Future perspectives of radiation therapy for Hodgkin Lymphoma: Risk-adapted, response-adapted, and safer than before.

Classical Hodgkin lymphoma is a lymphoproliferative disease with a good prognosis mainly seen in young people. Nevertheless secondary malignancy, cardiac disease and infertility may affect the long survivors with significant impact on quality of life, morbidity and overall survival. In the last decades several treatment strategies were evaluated to reduce the toxicity of first line treatment such as avoiding radiotherapy or its reduction in terms of dosage and extension. Many trials including interim Positron Emission Tomography evaluation fail to compare efficacy between combined modality treatment versus chemotherapy alone in particular in early stage disease. In this review we analyze which subset of patients could take advantage from proton therapy in terms of toxicity and cost effectiveness.

The new Systematic Coronary Risk Evaluation (SCORE2 and SCORE2-OP) estimates the risk of arterial occlusive events in chronic myeloid leukemia patients treated with nilotinib or ponatinib.

Patients with chronic myeloid leukemia (CML) treated with nilotinib or ponatinib may experience arterial occlusive events (AOEs). It is currently recommended to thoroughly assess cardiovascular risk factors before treating CML. We identified 455 consecutive CML adult patients, 335 treated with nilotinib and 120 with ponatinib; 380 patients without previous cardiovascular diseases or diabetes were stratified according to the Systematic Coronary Risk Evaluation (SCORE2) and SCORE2-Older Persons (SCORE2-OP). This updated algorithm from the European Society of Cardiology (ESC) estimates a 10-year risk of fatal and non-fatal cardiovascular diseases. It is based on sex, age, smoking habits, systolic blood pressure, non-high-density lipoprotein cholesterol, and European geographical region of cardiovascular risk. The SCORE2/SCORE2-OP algorithm translated more patients (50.2%) to the high-very high cardiovascular risk category than the previous SCORE (25.3%). Patients with a high to very high SCORE2/SCORE2-OP risk showed a significantly higher incidence rate of AOEs (69.2% vs. 46.5%, p < 0.001). The older SCORE was less specific in estimating AOEs in patients classified as low-intermediate risk (69.8 vs. 54.2%). In multivariate analysis, no associations were found between AOEs and gender, age, and type or dose of tyrosine kinase inhibitor. Only the SCORE2/SCORE2-OP risk was confirmed as a significant predictive factor (p = 0.028; hazard ratio = 2.2; 95% confidence interval = 1.1-4.5). Patients with AOEs required, in most cases, imaging diagnostic tests, additional drugs, and sometimes invasive procedures, increasing access to visits and hospital management. This real-life study suggested that the SCORE2 and SCORE2-OP charts could help identify cardiovascular fragility in CML patients providing them with more attention and a proper TKI selection.

Proton therapy for intracranial meningioma: a single-institution retrospective analysis of efficacy, survival and toxicity outcomes.

PURPOSE: To report the outcomes of a large series of intracranial meningiomas (IMs) submitted to proton therapy (PT) with curative intent. METHODS: We conducted a retrospective analysis on all consecutive IM patients treated between 2014 and 2021. The median PT prescription dose was 55.8 Gy relative biological effectiveness (RBE) and 66 GyRBE for benign/radiologically diagnosed and atypical/anaplastic IMs, respectively. Local recurrence-free survival (LRFS), distant recurrence-free survival (DRFS), overall survival (OS), and radionecrosis-free survival (RNFS) were evaluated with the Kaplan-Meier method. Univariable analysis was performed to identify potential prognostic factors for clinical outcomes. Toxicity was reported according to the latest Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. RESULTS: Overall, 167 patients were included. With a median follow-up of 41 months (range, 6-99), twelve patients (7%) developed tumor local recurrence after a median time of 39 months. The 5-year LRFS was 88% for the entire cohort, with a significant difference between benign/radiologically diagnosed and atypical/anaplastic IMs (98% vs. 47%, p < 0.001); this significant difference was maintained also for the 5-year OS and the 5-year DRFS rates. Patients aged ≤ 56 years reported significantly better outcomes, whereas lower prescription doses and skull base location were associated with better RNFS rates. Two patients experienced G3 acute toxicities (1.2%), and three patients G3 late toxicities (1.8%). There were no G4-G5 adverse events. CONCLUSION: PT proved to be effective with an acceptable toxicity profile. To the best of our knowledge this is one of the largest series including IM patients submitted to PT.

The role of neutrophil-lymphocytes ratio (NLR) in the prognosis of CIN2+ 2 recurrence after excisional treatment.

OBJECTIVES: The main risk factor involved in CIN2+ recurrence after treatment is the HPV persistent infection. The dysregulation of the immune system permits only HR-HPVs to become persistent infections, to promote cancer development and to increase the risk of recurrence after treatment. Therefore, there is a shift to a Th2-type cytokine pattern during the carcinogenesis pathway; for this reason, the neutrophil-lymphocytes ratio (NLR) could be a marker of this immunological change. The study aims to analyse the predictive role of NLR in the recurrence of High-grade CIN (CIN2+) after excisional treatment in a real-world life setting of patients treated for CIN2+ Design: cross-sectional study Participants/Materials, Setting, Methods: We examined a retrospective database of 444 patients, who attended the Colposcopy Service of our Department from 2011 to 2020 due to an abnormal screening pap smear and we compared the clinical characteristics to NLR performed at the time of diagnosis. All analysed patients were treated according to an established protocol (colposcopy every 6 months for the first two years, and every year for the over three years,) and HPV-DNA test and cervical biopsy were performed at entry and the end of follow-up. All patients underwent a blood sample examination, including complete white blood cell counts and collecting neutrophil and lymphocyte values expressed as 103/ml. Results The sensitivity (SE) and specificity (SP) of the NLR cut-off point of 1.34 for the diagnosis of CIN2+ recurrence were 0.76 and 0.67, respectively. We found that CIN2+ recurrences were significantly higher in patients with NLR < 1.34 (3.7% vs. 0.6%, p = 0.033) and the 5-year recurrence-free survival was higher in patients with NLR ≥ 1.34 (97% vs. 93%, p=0.030). Limitations First, the retrospective analysis and low incidence of recurrence may limit the conclusions. Second, for the retrospective design of the study, we did not take into consideration the patient's comorbidities and habits (smoking), that may influence the NLR. On the other hand, the median duration of follow-up in our study was 26 months (IQR 22-31), which fully reflects the incidence of recurrences. Conclusions It is well known that CIN2+ lesions are sustained by deregulation of the immune system caused by persistent HPV infection, which may lead to cervical cancer. Among the actors underlying dysregulation of immunity, lymphocytes are involved in the permission of persistent infection and for this reason, NRL could be a reliable and cost-effective biomarker in predicting the risk of recurrence, especially for high-grade cervical lesions.

Immune checkpoint inhibitors and Carbon iON radiotherapy In solid Cancers with stable disease (ICONIC).

ICONIC is a multicenter, open-label, nonrandomized phase II clinical trial aiming to assess the feasibility and clinical activity of the addition of carbon ion radiotherapy to immune checkpoint inhibitors in cancer patients who have obtained disease stability with pembrolizumab administered as per standard-of-care. The primary end point is objective response rate, and the secondary end points are safety, survival and disease control rate. Translational research is an exploratory aim. The planned sample size is 27 patients. The study combination will be considered worth investigating if at least four objective responses are observed. If the null hypothesis is rejected, ICONIC will be the first proof of concept of the feasibility and clinical activity of the addition of carbon ion radiotherapy to immune checkpoint inhibitors in oncology.

ICONIC is a multicenter, open-label, nonrandomized, phase II clinical trial aiming to evaluate the feasibility and clinical activity of the addition of carbon ion radiotherapy to immune checkpoint inhibitors in cancer patients who have obtained disease stability with pembrolizumab administered as per standard-of-care. Considering that no clinical trials have been conducted thus far to assess the safety of the association between immune checkpoint inhibitors and carbon ion radiotherapy, the current clinical study will provide controlled data about the safety of this unprecedented therapeutic combination. Clinical Trial Registration: NCT05229614 (ClinicalTrials.gov).

Quality of life changes over time and predictors in a large head and neck patients' cohort: secondary analysis from an Italian multi-center longitudinal, prospective, observational study-a study of the Italian Association of Radiotherapy and Clinical Oncology (AIRO) head and neck working group.

PURPOSE: The present study examined the longitudinal trajectories, through hierarchical modeling, of quality of life among patients with head and neck cancer, specifically symptoms burden, during radiotherapy, and in the follow-up period (1, 3, 6, and 12 months after completion of radiotherapy), through the M.D. Anderson Symptom Inventory Head and Neck questionnaire, formed by three factors. Furthermore, analyses were conducted controlling for socio-demographic as well as clinical characteristics. METHODS: Multi-level mixed-effects linear regression was used to estimate the association between quality of life and time, age, gender, household, educational level, employment status, ECOG performance status, human papilloma virus (HPV) status, surgery, chemotherapy, alcohol intake, and smoking. RESULTS: Among the 166 participants, time resulted to be a predictor of all the three questionnaire factors, namely, general and specific related symptoms and interference with daily life. Moreover, regarding symptom interference with daily activities factor, HPV-positive status played a significant role. Considering only HPV-negative patients, only time predicted patients' quality of life. Differently, among HPV-positive patients, other variables, such as gender, educational level, alcohol use, surgery, age at diagnosis, employment status, and ECOG status, resulted significant. CONCLUSION: It was evident that quality of life of patients with head and neck cancer declined during RT, whereas it slowly improved after ending treatment. Our results clarified the role of some socio-demographic and clinical variables, for instance, HPV, which would allow to develop treatments tailored to each patient.

Optimizing b-values schemes for diffusion MRI of the brain with segmented Intravoxel Incoherent Motion (IVIM) model.

PURPOSE: To define an optimal set of b-values for accurate derivation of diffusion MRI parameters in the brain with segmented Intravoxel Incoherent Motion (IVIM) model. METHODS: Simulations of diffusion signals were performed to define an optimal set of b-values targeting different perfusion regimes, by relying on an optimization procedure which minimizes the total relative error on estimated IVIM parameters computed with a segmented fitting procedure. Then, the optimal b-values set was acquired in vivo on healthy subjects and skull base chordoma patients to compare the optimized protocol with a clinical one. RESULTS: The total relative error on simulations decreased of about 40% when adopting the optimal set of 13 b-values (0 10 20 40 50 60 200 300 400 1200 1300 1400 1500 s/mm2 ), showing significant differences and increased precision on D and f estimates with respect to simulations with a non-optimized b-values set. Similarly, in vivo acquisitions demonstrated a dependency of IVIM parameters on the b-values array, with differences between the optimal set of b-values and a clinical non-optimized acquisition. IVIM parameters were compatible to literature values, with D (0.679/0.701 [0.022/0.008] ·10-3 mm2 /s), f (5.49/5.80 [0.70/1.14] %), and D* (8.25/7.67 [0.92/0.83] ·10-3 mm2 /s) median [interquartile range] estimates for white matter/gray matter in volunteers and D (0.709/0.715/1.06 [0.035/0.023/0.271] ·10-3 mm2 /s), f (7.08/7.84/21.54 [1.20/1.06/6.05] %), and D* (10.85/11.84/2.32 [1.38/2.32/4.94] ·10-3 mm2 /s) for white matter/gray matter/Gross Tumor Volume in patients with skull-base chordoma tumor. CONCLUSIONS: The definition of an optimal b-values set can improve the estimation of quantitative IVIM parameters. This allows setting up an optimized approach that can be adopted for IVIM studies in the brain.

Nasopharyngeal cancer: the impact of guidelines and teaching on radiation target volume delineation.

Target volume delineation in the radiation treatment of nasopharyngeal cancer is challenging due to several reasons such as the complex anatomy of the site, the need for the elective coverage of definite anatomical regions, the curative intent of treatment and the rarity of the disease, especially in non-endemic areas. We aimed to analyze the impact of educational interactive teaching courses on target volume delineation accuracy between Italian radiation oncology centers. Only one contour dataset per center was admitted. The educational course consisted in three parts: (1) The completely anonymized image dataset of a T4N1 nasopharyngeal cancer patient was shared between centers before the course with the request of target volume and organs at risk delineation; (2) the course was held online with dedicated multidisciplinary sessions on nasopharyngeal anatomy, nasopharyngeal cancer pattern of diffusion and on the description and explanation of international contouring guidelines. At the end of the course, the participating centers were asked to resubmit the contours with appropriate corrections; (3) the pre- and post-course contours were analyzed and quantitatively and qualitatively compared with the benchmark contours delineated by the panel of experts. The analysis of the 19 pre- and post-contours submitted by the participating centers revealed a significant improvement in the Dice similarity index in all the clinical target volumes (CTV1, CTV2 and CTV3) passing from 0.67, 0.51 and 0.48 to 0.69, 0.65 and 0.52, respectively. The organs at risk delineation was also improved. The qualitative analysis consisted in the evaluation of the inclusion of the proper anatomical regions in the target volumes; it was conducted following internationally validated guidelines of contouring for nasopharyngeal radiation treatment. All the sites were properly included in target volume delineation by >50% of the centers after correction. A significant improvement was registered for the skull base, the sphenoid sinus and the nodal levels. These results demonstrated the important role that educational courses with interactive sessions could have in such a challenging task as target volume delineation in modern radiation oncology.

Cardiotoxicity model-based patient selection for Hodgkin lymphoma proton therapy.

INTRODUCTION: Hodgkin lymphoma (HL) is a highly curable hematological malignancy. Consolidation radiation therapy techniques have made significant progresses to improve organ-at-risk sparing in order to reduce late radiation-induced toxicity. Recent technical breakthroughs notably include intensity modulated proton therapy (IMPT), which has demonstrated a major dosimetric benefit at the cardiac level for mediastinal HL patients. However, its implementation in clinical practice is still challenging, notably due to the limited access to proton therapy facilities. In this context, the purpose of this study was to estimate the benefit of IMPT for HL proton therapy for diverse cardiac adverse events and to propose a general frame for mediastinal HL patient selection strategy for IMPT based on cardiotoxicity reduction, patient clinical factors, and IMPT treatment availability. MATERIAL AND METHODS: This retrospective dosimetric study included 30 mediastinal HL patients treated with VMAT. IMPT plans were generated on the initial simulation scans. Dose to the heart, to the left ventricle and to the valves were retrieved to calculate the relative risk (RR) of ischemic heart disease (IHD), congestive heart failure (CHF) and valvular disease (VD). Composite relative risk reduction (cRRR) of late cardiotoxicity, between VMAT and IMPT, were calculated as the weighted mean of relative risk reduction for IHD, CHF and VD, calculated across a wide range of cardiovascular risk factor combinations. The proportion of mediastinal HL patients who could benefit from IMPT was estimated in European countries, based on the country population and on the number of active gantries, to propose country-specific cRRR thresholds for patient selection. RESULTS: Compared with VMAT, IMPT significantly reduced average mean doses to the heart (2.36 Gy vs 0.99 Gy, p < 0.01), to the left ventricle (0.67 Gy vs 0.03, p < 0.01) and to the valves (1.29 Gy vs. 0.06, p < 0.01). For a HL patient without cardiovascular risk factor other than anthracycline-based chemotherapy, the relative risks of late cardiovascular complications were significantly lower after IMPT compared with VMAT for ischemic heart disease (1.07 vs 1.17, p < 0.01), for congestive heart failure (2.84 vs. 3.00, p < 0.01), and for valvular disease (1.01 vs. 1.06, p < 0.01). The median cRRR of cardiovascular adverse events with IMPT was 4.8%, ranging between 0.1% and 30.5%, depending on the extent of radiation fields and on the considered cardiovascular risk factors. The estimated proportion of HL patients currently treatable with IMPT in European countries with proton therapy facilities ranged between 8.0% and 100% depending on the country, corresponding to cRRR thresholds ranging from 24.0% to 0.0%. CONCLUSION: While a statistically significant clinical benefit is theoretically expected for ischemic heart disease, cardiac heart failure and valvular disease for mediastinal HL patients with IMPT, the overall cardiotoxicity risk reduction is notable only for a minority of patients. In the context of limited IMPT availability, this study proposed a general model-based selection approach for mediastinal HL patient based on calculated cardiotoxicity reduction, taking into consideration patient clinical characteristics and IMPT facility availability.

Role of diffusion-weighted MRI in recurrent rectal cancer treated with carbon ion radiotherapy.

Aim: To evaluate the association between pretreatment diffusion-weighted MRI (DW-MRI) and 12-month radiological response in locally recurrent rectal cancer treated with carbon ion radiotherapy. Methods: Histogram analysis was performed on pretreatment DW-MRI for patients re-irradiated with carbon ion radiotherapy for local recurrence of rectal cancer. Results: A total of 17 patients were enrolled in the study. Pretreatment DW-MRI b-value of 1000 s/mm2 (b1000) and apparent diffusion coefficient (ADC) lesion median values for 1-year nonresponders (six patients) and responders (11 patients) demonstrated a median (interquartile of median values) of 62.5 (23.9) and 34.0 (13.0) and 953.0 (277.0) and 942.5 (339.0) µm2/s, respectively. All b1000 histogram features (h-features) and ADC h-kurtosis showed statistically significant differences, whereas only b1000 h-median, b1000 h-interquartile range and ADC h-kurtosis demonstrated remarkable diagnostic accuracy. Conclusion: DW-MRI showed promising results in predicting carbon ion radiotherapy outcome in local recurrence of rectal cancer, particularly with regard to b1000 h-median, b1000 h-interquartile range and ADC h-kurtosis.

Carbon ion radiotherapy is a form of advanced radiotherapy that is especially suitable for radioresistant and/or difficult-to-irradiate tumors. In case of recurrence of rectal cancer after pelvic photon beam radiotherapy, carbon ion radiotherapy may be an option. In this study, the authors looked at the potential role of specific MRI sequences performed before treatment to predict response to carbon ion radiotherapy. If confirmed in a larger prospective cohort, the findings of this study may drive clinical decisions toward a more tumor- and patient-tailored therapeutic approach.

Gynecological radio-induced secondary malignancy after a gynecological primary tumor: a rare entity and a challenge for oncologists.

The management of radiation-induced secondary malignancies in the female genital tract after pelvic radiation treatment for a primary gynecological tumor is a challenge for multidisciplinary teams that follow survivors. Considering the lack of data on the incidence of this disease and the absence of guidelines for its management, in this review, the available literature is analyzed to determine the characteristics and the clinical management of gynecological radiation-induced secondary malignancies. Gynecological radiation-induced secondary malignancies were found to be predominantly more aggressive, poorly differentiated, and had rare histologic types compared with sporadic tumors. The management is influenced by previous radiation doses and the localization of the radiation-induced secondary malignancies. Surgery, when feasible, was the cornerstone; re-irradiation was an option when a surgical approach was not feasible and high-dose conformal techniques should be preferred considering the need to spare previously irradiated surrounding normal tissues. Clinical outcomes, when reported, were poor in terms of local control and survival. Given the difficulty in managing these uncommon malignancies, a centralization of care in sites that are connected to research networks actively partaking in international discussions and with higher expertise in complicated surgery or radiotherapy should be considered to improve clinical outcomes.

Metastatic salivary gland carcinoma: A role for stereotactic body radiation therapy? A study of AIRO-Head and Neck working group.

OBJECTIVES: The role of radiotherapy (RT) for oligometastases is currently established in different oncological settings but data on salivary gland cancer (SGC) are lacking. We evaluated the role of RT in oligometastatic SGC patients, focusing on stereotactic body radiation therapy (SBRT). MATERIALS AND METHODS: We performed a retrospective, multicentric study of oligometastatic SGC treated with palliative RT or SBRT. Endpoints included response evaluation and local control (LC). RESULTS: Between 2006 and 2016, 64 patients were collected from 9 Italian Cancer Centers, on behalf of the Italian Association of Radiotherapy and Clinical Oncology (AIRO) Head and Neck Working Group. 37 patients (57.8%) were suffering from adenoid cystic carcinoma (ACC) and 27 patients (42.2%) had non-ACC. Thirty-four patients underwent palliative RT (53,1%), and 30 received SBRT (46,9%). Most common metastatic sites were bone for palliative RT and lung for SBRT. Among patients treated with SBRT, an objective response or a stability was observed in all treated lesions. After a median follow-up of 29.2 months (range 2.3-117.1), LC at 12 months was 57.5% for patients treated with SBRT and was higher in ACC subgroup. CONCLUSION: We confirmed the potential role of SBRT in the management of oligometastatic SGC patients to control limited burden of disease considering the absence of effective systemic therapies.

The impact of particle radiotherapy on the functioning of cardiac implantable electronic devices: a systematic review of in vitro and in vivo studies according to PICO criteria.

The number of oncological patients who may benefit from proton beam radiotherapy (PBT) or carbon ion radiotherapy (CIRT), overall referred to as particle radiotherapy (RT), is expected to strongly increase in the next future, as well as the number of cardiological patients requiring cardiac implantable electronic devices (CIEDs). The management of patients with a CIED requiring particle RT deserves peculiar attention compared to those undergoing conventional photon beam RT, mostly due to the potential generation of secondary neutrons by particle beams interactions. Current consensus documents recommend managing these patients as being at intermediate/high risk of RT-induced device malfunctioning regardless of the dose on the CIED and the beam delivery method used, despite the last one significantly affects secondary neutrons generation (very limited neutrons production with active scanning as opposed to the passive scattering technique). The key issues for the current review were expressed in four questions according to the Population, Intervention, Control, Outcome criteria. Three in vitro and five in vivo studies were included. Based on the available data, PBT and CIRT with active scanning have a limited potential to interfere with CIED that has only emerged from in vitro study so far, while a significant potential for neutron-related, not severe, CIED malfunctions (resets) was consistently reported in both clinical and in vitro studies with passive scattering.

Sinonasal cancers treatments: state of the art.

PURPOSE OF REVIEW: The present review provides the reader with the state-of-the-art concepts of sinonasal oncology in view of the latest literature data. RECENT FINDINGS: Most recent publications in sinonasal oncology assessed treatment timing, centralization, surgical approach, margin status, orbit/neck management, salvage strategies, emerging surgical technologies, intensity-modulated radiation therapy (IMRT), volumetric modulated arc therapy (VMAT), particle radiotherapy, and neoadjuvant chemotherapy. SUMMARY: Indications to endoscopic surgery for sinonasal cancer have plateaued and are unlikely to further expand. Endoscopic surgery provides noninferior results compared to open surgery and best suits timing constraints imposed by multimodal treatment. Management of orbit-encroaching sinonasal cancer is remarkably improving mostly owing to optimal use of nonsurgical strategies. Prognostic value of the margin status and management of the nodal basin and recurrent sinonasal tumors are far from being fully elucidated. Most promising surgical technologies are surgical navigation, optical imaging, and radiofrequency-aided ablation. IMRT and VMAT have theoretical technical advantages that are in the process of being clinically demonstrated. Pieces of evidence are progressively confirming the physical and radiobiological advantages offered by particle radiotherapy. Systemic therapy is being tested mostly in the neoadjuvant setting with the aim of improving outcomes in locally advanced sinonasal cancers; response to induction chemotherapy could better select a further locoregional approach.

Endometrial Cancer: When Upfront Surgery Is Not an Option.

Background and Summary: The management of endometrial cancer, in an ever-older population with considerable comorbidity, remains a challenge for gynecological and radiation oncologists. Key Message: The present paper reviews literature data on treatment options for endometrial cancer patients unfit for surgery.

Prognostic role of pre-treatment magnetic resonance imaging (MRI)-based radiomic analysis in effectively cured head and neck squamous cell carcinoma (HNSCC) patients.

OBJECTIVES: To identify and validate baseline magnetic resonance imaging (b-MRI) radiomic features (RFs) as predictors of disease outcomes in effectively cured head and neck squamous cell carcinoma (HNSCC) patients. MATERIALS AND METHODS: Training set (TS) and validation set (VS) were retrieved from preexisting datasets (HETeCo and BD2Decide trials, respectively). Only patients with both pre- and post-contrast enhancement T1 and T2-weighted b-MRI and at least 2 years of follow-up (FUP) were selected. The combination of the best extracted RFs was used to classify low risk (LR) vs. high risk (HR) of disease recurrence. Sensitivity, specificity, and area under the curve (AUC) of the radiomic model were computed on both TS and VS. Overall survival (OS) and 5-year disease-free survival (DFS) Kaplan-Meier (KM) curves were compared for LR vs. HR. The radiomic-based risk class was used in a multivariate Cox model, including well-established clinical prognostic factors (TNM, sub-site, human papillomavirus [HPV]). RESULTS: In total, 57 patients of TS and 137 of VS were included. Three RFs were selected for the signature. Sensitivity of recurrence risk classifier was 0.82 and 0.77, specificity 0.78 and 0.81, AUC 0.83 and 0.78 for TS and VS, respectively. VS KM curves for LR vs. HR groups significantly differed both for 5-year DFS (p<.0001) and OS (p=.0004). A combined model of RFs plus TNM improved prognostic performance as compared to TNM alone, both for VS 5-year DFS (C-index: 0.76 vs. 0.60) and OS (C-index: 0.74 vs. 0.64). CONCLUSIONS: Radiomics of b-MRI can help to predict recurrence and survival outcomes in HNSCC.

Intravoxel incoherent motion as a tool to detect early microstructural changes in meningiomas treated with proton therapy.

PURPOSE: To assess early microstructural changes of meningiomas treated with proton therapy through quantitative analysis of intravoxel incoherent motion (IVIM) and diffusion-weighted imaging (DWI) parameters. METHODS: Seventeen subjects with meningiomas that were eligible for proton therapy treatment were retrospectively enrolled. Each subject underwent a magnetic resonance imaging (MRI) including DWI sequences and IVIM assessments at baseline, immediately before the 1st (t0), 10th (t10), 20th (t20), and 30th (t30) treatment fraction and at follow-up. Manual tumor contours were drawn on T2-weighted images by two expert neuroradiologists and then rigidly registered to DWI images. Median values of the apparent diffusion coefficient (ADC), true diffusion (D), pseudo-diffusion (D*), and perfusion fraction (f) were extracted at all timepoints. Statistical analysis was performed using the pairwise Wilcoxon test. RESULTS: Statistically significant differences from baseline to follow-up were found for ADC, D, and D* values, with a progressive increase in ADC and D in conjunction with a progressive decrease in D*. MRI during treatment showed statistically significant differences in D values between t0 and t20 (p = 0.03) and t0 and t30 (p = 0.02), and for ADC values between t0 and t20 (p = 0.04), t10 and t20 (p = 0.02), and t10 and t30 (p = 0.035). Subjects that showed a volume reduction greater than 15% of the baseline tumor size at follow-up showed early D changes, whereas ADC changes were not statistically significant. CONCLUSION: IVIM appears to be a useful tool for detecting early microstructural changes within meningiomas treated with proton therapy and may potentially be able to predict tumor response.

The role of benzydamine in prevention and treatment of chemoradiotherapy-induced mucositis.

PURPOSE: To discuss the role of benzydamine in the prevention and treatment of radiation-induced oral mucositis (OM) in head and neck (H&N) cancer patients. This document represents an expert opinion paper on indications and key-role aspects in OM pathogenesis, prevention and treatment. ORAL MUCOSITIS: OM represents a common side effect of chemotherapy (CHT) and radiotherapy (RT). It consists in a painful erythema involving the oral cavity mucosa, which may progress to ulceration. Five biologically dynamic phases are considered crucial in mucositis: "initiation, signalling, amplification, ulceration and healing". Oral environment and microbiota are fundamental in mucositis development being involved in susceptibility to infections and in ulceration consequences. Different agents against mucositis have been studied and the use of benzydamine is strongly supported in literature. The Multinational Association of Supportive Care in Cancer and International Society for Oral Oncology (MASCC/ISOO) guidelines recommend its use for the prevention of OM in H&N patients undergoing RT and RT/CHT. BENZYDAMINE: Benzydamine is a local anti-inflammatory drug with analgesic properties. It can decrease TNF-α, IL-1ß and prostaglandin synthesis, also inhibiting leukocyte-endothelial interactions, neutrophil degranulation, vasodilation and vascular permeability. Literature agrees on the beneficial effects of benzydamine in preventing and reducing oral mucositis severity in H&N cancer patients undergoing RT/CHT. CONCLUSIONS: Mucositis represents a major concern in H&N cancer patients and a clinical and economical issue. A multimodal and multidisciplinary approach is needed for its management. International guidelines recommend benzydamine for OM prevention and treatment in H&N cancer patients, but further "real world" trials should be designed.

Management of loco-regionally advanced squamous laryngeal cancer in elderly patients.

PURPOSE: To describe the management and outcomes of loco-regionally advanced (stages III-IV) laryngeal cancer (LRALC) in elderly patients. METHODS: Clinical records of 88 LRALC patients treated at our Institution from 2002 to 2017 were retrospectively reviewed. Patients were divided in 2 subgroups: age > 65 years (elderly) and age ≤ 65 years (controls). Survivals were estimated with Kaplan-Meier method and compared with log-rank test, multivariate analysis were performed with Cox proportional hazard methods. RESULTS: Eighty-eight LRALC patients were included: 45 elderly and 43 controls. Median follow-up was 55.3 months. Median age was 66 years (range 41-84) in the overall population, 72 years (range 66-84) in the elderly cohort. The majority (98%) of elderly patients had at least one comorbidity (ACE27 1-3), while ACE27 was 0 in 37% of controls (p = 0.0001). ECOG PS was 0 in 42% of elderly vs 79% of controls (p = 0.0029). Clinical stage (TNM eighth edition) was III in 67%, IVA in 22% and IVB in 11%. Treatment consisted in total laryngectomy (TL) in 55%, chemo-radiation in 29%, exclusive radiotherapy in 9%, and conservative surgery in 7%. In elderly patients 2-year disease-free and overall survivals were 58% and 74%, respectively. Multivariate analysis performed on the overall group of 88 patients showed that age (HR 1.07, p = 0.0006) and TNM (for both 7th and 8th Editions HR 0.27 for stage III vs IV, p = 0.0005) maintained an independent statistical significant association with OS. CONCLUSIONS: In this monocentric cohort, age and TNM confirmed their independent prognostic role in LRALC patients. Organ-preservation is still an unmet need in a significant portion of elderly patients.

Convolutional Neural Networks Cascade for Automatic Pupil and Iris Detection in Ocular Proton Therapy.

Eye tracking techniques based on deep learning are rapidly spreading in a wide variety of application fields. With this study, we want to exploit the potentiality of eye tracking techniques in ocular proton therapy (OPT) applications. We implemented a fully automatic approach based on two-stage convolutional neural networks (CNNs): the first stage roughly identifies the eye position and the second one performs a fine iris and pupil detection. We selected 707 video frames recorded during clinical operations during OPT treatments performed at our institute. 650 frames were used for training and 57 for a blind test. The estimations of iris and pupil were evaluated against the manual labelled contours delineated by a clinical operator. For iris and pupil predictions, Dice coefficient (median = 0.94 and 0.97), Szymkiewicz-Simpson coefficient (median = 0.97 and 0.98), Intersection over Union coefficient (median = 0.88 and 0.94) and Hausdorff distance (median = 11.6 and 5.0 (pixels)) were quantified. Iris and pupil regions were found to be comparable to the manually labelled ground truths. Our proposed framework could provide an automatic approach to quantitatively evaluating pupil and iris misalignments, and it could be used as an additional support tool for clinical activity, without impacting in any way with the consolidated routine.