Dosimetric and NTCP analyses for selecting parotid gland cancer patients for proton therapy.

PURPOSE/OBJECTIVE: To perform a dosimetric and a normal tissue complication probability (NTCP) comparison between intensity modulated proton therapy and photon volumetric modulated arc therapy in a cohort of patients with parotid gland cancers in a post-operative or radical setting. MATERIALS AND METHODS: From May 2011 to September 2021, 37 parotid gland cancers patients treated at two institutions were eligible. Inclusion criteria were as follows: patients aged ⩾ 18 years, diagnosis of parotid gland cancers candidate for postoperative radiotherapy or definitive radiotherapy, presence of written informed consent for the use of anonymous data for research purposes. Organs at risk (OARs) were retrospectively contoured. Target coverage goal was defined as D95 > 98%. Six NTCP models were selected. NTCP profiles were calculated for each patient using an internally-developed Python script in RayStation TPS. Average differences in NTCP between photon and proton plans were tested for significance with a two-sided Wilcoxon signed-rank test. RESULTS: Seventy-four plans were generated. A lower Dmean to the majority of organs at risk (inner ear, cochlea, oral cavity, pharyngeal constrictor muscles, contralateral parotid and submandibular gland) was obtained with intensity modulated proton therapy vs volumetric modulated arc therapy with statistical significance (p < .05). Ten (27%) patients had a difference in NTCP (photon vs proton plans) greater than 10% for hearing loss and tinnitus: among them, seven qualified for both endpoints, two patients for hearing loss only, and one for tinnitus. CONCLUSIONS: In the current study, nearly one-third of patients resulted eligible for proton therapy and they were the most likely to benefit in terms of prevention of hearing loss and tinnitus.

Epidemiology of Paediatric Italian Food Allergy: Results of the EPIFA study.

Background: Updated epidemiologic data are important for defining effective public health strategies for pediatric food allergy (FA). Objective: The Epidemiology of Paediatric Italian Food Allergy (EPIFA) study was designed to investigate the epidemiology of pediatric FA in one of the most heavily populated Italian regions. Methods: A retrospective cohort study was performed in collaboration with family pediatricians aimed at investigating the epidemiology of Italian pediatric FA during 2009 to 2021. Family pediatricians in the Campania region were invited to use the Google Forms platform for online compilation of data forms. Data forms were reviewed by experienced pediatric allergists at the coordinating center. Results: A total population of 105,151 subjects (aged 0-14 years) was screened during the study period. Data from 752 FA patients were evaluated. A progressive increase in FA incidence and prevalence was observed from 2009 to 2021, with a relative increase up to 34% and 113.6%, respectively, at the end of study period. The relative increase in FA prevalence was higher in the 0-3-year-old age group in the same study period (+120.8%). The most frequent allergens were cow's milk, hen's egg, and nuts. Conclusion: The results of the EPIFA study showed an increase in pediatric FA incidence and prevalence from 2009 to 2021 in Italy. These results underline the necessity of new effective strategies for preventing and managing these conditions.

Effects of nuclear interaction corrections and trichrome fragment spectra modelling on dose and linear energy transfer distributions in carbon ion radiotherapy.

Background and Purpose: Nuclear interaction correction (NIC) and trichrome fragment spectra modelling improve relative biological effectiveness-weighted dose (DRBE) and dose-averaged linear energy transfer (LETd) calculation for carbon ions. The effect of those novel approaches on the clinical dose and LET distributions was investigated. Materials and Methods: The effect of the NIC and trichrome algorithm was assessed, creating single beam plans for a virtual water phantom with standard settings and NIC + trichrome corrections. Reference DRBE and LETd distributions were simulated using FLUKA version 2021.2.9. Thirty clinically applied scanned carbon ion treatment plans were recalculated applying NIC, trichrome and NIC + trichrome corrections, using the LEM low dose approximation and compared to clinical plans (base RS). Four treatment sites were analysed: six prostate adenocarcinoma, ten head and neck, nine locally advanced pancreatic adenocarcinoma and five sacral chordoma. The FLUKA and clinical plans were compared in terms of DRBE deviations for D98%, D50%, D2% for the clinical target volume (CTV) and D50% in ring-like dose regions retrieved from isodose curves in base RS plans. Additionally, region-based median LETd deviations and global gamma parameters were evaluated. Results: Dose deviations comparing base RS and evaluation plans were within ± 1% supported by γ-pass rates over 97% for all cases. No significant LETd deviations were reported in the CTV, but significant median LETd deviations were up to 80% for very low dose regions. Conclusion: Our results showed improved accuracy of the predicted DRBE and LETd. Considering clinically relevant constraints, no significant modifications of clinical protocols are expected with the introduction of NIC + trichrome.

Curative carbon ion radiotherapy in a head and neck mucosal melanoma series: Facing the future within multidisciplinarity.

PURPOSE: To evaluate efficacy and toxicity of carbon ion radiotherapy (CIRT) in locally advanced head and neck mucosal melanoma (HNMM) patients treated at our Institute. MATERIALS AND METHODS: Between June 2013 and June 2020, 40 HNMM patients were treated with CIRT. Prescription dose was 65.6-68.8 Gy relative biological effectiveness [RBE] in 16 fractions. Twelve (30%) patients received only biopsy, 28 (70%) surgical resection before CIRT. Immunotherapy was administered before and/or after CIRT in 45% of patients, mainly for distant progression (89%). RESULTS: Median follow-up was 18 months. 2-year Local Relapse Free Survival (LRFS), Overall Survival (OS), Progression Free Survival (PFS) and Distant Metastasis Free Survival (DMFS) were 84.5%, 58.6%, 33.2% and 37.3%, respectively. At univariate analysis, LRFS was significantly better for non-recurrent status, < 2 surgeries before CIRT and treatment started < 9 months from the initial diagnosis, with no significant differences for operated versus unresected patients. After relapse, immunotherapy provided longer median OS (17 months vs 3.6, p-value<0.001). Late toxicity ≥ G3 (graded with CTCAE 5.0 scale) was reported in 10% of patients. CONCLUSION: CIRT in advanced HNMM patients is safe and locally effective. Prospective trials are warranted to assess the role of targeted/immune- systemic therapy to improve OS.

Spatial predictors of immunotherapy response in triple-negative breast cancer.

Immune checkpoint blockade (ICB) benefits some patients with triple-negative breast cancer, but what distinguishes responders from non-responders is unclear1. Because ICB targets cell-cell interactions2, we investigated the impact of multicellular spatial organization on response, and explored how ICB remodels the tumour microenvironment. We show that cell phenotype, activation state and spatial location are intimately linked, influence ICB effect and differ in sensitive versus resistant tumours early on-treatment. We used imaging mass cytometry3 to profile the in situ expression of 43 proteins in tumours from patients in a randomized trial of neoadjuvant ICB, sampled at three timepoints (baseline, n = 243; early on-treatment, n = 207; post-treatment, n = 210). Multivariate modelling showed that the fractions of proliferating CD8+TCF1+T cells and MHCII+ cancer cells were dominant predictors of response, followed by cancer-immune interactions with B cells and granzyme B+ T cells. On-treatment, responsive tumours contained abundant granzyme B+ T cells, whereas resistant tumours were characterized by CD15+ cancer cells. Response was best predicted by combining tissue features before and on-treatment, pointing to a role for early biopsies in guiding adaptive therapy. Our findings show that multicellular spatial organization is a major determinant of ICB effect and suggest that its systematic enumeration in situ could help realize precision immuno-oncology.

Particle Reirradiation of Malignant Epithelial and Neuroectodermal Sinonasal Tumors: A Case Series from CNAO.

Sinonasal cancers (SNCs) are rare and heterogeneous in histology and biological behavior. The prognosis is generally unfavorable, especially in inoperable cases. In recent years, for some histologies, such as undifferentiated sinonasal carcinoma (SNUC), multimodal treatment with a combination of induction chemotherapy, surgery, and chemo/radiotherapy (RT) has improved the prognosis. Nevertheless, still about half of the patients treated incur a recurrence, in most of the cases at the local site. Surgery with and without RT is usually the treatment choice in cases of recurrence after previous RT in combination with systemic therapy or RT in a histology-driven fashion. In the case of inoperable disease or contraindications to surgery, RT is still a valid treatment option. In this context, hadron therapy with protons (PT) or carbon ions (CIRT) is often preferred due to the physical and biological characteristics of charged particles, allowing the administration of high doses to the tumor target while sparing the surrounding healthy tissues and potentially limiting the side effects due to the high cumulative dose. In the absence of a standard of care for the recurrent setting, we aimed to investigate the role of re-RT with PT or CIRT. We retrospectively analysed 15 patients with recurrent, previously irradiated, SNCs treated at our institution between 2013 and 2020. Local control (LC) and overall survival (OS) were estimated by the Kaplan-Meier method. Acute and late toxicities were scored according to the National Cancer Institute's Common Terminology Criteria for Adverse Events CTCAE version 5.0. A total of 13 patients received CIRT and 2 patients received PT. The median re-RT dose was 54 GyRBE (range 45-64 GyRBE) delivered in 3 or 4 GyRBE/fr (fraction) for the CIRT, and 2 Gy RBE/fr for the PT schedule. LC was 44% at the 1-year follow-up and 35.2% at the 3-year follow-up. OS at 1 and 3 years were 92.9% and 38.2%, respectively. Fourteen patients developed G1-G2 acute toxicity (dermatitis and mucositis), and no patients developed G3-G5. Regarding late toxicity, 10 patients encountered at maximum G1-2 events, and 4 did not experience any toxicity. Only for one patient G3 late toxicity was reported (dysphagia requiring a percutaneous endoscopic gastrostomy).

Clinical Markers of Panic and Generalized Anxiety Disorder: Overlapping Symptoms, Different Course and Outcome.

Generalized Anxiety Disorder (GAD) and Panic Disorder (PD) share underlying neurobiological mechanisms and several clinical features which, with medical comorbidities, may increase misdiagnosis and delay proper treatment. The aim of the study was to evaluate the association between clinical/socio-demographic markers and GAD/PD diagnosis. Outpatients (N = 290) with PD or GAD were identified in mental health services in Monza and Milan (Italy). Descriptive analyses and a binary logistic regression model were performed. Post-onset psychiatric (p = 0.05) and medical (p = 0.02) multiple co-morbidities were associated with GAD; treatment with selective serotonin reuptake inhibitors (SSRIs) was associated with PD, while GAD diagnosis was associated with treatment with atypical antipsychotics or GABAergic drugs (p = 0.03), as well as psychodynamic psychotherapy (p < 0.01). Discontinuation of the last pharmacological treatment was associated with GAD diagnosis rather than the PD one (p = 0.02). GAD patients may have a worse prognosis than PD patients because of more frequent multiple co-morbidities, relapses and poorer treatment compliance. The different treatment approaches were consistent with the available literature, while the association between GAD and psychodynamic psychotherapy is an original finding of our study. Further studies on larger samples are necessary to better characterize clinical factors associated with GAD or PD.

Characterization of a flat-panel detector for 2D dosimetry in scanned proton and carbon ion beams.

PURPOSE: To fully characterize the flat panel detector of the new Sphinx Compact device with scanned proton and carbon ion beams. MATERIALS AND METHODS: The Sphinx Compact is designed for daily QA in particle therapy. We tested its repeatability and dose rate dependence as well as its proportionality with an increasing number of particles and potential quenching effect. Potential radiation damage was evaluated. Finally, we compared the spot characterization (position and profile FWHM) with our radiochromic EBT3 film baseline. RESULTS: The detector showed a repeatability of 1.7% and 0.9% for single spots of protons and carbon ions, respectively, while for small scanned fields it was inferior to 0.2% for both particles. The response was independent from the dose rate (difference from nominal value < 1.5%). We observed an under-response due to quenching effect for both particles, mostly for carbon ions. No radiation damage effects were observed after two months of weekly use and approximately 1350 Gy delivered to the detector. Good agreement was found between the Sphinx and EBT3 films for the spot position (central-axis deviation within 1 mm). The spot size measured with the Sphinx was larger compared to films. For protons, the average and maximum differences over different energies were 0.4 mm (3%) and 1 mm (7%); for carbon ions they were 0.2 mm (4%) and 0.4 mm (6%). CONCLUSIONS: Despite the quenching effect the Sphinx Compact fulfills the requirements needed for constancy checks and could represent a time-saving tool for daily QA in scanned particle beams.

Effects of PM2.5 Exposure on the ACE/ACE2 Pathway: Possible Implication in COVID-19 Pandemic.

Particulate matter (PM) is a harmful component of urban air pollution and PM2.5, in particular, can settle in the deep airways. The RAS system plays a crucial role in the pathogenesis of pollution-induced inflammatory diseases: the ACE/AngII/AT1 axis activates a pro-inflammatory pathway counteracted by the ACE2/Ang(1-7)/MAS axis, which in turn triggers an anti-inflammatory and protective pathway. However, ACE2 acts also as a receptor through which SARS-CoV-2 penetrates host cells to replicate. COX-2, HO-1, and iNOS are other crucial proteins involved in ultrafine particles (UFP)-induced inflammation and oxidative stress, but closely related to the course of the COVID-19 disease. BALB/c male mice were subjected to PM2.5 sub-acute exposure to study its effects on ACE2 and ACE, COX-2, HO-1 and iNOS proteins levels, in the main organs concerned with the pathogenesis of COVID-19. The results obtained show that sub-acute exposure to PM2.5 induces organ-specific modifications which might predispose to greater susceptibility to severe symptomatology in the case of SARS-CoV-2 infection. The novelty of this work consists in using a molecular study, carried out in the lung but also in the main organs involved in the disease, to analyze the close relationship between exposure to pollution and the pathogenesis of COVID-19.

Optimizing CDK4/6 inhibitors in advanced HR+/HER2- breast cancer: A personalized approach.

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) are now a backbone of treatment for hormone receptor-positive/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. CDK4/6i plus ET is more effective than ET alone in this setting; however, the risk of grade 3-4 adverse events also increases. Approved agents in this class have similar efficacies, but important differences due to their structural and pharmacological properties. We review biomarkers and discuss determinants to inform a rational approach to therapy choice when selecting the most appropriate ET and CDK4/6i partners. We also identify subgroups that may benefit from specific ET-CDK4/6i combinations and discuss strategies to overcome resistance. This personalized approach aims to minimize treatment-related toxicities that may affect patient QoL and compliance, and ultimately therapy efficacy.

Dosimetric validation of a GPU-based dose engine for a fast in silico patient-specific quality assurance program in light ion beam therapy.

BACKGROUND: With rapid evolutions of fast and sophisticated calculation techniques and delivery technologies, clinics are almost facing a daily patient-specific (PS) plan adaptation, which would make a conventional experimental quality assurance (QA) workflow unlikely to be routinely feasible. Therefore, in silico approaches are foreseen by means of second-check independent dose calculation systems possibly handling machine log-files. PURPOSE: To validate the in-house developed GPU-dose engine, FRoG, for light ion beam therapy (protons and carbon ions) as a second-check independent calculation system and to integrate machine log-file analysis into the patient-specific quality assurance (PSQA) program. METHODS: Spot sizes, depth-dose distributions, and absolute dose calibrations were configured into FRoG and a set of nine regular-shaped targets in combination with more than 170 clinical treatment fields were tested against pinpoint ionization chamber measurements. Both the treatment planning system DICOM RTplans and machine treatment log-files were used as input for the dose kernel in water, and a 3D local γ (1 mm/2%) index was used as the main evaluation metric. RESULTS: Calculated configuration data matched experimental measurements with submillimetric agreement. For regular-shaped targets, the unsigned average relative difference between calculated and measured dose values was less than 2% for both protons and carbon ions. The mean γ passing rate (PR) was around 98% for both particle species. For clinical treatment beams, DICOM-based recalculations showed a γ-PR more than 99% for both particle species. The same level of agreement was preserved for protons when moving to log-file-based recalculations. A score of around 95% was registered for carbon ion beams, once excluding low-quality machine log-files. Unsigned average relative difference against acquired data was less than 2% also for real clinical beams. CONCLUSIONS: FRoG was proven as an accurate and reliable tool for PSQA in scanning light ion beam therapy. The proposed method allows for an extremely efficient workflow, without compromising the quality of the plan verification procedure.

Polymer aging affects the bioavailability of microplastics-associated contaminants in sea urchin embryos.

Microplastics (MPs) in the marine environment undergo complex weathering factors that can affect their ability to interact with different coexisting environmental contaminants (termed here co-contaminants). In this study, the influence of artificially aging using UV on the sorption of a complex mixture of co-contaminants onto MPs was investigated in order to provide meaningful hypotheses on their individual and combined toxicities on sea urchin embryos. A mixture of artificially aged MPs (PS particles and PA microfibers) combined with 2,2',4,4'-tetrabromodiphenyl ether (BDE-47), or Cd or Cu, both alone and in a mix, were used to expose embryos of Paracentrotus lividus. The effects of polymer aging on co-contaminants bioavailability were assessed by measuring changes in the transcriptional profile of genes involved in oxidative-stress response and skeletogenic and endo-mesodermal specification. Changes in the sorption ability of MPs to co-contaminants in the aqueous phase highlighted that aging did not affect the sorption of BDE-47 and Cd on MPs, although a certain influence on Cu sorption was found. Despite no morphological effects in embryos at the gastrula stage after MPs/contaminants combinatorial exposure emerged, the greatest influence of the aging process was mainly found for combined exposures which included BDE-47. Finally, the exposure to multiple contaminants generated transcriptional profiles poorly related to those activated by single contaminant, at times suggesting a mixture-dependent different aging influence. These results open new scenarios on the controversial role of vector of co-contaminants for MPs, especially when complex and different types of mixtures were considered.

The role of multiple anatomical scenarios in plan optimization for carbon ion radiotherapy of pancreatic cancer.

PURPOSE /OBJECTIVE: To quantify benefits of robust optimization on multiple 4DCT acquisitions combined with off-line treatment adaptation for neoadjuvant carbon ion therapy (CIRT) of pancreatic cancer. MATERIAL/METHODS: For 10 previously treated patients, 4DCTs were acquired around -15 (CTPlan), -5 (RE1), -1 (RE2) and +6 (RE3) days from RT start. Treatment plans were newly optimized to a dose prescription of 38.4 Gy(RBE) (8 fractions) with a constraint of 38 Gy(RBE) to 1% of the gastrointestinal organs at risk volume (D1%). Three strategies were tested: (A) robust optimization on CTPlan maximum exhale (0Ex) with 3 mm set-up, 3% range uncertainty, including 30%-inhale; (B) addition of the RE1-0Ex scenario; (C) plan recalculation at each REi and adaptation (RPi) according to deviation thresholds from clinical goals. The cumulative variation of target coverage and GI-OARs doses was evaluated. Duodenum contours of all 4DCTs of each patient were registered on CTPlan-0Ex. The capacity of pre-RT acquisitions to predict duodenum position was investigated by computing the intersection of contours at CTplan, RE1, or their union, with respect to subsequent 4DCTs and the CTV, coupled with increasing margin. RESULTS: (A) No recalculation exceeded the D1% constraint. (B) The inclusion of RE1-0Ex in the optimization problem improved inter-fraction robustness on a patient-specific basis, but was non-significant on average. (C) Half of the plans would be re-optimized to recover target coverage and/or minimize duodenum dose, at least once. A significant difference was observed between pre-RT duodenum contours when intersecting subsequent contours, either with a margin expansion. CONCLUSION: Anatomical variations highlighted at multiple REi proved that a fast and efficient online adaptation is essential to optimize treatment quality of CIRT for pancreatic cancer.

A Patient Selection Approach Based on NTCP Models and DVH Parameters for Definitive Proton Therapy in Locally Advanced Sinonasal Cancer Patients.

(1) Background: In this work, we aim to provide selection criteria based on normal tissue complication probability (NTCP) models and additional explanatory dose-volume histogram parameters suitable for identifying locally advanced sinonasal cancer patients with orbital invasion benefitting from proton therapy. (2) Methods: Twenty-two patients were enrolled, and two advanced radiation techniques were compared: intensity modulated proton therapy (IMPT) and photon volumetric modulated arc therapy (VMAT). Plans were optimized with a simultaneous integrated boost modality: 70 and 56 Gy(RBE) in 35 fractions were prescribed to the high risk/low risk CTV. Several endpoints were investigated, classified for their severity and used as discriminating paradigms. In particular, when NTCP models were already available, a first selection criterion based on the delta-NTCP was adopted. Additionally, an overall analysis in terms of DVH parameters was performed. Furthermore, a second selection criterion based on a weighted sum of the ΔNTCP and ΔDVH was adopted. (3) Results: Four patients out of 22 (18.2%) were suitable for IMPT due to ΔNTCP > 3% for at least one severe toxicity, 4 (18.2%) due to ΔNTCP > 20% for at least three concurrent intermediate toxicities and 16 (72.7%) due to the mixed sum of ΔNTCP and ΔDVH criterion. Since, for some cases, both criteria were contemporary fulfilled, globally 17/22 patients (77.3%) would benefit from IMPT. (4) Conclusions: For this rare clinical scenario, the use of a strategy including DVH parameters and NTCPs when comparing VMAT and IMPT is feasible. We showed that patients affected by sinonasal cancer could profit from IMPT compared to VMAT in terms of optical and central nervous system organs at risk sparing.

Multidisciplinary Team Meeting Proposal and Final Therapeutic Choice in Early Breast Cancer: Is There an Agreement?

Background: A multidisciplinary team meeting (MDM) approach in breast cancer (BC) management is a standard of care. One of the roles of MDMs is to identify the best diagnostic and therapeutic strategies for patients (pts) with new diagnosis of early BC. The purpose of this study was to define whether there was an agreement between the planned program (i.e., MDMs-based decision) and that actually applied. In addition, the study explored factors associated with discordance. Methods: We conducted a retrospective study of a consecutive series of 291 patients with new diagnosis of early BC, discussed at MDMs at the University Hospital of Udine (Italy), from January 2017 to June 2018. The association between clinico-biological factors and discordance between what was decided during the MDMs and what was consequently applied by the oncologist was explored through uni- and multivariate logistic regression analyses. Results: The median age was 62 years (range 27-88 years). Among invasive early BC patients, the most frequent phenotype was luminal A (38%), followed by luminal B (33%), HER2-positive (12%), and triple-negative (5%). In situ carcinoma (DCIS) represented 12% of cases. The median time from MDM discussion to first oncologic examination was 2 weeks. The rate of discordance between MDM-based decision and final choice, during a face-to-face consultation with the oncologist, was 15.8% (46/291). The most frequent reason for changing the MDM-based program was clinical decision (87%). Follow-up was preferred to the chemotherapy (CT) proposed within the MDMs in 15% of cases, and to the endocrine therapy (ET) in 39% of cases (among these, 44.5% had a diagnosis of DCIS). Therapeutic change from sequential CT-ET to ET alone was chosen in 16/46 pts (35%): among these patients, seven had a luminal B disease and six had an HER2-positive disease. On univariate analysis, factors associated with discordance were values of Ki-67 14%-30% (OR 3.91; 95% CI 1.19-12.9), age >70 years (OR 2.44, 95% CI 1.28-4.63), housewife/retired status (OR 2.35, 95% CI 1.14-4.85), polypharmacy (OR 1.95; 95% CI 1.02-3.72), postmenopausal status (OR 4.15; 95% CI 1.58-10.9), and high Charlson Comorbidity Index (OR 1.31; 95% CI 1.09-1.57). The association with marital status, educational level, alcohol and smoke habits, presence of a caregiver, parity, grading, histotype and phenotype, and stage was not statistically significant. On multivariate analysis, only Ki-67 value maintained its statistical significance. Conclusion: The results of our study could be useful for enhancing the role of MDMs in the clinical decision-making process in early BC.

Prospects and Pitfalls of Machine Learning in Nutritional Epidemiology.

Nutritional epidemiology employs observational data to discover associations between diet and disease risk. However, existing analytic methods of dietary data are often sub-optimal, with limited incorporation and analysis of the correlations between the studied variables and nonlinear behaviours in the data. Machine learning (ML) is an area of artificial intelligence that has the potential to improve modelling of nonlinear associations and confounding which are found in nutritional data. These opportunities notwithstanding, the applications of ML in nutritional epidemiology must be approached cautiously to safeguard the scientific quality of the results and provide accurate interpretations. Given the complex scenario around ML, judicious application of such tools is necessary to offer nutritional epidemiology a novel analytical resource for dietary measurement and assessment and a tool to model the complexity of dietary intake and its relation to health. This work describes the applications of ML in nutritional epidemiology and provides guidelines to avoid common pitfalls encountered in applying predictive statistical models to nutritional data. Furthermore, it helps unfamiliar readers better assess the significance of their results and provides new possible future directions in the field of ML in nutritional epidemiology.

Is there an association between inflammatory/anti-oxidant markers and the presence of psychotic symptoms or severity of illness in mood and psychotic disorders? A multi-centric study on a drug-free sample.

The immune and antioxidant systems are intimately connected and their role in the etiology of major psychiatric disorders is currently under study. The aim of this study was to evaluate the potential associations between inflammatory/antioxidant peripheral markers and presence of psychotic symptoms or severity of illness in patients affected by major psychiatric disorders. One hundred and twenty-six drug-free patients were included. A blood sample was collected to measure total/B/T lymphocytes and plasma levels of albumin, total bilirubin, uric acid, C-reactive protein, and vitamins A and E. Severity of illness was assessed using psychometric scales. Groups of patients divided according to diagnosis were compared in terms of measured markers using multivariate analyses of variance (MANOVAs). Linear and logistic regression analyses were performed to investigate the potential association between markers and severity of illness or presence/absence of psychotic symptoms. Albumin plasma levels were higher in patients with substance-induced psychotic disorder (SIPD) than subjects affected by schizophrenia (F â€‹= â€‹4.923; p â€‹= â€‹0.003). Lower vitamin E (OR â€‹= â€‹0.81; p â€‹= â€‹0.014) and T lymphocyte (OR â€‹= â€‹0.99; p â€‹= â€‹0.048) plasma levels were predictive of lifetime psychotic symptoms. Lower vitamin A levels were associated with higher Montgomery-Åsberg Depression Rating Scale scores (ߠ​= â€‹-24.26; p â€‹= â€‹0.029), independent of diagnosis. Patients with SIPD may be less vulnerable to oxidative stress. The severity of depressive symptoms, inversely associated with vitamin A plasma levels, is likely to be modulated by the degree of inflammation. Patients presenting with lifetime psychotic symptoms may be more vulnerable to oxidative stress and may have a higher activation of humoral immunity.

A hybrid Neural Network-SEIR model for forecasting intensive care occupancy in Switzerland during COVID-19 epidemics.

Anticipating intensive care unit (ICU) occupancy is critical in supporting decision makers to impose (or relax) measures that mitigate COVID-19 transmission. Mechanistic approaches such as Susceptible-Infected-Recovered (SIR) models have traditionally been used to achieve this objective. However, formulating such models is challenged by the necessity to formulate equations for plausible causal mechanisms between the intensity of COVID-19 transmission and external epidemic drivers such as temperature, and the stringency of non-pharmaceutical interventions. Here, we combined a neural network model (NN) with a Susceptible-Exposed-Infected-Recovered model (SEIR) in a hybrid model and attempted to increase the prediction accuracy of existing models used to forecast ICU occupancy. Between 1st of October, 2020 - 1st of July, 2021, the hybrid model improved performances of the SEIR model at different geographical levels. At a national level, the hybrid model improved, prediction accuracy (i.e., mean absolute error) by 74%. At the cantonal and hospital levels, the reduction on the forecast's mean absolute error were 46% and 50%, respectively. Our findings illustrate those predictions from hybrid model can be used to anticipate occupancy in ICU, and support the decision-making for lifesaving actions such as the transfer of patients and dispatching of medical personnel and ventilators.

Proton Radiation Therapy for Nasopharyngeal Cancer Patients: Dosimetric and NTCP Evaluation Supporting Clinical Decision.

(1) Background: we proposed an integrated strategy to support clinical allocation of nasopharyngeal patients between proton and photon radiotherapy. (2) Methods: intensity-modulated proton therapy (IMPT) plans were optimized for 50 consecutive nasopharyngeal carcinoma (NPC) patients treated with volumetric modulated arc therapy (VMAT), and differences in dose and normal tissue complication probability (ΔNTCPx-p) for 16 models were calculated. Patient eligibility for IMPT was assessed using a model-based selection (MBS) strategy following the results for 7/16 models describing the most clinically relevant endpoints, applying a model-specific ΔNTCPx-p threshold (15% to 5% depending on the severity of the complication) and a composite threshold (35%). In addition, a comprehensive toxicity score (CTS) was defined as the weighted sum of all 16 ΔNTCPx-p, where weights follow a clinical rationale. (3) Results: Dose deviations were in favor of IMPT (ΔDmean ≥ 14% for cord, esophagus, brainstem, and glottic larynx). The risk of toxicity significantly decreased for xerostomia (-12.5%), brain necrosis (-2.3%), mucositis (-3.2%), tinnitus (-8.6%), hypothyroidism (-9.3%), and trismus (-5.4%). There were 40% of the patients that resulted as eligible for IMPT, with a greater advantage for T3-T4 staging. Significantly different CTS were observed in patients qualifying for IMPT. (4) Conclusions: The MBS strategy successfully drives the clinical identification of NPC patients, who are most likely to benefit from IMPT. CTS summarizes well the expected global gain.

Dosimetric and Clinical Risk Factors for the Development of Maxillary Osteoradionecrosis in Adenoid Cystic Carcinoma (ACC) Patients Treated With Carbon Ion Radiotherapy.

Background: The present study aims to evaluate dosimetric and clinical risk factors for the development of maxillary osteoradionecrosis (ORN) in head and neck adenoid cystic carcinoma (ACC) patients treated with carbon ion radiotherapy (CIRT). Methods: Clinical data and treatment plans of ACC patients, consecutively treated from January 2013 to September 2016 within the phase II clinical trial CNAO S9/2012/C, were retrospectively reviewed. ORN and other treatment-related toxicity were graded according to the Common Terminology Criteria for Adverse Events (CTACE), version 4.0. The maxillary bone was contoured on the planning CT, and only patients receiving more than 10% of the prescription dose at their maxilla were considered for the analysis (67 patients). The volumes of maxilla receiving doses from 10 Gy (RBE) to 60 Gy (RBE) (VD), with an increment of 10 Gy (RBE), and additional clinical factors were correlated to the incidence of ORN with univariate analysis (Chi-square test). The logistic regression model was subsequently applied for multivariate analysis. Treatment plans calculated with a local effect model (LEM)-based optimization were recalculated with the modified microdosimetric kinetic model (MKM), and compared with literature data from the Japanese experience. Results: The median time interval from the start of CIRT to ORN appearance was 24 months (range, 8-54 months). Maxillary ORN was observed in 11 patients (16.4%). Grade 1 ORN was observed in 2 patients (18.1%), G2 in 4 (36.3%), G3 in 4 (36.3%) and G4 in 1 (9.3%). From univariate analysis, the site of the tumor, the presence of teeth within the PTV and acute mucositis correlated with the development of maxillary ORN. VD were significantly higher for all the dose levels tested in patients with maxillary ORN than patients without necrosis, according to both radiobiological models. The multivariate analysis showed that V60 significantly correlated with ORN risk. Conclusion: The volume of maxilla irradiated with high dose values was relevant for ORN development in our cohort of ACC patients. These results are in line with previously published data obtained with a different radiobiological model. Our findings might be helpful to prevent the risk of ORN in patients receiving CIRT.