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.

The efficacy and safety of enzalutamide with trastuzumab in patients with HER2+ and androgen receptor-positive metastatic or locally advanced breast cancer.

PURPOSE: Androgen receptor (AR) expression occurs in up to 86% of human epidermal growth factor receptor 2-positive (HER2+) breast cancers. In vitro, AR inhibitors enhance antitumor activity of trastuzumab, an anti-HER2 antibody, in trastuzumab-resistant HER2+ cell lines. This open-label, single-arm, phase II study evaluated the efficacy and safety of enzalutamide, an AR-signaling inhibitor, in patients with advanced HER2+ AR+ breast cancer previously treated with trastuzumab. METHODS: Eligible patients had measurable or non-measurable evaluable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, Eastern Cooperative Oncology Group status ≤ 1, no history of brain metastases, and previously received ≥ 1 anti-HER2 regimen for advanced disease. Patients received 160 mg oral enzalutamide daily and 6 mg/kg intravenous trastuzumab every 21 days until disease progression or unacceptable toxicity. Primary end point was clinical benefit rate at 24 weeks (CBR24); secondary end points included progression-free survival (PFS) and safety. RESULTS: Overall, 103 women were enrolled [median age 60 years (range 34-83)]; 62% had received ≥ 3 lines of prior anti-HER2 therapy. CBR24, comprising patients with confirmed partial responses (5%) and durable stable disease at 24 weeks (19%), was 24% in the efficacy evaluable set (n = 89). CBR24 did not seem related to AR-expression levels or hormone receptor status. Median PFS was 3.4 months (95% confidence interval 2.0-3.8). Overall, 97 (94%) patients experienced treatment-emergent adverse events (TEAEs), with fatigue most common (34%). Dyspnea (4%) and malignant neoplasm progression (3%) were the only TEAEs grade ≥ 3 reported in ≥ 3 patients. 22 patients (21%) reported serious TEAEs. Four patients (4%) experienced fatal, non-drug-related TEAEs. CONCLUSIONS: Enzalutamide plus trastuzumab was well tolerated, and a subset of patients in this heavily pretreated population had durable disease control. Determination of biomarkers is needed to identify patients most likely to benefit from this combination. CLINICALTRIALS. GOV NUMBER: NCT02091960.

Clinico-radiological monitoring strategies in patients with metastatic breast cancer: a real-world study.

Aim: A monitoring strategy for metastatic breast cancer patients (M-MBC) has been little studied. Materials & methods: This retrospective study analyzed a consecutive cohort of 382 MBC patients to analyze different M-MBC strategies to identify factors influencing intensive M-MBC. Results: Elevated baseline serum tumor markers (STM) was the strongest factor associated with increased use of STM tests. Having more frequent oncology office visits was associated with more intensive chemotherapy/magnetic resonance imaging (MRI) using. Increased use of imaging tests was associated with participation to clinical trial. Single and elderly patients were less likely to have frequent testing. Having clinically measurable disease was less likely to have more intensive M-MBC. Conclusion: STM testing and scans were frequently ordered in M-MBC. In the present study, strategies are little influenced by clinico-pathological characteristics.

Comparison of primary breast cancer and paired metastases: biomarkers discordance influence on outcome and therapy.

AIM: Discordance between primary tumor and paired metastases biology has been widely detected in metastatic breast cancer. The aim of this study was to evaluate the prognostic impact of Ki67, estrogen receptor (ER), progesterone receptor (PR) and HER2 discordance. METHODS: We retrospectively analyzed a cohort of 544 patients affected by metastatic breast cancer. Variation in ER, PR, Ki67 and HER2 expression between primary site and recurrence was tested through the McNemar test. RESULTS: A significant variation was observed in respect to ER, PR and Ki67 status (12.65%, p = 0.0072; 49.71%, p < 0.0001; 35%, p < 0.0001, respectively). Among patients with ER or PR discordance, the driver of therapeutic decisions was the ER status. Moreover, we observed a therapy-related reduction of ER in taxanes or aromatase inhibitors-exposed patients (odds ratio: 3.59; 95% CI: 1.66-7.77; p = 0.001 and odds ratio: 2.07; 95% CI: 0.96-4.44; p = 0.06, respectively). CONCLUSION: Biopsy of metastatic lesions may influence the decision-making process translating into better outcome.

A Quantitative Evaluation of Drive Pattern Selection for Optimizing EIT-Based Stretchable Sensors.

Electrical Impedance Tomography (EIT) is a medical imaging technique that has been recently used to realize stretchable pressure sensors. In this method, voltage measurements are taken at electrodes placed at the boundary of the sensor and are used to reconstruct an image of the applied touch pressure points. The drawback with EIT-based sensors, however, is their low spatial resolution due to the ill-posed nature of the EIT reconstruction. In this paper, we show our performance evaluation of different EIT drive patterns, specifically strategies for electrode selection when performing current injection and voltage measurements. We compare voltage data with Signal-to-Noise Ratio (SNR) and Boundary Voltage Changes (BVC), and study image quality with Size Error (SE), Position Error (PE) and Ringing (RNG) parameters, in the case of one-point and two-point simultaneous contact locations. The study shows that, in order to improve the performance of EIT based sensors, the electrode selection strategies should dynamically change correspondingly to the location of the input stimuli. In fact, the selection of one drive pattern over another can improve the target size detection and position accuracy up to 4.7% and 18%, respectively.

Measures of outcome in metastatic breast cancer: insights from a real-world scenario.

No gold standard treatment exists for metastatic breast cancer (MBC). Clinical decision making is based on knowledge of prognostic and predictive factors that are extrapolated from clinical trials and, sometimes, are not reliably transferable to a real-world scenario. Moreover, misalignment between endpoints used in drug development and measures of outcome in clinical practice has been noted. The roles of overall survival (OS) and progression-free survival (PFS) as primary endpoints in the context of clinical trials are the subjects of lively debate. Information about these parameters in routine clinical practice is potentially useful to design new studies and/or to interpret the results of clinical research. This study analyzed the impact of patient and tumor characteristics on the major measures of outcome across different lines of treatment in a cohort of 472 patients treated for MBC. OS, PFS, and postprogression survival (PPS) were analyzed. The study showed how biological and clinical characteristics may have different prognostic value across different lines of therapy for MBC. After first-line treatment, the median PPS of luminal A, luminal B, and human epidermal growth factor receptor 2 (HER2)-positive groups was longer than 12 months. The choice of OS as a primary endpoint for clinical trials could not be appropriate with these subtypes. In contrast, OS could be an appropriate endpoint when PPS is expected to be low (e.g., triple-negative subtype after the first line; other subtypes after the third line). The potential implications of these findings are clinical and methodological.

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.

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.

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.

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.

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.

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).

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.

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.

Exploratory predictive and prognostic factors in advanced breast cancer treated with metronomic chemotherapy.

The aim of the present study is to evaluate the clinical and biological factors (including markers of angiogenesis) as potential predictors of prognosis and benefit from metronomic therapy in patients with advanced breast cancer (ABC). Recent data suggest antiangiogenic activity of metronomic therapy. The study population included 62 patients with pretreated ABC who received cyclophosphamide and methotrexate orally. Tumour samples were analysed by immunohistochemistry for HER2, Ki-67, thymidine phosphorylase (TP), vascular endothelial growth factor and vascular endothelial growth factor receptor. The results from immunohistochemical analysis and clinico-pathological variables were studied to test their potential association with benefit from metronomic therapy. The median overall survival, progression-free survival and survival postprogression were 7.1 (range 0.2-38.3), 2.6 (range 0.2-28.9) and 3 (range 0-34.2) months, respectively. Among the clinical variables, age, performance status and previous therapy with taxanes were significantly associated with outcomes. Among the molecular markers, TP was found to be associated with progression-free survival. Metronomic therapy is an effective choice for ABC. Young women with a more indolent disease had the greatest benefit from this treatment. TP tumour expression might aid decision making but these findings must be confirmed in larger prospective, properly designed studies.

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.

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.

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.

The impact of COVID-19 on the psychiatric emergency departments of two Italian hospitals in Milan.

During the first wave of the SARS-CoV-2 contagion in Italy, mental health care services continuity has been granted to the general population. Emergent and urgent conditions, however, are managed in collaboration with Emergency Departments (EDs). This collaboration may have suffered from the overload of the EDs due to the high number of SARS-CoV-2 positive patients. In this perspective, we analysed the possible impact of COVID-19 on the EDs accesses of psychiatric patients in two of the main hospitals of Milan, the "Luigi Sacco" Hospital and the "Fatebenefratelli" Hospital, comparing their admissions between the periods of March, April and May 2019 and 2020. We found a significant reduction in the number of evaluated patients in 2020 in both EDs. Emergency Medical Services (EMSs) brought a significant lower number of patients to the ED of Sacco Hospital during 2020, while this number increased for the ED of Fatebenefratelli Hospital, confirming the hypothesis that the overload of the Sacco Hospital ED significantly influenced the possibility to receive a psychiatric evaluation there. Moreover, we found a significant difference between diagnosis at discharge of the different samples.

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.