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Absorbed dose heterogeneity in kidney tissues is an important issue in radiopharmaceutical therapy. The effect of absorbed dose heterogeneity in nephrotoxicity is, however, not fully understood yet, which hampers the implementation of treatment optimization by obscuring the interpretation of clinical response data and the selection of optimal treatment options. Although some dosimetry methods have been developed for kidney dosimetry to the level of microscopic renal substructures, the clinical assessment of the microscopic distribution of radiopharmaceuticals in kidney tissues currently remains a challenge. This restricts the anatomical resolution of clinical dosimetry, which hinders a thorough clinical investigation of the impact of absorbed dose heterogeneity. The potential of absorbed dose–response modelling to support individual treatment optimization in radiopharmaceutical therapy is recognized and gaining attraction. However, biophysical modelling is currently underexplored for the kidney, where particular modelling challenges arise from the convolution of a complex functional organization of renal tissues with the function-mediated dose distribution of radiopharmaceuticals. This article reviews and discusses the heterogeneity of absorbed dose distribution in kidney tissues and the absorbed dose–response modelling of nephrotoxicity in radiopharmaceutical therapy. The review focuses mainly on the peptide receptor radionuclide therapy with beta-particle emitting somatostatin analogues, for which the scientific literature reflects over two decades of clinical experience. Additionally, detailed research perspectives are proposed to address various identified challenges to progress in this field.

Abstract Abemaciclib demonstrated clinical benefit in women affected by HR+/HER2− advanced breast cancer (aBC). Drug-drug interactions (DDIs) can lead to reduced treatment efficacy or increased toxicity. This retro-prospective study aimed to evaluate outcomes, DDIs’ impact, and toxicities of abemaciclib combined with endocrine therapy in a real-world setting. Patients from 12 referral Italian hospitals with HR+/HER2− aBC who received abemaciclib were included. Clinical data about comorbidities, concurrent medications, outcomes, and adverse events (AE) were collected. Drug-PIN® (Personalized Interactions Network) is a tool recognizing the role of multiple interactions between active and/or pro-drug forms combined with biochemical and demographic patient data. The software was used to define the Drug-PIN score and Drug-PIN tier (green, yellow, dark yellow, and red) for each patient. Univariate and multivariate analyses were performed to identify predictors of patients’ PFS or toxicity. One hundred seventy-three patients were included. 13% of patients had >75years. The overall response rate (ORR) was 63%. The general population’s median PFS (mPFS) was 22 months (mo), while mOS were not reached. Patients treated with abemaciclib in combination with AI and fulvestrant had a mPFS of 36 and 19 mo, respectively. The most common toxicities were diarrhea, asthenia, and neutropenia detected in 63%,49%, and 49% of patients. The number of concomitant medications and comorbidities were not associated with survival outcomes (22 vs 17 mo, p = 0.068, p = 0.99). Drug-PIN tier from dark yellow to red and Drug-PIN score >12 were associated with shorter PFS compared to no/low-risk DDIs and score

This review explores the integration of artificial intelligence (AI) in interventional radiotherapy (IRT), emphasizing its potential to streamline workflows and enhance patient care. Through a systematic analysis of 78 relevant papers spanning from 2002 to 2024, we identified significant advancements in contouring, treatment planning, outcome prediction, and quality assurance. AI-driven approaches offer promise in reducing procedural times, personalizing treatments, and improving treatment outcomes for oncological patients. However, challenges such as clinical validation and quality assurance protocols persist. Nonetheless, AI presents a transformative opportunity to optimize IRT and meet evolving patient needs.

Abstract Background Immune checkpoint inhibitors (ICIs), administered alone or combined with chemotherapy, are the standard of care in advanced non-oncogene addicted Non-Small Cell Lung Cancer (NSCLC). Despite these treatments' success, most long-term survival benefit is restricted to approximately 20% of patients, highlighting the need to identify novel biomarkers to optimize treatment strategies. In several solid tumors, immune soluble factors, the activatory CD137+ Tcells, and the immunosuppressive cell subsets Tregs and MDSCs (PMN(Lox1+)-MDSC and M-MDSCs) correlated with responses to ICIs and clinical outcomes thus becoming appealing predictive and prognostic factors. This study investigated the role of distinct CD137+ Tcell subsets, Tregs, MDSCs, and immune-soluble factors in NSCLC patients as possible biomarkers. Methods The levels of T cells, MDSCs and soluble factors were evaluated in 89 metastatic NSCLC patients who underwent ICIs as first- or second-line treatment. T cell analysis was performed by cytoflurimetry evaluating Tregs and different CD137+ Tcell subsets also combined with CD3+, CD8+, PD1+, and Ki67+ markers. Circulating cytokines and immune checkpoints were also evaluated by Luminex analysis. All these parameters were correlated with several clinical factors (age, sex, smoking status, PS and TPS), response to therapy, PFS , and OS . The analyses were conducted in the overall population and in patients treated with ICIs as first-line (naïve patients). Results In both groups of patients, high levels of circulating CD137+ and CD137+PD1+ T cells (total, CD4 and CD8) and the soluble factor LAG3 positively correlated with response to therapy. In naïve patients, PMN(Lox1+)-MDSCs negatively correlated with clinical response, and a high percentage of Tregs was associated with favorable survival. Moreover, the balance between Treg/CD137+ Tcells or PMN(Lox1+)-MDSC/CD137+ Tcells was higher in non-responding patients and was associated with poor survival. CD137+ Tcells and Tregs resulted as two positive independent prognostic factors. Conclusion High levels of CD137+, CD137+PD1+ Tcells and sLAG3 could predict the response to ICIs in NSCLC patients independently by previous therapy. Combining the evaluation of CD137+ Tcells and Tregs also as Treg/CD137+ T cells ratio it is possible to identify naive patients with longer survival.

Brachytherapy (BRT) plays a pivotal role in the treatment of tumors, offering precise radiation therapy directly to the affected area. However, this technique demands extensive training and skills development, posing challenges for widespread adoption and ensuring patient safety. This narrative review explored the utilization of augmented reality (AR) in BRT, seeking to summarize existing evidence, discuss key findings, limitations, and quality of research as well as outline future research directions. The review revealed promising findings regarding the integration of AR in BRT. Studies have suggested the feasibility and potential benefits of AR in education, training, intra-operative guidance, and treatment planning. However, the evidence remains limited and heterogeneous, with most studies in preliminary phases. Standardization, prospective clinical trials, patient-centered outcomes assessment, and cost-effectiveness analysis emerge as critical areas for future research. Augmented reality holds transformative potential for BRT by enhancing precision, safety, and training efficiency. To fully implement these benefits, the field requires standardized protocols, rigorous clinical trials, and in-depth patient-centered investigations. Policy-makers and healthcare providers should closely monitor developments in AR and consider its implementation in clinical practice, contingent and robust evidence, and cost-effectiveness analysis. The pro-active pursuit of evidence-based practices will contribute to optimizing patient care in BRT.

Abstract Background About 30% of Prostate cancer (PCa) patients progress to metastatic PCa that remains largely incurable. This evidence underlines the need for the development of innovative therapies. In this direction, the potential research focus might be on long non-coding RNAs (lncRNAs) like H19, which serve critical biological functions and show significant dysregulation in cancer. Previously, we showed a transcriptional down-regulation of H19 under combined pro-tumoral estrogen and hypoxia treatment in PCa cells that, in turn, induced both E-cadherin and β4 integrin expression. H19, indeed, acts as transcriptional repressor of cell adhesion molecules affecting the PCa metastatic properties. Here, we investigated the role of H19/cell adhesion molecules circuitry on in vivo PCa experimental tumor growth and metastatic dissemination models. Methods H19 was silenced in luciferase-positive PC-3 and 22Rv1 cells and in vitro effect was evaluated by gene expression, proliferation and invasion assays before and after treatment with the histone lysine demethylase inhibitor, GSK-J4. In vivo tumor growth and metastasis dissemination, in the presence or absence of GSK-J4, were analyzed in two models of human tumor in immunodeficient mice by in vivo bioluminescent imaging and immunohistochemistry (IHC) on explanted tissues. Organotypic Slice Cultures (OSCs) from fresh PCa-explant were used as ex vivo model to test GSK-J4 effects. Results H19 silencing in both PC-3 and 22Rv1 cells increased: i) E-cadherin and β4 integrin expression as well as proliferation and invasion, ii) in vivo tumor growth, and iii) metastasis formation at bone, lung, and liver. Of note, treatment with GSK-J4 reduced lesions. In parallel, GSK-J4 efficiently induced cell death in PCa-derived OSCs. Conclusions Our findings underscore the potential of the H19/cell adhesion molecules circuitry as a targeted approach in PCa treatment. Modulating this interaction has proven effective in inhibiting tumor growth and metastasis, presenting a logical foundation for targeted therapy.

In the management of symptomatic inoperable retroperitoneal sarcomas (RPS), palliative radiotherapy (RT) is a potential treatment option. However, the efficacy of low doses used in palliative RT is limited in these radioresistant tumors. Therefore, exploring dose escalation strategies targeting specific regions of the tumor may enhance the therapeutic effect of RT in relieving or preventing symptoms.In this case report, we present the case of an 87-year-old patient with rapidly growing undifferentiated liposarcoma in the retroperitoneum, where surgical and systemic therapies were ruled out due to age and comorbidities. RT was administered using volumetric modulated arc therapy, delivering 20 Gy in 4 fractions twice daily to the macroscopic tumor and 40 Gy in 4 fractions twice daily (simultaneous integrated boost) to the central part of the tumor (Gross Tumor Volume minus 2 cm). An 18F−FDG-PET-CT scan performed after RT demonstrated a complete metabolic response throughout the entire tumor mass. Although the patient eventually succumbed to metastatic spread to the bone, liver, and lung after 9 months, no local disease progression or pain/obstructive symptoms were observed.This case highlights the technical and clinical feasibility of delivering ablative doses of RT to the central region of the tumor and suggests the potential for achieving a complete metabolic response and durable tumor control.

(1) Background: The visual and semiquantitative analysis of Technetium-99metastable-3,3-diphospono-1,2-propanodicarboxylic acid (99mTc-DPD) bone scintigraphy is promising for diagnosing cardiac amyloidosis but time-consuming. We validated a faster method, the geometric mean (GM) method with a semi-automated workflow, for heart–whole body (WB) ratio (H/WBr), heart retention (Hr), and WB retention (WBr) calculations compared to the classic method (CM) established in the literature. The capability of semiquantitative scintigraphy indexes to differentiate the etiology in transthyretin-related cardiac amyloidosis (cATTR) patients was investigated. (2) Methods: H/WBr, Hr, and WBr were calculated by extracting counts for WB, kidneys, bladder, and heart on early and late planar image scans and applying background, scan-time, and decay corrections, using CM and GM both on a referring workstation and on a semi-automated workflow in external software. The comparison between CM and GM was assessed with Pearson’s correlation, Lin’s Concordance Correlation Coefficient (CCC), and Bland–Altman analysis. H/WBr, Hr, and WBr and several clinical variables were used to implement LASSO, Random Forest (RF), and Neural Network (NN) models to predict mutated and wild-type ATTR etiologies. ROC curves and AUC were calculated. (3) Results: Hr, WBr, and H/WBr using CM and GM were highly correlated. Bland–Altman analysis between CM and GM showed biases of 0.12% [CI:0.04%;0.19%] for H/WBr, 0.07% [CI: 0.01%; 0.13%] for Hr, and -0.50% [CI: −1.22%; 0.22%] for WBr. LASSO and NN models had good performance in predicting etiologies with AUC values of 87.3% and 73.6%, respectively. The RF model showed a poorer AUC of 55.8%. (4) Conclusions: The GM in the assisted workflow was validated against the CM. LASSO and NN approaches allowed a good prediction performance to be obtained for patient etiology.

Introduction: Metastatic prostate cancer (PCa) presents a significant challenge in oncology due to its high mortality rate and the absence of effective biomarkers for predicting patient outcomes. Building on previous research that highlighted the critical role of the long noncoding RNA (lncRNA) H19 and cell adhesion molecules in promoting tumor progression under hypoxia and estrogen stimulation, this study aimed to assess the potential of these components as prognostic biomarkers for PCa at the biopsy stage. Methods: This research utilized immunohistochemistry and droplet digital PCR to analyze formalin-fixed paraffin-embedded (FFPE) biopsies, focusing on specific markers within the H19/cell adhesion molecules pathway. Results: A novel multivariate analysis led to a “BioScore”, a composite biomarker score to predict disease progression. This score is based on evaluating five key markers: the expression levels of Hypoxia-Inducible Factor 2 Alpha (HIF-2α), endothelial Nitric Oxide Synthase (eNOS), β4 integrin, E-cadherin transcript (CDH1), and lncRNA H19. The criteria for the “BioScore” involve identifying three out of these five markers, combining elevated levels of HIF-2α, eNOS, β4 integrin, and CDH1 with reduced H19 expression. Conclusions: This finding suggests the possibility of identifying, at the time of biopsy, PCa patients at higher risk of metastasis based on dysregulation in the H19/cell adhesion molecules circuitry. This study provides a valuable opportunity for early intervention in managing PCa, potentially contributing to personalized treatment strategies.

Different options for locally advanced pancreatic cancer (LAPC) are available based on international guidelines: chemotherapy (CHT), chemoradiation (CRT), and stereotactic body radiotherapy (SBRT). However, the role of radiotherapy is debated in LAPC. We retrospectively compared CHT, CRT, and SBRT ± CHT in a real-world setting in terms of overall survival (OS), local control (LC), and distant metastasis-free survival (DMFS). LAPC patients from a multicentric retrospective database were included (2005–2018). Survival curves were calculated using the Kaplan–Meier method. Multivariable Cox analysis was performed to identify predictors of LC, OS, and DMFS. Of the 419 patients included, 71.1% were treated with CRT, 15.5% with CHT, and 13.4% with SBRT. Multivariable analysis showed higher LC rates for CRT (HR: 0.56, 95%CI 0.34–0.92, p = 0.022) or SBRT (HR: 0.27, 95%CI 0.13–0.54, p < 0.001), compared to CHT. CRT (HR: 0.44, 95%CI 0.28–0.70, p < 0.001) and SBRT (HR: 0.40, 95%CI 0.22–0.74, p = 0.003) were predictors of prolonged OS with respect to CHT. No significant differences were recorded in terms of DMFS. In selected patients, the addition of radiotherapy to CHT is still an option to be considered. In patients referred for radiotherapy, CRT can be replaced by SBRT considering its duration, higher LC rate, and OS rate, which are at least comparable to that of CRT.

BackgroundThe objective of this study was to assess the impact of age and other patient and treatment characteristics on toxicity in prostate cancer patients receiving adjuvant radiotherapy (RT).Materials and methodsThis observational study (ICAROS-1) evaluated both acute (RTOG) and late (RTOG/EORTC) toxicity. Patient- (age; Charlson’s comorbidity index) and treatment-related characteristics (nodal irradiation; previous TURP; use, type, and duration of ADT, RT fractionation and technique, image-guidance systems, EQD2 delivered to the prostate bed and pelvic nodes) were recorded and analyzed.ResultsA total of 381 patients were enrolled. The median EQD2 to the prostate bed (α/β=1.5) was 71.4 Gy. The majority of patients (75.4%) were treated with intensity-modulated radiation therapy (IMRT) or volumetric-modulated arc therapy (VMAT). Acute G3 gastrointestinal (GI) and genitourinary (GU) toxicity rates were 0.5% and 1.3%, respectively. No patients experienced >G3 acute toxicity. The multivariable analysis of acute toxicity (binomial logistic regression) showed a statistically significant association between older age (> 65) and decreased odds of G≥2 GI acute toxicity (OR: 0.569; 95%CI: 0.329-0.973; p: 0.040) and decreased odds of G≥2 GU acute toxicity (OR: 0.956; 95%CI: 0.918-0.996; p: 0.031). The 5-year late toxicity-free survival rates for G≥3 GI and GU toxicity were 98.1% and 94.5%, respectively. The only significant correlation found (Cox’s regression model) was a reduced risk of late GI toxicity in patients undergoing hypofractionation (HR: 0.38; 95% CI: 0.18-0.78; p: 0.008).ConclusionsThe unexpected results of this analysis could be explained by a “response shift bias” concerning the protective effect of older age and by treatment in later periods (using IMRT/VMAT) concerning the favorable effect of hypofractionation. However, overall, the study suggests that age should not be a reason to avoid adjuvant RT and that the latter is well-tolerated even with moderately hypofractionated regimens.

Sarcopenia (SP) is a syndrome characterized by age-associated loss of skeletal muscle mass and function. SP worsens both acute and late radiation-induced toxicity, prognosis, and quality of life. Myosteatosis is a pathological infiltration of muscle tissue by adipose tissue which often precedes SP and has a proven correlation with prognosis in cancer patients. Sarcopenic obesity is considered a “hidden form” of SP (due to large fat mass) and is independently related to higher mortality and worse complications after surgery and systemic treatments with worse prognostic impact compared to SP alone. The evaluation of SP is commonly based on CT images at the level of the middle of the third lumbar vertebra. On this scan, all muscle structures are contoured and then the outlined surface area is calculated. Several studies reported a negative impact of SP on overall survival in patients undergoing RT for tumors of the head and neck, esophagus, rectum, pancreas, cervix, and lung. Furthermore, several appetite-reducing side effects of RT, along with more complex radiation-induced mechanisms, can lead to SP through, but not limited to, reduced nutrition. In particular, in pediatric patients, total body irradiation was associated with the onset of SP and other changes in body composition leading to an increased risk of cardiometabolic morbidity in surviving adults. Finally, some preliminary studies showed the possibility of effectively treating SP and preventing the worsening of SP during RT. Future studies should be able to provide information on how to prevent and manage SP before, during, or after RT, in both adult and pediatric patients.

Background: The safe use of radiotherapy (RT) requires compliance with dose/volume constraints (DVCs) for organs at risk (OaRs). However, the available recommendations are sometimes conflicting and scattered across a number of different documents. Therefore, the aim of this work is to provide, in a single document, practical indications on DVCs for OaRs in external beam RT available in the literature. Material and Methods: A multidisciplinary team collected bibliographic information on the anatomical definition of OaRs, on the imaging methods needed for their definition, and on DVCs in general and in specific settings (curative RT of Hodgkin’s lymphomas, postoperative RT of breast tumors, curative RT of pediatric cancers, stereotactic ablative RT of ventricular arrythmia). The information provided in terms of DVCs was graded based on levels of evidence. Results: Over 650 papers/documents/websites were examined. The search results, together with the levels of evidence, are presented in tabular form. Conclusions: A working tool, based on collected guidelines on DVCs in different settings, is provided to help in daily clinical practice of RT departments. This could be a first step for further optimizations.

BackgroundA CE- and FDA-approved cloud-based Deep learning (DL)-tool for automatic organs at risk (OARs) and clinical target volumes segmentation on computer tomography images is available. Before its implementation in the clinical practice, an independent external validation was conducted.MethodsAt least a senior and two in training Radiation Oncologists (ROs) manually contoured the volumes of interest (VOIs) for 6 tumoral sites. The auto-segmented contours were retrieved from the DL-tool and, if needed, manually corrected by ROs. The level of ROs satisfaction and the duration of contouring were registered. Relative volume differences, similarity indices, satisfactory grades, and time saved were analyzed using a semi-automatic tool.ResultsSeven thousand seven hundred sixty-five VOIs were delineated on the CT images of 111 representative patients. The median (range) time for manual VOIs delineation, DL-based segmentation, and subsequent manual corrections were 25.0 (8.0-115.0), 2.3 (1.2-8) and 10.0 minutes (0.3-46.3), respectively. The overall time for VOIs retrieving and modification was statistically significantly lower than for manual contouring (p

Severe pain is frequent in patients with locally advanced pancreatic ductal adenocarcinoma (PDCA). Stereotactic body radiotherapy (SBRT) provides high local control rates in these patients. The aim of this review was to systematically analyze the available evidence on pain relief in patients with PDCA. We updated our previous systematic review through a search on PubMed of papers published from 1 January 2018 to 30 June 2021. Studies with full available text, published in English, and reporting pain relief after SBRT on PDCA were included in this analysis. Statistical analysis was carried out using the MEDCALC statistical software. All tests were two-sided. The I2 statistic was used to quantify statistical heterogeneity (high heterogeneity level: >50%). Nineteen papers were included in this updated literature review. None of them specifically aimed at assessing pain and/or quality of life. The rate of analgesics reduction or suspension ranged between 40.0 and 100.0% (median: 60.3%) in six studies. The pooled rate was 71.5% (95% CI, 61.6–80.0%), with high heterogeneity between studies (Q2 test: p < 0.0001; I2 = 83.8%). The rate of complete response of pain after SBRT ranged between 30.0 and 81.3% (median: 48.4%) in three studies. The pooled rate was 51.9% (95% CI, 39.3–64.3%), with high heterogeneity (Q2 test: p < 0.008; I2 = 79.1%). The rate of partial plus complete pain response ranged between 44.4 and 100% (median: 78.6%) in nine studies. The pooled rate was 78.3% (95% CI, 71.0–84.5%), with high heterogeneity (Q2 test: p < 0.0001; I2 = 79.4%). A linear regression with sensitivity analysis showed significantly improved overall pain response as the EQD2α/β:10 increases (p: 0.005). Eight papers did not report any side effect during and after SBRT. In three studies only transient acute effects were recorded. The results of the included studies showed high heterogeneity. However, SBRT of PDCA resulted reasonably effective in producing pain relief in these patients. Further studies are needed to assess the impact of SBRT in this setting based on Patient-Reported Outcomes.

IntroductionTotal body irradiation (TBI) is an important component of the conditioning regimen in patients undergoing hematopoietic stem cell transplants. TBI is used in very few patients and therefore it is generally delivered with standard linear accelerators (LINACs) and not with dedicated devices. Severe pulmonary toxicity is the most common adverse effect after TBI, and patient-specific lead blocks are used to reduce mean lung dose. In this context, online treatment setup is crucial to achieve precise positioning of the lung blocks. Therefore, in this study we aim to report our experience at generating 3D-printed patient-specific lung blocks and coupling a dedicated couch (with an integrated onboard image device) with a modern LINAC for TBI treatment.Material and methodsTBI was planned and delivered (2Gy/fraction given twice a day, over 3 days) to 15 patients. Online images, to be compared with planned digitally reconstructed radiographies, were acquired with the couch-dedicated Electronic Portal Imaging Device (EPID) panel and imported in the iView software using a homemade Graphical User Interface (GUI). In vivo dosimetry, using Metal-Oxide Field-Effect Transistors (MOSFETs), was used to assess the setup reproducibility in both supine and prone positions.Results3D printing of lung blocks was feasible for all planned patients using a stereolithography 3D printer with a build volume of 14.5×14.5×17.5 cm3. The number of required pre-TBI EPID-images generally decreases after the first fraction. In patient-specific quality assurance, the difference between measured and calculated dose was generally

Abstract The aim of this standard operational procedure is to standardize the methodology employed for the evaluation of pre- and post-treatment absorbed dose calculations in 90Y microsphere liver radioembolization. Basic assumptions include the permanent trapping of microspheres, the local energy deposition method for voxel dosimetry, and the patient–relative calibration method for activity quantification.The identity of 99mTc albumin macro-aggregates (MAA) and 90Y microsphere biodistribution is also assumed. The large observed discrepancies in some patients between 99mTc-MAA predictions and actual 90Y microsphere distributions for lesions is discussed. Absorbed dose predictions to whole non-tumoural liver are considered more reliable and the basic predictors of toxicity. Treatment planning based on mean absorbed dose delivered to the whole non-tumoural liver is advised, except in super-selective treatments. Given the potential mismatch between MAA simulation and actual therapy, absorbed doses should be calculated both pre- and post-therapy. Distinct evaluation between target tumours and non-tumoural tissue, including lungs in cases of lung shunt, are vital for proper optimization of therapy. Dosimetry should be performed first according to a mean absorbed dose approach, with an optional, but important, voxel level evaluation. Fully corrected 99mTc-MAA Single Photon Emission Computed Tomography (SPECT)/computed tomography (CT) and 90Y TOF PET/CT are regarded as optimal acquisition methodologies, but, for institutes where SPECT/CT is not available, non-attenuation corrected 99mTc-MAA SPECT may be used. This offers better planning quality than non dosimetric methods such as Body Surface Area (BSA) or mono-compartmental dosimetry. Quantitative 90Y bremsstrahlung SPECT can be used if dedicated correction methods are available. The proposed methodology is feasible with standard camera software and a spreadsheet. Available commercial or free software can help facilitate the process and improve calculation time.

Abstract Background 223Ra is currently used for treatment of metastatic castration resistant prostate cancer patients (mCRPC) bone metastases with fixed standard activity. Individualized treatments, based on adsorbed dose (AD) in target and non-target tissue, are absolutely needed to optimize efficacy while reducing toxicity of α-emitter targeted therapy. This is a pilot first in human clinical trial aimed to correlate dosimetry, clinical response and biological side effects to personalize 223Ra treatment. Methods Out of 20 mCRPC patients who underwent standard 223Ra treatment and dosimetry, in a subset of 5 patients the AD to target and non-target tissues was correlated with clinical effects and radiation-induced chromosome damages. Before each 223Ra administrations, haematological parameters, PSA and ALP values were evaluated. Additional blood samples were obtained baseline (T0), at 7 days (T7), 30 days (T30) and 180 days (T180) to evaluate chromosome damage. After administration WB planar 223Ra images were obtained at 2–4 and 18–24 h. Treatment response and toxicity were monitored with clinical evaluation, bone scan, 18F-choline-PET/CT, PSA value and ALP while haematological parameters were evaluated weekly after 223Ra injection and 2 months after last cycle. Results 1. a correlation between AD to target and clinical response was evidenced with threshold of 20 Gy as a cut-off to obtain tumor control; 2. the AD to red marrow was lower than 2 Gy in all the patients with no apparently correlation between dosimetry and clinical toxicity. 3. a high dose dependent increase of the number of dicentrics and micronuclei during the course of 223Ra therapy was observed and a linear correlation has been found between blood AD (BAD) and number of dicentrics. Conclusions This study provides some interesting preliminary evidence to be further investigated: dosimetry may be useful to identify a more appropriate 223Ra administered activity predicting AD to target tissue; a dose dependent complex chromosome damage occurs during 223Ra administration and this injury is more evident in heavily pre-treated patients; dosimetry could be used for radioprotection purpose. Trial registration The pilot study has been approved from the Ethics Committee of Regina Elena National Cancer Institute (N:RS1083/18–2111).

Background: In our department, we provided guidelines to the radiation oncologists (ROs) regarding the omission, delay, or shortening of radiotherapy (RT). The purpose was to reduce the patients’ exposure to the hospital environment and to minimize the departmental overcrowding. The aim was to evaluate the ROs’ compliance to these guidelines. Methods: ROs were asked to fill out a data collection form during patients’ first visits in May and June 2020. The collected data included the ROs’ age and gender, patient age and residence, RT purpose, treated tumor, the dose and fractionation that would have been prescribed, and RT changes. The chi-square test and binomial logistic regression were used to analyze the correlation between the treatment prescription and the collected parameters. Results: One hundred and twenty-six out of 205 prescribed treatments were included in this analysis. Treatment was modified in 61.1% of cases. More specifically, the treatment was omitted, delayed, or shortened in 7.9, 15.9, and 37.3% of patients, respectively. The number of delivered fractions was reduced by 27.9%. A statistically significant correlation (p = 0.028) between younger patients’ age and lower treatment modifications rate was recorded. Conclusion: Our analysis showed a reasonably high compliance of ROs to the pandemic-adapted guidelines. The adopted strategy was effective in reducing the number of admissions to our department.

Abstract A radiological or nuclear attack could involve such a large number of subjects as to overwhelm the emergency facilities in charge. Resources should therefore be focused on those subjects needing immediate medical attention and care. In such a scenario, for the triage management by first responders, it is necessary to count on efficient biological dosimetry tools capable of early detection of the absorbed dose. At present the validated assays for measuring the absorbed dose are dicentric chromosomes and micronuclei counts, which require more than 2–3 days to obtain results. To overcome this limitation the NATO SPS Programme funded an Italian–Egyptian collaborative project aimed at validating a fast, accurate and feasible tool for assessing the absorbed dose early after radiation exposure. Biomarkers as complete blood cell counts, DNA breaks and radio-inducible proteins were investigated on blood samples collected before and 3 h after the first fraction of radiotherapy in patients treated in specific target areas with doses/fraction of about: 2, 3.5 or > 5 Gy and compared with the reference micronuclei count. Based on univariate and multivariate multiple linear regression correlation, our results identify five early biomarkers potentially useful for detecting the extent of the absorbed dose 3 h after the exposure.

Abstract Background Recent developments in abscopal effect strongly support the use of radiotherapy for the treatment of metastatic disease. However, deeper understanding of the molecular mechanisms underlying the abscopal effect are required to best benefit a larger proportion of patients with metastasis. Several groups including ours, reported the involvement of wild-type (wt) p53 in radiation-induced abscopal effects, however very little is known on the role of wtp53 dependent molecular mechanisms. Methods We investigated through in vivo and in vitro approaches how wtp53 orchestrates radiation-induced abscopal effects. Wtp53 bearing (A549) and p53-null (H1299) NSCLC lines were xenotransplanted in nude mice, and cultured in 2D monolayers and 3D tumor spheroids. Extracellular vesicles (EVs) were isolated from medium cell culture by ultracentrifugation protocol followed by Nanoparticle Tracking Analysis. Gene expression was evaluated by RT-Real Time, digital qRT-PCR, and dot blot technique. Protein levels were determined by immunohistochemistry, confocal anlysis, western blot techniques, and immunoassay. Results We demonstrated that single high-dose irradiation (20 Gy) induces significant tumor growth inhibition in contralateral non-irradiated (NIR) A549 xenograft tumors but not in NIR p53-null H1299 or p53-silenced A549 (A549sh/p53) xenografts. We further demonstrates that irradiation of A549 cells in vitro induces a senescence-associated secretory phenotype (SASP) producing extracellular vesicles (EVs) expressing CD63 and carrying DNA:RNA hybrids and LINE-1 retrotransposon. IR-A549 EVs also hamper the colony-forming capability of recipient NIR A549 cells, induce senescent phenotype, nuclear expression of DNA:RNA hybrids, and M1 macrophage polarization. Conclusions In our models, we demonstrate that high radiation dose in wtp53 tumors induce the onset of SASP and secretion of CD63+ EVs loaded with DNA:RNA hybrids and LINE-1 retrotransposons that convey senescence messages out of the irradiation field triggering abscopal effect in NIR tumors.

Abstract The current framework of radiological protection of occupational exposed medical workers reduced the eye-lens equivalent dose limit from 150 to 20 mSv per year requiring an accurate dosimetric evaluation and an increase understanding of radiation induced effects on Lens cells considering the typical scenario of occupational exposed medical operators. Indeed, it is widely accepted that genomic damage of Lens epithelial cells (LEC) is a key mechanism of cataractogenesis. However, the relationship between apoptosis and cataractogenesis is still controversial. In this study biological and physical data are combined to improve the understanding of radiation induced effects on LEC. To characterize the occupational exposure of medical workers during angiographic procedures an INNOVA 4100 (General Electric Healthcare) equipment was used (scenario A). Additional experiments were conducted using a research tube (scenario B). For both scenarios, the frequencies of binucleated cells, micronuclei, p21-positive cells were assessed with different doses and dose rates. A Monte-Carlo study was conducted using a model for the photon generation with the X-ray tubes and with the Petri dishes considering the two different scenarios (A and B) to reproduce the experimental conditions and validate the irradiation setups to the cells. The simulation results have been tallied using the Monte Carlo code MCNP6. The spectral characteristics of the different X-ray beams have been estimated. All irradiated samples showed frequencies of micronuclei and p21-positive cells higher than the unirradiated controls. Differences in frequencies increased with the delivered dose measured with Gafchromic films XR-RV3. The spectrum incident on eye lens and Petri, as estimated with MCNP6, was in good agreement in the scenario A (confirming the experimental setup), while the mean energy spectrum was higher in the scenario B. Nevertheless, the response of LEC seemed mainly related to the measured absorbed dose. No effects on viability were detected. Our results support the hypothesis that apoptosis is not responsible for cataract induced by low doses of X-ray (i.e. 25 mGy) while the induction of transient p21 may interfere with the disassembly of the nuclear envelop in differentiating LEC, leading to cataract formation. Further studies are needed to better clarify the relationship we suggested between DNA damage, transient p21 induction and the inability of LEC enucleation.

Summary: Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are innovative small target molecules that, in combination with endocrine therapy, have recently been employed in the treatment of patients with HR+/HER2− metastatic breast cancer (mBC). In this prospective study, we investigate the impact of CDK4/6i on the immune profile of patients with HR+/HER2− mBC. Methods: Immune cell subsets were analysed using flow cytometry of peripheral blood mononuclear cells (PBMCs) isolated from patients with HR+/HER2− mBC, both before and during treatment. Regulatory T cells (Tregs) were identified using the markers CD4, CD25, CTLA4, CD45RA, and intracellular FOXP3. Monocytic and polymorphonuclear myeloid-derived suppressor cells (M-MDSCs and PMN-MDSCs) and other immune populations were analysed using CD45, CD14, CD66b, CD11c, HLA-DR, CD3, CD8, CD28, CD137, PD1, CD45RA, CCR7, and Ki67. Findings: The percentage of circulating Tregs and M/PMN-MDSCs was significantly downregulated from baseline during CDK4/6i-treatment (p

BackgroundSarcopenia (SP) is defined as the quantitative and functional impairment of skeletal muscles. SP is commonly related to older age and is frequent in patients with cancer. To provide an overview of SP in patients treated with radiotherapy (RT) and to evaluate the current evidence, we analyzed the available systematic reviews and meta-analyses.MethodsReviews were identified using PubMed, Scopus, and Cochrane library databases, without date restriction. Only systematic reviews and meta-analyses on the prognostic impact of SP and on any treatments aimed at reducing SP effect, in patients undergoing RT, were included in this review. The analyses not separately reporting the results in patients treated with RT were excluded. The quality assessment was performed using AMSTAR-2 (A MeaSurement Tool to Assess systematic Reviews).ResultsFrom the 84 papers identified, five reviews met the inclusion criteria with four reports mainly including non-randomized trials. Three reviews on the effect of SP showed a significantly negative impact on overall survival in patients undergoing RT and/or chemoradiation for H&N cancers (HR: 1.63-2.07). Two reviews on interventional studies showed the possibility of 1) improving physical functions through nutritional and physical interventions and 2) avoiding muscle wasting by means of sufficient protein intake. The quality assessment of the included review showed that two and three analyses are classifiable as having low and moderate overall confidence rating, respectively.ConclusionsThe analyzed reviews uniformly confirmed the negative impact of SP in patients with H&N tumors undergoing RT and the possibility of improving muscle mass and function through nutritional and physical interventions. These results justify further research on this topic based on a more uniform SP definition and on a complete evaluation of the potentially confounding parameters.

Proton beam therapy (PBT) is often more attractive for its high gradient dose distributions than other treatment modalities with external photon beams. However, in thoracic lesions treated particularly with pencil beam scanning (PBS) proton beams, several dosimetric issues are addressed. The PBS approach may lead to large hot or cold spots in dose distributions delivered to the patients, potentially affecting the tumor control and/or increasing normal tissue side effects. This delivery method particularly benefits image-guided approaches. Our paper aims at reviewing imaging strategies and their technological trends for PBT in thoracic lesions. The focus is on the use of imaging strategies in simulation, planning, positioning, adaptation, monitoring, and delivery of treatment and how changes in the anatomy of thoracic tumors are handled with the available tools and devices in PBT. Starting from bibliographic research over the past 5 years, retrieving 174 papers, major key questions, and implemented solutions were identified and discussed; the results aggregated and presented following the methodology of analysis of expert interviews.

BackgroundPrimary intracranial ependymomas (IE) are rare brain tumors rarely metastasizing outside the central nervous system. We systematically reviewed the literature on extra-neural metastases from primary IEs.MethodsPubMed, Scopus, Web-of-Science, and Cochrane were searched following the PRISMA guidelines to include studies of extra-neural metastases from primary IEs. Clinical features, management strategies, and survival were analyzed.ResultsWe collected 48 patients from 43 studies. Median age was 13 years (range, 2-65). Primary IEs were frequently located in the parietal (22.9%) and frontal (16.7%) lobes, and mostly treated with resection (95.8%) and/or radiotherapy (62.5%). Most IEs were of grade-III (79.1%), and few of grade-I (6.3%) or grade-II (14.6%). 45 patients experienced intracranial recurrences, mostly treated with resection (86.7%), radiotherapy (60%), and/or chemotherapy (24.4%). Median time-interval from primary IEs was 28 months (range, 0-140). Most extra-neural metastases were diagnosed at imaging (37.5%) or autopsy (35.4%). Extra-neural metastases were multifocal in 38 patients (79.1%), mostly involving cervical or hilar lymph-nodes (66.7%), lung/pleura (47.9%), and/or scalp (29.1%). Surgical resection (31.3%), chemotherapy (31.3%) and locoregional radiotherapy (18.8%) were the most common treatments for extra-neural metastases, but 28 (58.3%) patients were not treated. At last follow-up, 37 patients died with median overall-survivals from primary IEs of 36 months (range, 1-239), and from extra-neural metastases of 3 months (range, 0.1-36). Overall-survival was significantly longer in patients with grade-I and II IEs (P=0.040).ConclusionExtra-neural metastases from primary IEs are rare, but mostly occur at later disease stages. Multidisciplinary management strategies should be intended mostly for palliation.

BackgroundArterial vasospasm has been ascribed as the responsible etiology of delayed cerebral infarction in patients with aneurysmal subarachnoid hemorrhage (aSAH), but other neurovascular structures may be involved. We present the protocol for a multicenter, prospective, observational study focused on analyzing morphological changes in cerebral veins of patients with aSAH.Methods and AnalysisIn a retrospective arm, we will collect head arterial and venous CT angiograms (CTA) of 50 patients with aSAH and 50 matching healthy controls at days 0–2 and 7–10, comparing morphological venous changes. A multicenter prospective observational study will follow. Patients aged ≥18 years of any gender with aSAH will be enrolled at 9 participating centers based on the predetermined eligibility criteria. A sample size of 52 aSAH patients is expected, and 52 healthy controls matched per age, gender, and comorbidities will be identified. For each patient, sequential CTA will be conducted upon admission (day 0–2), at 7–10 days, and at 14–21 days after aSAH, evaluating volumes and morphology of the cerebral deep veins and main cortical veins. One specialized image collecting center will analyze all anonymized CTA scans, performing volumetric calculation of targeted veins. Morphological venous changes over time will be evaluated using the Dice coefficient and the Jaccard index and scored using the Boeckh–Behrens system. Morphological venous changes will be correlated to clinical outcomes and compared between patients with aSAH and healthy-controls, and among groups based on surgical/endovascular treatments for aSAH.Ethics and DisseminationThis protocol has been approved by the ethics committee and institutional review board of Ethikkommission, SALK, Salzburg, Austria, and will be approved at all participating sites. The study will comply with the Declaration of Helsinki. Written informed consent will be obtained from all enrolled patients or their legal tutors. We will present our findings at academic conferences and peer-reviewed journals.Approved Protocol Version and RegistrationVersion 2, 09 June 2021.

Immune checkpoint inhibitors have improved the survival in patients affected by an increasing number of malignancies, but they may also trigger various autoimmune side-effects, including endocrinopathies. Very rarely, immune checkpoint inhibitors have been reported to cause central diabetes insipidus. However, with their expanding use, the likelihood that oncologists will face this endocrine adverse event is expected to increase. By reviewing the limited literature on central diabetes insipidus induced by immune checkpoint inhibitors, some inconsistencies emerge in the diagnosis and the management of patients presenting with this toxicity, together with difficulties related to classifying its severity. Until now, specific guidelines on the management of central diabetes insipidus induced by immune checkpoint inhibitors are lacking. In clinical practice, endocrinological consultation may relieve medical oncologists from difficulties in treating this side-effect; oncologists, however, remain responsible for its early diagnose and the management of the causative drugs. To this aim, some practical suggestions are advised for the multidisciplinary management of cancer patients presenting with central diabetes insipidus induced by immune checkpoint inhibitors.

Central diabetes insipidus (CDI) is a rare endocrine disease deriving from an insufficient production or secretion of anti-diuretic hormone. Recently, CDI has been reported as a rare side effect triggered by immune checkpoint inhibitors (ICI) in cancer patients. Despite its current rarity, CDI triggered by ICI is expected to affect an increasing number of patients because of the expanding use of these effective drugs in a growing number of solid and hematologic malignancies. An appropriate assessment of the severity of adverse events induced by anticancer agents is crucial in their management, including dosing adjustment and temporary withdrawal or discontinuation treatment. However, assessment of the severity of CDI induced by ICI may be challenging, as its main signs and symptoms (polyuria, dehydration, weight loss, and hypernatremia) can be incompletely graded. Indeed, the current grading system of toxicity induced by anticancer treatments does not include polyuria. Additionally, dehydration in patients affected by diabetes insipidus, including ICI-induced CDI, is different in certain aspects from that due to other conditions seen in cancer patients, such as vomiting and diarrhea. This prompted us to reflect on the need to grade polyuria, and how to grade it, and to consider a specific grading system for dehydration associated with CDI induced by ICI. Here we propose a new grading system for polyuria and dehydration, as critical symptoms of the CDI syndrome occurring in patients on ICI treatment, to obtain better management of both the adverse event and the triggering drugs.

Abstract Advanced malignant melanoma represents a public health matter due to its rising incidence and aggressiveness. Novel therapies such as immunotherapy are showing promising results with improved progression free and overall survival in melanoma patients. However, novel targeted and immunotherapies could generate atypical patterns of response which are nowadays a big challenge since imaging criteria (ie Recist 1.1) have not been proven to be always reliable to assess response. Radiomics and in particular texture analysis (TA) represent new quantitative methodologies which could reduce the impact of these limitations providing most robust data in support of clinical decision process. The aim of this paper was to review the state of the art of radiomics/TA when it is applied to the imaging of metastatic melanoma patients.

Abstract Background It has been hypothesized that radiotherapy (RT) techniques delivering radiations to larger volumes (IMRT, VMAT) are potentially associated with a higher risk of second primary tumors. The aim of this study was to analyse the impact of RT technique (3D-CRT vs IMRT/VMAT) on the incidence of second tumors in prostate cancer (PCa) patients. Methods A retrospective study on 2526 previously irradiated PCa patients was performed. Patients were treated with 3D-CRT (21.3%), IMRT (68.1%), or VMAT (10.6%). Second tumors incidence was analysed in 3 categories: pelvic, pelvic and abdominal, and “any site”. The correlation with RT technique was analysed using log-rank test and Cox’s proportional hazard method. Results With a median follow-up of 72 months (range: 9–185), 92 (3.6%) cases of second tumors were recorded with 48 months (range: 9–152) median interval from RT. Actuarial 10-year second tumor free survival (STFS) was 87.3%. Ten-year STFS in patients treated with 3D-CRT and IMRT/VMAT was 85.8 and 84.5%, respectively (p: .627). A significantly higher 10-year cumulative incidence of second tumors in the pelvis was registered in patients treated with IMRT/VMAT compared to 3D-CRT (10.7% vs 6.0%; p: .033). The lower incidence of second pelvic cancers in patients treated with 3D-CRT was confirmed at multivariable analysis (HR: 2.42, 95%CI: 1.07–5.47, p: .034). Conclusions The incidence of second pelvic tumors after RT of PCa showed a significant correlation with treatment technique. Further analyses in larger series with prolonged follow-up are needed to confirm these results.

Treatment personalization in Molecular Radiotherapy (MRT) relies on pre- and post-treatment SPECT/ PET-based images and measurements to obtain a patient-specific absorbed dose-rate distribution map and its evolution over time. Unfortunately, the number of time points that are available per patient to investigate individual pharmacokinetics is often reduced by limited patient compliance or SPECT or PET/CT scanner availability for dosimetry in busy departments. The adoption of portable sensors for in-vivo dose monitoring during the entire treatment could improve the assessment of individual biokinetics in MRT and, thus, the treatment personalization. The evolution of portable devices, non-SPECT/PET-based options, already used for monitoring radionuclide activity transit and accumulation during therapy with radionuclides (i.e., MRT or brachytherapy), is presented to identify valuable ones, which combined with conventional nuclear medicine imaging systems could be effective in MRT. External probes, integration dosimeters and active detecting systems were included in the study. The devices and their technology, the range of applications, the features and limitations are discussed. Our overview of the available technologies encourages research and development of portable devices and dedicated algorithms for MRT patient-specific biokinetics study. This would represent a crucial advancement towards personalized treatment in MRT.

This proof-of-concept study lays the foundations for the development of a delivery strategy for radioactive lanthanides, such as Yttrium-90, against recurrent glioblastoma. Our appealing hypothesis is that by taking advantage of the combination of biocompatible polyvinyl alcohol (PVA) microbubbles (MBs) and endovascular radiopharmaceutical infusion, a minimally invasive selective radioembolization can be achieved, which can lead to personalized treatments limiting off-target toxicities for the normal brain. The results show the successful formulation strategy that turns the ultrasound contrast PVA-shelled microbubbles into a microdevice, exhibiting good loading efficiency of Yttrium cargo by complexation with a bifunctional chelator. The selective targeting of Yttrium-loaded MBs on the glioblastoma-associated tumor endothelial cells can be unlocked by the biorecognition between the overexpressed αVβ3 integrin and the ligand Cyclo(Arg-Gly-Asp-D-Phe-Lys) at the PVA microbubble surface. Hence, we show the suitability of PVA MBs as selective Y-microdevices for in situ injection via the smallest (i.e., 1.2F) neurointerventional microcatheter available on the market and the accumulation of PVA MBs on the HUVEC cell line model of integrin overexpression, thereby providing ~6 × 10−15 moles of Y90 per HUVEC cell. We further discuss the potential impact of using such versatile PVA MBs as a new therapeutic chance for treating glioblastoma multiforme recurrence.

Background: Transarterial radioembolization (TARE) relies on directly injected 90Y- or 166Ho-loaded microspheres in the hepatic arteries. The activity to be injected is generally based on pre-TARE 99mTc-macro-aggregated-albumin (MAA) imaging, while the actual dose distribution is based on post-treatment images. The volume of interest (VOIs) propagation methods (i.e., rigid and deformable) from pre- to post-TARE imaging might affect the estimation of the mean absorbed dose in the tumor and non-tumoral liver (NTL), i.e., DT and DNTL, respectively. Methods: In 101 consecutive patients, liver and tumor were delineated on pre-TARE images and semi-automatically transferred on 90Y-PET/CT images with a rigid or deformable registration approach. Pre- and post-TARE volumes and DT/DNTL/DL were compared using correlation coefficient (CC) indexes, such as intra-class (ICC), Pearson’s (PCC), concordance (CCCo) and Bland–Altman analyses. The Kaplan–Meier curves of overall survival (OS) were calculated according to DT. Results: All computed CCs indicated very good (>0.92) agreement for volume comparison, while they suggested good (ICC ≥ 0.869, PCC ≥ 0.876 and CCCo ≥ 0.790) and moderate agreement in the intra- and inter-modality DT/DNTL/DL comparisons, respectively. Bland–Altman analyses showed percentage differences between the manual and deformable approaches of up to about −31%, 9% and 62% for tumoral volumes, DT and DNTL, respectively. The overall survival analysis showed statistically significant differences using DT cutoffs of 110, 90 and 85 Gy for the manual, rigid and deformable approaches, respectively. Conclusions: The semi-automatic transfer of VOIs from pre- and post-TARE imaging is feasible, but the selected method might affect prognostic DT/DNTL constraints.

Space radiobiology is an interdisciplinary science that examines the biological effects of ionizing radiation on humans involved in aerospace missions. The dose-effect models are one of the relevant topics of space radiobiology. Their knowledge is crucial for optimizing radioprotection strategies (e.g., spaceship and lunar space station-shielding and lunar/Mars village design), the risk assessment of the health hazard related to human space exploration, and reducing damages induced to astronauts from galactic cosmic radiation. Dose-effect relationships describe the observed damages to normal tissues or cancer induction during and after space flights. They are developed for the various dose ranges and radiation qualities characterizing the actual and the forecast space missions [International Space Station (ISS) and solar system exploration]. Based on a Pubmed search including 53 papers reporting the collected dose-effect relationships after space missions or in ground simulations, 7 significant dose-effect relationships (e.g., eye flashes, cataract, central nervous systems, cardiovascular disease, cancer, chromosomal aberrations, and biomarkers) have been identified. For each considered effect, the absorbed dose thresholds and the uncertainties/limitations of the developed relationships are summarized and discussed. The current knowledge on this topic can benefit from further in vitro and in vivo radiobiological studies, an accurate characterization of the quality of space radiation, and the numerous experimental dose-effects data derived from the experience in the clinical use of ionizing radiation for diagnostic or treatments with doses similar to those foreseen for the future space missions. The growing number of pooled studies could improve the prediction ability of dose-effect relationships for space exposure and reduce their uncertainty level. Novel research in the field is of paramount importance to reduce damages to astronauts from cosmic radiation before Beyond Low Earth Orbit exploration in the next future. The study aims at providing an overview of the published dose-effect relationships and illustrates novel perspectives to inspire future research.

AimThe efficacy of low-dose fractionated radiotherapy (LDFRT) and chemotherapy (CHT) combination has large preclinical but little clinical evidence. Therefore, the aim of this review was to collect and analyze the clinical results of LDRT plus concurrent CHT in patients with advanced cancers.MethodsA systematic literature search was conducted on PubMed using the PRISMA methodology. Only studies based on the combination of LDFRT (< 1 Gy/fraction) and CHT were included. Endpoints of the analysis were tumor response, toxicity, and overall survival, with particular focus on any differences between LDFRT-CHT and CHT alone.ResultsTwelve studies (307 patients) fulfilled the selection criteria and were included in this review. Two studies were retrospective, one was a prospective pilot trial, six were phase II studies, two were phase I trials, and one was a phase I/II open label study. No randomized controlled trials were found. Seven out of eight studies comparing clinical response showed higher rates after LDFRT-CHT compared to CHT alone. Three out of four studies comparing survival reported improved results after combined treatment. Three studies compared toxicity of CHT and LDFRT plus CHT, and all of them reported similar adverse events rates. In most cases, toxicity was manageable with only three likely LDFRT-unrelated fatal events (1%), all recorded in the same series on LDFRT plus temozolomide in glioblastoma multiforme patients.ConclusionNone of the analyzed studies provided level I evidence on the clinical impact of LDFRT plus CHT. However, it should be noted that, apart from two small series of breast cancers, all studies reported improved therapeutic outcomes and similar tolerability compared to CHT alone. Systematic Review Registrationwww.crd.york.ac.uk/prospero/, identifier CRD42020206639.

Noise in hospital wards adversely affects the physiological processes of both patients and staff and it is a potential risk for communication breakdowns and errors, causing discomfort and problems regarding the healing of patients, as well as stress, fatigue, and annoyance for staff. Several noise sources are present in the wards, such as HVAC systems, alarms, paging, speech, calls, diagnostic equipment, medical devices, and so forth. This paper describes two surveys carried out at an Italian hospital in Rome to investigate the noise in some wards and to collect self-reported assessments from staff about their working environments, even if such assessments were not required for occupational noise exposure evaluation. Self-reported staff evaluations of the working environment quality and the effects of noise on their performances should be investigated. For this purpose, in this study, questionnaires were designed and submitted to staff members. In addition, noise measurements were taken from short-, medium-, and long-term audio recordings processed to determine psychoacoustic parameters, e.g., loudness, sharpness, roughness, and fluctuation strength. Their applications in enclosed spaces can provide additional information on some features of the noise observed in hospital wards, which may influence the perceptions and relevant extra-auditory effects. Even though the results cannot be generalized, they encourage the development of a methodology for noise surveys in hospital wards, including noise measurements and “ad hoc” questionnaires to collect self-reported reactions from exposed staff members.

Background: Few studies have focused on predicting the overall survival (OS) of patients affected by SARS-CoV-2 (i.e., COVID-19) using radiomic features (RFs) extracted from computer tomography (CT) images. Reconstruction of CT scans might potentially affect the values of RFs. Methods: Out of 435 patients, 239 had the scans reconstructed with a single modality, and hence, were used for training/testing, and 196 were reconstructed with two modalities were used as validation to evaluate RFs robustness to reconstruction. During training, the dataset was split into train/test using a 70/30 proportion, randomizing the procedure 100 times to obtain 100 different models. In all cases, RFs were normalized using the z-score and then given as input into a Cox proportional-hazards model regularized with the Least Absolute Shrinkage and Selection Operator (LASSO-Cox), used for feature selection and developing a robust model. The RFs retained multiple times in the models were also included in a final LASSO-Cox for developing the predictive model. Thus, we conducted sensitivity analysis increasing the number of retained RFs with an occurrence cut-off from 11% to 60%. The Bayesian information criterion (BIC) was used to identify the cut-off to build the optimal model. Results: The best BIC value indicated 45% as the optimal occurrence cut-off, resulting in five RFs used for generating the final LASSO-Cox. All the Kaplan-Meier curves of training and validation datasets were statistically significant in identifying patients with good and poor prognoses, irrespective of CT reconstruction. Conclusions: The final LASSO-Cox model maintained its predictive ability for predicting the OS in COVID-19 patients irrespective of CT reconstruction algorithms.

At a time of increasing evidence for dose-effect relationships in radioembolization (RE) with 90Y-microspheres, the general consensus is that there is an urgent need for accurate treatment planning and dose assessment in patients undergoing RE treatment. This work aimed at assessing the usefulness of 99mTc macroaggregated albumin (MAA) SPECT/CT imaging for personalized provisional RE dosimetry considering a 3D-printed patientlike phantom (AdboMan phantom). A homemade tool was developed in MATLAB for image analysis and absorbed dose calculation. Two dose calculaton methods were implemented and used to calculate dose volume histograms: (I) dose kernel method and (II) local energy deposition method. The accuracy of the two different dosimetric methods was evaluated by means of 3D γ-index (1%–1 mm and 2%–2 mm) implemented in the tool. Differences between the two dose calculation methods using the 3D γ-index are within 1%–1 mm and 2%–2 mm for all AbdoMan inserts, with a passing rate of 99.9% and 100%, respectively, proving a good agreement between the two calculation methods. The present study supports the use of 99mTc-MAA SPECT acquisition for provisional dosimetry along with the local energy deposition method to convert reconstructed SPECT data into absorbed dose maps. As long as 99mTc-MAA SPECT acquisitions are performed on liver lesions larger than 40 mm, the absorbed dose computed by means of the local energy deposition method can lead to results in line with those obtained by Monte Carlo calculations.

Radioembolization (RE) with 90Y-microspheres has gained widespread acceptance as a safe and effective technique for treating liver malignancies. Accurate quantification in RE is a key step in treatment planning optimization and is becoming a pressing issue in light of the Directive 2013/59/EURATOM. The aim of this study was to develop a SPECT/CT imaging protocol for quantitative imaging optimization in RE based on cutting edge imaging technology (Symbia IntevoTM system provided with the innovative xSPECT software) and a novel anthropomorphic 3D-printed phantom. In the present study, 99mTc-labeled macroaggregated albumin was used as a surrogate radiopharmaceutical for treatment planning. Gamma camera calibration factors and recovery coefficients were determined performing preliminary SPECT/CT acquisitions of a point source, a cylindrical homogeneous phantom and the NEMA/IEC phantom. Data reconstruction was performed using the built-in xSPECT package, using both the Ordered Subset Expectation–Maximization (OSEM) and the Ordered Subset Conjugated Gradient (OSCG) algorithm. Specific regions of interest (ROIs) were drawn on the MIM 6.1.7 system according to the physical volume. The quantification procedure was validated using the anthropomorphic phantom provided with a fillable liver section and spheres of different diameters (20 mm, 40 mm and a 40 mm spherical shell). The measured activity concentration in all geometries is consistent within 4%, demonstrating that the xSPECT software permit an absolute quantification in anthropomorphic geometry largely within the 10% recommended from the manufacturer. Caution is advised in the presence of spherical objects with a necrotic core, as underestimations in the order of 20% were obtained.

ObjectiveThe monoclonal antibodies anti-programmed death protein-1 (anti–PD-1) nivolumab and pembrolizumab are the first immune checkpoint inhibitors (ICIs) approved for treatment of recurrent/metastatic head and neck carcinoma R/M HNSCC in first line and in platinum refractory disease. This network meta-analysis aims to investigate the efficacy of anti–PD-1- vs anti–PD-L1-based therapy in R/M HNSCC cancer patients through a systematic review of the literature to provide support for evidence-based treatment decisions. In particular, the effectiveness of ICIs for R/M HNSCC is analyzed according to the different mechanisms of action of the check-points inhibitory drugs in different subgroups of patients.MethodsWe did a systematic literature review and network meta-analysis (NMA) of randomized controlled trials (RCTs) in PubMed, ClinicalTrials.gov, Embase, Medline, the Cochrane Central Register of Controlled Trials, Web of Science. Our search identified a total of five randomized controlled trials: Keynote 040, Keynote 048, Eagle, Condor, Checkmate 141. These trials included 3001 patients. Treatment was sub-categorized into PD-L1–based, PD-1–based, and standard chemotherapy. Treatments were indirectly compared with anti–PD-L1-based therapy.ResultsThe network meta-analysis demonstrated no significant differences in OS between different subgroups except for the metastatic patients in which anti–PD-1-based therapy was associated with significantly less risk of death. Furthermore, anti–PD-1-based therapy appeared to be effective in smoker patients and in human papilloma–negative (HPV) patients. Conversely, anti–PD-L1-based therapy seems to be better efficient in female patients, in locally recurrent setting and in HPV positive patients.ConclusionThis is the first NMA study that aimed to indirectly compare anti–PD-1- and anti–PD-L1-based therapy in HNSCC patients. The results of our NMA could help define a profile of patient responder or resistant to specific classes of immune drugs and can be used to guide/design future studies in the novel scenario of precision immune-oncology.

Introduction: An education strategy was employed in our department to increase the rate of patients with uncomplicated painful bone metastases undergoing single fractionation radiotherapy (SFRT). The purpose of this report is to analyze the results of this strategy over a 5 year period. Materials and Methods: In January 2015, two meetings were organized in our department. In the first, data from an audit on the current SFRT rate were shown. In the second, evidence of SFRT efficacy in the relief of pain from uncomplicated bone metastases was presented. In addition, during the weekly discussion of clinical cases, the opportunity to use the SFRT was systematically recalled. Using our institutional database, all patients treated with radiotherapy for uncomplicated painful bone metastases in the period between 2014 (year considered as a reference) and 2019 were retrieved. Data regarding treatment date (year), radiotherapy fractionation, and tumor, patients, and radiation oncologists characteristics were collected. Results: A total of 627 patients were included in the analysis. The rate of patients undergoing SFRT increased from 4.0% in 2014 to 63.5% in 2019 ( p 80 years), lung cancer as the primary tumor, treatment prescribed by a radiation oncologist dedicated to palliative treatments, and treatment date (2014 vs 2015–2019). Conclusions: This retrospective single-center analysis showed that a simple but intensive and prolonged departmental education strategy can increase the rate of patients treated with SFRT by nearly 16 times.

BackgroundIn radiation oncology, automation of treatment planning has reported the potential to improve plan quality and increase planning efficiency. We performed a comprehensive dosimetric evaluation of the new Personalized algorithm implemented in Pinnacle3 for full planning automation of VMAT prostate cancer treatments.Material and MethodsThirteen low-risk prostate (without lymph-nodes irradiation) and 13 high-risk prostate (with lymph-nodes irradiation) treatments were retrospectively taken from our clinical database and re-optimized using two different automated engines implemented in the Pinnacle treatment system. These two automated engines, the currently used Autoplanning and the new Personalized are both template-based algorithms that use a wish-list to formulate the planning goals and an iterative approach able to mimic the planning procedure usually adopted by experienced planners. In addition, the new Personalized module integrates a new engine, the Feasibility module, able to generate an “a priori” DVH prediction of the achievability of planning goals. Comparison between clinically accepted manually generated (MP) and automated plans generated with both Autoplanning (AP) and Personalized engines (Pers) were performed using dose-volume histogram metrics and conformity indexes. Three different normal tissue complication probabilities (NTCPs) models were used for rectal toxicity evaluation. The planning efficiency and the accuracy of dose delivery were assessed for all plans.ResultsFor similar targets coverage, Pers plans reported a significant increase of dose conformity and less irradiation of healthy tissue, with significant dose reduction for rectum, bladder, and femurs. On average, Pers plans decreased rectal mean dose by 11.3 and 8.3 Gy for low-risk and high-risk cohorts, respectively. Similarly, the Pers plans decreased the bladder mean doses by 7.3 and 7.6 Gy for low-risk and high-risk cohorts, respectively. The integral dose was reduced by 11–16% with respect to MP plans. Overall planning times were dramatically reduced to about 7 and 15 min for Pers plans. Despite the increased complexity, all plans passed the 3%/2 mm γ-analysis for dose verification.ConclusionsThe Personalized engine provided an overall increase of plan quality, in terms of dose conformity and sparing of normal tissues for prostate cancer patients. The Feasibility “a priori” DVH prediction module provided OARs dose sparing well beyond the clinical objectives. The new Pinnacle Personalized algorithms outperformed the currently used Autoplanning ones as solution for treatment planning automation.

BackgroundExternal ventricular drain (EVD) placement is mandatory for several pathologies. The misplacement rate of the EVD varies widely in literature, ranging from 12.3 to 60%. The purpose of this simulation study is to provide preliminary data about the possibility of increasing the safety of one of the most common life-saving procedures in neurosurgery by testing a new device for EVD placement.MethodsWe used a novel guide for positioning the ventricular catheter (patent RM2014A000376). The trajectory was assessed using 25 anonymized head CT scans. The data sets were used to conduct three-dimensional computer-based and combined navigation and augmented reality-based simulations using plaster models. The data set inclusion criteria were volumetric head CT scan, without midline shift, of patients older than 18. Evans’ index was used to quantify the ventricle’s size. We excluded patients with slit ventricles, midline shift, skull fractures, or complex skull malformations. The proximal end of the device was tested on the cadaver.ResultsThe cadaveric tests proved that a surgeon could use the device without any external help. The multimodal simulation showed Kakarla grade 1 in all cases but one (grade 2) on both sides, after right and left EVD placement. The mean Evans’ index was 0.28. The geometric principles that explain the device’s efficacy can be summarized by studying the properties of circumference and chord. The contact occurs, for each section considered, at the extreme points of the chord. Its axis, perpendicular to the plane tangent to the spherical surface at the entry point, corresponds to the direction of entry of the catheter guided by the instrument.ConclusionAccording to our multimodal simulation on cadavers, 3D computer-based simulation, 3D plaster modeling, 3D neuronavigation, and augmented reality, the device promises to offer safer and effective EVD placement. Further validation in future clinical studies is recommended.

Abstract Background Head and neck squamous cell carcinoma (HNSCC) is the sixth leading cancer worldwide. They are typically characterized by a high incidence of local recurrence, which is the most common cause of death in HNSCC patients. TP53 is the most frequently mutated gene in HNSCC and patients carrying TP53 mutations are associated with a higher probability to develop local recurrence. MiRNAs, which are among the mediators of the oncogenic activity of mt-p53 protein, emerge as an appealing tool for screening, diagnosis and prognosis of cancer. We previously identified a signature of 12 miRNAs whose aberrant expression associated with TP53 mutations and was prognostic for HNSCC. Among them miR-96-5p emerges as an oncogenic miRNAs with prognostic significance in HNSCC. Methods To evaluate the oncogenic role of miR-96-5p in a tumoral context, we performed colony formation, cell migration and cell viability assays in two HNSCC cell lines transfected for miR-96-5p mimic or inhibitor and treated with or without radio/chemo-therapy. In addition, to identify genes positively and negatively correlated to miR-96-5p expression in HNSCC, we analyzed the correlation between gene expression and miR-96-5p level in the subset of TCGA HNSCC tumors carrying missense TP53 mutations by Spearman and Pearson correlation. To finally identify targets of miR-96-5p, we used in silico analysis and the luciferase reporter assay to confirm PTEN as direct target. Results Our data showed that overexpression of miR-96-5p led to increased cell migration and radio-resistance, chemotherapy resistance in HNSCC cells. In agreement with these results, among the most statistically significant pathways in which miR-96-5p is involved, are focal Adhesion, extracellular matrix organization and PI3K-Akt-mTOR-signaling pathway. As a direct target of miR-96-5p, we identified PTEN, the main negative regulator of PI3K-Akt signalling pathway activation. Conclusions These results highlight a new mechanism of chemo/radio-resistance insurgence in HNSCC cells and support the possibility that miR-96-5p expression could be used as a novel promising biomarker to predict radiotherapy response and local recurrence development in HNSCC patients. In addition, the identification of pathways in which miR-96-5p is involved could contribute to develop new therapeutic strategies to overcome radio-resistance.

Abstract Background The advent of immune checkpoint inhibitors (ICIs) has considerably expanded the armamentarium against non-small cell lung cancer (NSCLC) contributing to reshaping treatment paradigms in the advanced disease setting. While promising tissue- and plasma-based biomarkers are under investigation, no reliable predictive factor is currently available to aid in treatment selection. Methods Patients with stage IIIB–IV NSCLC receiving nivolumab at Sant’Andrea Hospital and Regina Elena National Cancer Institute from June 2016 to July 2017 were enrolled onto this study. Major clinicopathological parameters were retrieved and correlated with patients’ survival outcomes in order to assess their prognostic value and build a useful tool to assist in the decision making process. Results A total of 102 patients were included in this study. The median age was 69 years (range 44–85 years), 69 (68%) were male and 52% had ECOG PS 0. Loco-regional/distant lymph nodes were the most commonly involved site of metastasis (71%), followed by lung parenchyma (67%) and bone (26%). Overall survival (OS) in the whole patients’ population was 83.6%, 63.2% and 46.9% at 3, 6 and 12 months, respectively; while progression-free survival (PFS) was 66.5%, 44.4% and 26.4% at 3, 6 and 12 months, respectively. At univariate analysis, age ≥ 69 years (P = 0.057), ECOG PS (P

Abstract Background The possibility to combine Low Intensity UltraSound (LIUS) and Nanoparticles (NP) could represent a promising strategy for drugs delivery in tumors difficult to treat overcoming resistance to therapies. On one side the NP can carry drugs that specifically target the tumors on the other the LIUS can facilitate and direct the delivery to the tumor cells. In this study, we investigated whether Very Low Intensity UltraSound (VLIUS), at intensities lower than 120 mW/cm2, might constitute a novel strategy to improve delivery to tumor cells. Thus, in order to verify the efficacy of this novel modality in terms of increase selective uptake in tumoral cells and translate speedily in clinical practice, we investigated VLIUS in three different in vitro experimental tumor models and normal cells adopting three different therapeutic strategies. Methods VLIUS at different intensities and exposure time were applied to tumor and normal cells to evaluate the efficiency in uptake of labeled human ferritin (HFt)-based NP, the delivery of NP complexed Firefly luciferase reported gene (lipoplex-LUC), and the tumor-killing of chemotherapeutic agent. Results Specifically, we found that specific VLIUS intensity (120 mW/cm2) increases tumor cell uptake of HFt-based NPs at specific concentration (0.5 mg/ml). Similarly, VLIUS treatments increase significantly tumor cells delivery of lipoplex-LUC cargos. Furthermore, of interest, VLIUS increases tumor killing of chemotherapy drug trabectedin in a time dependent fashion. Noteworthy, VLIUS treatments are well tolerated in normal cells with not significant effects on cell survival, NPs delivery and drug-induced toxicity, suggesting a tumor specific fashion. Conclusions Our data shed novel lights on the potential application of VLIUS for the design and development of novel therapeutic strategies aiming to efficiently deliver NP loaded cargos or anticancer drugs into more aggressive and unresponsive tumors niche.

Background: Radiomics is a field of research medicine and data science in which quantitative imaging features are extracted from medical images and successively analyzed to develop models for providing diagnostic, prognostic, and predictive information. The purpose of this work was to develop a machine learning model to predict the survival probability of 85 cervical cancer patients using PET and CT radiomic features as predictors. Methods: Initially, the patients were divided into two mutually exclusive sets: a training set containing 80% of the data and a testing set containing the remaining 20%. The entire analysis was separately conducted for CT and PET features. Genetic algorithms and LASSO regression were used to perform feature selection on the initial PET and CT feature sets. Two different survival models were employed: the Cox proportional hazard model and random survival forest. The Cox model was built using the subset of features obtained with the feature selection process, while all the available features were used for the random survival forest model. The models were trained on the training set; cross-validation was used to fine-tune the models and to obtain a preliminary measurement of the performance. The models were then validated on the test set, using the concordance index as the metric. In addition, alternative versions of the models were developed using tumor recurrence as an adjunct feature to evaluate its impact on predictive performance. Finally, the selected CT and PET features were combined to build a further Cox model. Results: The genetic algorithm was superior to the LASSO regression for feature selection. The best performing model was the Cox model, which was built using the selected CT features; it achieved a concordance index score of 0.707. With the addition of tumor recurrence as a predictive feature, the Cox CT model reached a concordance index score of 0.776. PET features, however, proved to be inadequate for survival prediction. The CT model performed better than the model with combined PET and CT features. Conclusions: The results showed that radiomic features can be used to successfully predict survival probability in cervical cancer patients. In particular, CT radiomic features proved to be better predictors than PET radiomic features in this specific case.

Background: ICIs have strongly improved the outcome of NSCLC patients. However, primary and secondary resistance occur during treatment in most of the patients, with several of them developing fast progressions. Autoantibodies can be related with a dysfunctional immune system, although their association with immune-based anti-cancer therapies has never been investigated. Moreover, so far no reliable predictive factor is currently available to aid in treatment selection. CD137+T-cells are largely known to be the anti-tumor activated effector cells, but they have never been associated with the response to immunotherapies. Methods: Forty-two patients with metastatic NSCLC receiving anti-PD-1 ICIs at Sant'Andrea Hospital and Policlinico Umberto I, from June 2016 to September 2018 were enrolled. Circulating levels of IgM-Rheumatoid Factor were evaluated at baseline and correlated with patients clinical response following the anti-PD-1 treatment. IgM-RF interaction and effect on T-cells in vivo and in vitro were investigated. Findings: IgM-RF in NSCLC patient sera strongly predicted the development of early progression to ICIs. Also, a significant reduction of progression-free survival rate in anti-PD-1 treated patients could be identified when patients were stratified based on IgM-RF positivity and titers. IgM-RF bound preferentially circulating naïve and central memory T-cells and a significant reduction of CD137+ anti-tumor T effector cells was found in IgM-RF positive patients. In addition, a higher percentage of CD137+T-cells in peripheral blood of NSCLC patients at baseline resulted as a strong independent prognostic factor for a better outcome in terms of PFS and OS after the anti-PD-1 treatment. Furthermore, T-cells exposed to IgM-RF showed a robust defect in their migratory ability in response to CCL19 chemokine. Interpretation: In this study we showed that serum IgM-RF can be regarded as predictive factor for the development of early progression and prognostic factor of a reduced progression-free survival and overall-survival in anti-PD-1 treated NSCLC patients. The ability of IgM-RF to bind naïve and central memory T-cells and impair their migration could make account for the reduction of the tumor-reactive CD137+ T-cells population that may cause a non-effectiveness of these T-cells targeting drugs. Fundings: AIRC, MIUR and Sapienza University of Rome.