Combined Ferritin Nanocarriers with ICG for Effective Phototherapy Against Breast Cancer.

Introduction: Photodynamic Therapy (PDT) is a promising, minimally invasive treatment for cancer with high immunostimulatory potential, no reported drug resistance, and reduced side effects. Indocyanine Green (ICG) has been used as a photosensitizer (PS) for PDT, although its poor stability and low tumor-target specificity strongly limit its efficacy. To overcome these limitations, ICG can be formulated as a tumor-targeting nanoparticle (NP). Methods: We nanoformulated ICG into recombinant heavy-ferritin nanocages (HFn-ICG). HFn has a specific interaction with transferrin receptor 1 (TfR1), which is overexpressed in most tumors, thus increasing HFn tumor tropism. First, we tested the properties of HFn-ICG as a PS upon irradiation with a continuous-wave diode laser. Then, we evaluated PDT efficacy in two breast cancer (BC) cell lines with different TfR1 expression levels. Finally, we measured the levels of intracellular endogenous heavy ferritin (H-Fn) after PDT treatment. In fact, it is known that cells undergoing ROS-induced autophagy, as in PDT, tend to increase their ferritin levels as a defence mechanism. By measuring intracellular H-Fn, we verified whether this interplay between internalized HFn and endogenous H-Fn could be used to maximize HFn uptake and PDT efficacy. Results: We previously demonstrated that HFn-ICG stabilized ICG molecules and increased their delivery to the target site in vitro and in vivo for fluorescence guided surgery. Here, with the aim of using HFn-ICG for PDT, we showed that HFn-ICG improved treatment efficacy in BC cells, depending on their TfR1 expression. Our data revealed that endogenous H-Fn levels were increased after PDT treatment, suggesting that this defence reaction against oxidative stress could be used to enhance HFn-ICG uptake in cells, increasing treatment efficacy. Conclusion: The strong PDT efficacy and peculiar Trojan horse-like mechanism, that we revealed for the first time in literature, confirmed the promising application of HFn-ICG in PDT.

Optical signatures of thermal damage on ex-vivo brain, lung and heart tissues using time-domain diffuse optical spectroscopy.

Thermal therapies treat tumors by means of heat, greatly reducing pain, post-operation complications, and cost as compared to traditional methods. Yet, effective tools to avoid under- or over-treatment are mostly needed, to guide surgeons in laparoscopic interventions. In this work, we investigated the temperature-dependent optical signatures of ex-vivo calf brain, lung, and heart tissues based on the reduced scattering and absorption coefficients in the near-infrared spectral range (657 to 1107 nm). These spectra were measured by time domain diffuse optics, applying a step-like spatially homogeneous thermal treatment at 43 °C, 60 °C, and 80 °C. We found three main increases in scattering spectra, possibly due to the denaturation of collagen, myosin, and the proteins' secondary structure. After 75 °C, we found the rise of two new peaks at 770 and 830 nm in the absorption spectra due to the formation of a new chromophore, possibly related to hemoglobin or myoglobin. This research marks a significant step forward in controlling thermal therapies with diffuse optical techniques by identifying several key markers of thermal damage. This could enhance the ability to monitor and adjust treatment in real-time, promising improved outcomes in tumor therapy.

The new Italian SIDAPA Baseline Series for patch testing (2023): an update according to the new regulatory pathway for contact allergens.

Allergic contact dermatitis (ACD) is a common inflammatory skin disease caused by delayed hypersensitivity to chemical and biotic contact allergens. ACD significantly affects the patients' quality of life negatively impacting both occupational and non-occupational settings. Patch testing is the gold standard diagnostic in vivo test to precise the ACD etiology and to correctly perform prevention. According to the Italian Medicines Agency (AIFA) legislative decree no. 178 of 29th May 1991, allergens are defined as medicines and therefore they are subject to strict regulation. In 2017, AIFA (decree no. 2130/2017) started a procedure to regulate contact allergens on the Italian market and actually the contact allergens temporarily authorized are reported in AIFA decree no. 98/2022, valid until November 2023. The availability on the market of contact allergens to diagnose ACD and continuous updating on the basis of new epidemiological trends are mandatory, jointly with the continuous update of the baseline and integrative series for patch testing. For this reason, the scientific community represented in Italy by the Skin Allergies Study Group of SIDeMaST (Italian Society of Dermatology and Venereology) and SIDAPA (Italian Society of Allergological, Occupational and Environmental Dermatology) are constantly working, in close relationship with the European scientific communities with large expertise in this important sector of the modern Dermatology. Herein, we report the setting up of regulatory legislation by AIFA and the new Italian Adult Baseline Series for patch testing.

Non-Fourier Bioheat Transfer Analysis in Brain Tissue During Interstitial Laser Ablation: Analysis of Multiple Influential Factors.

This work presents the dual-phase lag-based non-Fourier bioheat transfer model of brain tissue subjected to interstitial laser ablation. The finite element method has been utilized to predict the brain tissue's temperature distributions and ablation volumes. A sensitivity analysis has been conducted to quantify the effect of variations in the input laser power, treatment time, laser fiber diameter, laser wavelength, and non-Fourier phase lags. Notably, in this work, the temperature-dependent thermal properties of brain tissue have been considered. The developed model has been validated by comparing the temperature obtained from the numerical and ex vivo brain tissue during interstitial laser ablation. The ex vivo brain model has been further extended to in vivo settings by incorporating the blood perfusion effects. The results of the systematic analysis highlight the importance of considering temperature-dependent thermal properties of the brain tissue, non-Fourier behavior, and microvascular perfusion effects in the computational models for accurate predictions of the treatment outcomes during interstitial laser ablation, thereby minimizing the damage to surrounding healthy tissue. The developed model and parametric analysis reported in this study would assist in a more accurate and precise prediction of the temperature distribution, thus allowing to optimize the thermal dosage during laser therapy in the brain.

An anthropomorphic thyroid phantom for ultrasound-guided radiofrequency ablation of nodules.

BACKGROUND: Needle-based procedures, such as fine needle aspiration and thermal ablation, are often applied for thyroid nodule diagnosis and therapeutic purposes, respectively. With blood vessels and nerves nearby, these procedures can pose risks in damaging surrounding critical structures. PURPOSE: The development and validation of innovative strategies to manage these risks require a test object with well-characterized physical properties. For this work, we focus on the application of ultrasound-guided thermal radiofrequency ablation. METHODS: We have developed a single-use anthropomorphic phantom mimicking the thyroid and surrounding anatomical and physiological structures that are relevant to ultrasound-guided thermal ablation. The phantom was composed of a mixture of polyacrylamide, water, and egg white extract and was cast using molds in multiple steps. The thermal, acoustical, and electrical characteristics were experimentally validated. The ablation zones were analyzed via non-destructive T2 -weighted magnetic resonance imaging scans utilizing the relaxometry changes of coagulated egg albumen, and the temperature distribution was monitored using an array of fiber Bragg grating sensors. RESULTS: The physical properties of the phantom were verified both on ultrasound as well as in terms of the phantom response to thermal ablation. The final temperature achieved (92°C), the median percentage of the nodule ablated (82.1%), the median volume ablated outside the nodule (0.8 mL), and the median number of critical structures affected (0) were quantified. CONCLUSION: An anthropomorphic phantom that can provide a realistic model for development and training in ultrasound-guided needle-based thermal interventions for thyroid nodules has been presented.

Theoretical Estimation of Tissue Thermal Response and Associated Thermal Damage During Gold Nanorod-enhanced Photothermal Therapy of Tumors.

In the present work, we implemented a computational framework of in vivo gold nanorod (GNR)-enhanced photothermal therapy (PTT) for tumor treatment. The temperature-dependent thermophysical properties of biological tissue and the optical properties of both GNRs and the biological media were included. The latter were modulated during the treatment simulation to account for their variation, from the native to the coagulated state. The contribution of tissue injury-dependent blood perfusion was also considered. The developed model allowed for the estimation of temperature distribution during the photothermal procedure at different procedural settings and amounts of GNRs embedded in the tumor region (i.e., 12.5 µg, 25 µg, and 50 µg). Furthermore, the influence of GNRs on thermal injury, estimated with different damage models, was assessed. The inclusion of GNRs in the tumor entailed an increment of maximum tissue temperature, and faster heating kinetics, as witnessed by the lower time needed to reach complete thermal damage at the tumor center. The percentage of tumor thermal damage evaluated at the end of the simulated treatment was 48%, 69%, and 90%, for PTT in the presence of 12.5 µg, 25 µg, and 50 µg of GNRs, respectively.Clinical Relevance-This establishes that simulation-based tools, modeling the tissue properties variation during the photothermal treatment, can serve as promising preplanning platforms for nanoparticle-assisted light therapies.

Preliminary Results of Laser Ablation during In Vivo Experiments: Comparison of Thermal Effects Obtained with Bare and Diffuser Tip Applicators.

This work is a step towards the analysis of the effect of different laser applicator tips used for laser ablation of liver for in vivo experiments. As the thermal outcome of this minimally invasive treatment for tumors depends upon the interaction between the tissue and the light, the emission pattern of the laser applicator has a key role in the shape and size of the final treated region. Hence, we have compared two different laser applicators: a bare tip fiber (emitting light from the tip and forward) and a diffuser tip fiber (emitting light at 360° circumferentially from the side of the fiber). The experiments have been carried out percutaneously in a preclinical scenario (anesthetized pigs), under computed tomography (CT) guidance. The thermal effects of the two applicators have been assessed in terms of real-time temperature distribution, by means of an array of 40 fiber Bragg grating (FBG) sensors, and in terms of cavitation and ablation volumes, measured through CT post-temperature due to breathing motion has been analyzed and filtered out. Results show that the maximum temperature reached 50.5 °C for the bare tip fiber experiment (measured at 6.24 mm distance from the applicator) and 60.9 °C for the diffuser tip fiber experiment (measured at 5.23 mm distance from the applicator). The diffuser tip fiber allowed to achieve a more symmetrical heat distribution than the bare tip fiber, and without cavitation volume.Clinical Relevance-This work shows the analysis of the thermal effects of different laser fiber tips to improve laser ablation treatment. The results obtained in the preclinical scenario well represent the expected clinical outcome in the treatment of hepatic tumors. Moreover, these findings can be applied to other fields in which laser ablation is the optimal therapeutic choice, such as neurosurgery.

Characterization of the Optical and Thermal Properties of Cardiac Tissue as a Function of Temperature.

In this work, we devised the first characterization of the optical and thermal properties of ex vivo cardiac tissue as a function of different selected temperatures, ranging from room temperature to hyperthermic and ablative temperatures. The broadband (i.e., from 650 nm to 1100 nm) estimation of the optical properties, i.e., absorption coefficient (µa) and reduced scattering coefficient $({\mu ^{\prime}}_s)$, was performed by means of time-domain diffuse optics. Besides, the measurement of the thermal properties was based on the transient hot-wire technique, employing a dual-needle probe to estimate the tissue thermal conductivity (k), thermal diffusivity (α), and volumetric heat capacity (Cv). Increasing the tissue temperature led to variations in the spectral characteristics of µa (e.g., the redshift of the 780 nm peak, the rise of a new peak at 840 nm, and the formation of a valley at 900 nm). Moreover, an increase in the values of ${\mu ^{\prime}}_s$ was assessed as tissue temperature raised (e.g., for 800 nm, at 25 °C ${\mu ^{\prime}}_s = 9.8{\text{ c}}{{\text{m}}^{{\text{ - 1}}}}$, while at 77 °C ${\mu ^{\prime}}_s = 29.1{\text{ c}}{{\text{m}}^{{\text{ - 1}}}}$). Concerning the thermal properties characterization, k was almost constant in the selected temperature interval. Conversely, α and Cv were subjected to an increase and a decrease with temperature, respectively; thus, they registered values of 0.190 mm2/s and 3.03 MJ/(m3•K) at the maximum investigated temperature (79 °C), accordingly.Clinical Relevance- The experimentally obtained optical and thermal properties of cardiac tissue are useful to improve the accuracy of simulation-based tools for thermal therapy planning. Furthermore, the measured properties can serve as a reference for the realization of tissue-mimicking phantoms for medical training and testing of medical instruments.

On the role of polymeric hydrogels in the thermal response of gold nanorods under NIR laser irradiation.

Hydrogels are 3D cross-linked networks of polymeric chains designed to be used in the human body. Nowadays they find widespread applications in the biomedical field and are particularly attractive as drug delivery vectors. However, despite many good results, their release performance is sometimes very quick and uncontrolled, being forced by the high in vivo clearance of body fluids. In this direction, the development of novel responsive nanomaterials promises to overcome the drawbacks of common hydrogels, inducing responsive properties in three-dimensional polymeric devices. In this study, we synthesized and then loaded gold nanorods (Au NRs) within an agarose-carbomer (AC)-based hydrogel obtained from a microwave-assisted polycondensation reaction between carbomer 974P and agarose. The photothermal effect of the composite device was quantified in terms of maximum temperature and spatial-temporal temperature distribution, also during consecutive laser irradiations. This work shows that composite Au NRs loaded within AC hydrogels can serve as a stable photothermal treatment agent with enhanced photothermal efficiency and good thermal stability after consecutive laser irradiations. These results confirm that the composite system produced can exhibit an enhanced thermal effect under NIR laser irradiation, which is expected to lead to great therapeutic advantages for the localized treatment of different diseases.

Measurement of Thermal Conductivity and Thermal Diffusivity of Porcine and Bovine Kidney Tissues at Supraphysiological Temperatures up to 93 °C.

This experimental study aimed to characterize the thermal properties of ex vivo porcine and bovine kidney tissues in steady-state heat transfer conditions in a wider thermal interval (23.2-92.8 °C) compared to previous investigations limited to 45 °C. Thermal properties, namely thermal conductivity (k) and thermal diffusivity (α), were measured in a temperature-controlled environment using a dual-needle probe connected to a commercial thermal property analyzer, using the transient hot-wire technique. The estimation of measurement uncertainty was performed along with the assessment of regression models describing the trend of measured quantities as a function of temperature to be used in simulations involving heat transfer in kidney tissue. A direct comparison of the thermal properties of the same tissue from two different species, i.e., porcine and bovine kidney tissues, with the same experimental transient hot-wire technique, was conducted to provide indications on the possible inter-species variabilities of k and α at different selected temperatures. Exponential fitting curves were selected to interpolate the measured values for both porcine and bovine kidney tissues, for both k and α. The results show that the k and α values of the tissues remained rather constant from room temperature up to the onset of water evaporation, and a more marked increase was observed afterward. Indeed, at the highest investigated temperatures, i.e., 90.0-92.8 °C, the average k values were subject to 1.2- and 1.3-fold increases, compared to their nominal values at room temperature, in porcine and bovine kidney tissue, respectively. Moreover, at 90.0-92.8 °C, 1.4- and 1.2-fold increases in the average values of α, compared to baseline values, were observed for porcine and bovine kidney tissue, respectively. No statistically significant differences were found between the thermal properties of porcine and bovine kidney tissues at the same selected tissue temperatures despite their anatomical and structural differences. The provided quantitative values and best-fit regression models can be used to enhance the accuracy of the prediction capability of numerical models of thermal therapies. Furthermore, this study may provide insights into the refinement of protocols for the realization of tissue-mimicking phantoms and the choice of tissue models for bioheat transfer studies in experimental laboratories.

Optimization of laser dosimetry based on patient-specific anatomical models for the ablation of pancreatic ductal adenocarcinoma tumor.

Laser-induced thermotherapy has shown promising potential for the treatment of unresectable primary pancreatic ductal adenocarcinoma tumors. Nevertheless, heterogeneous tumor environment and complex thermal interaction phenomena that are established under hyperthermic conditions can lead to under/over estimation of laser thermotherapy efficacy. Using numerical modeling, this paper presents an optimized laser setting for Nd:YAG laser delivered by a bare optical fiber (300 µm in diameter) at 1064 nm working in continuous mode within a power range of 2-10 W. For the thermal analysis, patient-specific 3D models were used, consisting of tumors in different portions of the pancreas. The optimized laser power and time for ablating the tumor completely and producing thermal toxic effects on the possible residual tumor cells beyond the tumor margins were found to be 5 W for 550 s, 7 W for 550 s, and 8 W for 550 s for the pancreatic tail, body, and head tumors, respectively. Based on the results, during the laser irradiation at the optimized doses, thermal injury was not evident either in the 15 mm lateral distances from the optical fiber or in the nearby healthy organs. The present computational-based predictions are also in line with the previous ex vivo and in vivo studies, hence, they can assist in the estimation of the therapeutic outcome of laser ablation for pancreatic neoplasms prior to clinical trials.

Delayed hypersensitivity reactions to iodinated contrast media: A diagnostic approach by skin tests.

BACKGROUND: Adverse drug reactions to iodinated contrast media (ICM) have risen due to their increasing use in x-ray-based imaging modalities. Delayed hypersensitivity reactions are mainly caused by nonionic monomeric compounds and represent an issue impacting the diagnostic-therapeutic pathways of cancer, cardiology and surgery patients. OBJECTIVES: To prospectively evaluate the usefulness of skin tests in delayed hypersensitivity reactions to ICM and to evaluate the tolerability of iobitridol, a monomeric nonionic low osmolality compound, as a possible safe alternative. METHODS: Patients with delayed hypersensitivity reactions to ICM referred to us from 2020 to 2022 were prospectively enrolled in the study. All patients underwent patch test and, if negative, intradermal test with the culprit ICM and iobitridol as alternative. RESULTS: A total of 37 patients (females 24, 64.9%) were enrolled in the study. Iodixanol and iomeprol were the most frequently involved ICM (48.5% and 35.2%, respectively); 62.2% of patients presented maculopapular eruption, while 37.8% reported delayed urticaria-like rash. Skin tests resulted positive to the culprit ICM in 19 patients (51.4%), 16 to patch test and 3 to intradermal test. Skin tests with iobitridol, tested as alternative, resulted positive in 3/19 patients (15.8%). All 16 patients with negative results to iobitridol were administered this ICM and tolerated it. CONCLUSIONS: In at least half of patients, delayed-type hypersensitivity was demonstrated by skin tests, particularly by patch test. This diagnostic approach resulted simple, cost-effective and safe, not only to confirm the culprit ICM but also to identify iobitridol as feasible alternative.

Advancing the understanding of allergic contact dermatitis: from pathophysiology to novel therapeutic approaches.

Allergic contact dermatitis (ACD) is a common inflammatory skin disease that, especially when the condition becomes chronic, has a high impact on the quality of life and represents a significant disease burden. ACD represents a type IV delayed-type hypersensitivity reaction that is triggered by contact with an allergen in previously sensitized individuals through the activation of allergen-specific T cells. In the acute phase, it is characterized by eczematous dermatitis, which presents with erythema, edema, vesicles, scaling, and intense itch. Non-eczematous clinical forms are also described (lichenoid, bullous, and lymphomatosis). Lichenification is the most common clinical picture in the chronic phase if the culprit allergen is not found or eliminated. ACD can be associated with both occupational and non-occupational exposure to allergens, representing approximately 90% of occupational skin disorders along with irritant contact dermatitis. Patch testing with suspected allergens is required for a diagnosis. Metals, especially nickel, fragrance mix, isothiazolinones, and para-phenylenediamine, are the most commonly positive allergens in patients patch tested for suspected ACD. The treatment goal is to avoid contact with the culprit agent and use topical and/or systemic corticosteroid therapy.

Sex differences in the relationship between hepatic steatosis, mood and anxiety disorders.

OBJECTIVE: To investigate the association between non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), mental symptoms (mood, anxiety disorders and distress) by sex. METHODS: This a cross-sectional study performed in working-age adults from a Health Promotion Center (primary care) in São Paulo, Brazil. Self-reported mental symptoms from rating scales (21-item Beck Anxiety Inventory, Patient Health Questionnaire-9, and K6 distress scale) were evaluated by hepatic steatosis (NAFLD and ALD). Logistic regression models estimated the association between hepatic steatosis subtypes and mental symptoms by Odds ratios (OR) adjusted by confounders in the total sample and sex stratified. RESULTS: Among 7241 participants (70.5% men, median age: 45 years), the frequency of steatosis was of 30.7% (25.1% NAFLD), being higher in men than women (70.5% vs. 29.5%, p < 0.0001), regardless of the steatosis subtype. Metabolic risk factors were similar in both subtypes of steatosis, but not mental symptoms. Overall, NAFLD was inversely associated with anxiety (OR = 0.75, 95%CI 0.63-0.90) and positively associated with depression (OR = 1.17, 95%CI 1.00-1.38). On the other hand, ALD was positively associated with anxiety (OR = 1.51; 95%CI 1.15-2.00). In sex-stratified analyses, only men presented an association of anxiety symptoms with NAFLD (OR = 0.73; 95%CI 0.60-0.89) and ALD (OR = 1.60; 95%CI 1.18-2.16). CONCLUSIONS: The complex association between different types of steatosis (NAFLD and ALD), mood and anxiety disorders indicates the need for a deeper understanding of their common causal pathways.

Human ectoparasitosis by mites of the genus Pyemotes Amerling 1861 (Acarina: Pyemotidae).

The mites of the family Pyemotidae Berlese (1897) are a large family of ectoparasitoids arthropods, known as pathogen for humans since the 18th century and responsible for the so-called "straw itch" or "grain itch" in granary and dock workers. The identified species of the genus Pyemotes are divided into two groups: the scolyti group (P. scolyti, P. parviscolyti and P. dimorphus) and the ventricosus group (P. tritici and P. ventricosus). The first group is characterized by nonvenomous mites usually parasitizing bark beetles; the ventricosus group includes species associated with a large number of hosts (Coleoptera, Lepidoptera, Hymenoptera, Diptera and Rhynchota), parasitizing all host stages, often highly poisonous and responsible for itchy skin lesions for humans. Several species of Pyemotes mites can be pathogenic to humans, especially in spring and summer and in indoor environments, where worm-eaten wood or infested foodstuffs are present. The most frequent clinical feature is the "strophulus," characterized by small erythematous, edematous, and papular lesions centered by a tiny vescicle evolving into a small erosion covered by crust, or by a central hemorrhagic punctum. Other less frequently observed clinical features are urticaria-like lesions, erythematous excoriated papular and pustular lesions, and rarely scabies-like eruptions. The parasitological diagnosis together with the environmental disinfestation and removing of each substrate infested by insects parasitized by Pyemotidae is mandatory to definitely solve Pyemotes dermatitis.

Temperature Dependence of Thermal Properties of Ex Vivo Porcine Heart and Lung in Hyperthermia and Ablative Temperature Ranges.

This work proposes the characterization of the temperature dependence of the thermal properties of heart and lung tissues from room temperature up to > 90 °C. The thermal diffusivity (α), thermal conductivity (k), and volumetric heat capacity (Cv) of ex vivo porcine hearts and deflated lungs were measured with a dual-needle sensor technique. α and k associated with heart tissue remained almost constant until ~ 70 and ~ 80 °C, accordingly. Above ~ 80 °C, a more substantial variation in these thermal properties was registered: at 94 °C, α and k respectively experienced a 2.3- and 1.5- fold increase compared to their nominal values, showing average values of 0.346 mm2/s and 0.828 W/(m·K), accordingly. Conversely, Cv was almost constant until 55 °C and decreased afterward (e.g., Cv = 2.42 MJ/(m3·K) at 94 °C). Concerning the lung tissue, both its α and k were characterized by an exponential increase with temperature, showing a marked increment at supraphysiological and ablative temperatures (at 91 °C, α and k were equal to 2.120 mm2/s and 2.721 W/(m·K), respectively, i.e., 13.7- and 13.1-fold higher compared to their baseline values). Regression analysis was performed to attain the best-fit curves interpolating the measured data, thus providing models of the temperature dependence of the investigated properties. These models can be useful for increasing the accuracy of simulation-based preplanning frameworks of interventional thermal procedures, and the realization of tissue-mimicking materials.