Francesco Pastore

Objectives: To evaluate (a) changes in caries experience, (b) changes in periodontal status, and (c) the need for dental extractions in a cohort of patients treated with radiotherapy (RT) and chemoradiotherapy (RTCT) for head and neck cancer (HNC). Methods: This prospective cohort study was approved by the local Ethics Committee (Ref. 22858/18) and registered at ClinicalTrials.gov (ID: NCT04009161). The study population consisted of patients with HNC who, prior to RT, underwent a dental examination followed by the elimination of oral foci of infection and were then enrolled in a follow-up program. The primary outcome was oral health worsening, defined as the onset of severe periodontitis and/or a DMFt score ≥ 13. Oral cavity RT dose was obtained contouring the ‘buccal mucosa’ organ at risk (OAR). Results: In total, 113 patients were included (median follow-up: 44.77 months). The sample mainly included oral, oropharyngeal, nasopharyngeal and laryngeal cancers (89/113, 78.8%). Salivary glands, hypopharynx and other sites accounted for a minority of the cases (24/113, 21.2%). Seventeen patients (34.7%) experienced worsening of oral health status over time, which was associated with smoking (OR = 4.7, 95% CI: 1.27–17.37; p = 0.02). The DMFt index increased (difference: 4.08; 95% CI: 1.60–6.56; p = 0.001), and this increase was associated with smoking (β = 2.05, 95% CI: 0.27–3.83; p = 0.02). Although worsening of periodontitis stage was not statistically significant (p = 0.35), localized deterioration was observed, with an increase in sites with PPD ≥ 5 mm (p = 0.02). Forty-nine patients (43.4%) experienced tooth loss. Mean tooth loss was 2.12 teeth per patient (p = 0.05), primarily due to caries (48.5%) and periodontitis (48.1%). Independent risk factors for tooth loss were age (p = 0.025) and an RT dose > 60 Gy to the ‘buccal mucosa’ OAR (p = 0.023). Conclusions: Patients treated with RT experienced significant deterioration in dental and periodontal health, and oral cavity dosimetric parameters might be associated with tooth loss, although this association requires confirmation in further studies.

Background: Orbital exenteration is a radical procedure used in selected orbital malignancies, yet survival outcomes vary widely, particularly in recurrent or previously treated disease. We evaluated the association of pathological stage (nodal and/or distant metastasis status) and margin status with overall survival (OS) and disease-free survival (DFS) in patients undergoing exenteration for recurrent or previously treated orbital cancers. Methods: We retrospectively analyzed 39 patients who underwent orbital exenteration between 2017 and 2024. Patients were categorized as localized disease (pN0/pM0) or advanced disease with nodal and/or distant metastasis (pN + and/or pM+). Survival was estimated using Kaplan–Meier analysis and compared using the log-rank test. Median follow-up was 365 days. Margins were classified as R0 or R1. Results: Of the 39 patients, 24 (61.5%) had localized disease and 15 (38.5%) had advanced disease with nodal and/or distant metastasis; 6 patients (15.4%) had positive margins. 24-month OS was 78% in localized disease versus 33% in patients with nodal and/or distant metastasis ( p = 0.011). Median OS was not reached in localized disease and was 13 months in patients with nodal and/or distant metastasis. 24-month DFS was 62.5% versus 33% ( p = 0.017). R1 margins were associated with markedly worse outcomes: 24-month OS 0% vs. 75.8% for R0, and all R1 patients recurred within 12 months. Sensitivity analysis excluding < 6-month follow-up confirmed these findings. Conclusions: Nodal and/or distant metastatic status and positive surgical margins were associated with worse survival outcomes after orbital exenteration for recurrent or previously treated orbital malignancies. Most adverse events occurred within the first postoperative year, suggesting a clinically relevant early risk period. Given the histological heterogeneity of the cohort, these findings should be interpreted as prognostic patterns in a salvage orbital oncology population and require validation in larger disease-specific series.

Patients with head and neck cancer (HNC) face a high risk of malnutrition and sarcopenia, often exacerbated by the toxicities of chemoradiotherapy, such as dysphagia, xerostomia, and mucositis. These Nutritional Impact Symptoms significantly compromise oral intake and negatively affect quality of life. This paper presents a conceptual framework designed to support clinicians in optimizing oral intake through personalized nutritional management. Central to this approach is the integration of systematic screening using MUST, the Malnutrition Universal Screening Tool (MUST), and the Nutritional Risk Screening 2002 (NRS-2002). Furthermore, functional assessment of swallowing via instrumental studies (VFSS/FEES) is essential for tailoring dietary textures according to the International Dysphagia Diet Standardization Initiative framework. Key nutritional strategies include high-energy and high-protein oral fortification, the use of oral nutritional supplements, and specific dietary adjustments addressing pain management and sensory alterations. A multidisciplinary approach involving nutritionists, speech-language pathologists, and oncologists is paramount to transition from reactive symptom management to proactive “adaptive nutrition,” ultimately improving clinical outcomes and patient survival.

Numerous studies suggest that abnormal upregulation of the complement cascade, a key component of the innate immune system, is involved in the pathogenesis

Background/Objectives: The anatomical complexity of the auricular region poses a unique challenge for contact interventional radiotherapy (IRT, modern brachytherapy), especially in maintaining close conformity between the applicator and skin surface. Air gaps can arise due to the irregular shape of the ear, potentially compromising dose coverage. This study evaluates the dosimetric impact of air gaps in HDR IRT for non-melanoma skin cancer (NMSC) of the ear. Methods: Ten patients treated with contact IRT using alginate as supporting material were retrospectively analyzed. Treatment plans were recalculated using both the TG-43 and the TG-186 formalism. CTV coverage and organ-at-risk dose parameters were evaluated within the two formalisms. Results: CTV coverage was comparable between algorithms (mean V95% 96.2% vs. 94.4%, V100% 89.6% vs. 86.7%, and V150% 2.6% vs. 2.5% for TG-43 vs. TG-186; p > 0.05), while the ipsilateral eye D2cc decreased from 4.0% (TG-43) to 3.2% (TG-186). In silico simulations showed that increasing air gaps reduced skin dose progressively (up to ~15% at 5 mm), whereas alginate thickness produced only a mild dose increase (<5%) across the tested range. Overall, small air pockets (<1 mm) did not substantially alter global dosimetric metrics, although local underdosage may occur at gap locations. Conclusions: This study underscores the importance of accounting for material heterogeneities and geometric uncertainties in anatomically complex regions through advanced dose calculation algorithms.

Background/Objectives: This study investigates the dosimetric impact of a 3D-printed applicator integrating multilayer catheter geometry and high-density shielding, designed for contact interventional radiotherapy (IRT) in non-melanoma skin cancer (NMSC) treatment. The aim is to assess its potential to enhance target coverage and reduce doses in organs at risk (OARs). Methods: A virtual prototype of a multilayer applicator was designed using 3D modeling software and realized through fused deposition modeling. Dosimetric simulations were performed using both TG-43 and TG-186 formalisms on CT scans of a water-equivalent phantom. A five-catheter array was reconstructed, and lead-cadmium-based alloy shielding of varying thicknesses (3–15 mm) was contoured. CTVs of 5 mm and 8 mm thickness were analyzed along with a neighboring OAR. Dosimetric endpoints included V95%, V100%, V150% (CTV), D_2cc (OAR), and therapeutic window (TW). Results: Compared to TG-43, the TG-186 algorithm yielded lower OAR doses while maintaining comparable CTV coverage. Progressive increase in shielding thickness led to improved V95% and V100% values and a notable reduction in OAR dose, with an optimal trade-off observed between 6 and 9 mm of shielding. The TW remained above 7 mm across all configurations, supporting its use in lesions thicker than conventional guidelines recommend. Conclusions: The integration of multilayer catheter geometry with high-density shielding in a customizable 3D-printed applicator enables enhanced dose modulation and OAR sparing in superficial IRT. This approach represents a step toward personalized brachytherapy, aligning with the broader movement in radiation oncology toward patient-specific solutions, adaptive planning, and precision medicine. Future directions should include prototyping and mechanical testing of the applicator, experimental dosimetric validation in phantoms, and pilot clinical feasibility studies to translate these promising in silico results into clinical practice.

Synaptic plasticity plays a crucial role in memory formation by regulating the communication between neurons. Although actin polymerization has been linked to synaptic plasticity and dendritic spine stability, the causal link between actin polymerization and memory encoding has not been identified yet. It is not clear whether actin polymerization and structural changes in dendritic spines are a driver or a consequence of learning and memory. Using an extrinsically disordered form of the protein kinase LIMK1, which rapidly and precisely acts on ADF/cofilin, a direct modifier of actin, we induced long-term enlargement of dendritic spines and enhancement of synaptic transmission in the hippocampus on command. The activation of extrinsically disordered LIMK1 in vivo improved memory encoding and slowed cognitive decline in aged mice exhibiting reduced cofilin phosphorylation. The engineered memory by an extrinsically disordered LIMK1 supports a direct causal link between actin-mediated synaptic transmission and memory.

A Disintegrin and Metalloprotease 10, also known as ADAM10, is a cell surface protease ubiquitously expressed in mammalian cells where it cuts several membrane proteins implicated in multiple physiological processes. The dysregulation of ADAM10 expression and function has been implicated in pathological conditions, including Alzheimer’s disease (AD). Although it has been suggested that ADAM10 is expressed as a zymogen and the removal of the prodomain results in its activation, other potential mechanisms for the ADAM10 proteolytic function and activation remain unclear. Another suggested mechanism is post-translational modification of the cytoplasmic domain, which regulates ADAM10-dependent protein ectodomain shedding. Therefore, the precise and temporal activation of ADAM10 is highly desirable to reveal the fine details of ADAM10-mediated cleavage mechanisms and protease-dependent therapeutic applications. Here, we present a strategy to control prodomain and cytosolic tail cleavage to regulate ADAM10 shedding activity without the intervention of small endogenous molecule signaling pathways. We generated a series of engineered ADAM10 analogs containing Tobacco Etch Virus protease (TEV) cleavage site (TEVcs), rendering ADAM10 cleavable by TEV. This strategy revealed that, in the absence of other stimuli, the TEV-mediated removal of the prodomain could not activate ADAM10. However, the TEV-mediated cleavage of the cytosolic domain significantly increased ADAM10 activity. Then, we generated ADAM10 with a minimal constitutively catalytic activity that increased significantly in the presence of TEV or after activating a chemically activatable TEV. Our results revealed a bioengineering strategy for controlling the ADAM10 activity in living cells, paving the way to obtain spatiotemporal control of ADAM10. Finally, we proved that our approach of controlling ADAM10 promoted α-secretase activity and the non-amyloidogenic cleavage of amyloid-β precursor protein (APP), thereby increasing the production of the neuroprotective soluble ectodomain (sAPPα). Our bioengineering strategy has the potential to be exploited as a next-generation gene therapy for AD.

Synapses connect discrete neurons into vast networks that send, receive, and encode diverse forms of information. Synaptic function and plasticity, the neuronal process of adapting to diverse and variable inputs, depend on the dynamic nature of synaptic molecular components, which is mediated in part by cell adhesion signaling pathways. Here, we found that the enzyme biliverdin reductase (BVR) physically links together key focal adhesion signaling molecules at the synapse. BVR -null ( BVR ^−/− ) mice exhibited substantial deficits in learning and memory on neurocognitive tests, and hippocampal slices in which BVR was postsynaptically depleted showed deficits in electrophysiological responses to stimuli. RNA sequencing, biochemistry, and pathway analyses suggested that these deficits were mediated through the loss of focal adhesion signaling at both the transcriptional and biochemical level in the hippocampus. Independently of its catalytic function, BVR acted as a bridge between the primary focal adhesion signaling kinases FAK and Pyk2 and the effector kinase Src. Without BVR, FAK and Pyk2 did not bind to and stimulate Src, which then did not phosphorylate the N -methyl- d -aspartate (NMDA) receptor, a critical posttranslational modification for synaptic plasticity. Src itself is a molecular hub on which many signaling pathways converge to stimulate NMDAR-mediated neurotransmission, thus positioning BVR at a prominent intersection of synaptic signaling.

Aims: Several studies reported that astrocytes support neuronal communication by the release of gliotransmitters, including ATP and glutamate. Astrocytes also play a fundamental role in buffering extracellular glutamate in the synaptic cleft, thus limiting the risk of excitotoxicity in neurons. We previously demonstrated that extracellular tau oligomers (ex‐oTau), by specifically targeting astrocytes, affect glutamate‐dependent synaptic transmission via a reduction in gliotransmitter release. The aim of this work was to determine if ex‐oTau also impair the ability of astrocytes to uptake extracellular glutamate, thus further contributing to ex‐oTau‐dependent neuronal dysfunction.Methods: Primary cultures of astrocytes and organotypic brain slices were exposed to ex‐oTau (200 nM) for 1 h. Extracellular glutamate buffering by astrocytes was studied by: Na⁺ imaging; electrophysiological recordings; high‐performance liquid chromatography; Western blot and immunofluorescence. Experimental paradigms avoiding ex‐oTau internalisation (i.e. heparin pre‐treatment and amyloid precursor protein knockout astrocytes) were used to dissect intracellular vs extracellular effects of oTau.Results: Ex‐oTau uploading in astrocytes significantly affected glutamate‐transporter‐1 expression and function, thus impinging on glutamate buffering activity. Ex‐oTau also reduced Na‐K‐ATPase activity because of pump mislocalisation on the plasma membrane, with no significant changes in expression. This effect was independent of oTau internalisation and it caused Na⁺ overload and membrane depolarisation in ex‐oTau‐targeted astrocytes.Conclusions: Ex‐oTau exerted a complex action on astrocytes, at both intracellular and extracellular levels. The net effect was dysregulated glutamate signalling in terms of both release and uptake that relied on reduced expression of glutamate‐transporter‐1, altered function and localisation of NKA1A1, and NKA1A2. Consequently, Na⁺ gradients and all Na⁺‐dependent transports were affected.