22), and after 2 years (RR =0.07). For 9 studies that reported hemorrhage rate of the brainstem only, the pooled RR shows a decrease of hemorrhage rate after SRS compared to pre-SRS over the total follow-up period (RR =0.13), initial 2 years (RR =0.19), and after 2 years (RR =0.07). Volumetric regression was achieved in 44.25% and stability in 56.1%. The pooled incidence of symptomatic and permanent radiation injury was 9% (95% CI, 7-11) and 3% (95% CI, 0-1.9%), respectively. CONCLUSION: SRS appears effective in reducing hemorrhage rates for deep-seated ICMs. The risk of symptomatic radiation injury is low. Given the high risk of surgical morbidity, SRS is a reasonable treatment option for patients with deep-seated ICMs with at least one prior hemorrhage.

BF2-Bridged Azafulvene Dimer-Based 1064 nm Laser-Driven Superior Photothermal Agent for Deep-Seated Tumor Therapy.

Small organic photothermal agents (PTAs) with absorption bands located in the second near-infrared (NIR-II, 1000-1700 nm) window are highly desirable for effectively combating deep-seated tumors. However, the rarely reported NIR-II absorbing PTAs still suffer from a low molar extinction coefficient (MEC, ϵ), inadequate chemostability and photostability, as well as the high light power density required during the therapeutic process. Herein, we developed a series of boron difluoride bridged azafulvene dimer acceptor-integrated small organic PTAs. The B-N coordination bonds in the π-conjugated azafulvene dimer backbone endow it the strong electron-withdrawing ability, facilitating the vigorous donor-acceptor-donor (D-A-D) structure PTAs with NIR-II absorption. Notably, the PTA namely OTTBF shows high MEC (7.21×104 M-1 cm-1), ultrahigh chemo- and photo-stability. After encapsulated into water-dispersible nanoparticles, OTTBF NPs can achieve remarkable photothermal conversion effect under 1064 nm irradiation with a light density as low as 0.7 W cm-2, which is the lowest reported NIR-II light power used in PTT process as we know. Furthermore, OTTBF NPs have been successfully applied for in vitro and in vivo deep-seated cancer treatments under 1064 nm laser. This study provides an insight into the future exploration of versatile D-A-D structured NIR-II absorption organic PTAs for biomedical applications.

A NIR-Light-Activated and Lysosomal-Targeted Pt(II) Metallacycle for Highly Potent Evoking of Immunogenic Cell Death that Potentiates Cancer Immunotherapy of Deep-Seated Tumors.

Though platinum (Pt)-based complexes have been recently exploited as immunogenic cell death (ICD) inducers for activating immunotherapy, the effective activation of sufficient immune responses with minimal side effects in deep-seated tumors remains a formidable challenge. Herein, we propose the first example of a near-infrared (NIR) light-activated and lysosomal targeted Pt(II) metallacycle (1) as a supramolecular ICD inducer. 1 synergistically potentiates immunomodulatory response in deep-seated tumors via multiple-regulated approaches, involving NIR light excitation, boosted reactive oxygen species (ROS) generation, good selectivity between normal and tumor cells, and enhanced tumor penetration/retention capabilities. Specifically, 1 has excellent depth-activated ROS production (~7 mm), accompanied by strong anti-diffusion and anti-ROS quenching ability. In vitro experiments demonstrate that 1 exhibits significant cellular uptake and ROS generation in tumor cells as well as respective multicellular tumor spheroids. Based on these advantages, 1 induces a more efficient ICD in an ultralow dose (i.e., 5 µM) compared with the clinical ICD inducer-oxaliplatin (300 µM). In vivo, vaccination experiments further demonstrate that 1 serves as a potent ICD inducer through eliciting CD8+/CD4+ T cell response and Foxp3+ T cell depletion with negligible adverse effects. This study pioneers a promising avenue for safe and effective metal-based ICD agents in immunotherapy.

MRI-guided laser interstitial thermal therapy for deep-seated gliomas in children with neurofibromatosis type 1: report of two cases.

PURPOSE: Nearly a quarter of neurofibromatosis type 1 (NF 1)- associated diencephalic low-grade tumors are refractory to chemotherapy. Addition of alternative treatment options with laser interstitial thermal therapy will have a positive impact on the outcome of these patients. METHODS: We report on two illustrated cases of pediatric NF1- associated, chemoresistant, WHO grade 1 pilocytic astrocytomas treated with laser interstitial thermal therapy (LITT). RESULTS: Both tumors responded favorably to LITT. CONCLUSION: LITT should be considered as a treatment option for chemoresistant deep-seated NF1-associated low-grade gliomas.

Performance of existing clinical scores and laboratory tests for the diagnosis of invasive candidiasis in critically ill, nonneutropenic, adult patients: A systematic review with qualitative evidence synthesis.

BACKGROUND: The Fungal Infections Definitions in Intensive Care Unit (ICU) patients (FUNDICU) project aims to provide standard sets of definitions for invasive fungal diseases in critically ill, adult patients. OBJECTIVES: To summarise the available evidence on the diagnostic performance of clinical scores and laboratory tests for invasive candidiasis (IC) in nonneutropenic, adult critically ill patients. METHODS: A systematic review was performed to evaluate studies assessing the diagnostic performance for IC of clinical scores and/or laboratory tests vs. a reference standard or a reference definition in critically ill, nonneutropenic, adult patients in ICU. RESULTS: Clinical scores, despite the heterogeneity of study populations and IC prevalences, constantly showed a high negative predictive value (NPV) and a low positive predictive value (PPV) for the diagnosis of IC in the target population. Fungal antigen-based biomarkers (with most studies assessing serum beta-D-glucan) retained a high NPV similar to that of clinical scores, with a higher PPV, although the latter showed important heterogeneity across studies, possibly reflecting the targeted or untargeted use of these tests in patients with a consistent clinical picture and risk factors for IC. CONCLUSIONS: Both clinical scores and laboratory tests showed high NPV for the diagnosis of IC in nonneutropenic critically ill patients. The PPV of laboratory tests varies significantly according to the baseline patients' risk of IC. This qualitative synthesis will provide the FUNDICU panel with baseline evidence to be considered during the development of definitions of IC in critically ill, nonneutropenic adult patients in ICU.

A new simple and free tubular device for microscopic transcortical approach to deep-seated lesions: technical note and case example.

BACKGROUND: Surgery for deep-seated brain tumors remains challenging. Transcortical approaches often require brain retraction to ensure an adequate surgical corridor, thus possibly leading to brain damage. Various techniques have been developed to minimize brain retraction such as self-retaining retractors, endoscopic approaches, or tubular retractor systems. Even if they evenly distribute the mechanical pressure over the parenchyma, rigid retractors can also cause some degree of brain damage and have significant disadvantages. We propose here a soft cottonoid retractor for microscopic resection of deep-seated and ventricular lesions. METHODS: Through a small corticectomy, a channel route with a blunt cannula is developed until the lesion is reached. Then, a "balloon-like system" made with a surgical glove is progressively inflated, dilatating the surgical corridor. A mini-tubular device, handmade by suturing a surgical cottonoid, is positioned into the corridor, unfolded, and sutured to the edge of the dura, to prevent it from being progressively expelled from the working channel. This allows a good visualization of the lesion and surrounding structures under the microscope. RESULTS: Advantages of this technique are the softness of the tube walls, the absence of rigid arm to hold the tube, and the possibility for the tube to follow the movements of the instruments and to modify its orientation according to the working area. CONCLUSION: This simple and inexpensive tubular working channel for microscopic transcortical approach is a valuable alternative technique to traditional self-retaining retractor and rigid tube for the microsurgical resection of deep-seated brain tumors.

Laser interstitial thermal therapy for newly diagnosed glioblastoma.

Gliomas are the most frequent primary brain tumor in adults. Patients with glioblastoma (GBM) tumors deemed inoperable with open surgical techniques and treated only with chemo/radiation have a median overall survival of less than 9 months. Laser interstitial thermal therapy (LITT) has emerged as a cytoreductive alternative to surgery for these patients. The present study describes the outcomes of twenty patients with newly diagnosed, IDH wild-type glioblastoma treated with LITT. We retrospectively reviewed patients with newly diagnosed, unresectable GBM who underwent LITT at our institution. Progression-free survival (PFS) was the primary endpoint measured in our study, defined as time from LITT to disease progression. Results Twenty patients were identified with newly diagnosed, inoperable GBM lesions who underwent LITT. The overall median PFS was 4 months (95% CI = 2 - N/A, upper limit not reached). The median progression-free survival (PFS) for patients with less than 1 cm 3 residual tumor (gross total ablation, GTA) was 7 months (95% CI = 6 - N/A, upper limit not reached), compared to 2 months (95% CI = 1 - upper limit not reached) for patients with a lower GTA (p = .0019). The median overall survival was 11 months (95% CI = 6 - upper limit not reached). Preoperative Karnofsky performance score (KPS) less than or equal to 80 and deep-seated tumor location were significantly associated with decreased PFS (HR, .18, p = .03; HR, .08, p = .03, respectively). At the end of 1 month, only 4 patients (20%) experienced persistent motor deficits. LITT is a safe and effective treatment for patients with unresectable, untreated GBM with rates of survival and local recurrence comparable to patients with surgically accessible lesions treated with conventional resection. Careful patient selection is needed to determine if GTA is attainable.

Tailored Engineering of Novel Xanthonium Polymethine Dyes for Synergetic PDT and PTT Triggered by 1064 nm Laser toward Deep-Seated Tumors.

Small molecular dye that simultaneously exerts dual PDT/PTT effects as well as florescence imaging triggered by a single NIR-II light has never been reported to date. Apart from the huge challenge in pushing absorption profile into NIR-II region, fine-tuning dyes' excited state via rational structure design to meet all three functions, especially oxygen photosensitization, remains the most prominent throttle. Herein, five novel NIR-II dyes (BHs) are productively developed by strategically conjugating dyad innovative xanthonium with sequentially extended polymethine bridges, enabling intense absorption from 890 to 1206 nm, significantly 400 nm longer than conventional cyanine dyes with same polymethines. More importantly, owning to high resonance and favorable excited state energy population induced by greater rigidity via ring-fused amino, BH 1024 exhibits best singlet oxygen generation capability, moderate photothermal heating, and considerable fluorescence under 1064 nm laser irradiation. Furthermore, BH 1024 is encapsulated into folate-functionalized polymer, which demonstrated a synergetic PDT/PTT effect in vitro and in vivo, eventually achieving solid tumors elimination under NIR-II fluorescence guide. As far as it is known, this is the first time small molecular dyes for NIR-II PDT or NIR-II PDT/PTT are explored and designed.

Active Faulting and Deep-Seated Gravitational Slope Deformation in Carbonate Rocks (Central Apennines, Italy): A New "Close-Up" View.

Active faulting and deep-seated gravitational slope deformation (DGSD) are common geological hazards in mountain belts worldwide. In the Italian central Apennines, kilometer-thick carbonate sedimentary sequences are cut by major active normal faults that shape the landscape, generating intermontane basins. Geomorphological observations suggest that the DGSDs are commonly located in fault footwalls. We selected five mountain slopes affected by DGSD and exposing the footwall of active seismogenic normal faults exhumed from 2 to 0.5 km depth. Field structural analysis of the slopes shows that DGSDs exploit preexisting surfaces formed both at depth and near the ground surface by tectonic faulting and, locally, by gravitational collapse. Furthermore, the exposure of sharp scarps along mountain slopes in the central Apennines can be enhanced either by surface seismic rupturing or gravitational movements (e.g., DGSD) or by a combination of the two. At the microscale, DGSDs accommodate deformation mechanisms similar to those associated with tectonic faulting. The widespread compaction of micro-grains (e.g., clast indentation), observed in the matrix of both normal faults and DGSD slip zones, is consistent with clast fragmentation, fluid-infiltration, and congruent pressure-solution active at low ambient temperatures (<60°C) and lithostatic pressures (<80 MPa). Although clast comminution is more intense in the slip zones of normal faults because of the larger displacement accommodated, we are not able to find microstructural markers that allow us to uniquely distinguish faults from DGSDs.

Predictive variables for the presence of vascular malformations as the cause of basal ganglia hemorrhages.

To evaluate potential bleeding sources and predictive variables for basal ganglia hemorrhage. Fifty-seven patients with basal ganglia hemorrhage admitted to our neurosurgical ICU between 2005 and 2016 were retrospectively reviewed. Univariate and multivariate logistic analyses were used to assess predictive variables for identifying the bleeding source and outcome. ROC curves were plotted for a cutoff value for age and hematoma volume in patients with a vascular pathology and patients without a vascular pathology. In 19 patients, a vascular pathology was found as a bleeding source for basal ganglia hemorrhage (33.3%; 95% CI 0.33 [0.21; 0.47]). Most of the arteriovenous malformations (AVMs) were small sized (61.1%) with deep venous drainage (94.4%). A single vein was found in 17 (77.8%) AVMs. Patients younger than 50 years were more likely to have a vascular pathology (AUC of 0.85 [95% CI 0.73; 0.98]; p = 0.001; cutoff value 46.5 years). Four (21.1%) patients older than 50 years suffered an AVM hemorrhage; 75% of them were located ventricular or thalamic. Hematoma volume in patients with AVM hemorrhage was predominantly less than 30 cm3 (AUC of 0.86 [95% CI 0.76; 0.96]; p = 0.001; cutoff value 12.6 cm3). Outcome in patients with a vascular pathology was more often favorable as in patients with a spontaneous hemorrhage (92.9% vs. 7.1%; p = 0.001). Young age and hematoma volume are significant predictors for presence of a bleeding source and outcome in basal ganglia hemorrhage. These criteria must be taken into account in the emergency diagnostics and therapy in order to achieve a rapid and sufficient result. Outcome in patients with AVM hemorrhage in basal ganglia is more often favorable.

Machine Learning: New Potential for Local and Regional Deep-Seated Landslide Nowcasting.

Nowcasting and early warning systems for landslide hazards have been implemented mostly at the slope or catchment scale. These systems are often difficult to implement at regional scale or in remote areas. Machine Learning and satellite remote sensing products offer new opportunities for both local and regional monitoring of deep-seated landslide deformation and associated processes. Here, we list the key variables of the landslide process and the associated satellite remote sensing products, as well as the available machine learning algorithms and their current use in the field. Furthermore, we discuss both the challenges for the integration in an early warning system, and the risks and opportunities arising from the limited physical constraints in machine learning. This review shows that data products and algorithms are available, and that the technology is ready to be tested for regional applications.

Quantitative assessment of deep-seated CO2 leakage around CO2-rich springs with low soil CO2 efflux using end-member mixing analysis and carbon isotopes.

This study examined a mountainous area with two hydrochemically distinct CO2-rich springs to understand the origin, flow, and leakage of CO2, which may provide implications for precise monitoring of CO2 leakage in geological carbon storage (GCS) sites. The carbon isotopic compositions of dissolved inorganic carbon (DIC) in CO2-rich water (δ13CDIC) and those of soil CO2 (δ13CCO2) indicated a deep-seated CO2 supply to the near-surface environment in the study area. The hydrochemical difference (e.g. pH, total dissolved solids) for the two CO2-rich springs separated by 7 m, despite similar δ13CDIC and partial pressure of CO2, was considered as the result of different evolution of shallow groundwater affected by deep-seated CO2 preferentially rising along fracture zones. Electrical resistivity tomography also suggested flow through fracture zones beneath the CO2-rich springs, showing low resistivity compared to other surveyed zones. However, soil CO2 efflux was low compared to that in other natural CO2 emission sites, and in particular it was noticeably low near the CO2-rich springs, whereas δ13CCO2 was high close the CO2-rich springs. The dissolution of CO2 in the near-surface water body seemed to decrease the deep-seated CO2 leakage through the soil layer, while δ13CCO2 imprinted the source. End-member mixing analysis was performed to assess the contribution of deep-seated CO2 to the low soil CO2 efflux by assuming that atmospheric CO2 and soil CO2 (by respiration) as well as deep-seated CO2 contribute to the soil CO2 efflux. For each end-member, characteristic δ13CCO2 and CO2 concentrations were defined, and then their apportionment to soil CO2 efflux was estimated. The resultant proportion of deep-seated CO2 was up to 8.8%. Unlike the spatial distribution of high soil CO2 efflux, high proportions exceeding 3% were found around the CO2-rich springs along the east-west valley. The study results indicate that soil CO2 efflux measurement should be combined with carbon isotopic analysis in GCS sites for CO2 leakage detection because CO2 dissolution in the underground water body may blur leakage detection on the surface. The implication of this study is the need to quantitatively assess the contribution of deep-seated CO2 using the soil CO2 concentration, soil CO2 efflux, and δ13CCO2 at each measurement site.

What is the best therapeutic approach to a pediatric patient with a deep-seated brain AVM?

Although brain arteriovenous malformations (bAVMs) account for a very small proportion of cerebral pathologies in the pediatric population, they are the cause of roughly 50% of spontaneous intracranial hemorrhages. Pediatric bAVMs tend to rupture more frequently and seem to have higher recurrence rates than bAVMs in adults. Thus, the management of pediatric bAVMs is particularly challenging. In general, the treatment options are conservative treatment, microsurgery, endovascular therapy (EVT), gamma knife radiosurgery (GKRS), proton-beam stereotactic radiosurgery (PSRS), or a combination of the above. In order to identify the best approach to deep-seated pediatric bAVMs, we performed a systematic review, according to the PRISMA guidelines. None of the options seem to offer a clear advantage over the others when used alone. Microsurgery provides the highest obliteration rate, but has higher incidence of neurological complications. EVT may play a role when used as adjuvant therapy, but as a stand-alone therapy, the efficacy is low and the long-term side effects of radiation from the multiple sessions required in deep-seated pediatric bAVMs are still unknown. GKRS has a low risk of complication, but the obliteration rates still leave much to be desired. Finally, PSRS offers promising results with a more accurate radiation that avoids the surrounding tissue, but data is limited due to its recent introduction. Overall, a multi-modal approach, or even an active surveillance, might be the most suitable when facing deep-seated bAVM, considering the difficulty of their management and the high risk of complications in the pediatric population.

Frame-based stereotactic biopsy of deep-seated and midline structures in 511 procedures: feasibility, risk profile, and diagnostic yield.

OBJECTIVES: We evaluated the feasibility, safety, and diagnostic yield of frame-based stereotactic biopsies (SB) in lesions located in deep-seated and midline structures of the brain to analyze these parameters in comparison to other brain areas. PATIENTS AND METHODS: In a retrospective, tertiary care single-center analysis, we identified all patients who received SB for lesions localized in deep-seated and midline structures (corpus callosum, basal ganglia, pineal region, sella, thalamus, and brainstem) between January 1996 and June 2015. Study participants were between 1 and 82 years. We evaluated the feasibility, procedural complications (mortality, transient and permanent morbidity), and diagnostic yield. We further performed a risk analysis of factors influencing the latter parameters. Chi-square test, Student t test, and Mann-Whitney rank-sum test were used for statistical analysis. RESULTS: Four hundred eighty-nine patients receiving 511 SB procedures (median age 48.5 years, range 1-82; median Karnofsky Performance Score 80%, range 50-100%, 43.8% female/56.2% male) were identified. Lesions were localized in the corpus callosum (29.5%), basal ganglia (17.0%), pineal region (11.5%), sella (7.8%), thalamus (4.3%), brainstem (28.8%), and others (1.1%). Procedure-related mortality was 0%, and permanent morbidity was 0.4%. Transient morbidity was 9.6%. Histological diagnosis was possible in 99.2% (low-grade gliomas 16.2%, high-grade gliomas 40.3%, other tumors in 27.8%, no neoplastic lesions 14.5%, no definitive histological diagnosis 0.8%). Only the pons location correlated significantly with transient morbidity (p < 0.001). CONCLUSION: In experienced centers, frame-based stereotactic biopsy is a safe diagnostic tool with a high diagnostic yield also for deep-seated and midline lesions.

Comparison of treatment planning approaches for spatially fractionated irradiation of deep tumors.

PURPOSE: The purpose of this work was to compare the dosimetry and delivery times of 3D-conformal (3DCRT)-, volumetric modulated arc therapy (VMAT)-, and tomotherapy-based approaches for spatially fractionated radiation therapy for deep tumor targets. METHODS: Two virtual GRID phantoms were created consisting of 7 "target" cylinders (1-cm diameter) aligned longitudinally along the tumor in a honey-comb pattern, mimicking a conventional GRID block, with 2-cm center-to-center spacing (GRID2 cm ) and 3-cm center-to-center spacing (GRID3 cm ), all contained within a larger cylinder (8 and 10 cm in diameter for the GRID2 cm and GRID3 cm , respectively). In a single patient, a GRID3 cm structure was created within the gross tumor volume (GTV). Tomotherapy, VMAT (6 MV + 6 MV-flattening-filter-free) and multi-leaf collimator segment 3DCRT (6 MV) plans were created using commercially available software. Two tomotherapy plans were created with field widths (TOMO2.5 cm ) 2.5 cm and (TOMO5 cm ) 5 cm. Prescriptions for all plans were set to deliver a mean dose of 15 Gy to the GRID targets in one fraction. The mean dose to the GRID target and the heterogeneity of the dose distribution (peak-to-valley and peak-to-edge dose ratios) inside the GRID target were obtained. The volume of normal tissue receiving 7.5 Gy was determined. RESULTS: The peak-to-valley ratios for GRID2 cm /GRID3 cm /Patient were 2.1/2.3/2.8, 1.7/1.5/2.8, 1.7/1.9/2.4, and 1.8/2.0/2.8 for the 3DCRT, VMAT, TOMO5 cm , and TOMO2.5 cm plans, respectively. The peak-to-edge ratios for GRID2 cm /GRID3 cm /Patient were 2.8/3.2/5.4, 2.1/1.8/5.4, 2.0/2.2/3.9, 2.1/2.7/5.2 and for the 3DCRT, VMAT, TOMO5 cm , and TOMO2.5 cm plans, respectively. The volume of normal tissue receiving 7.5 Gy was lowest in the TOMO2.5 cm plan (GRID2 cm /GRID3 cm /Patient = 54 cm3 /19 cm3 /10 cm3 ). The VMAT plans had the lowest delivery times (GRID2 cm /GRID3 cm /Patient = 17 min/8 min/9 min). CONCLUSION: Our results present, for the first time, preliminary evidence comparing IMRT-GRID approaches which result in high-dose "islands" within a target, mimicking what is achieved with a conventional GRID block but without high-dose "tail" regions outside of the target. These approaches differ modestly in their ability to achieve high peak-to-edge ratios and also differ in delivery times.

Structure from Motion Multisource Application for Landslide Characterization and Monitoring: The Champlas du Col Case Study, Sestriere, North-Western Italy.

Structure from Motion (SfM) is a powerful tool to provide 3D point clouds from a sequence of images taken from different remote sensing technologies. The use of this approach for processing images captured from both Remotely Piloted Aerial Vehicles (RPAS), historical aerial photograms, and smartphones, constitutes a valuable solution for the identification and characterization of active landslides. We applied SfM to process all the acquired and available images for the study of the Champlas du Col landslide, a complex slope instability reactivated in spring 2018 in the Piemonte Region (north-western Italy). This last reactivation of the slide, principally due to snow melting at the end of the winter season, interrupted the main road used to reach Sestriere, one of the most famous ski resorts in north-western Italy. We tested how SfM can be applied to process high-resolution multisource datasets by processing: (i) historical aerial photograms collected from five diverse regional flights, (ii) RGB and multi-spectral images acquired by two RPAS, taken in different moments, and (iii) terrestrial sequences of the most representative kinematic elements due to the evolution of the landslide. In addition, we obtained an overall framework of the historical development of the area of interest, and distinguished several generations of landslides. Moreover, an in-depth geomorphological characterization of the Champlas du Col landslide reactivation was done, by testing a cost-effective and rapid methodology based on SfM principles, which is easily repeatable to characterize and investigate active landslides.

Development of a functionalized UV-emitting nanocomposite for the treatment of cancer using indirect photodynamic therapy.

BACKGROUND: Photodynamic therapy is a promising cancer therapy modality but its application for deep-seated tumor is mainly hindered by the shallow penetration of visible light. X-ray-mediated photodynamic therapy (PDT) has gained a major attention owing to the limitless penetration of X-rays. However, substantial outcomes have still not been achieved due to the low luminescence efficiency of scintillating nanoparticles and weak energy transfer to the photosensitizer. The present work describes the development of Y2.99Pr0.01Al5O12-based (YP) mesoporous silica coated nanoparticles, multifunctionalized with protoporphyrin IX (PpIX) and folic acid (YPMS@PpIX@FA) for potential application in targeted deep PDT. RESULTS: A YP nanophosphor core was synthesized using the sol-gel method to be used as X-ray energy transducer and was then covered with a mesoporous silica layer. The luminescence analysis indicated a good spectral overlap between the PpIX and nanoscintillator at the Soret as well as Q-band region. The comparison of the emission spectra with or without PpIX showed signs of energy transfer, a prerequisite for deep PDT. In vitro studies showed the preferential uptake of the nanocomposite in cancer cells expressing the folate receptorFolr1, validating the targeting efficiency. Direct activation of conjugated PpIX with UVA in vitro induced ROS production causing breast and prostate cancer cell death indicating that the PpIX retained its activity after conjugation to the nanocomposite. The in vivo toxicity analysis showed the good biocompatibility and non-immunogenic response of YPMS@PpIX@FA. CONCLUSION: Our results indicate that YPMS@PpIX@FA nanocomposites are promising candidates for X-ray-mediated PDT of deep-seated tumors. The design of these nanoparticles allows the functionalization with exchangeable targeting ligands thus offering versatility, in order to target various cancer cells, expressing different molecular targets on their surface.