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IntroductionCigarette smoking has been recognized as a risk factor for breast cancer (BC) also if the biological mechanism remains poorly understood. High mammographic breast density (MBD) is associated with BC risk and many BC risk factors, such as genetic, anthropometric, reproductive and lifestyle factors and age, are also able to modulate MBD. The aim of the present study was to prospectively explore, in post-menopausal women, the association between smoking habits and MBD, assessed using an automated software, considering duration and intensity of smoking.MethodsThe analysis was carried out in 3,774 women enrolled in the European Prospective Investigation into Cancer and Nutrition (EPIC) Florence cohort in 1993-98, participating in the 2004-06 follow up (FU) and with at least one full-field digital mammography (FFDM) performed after FU. For each woman, detailed information on smoking habits, anthropometry, lifestyle and reproductive history was collected at enrollment and at FU. Smoking information at baseline and at FU was integrated. The fully automated Volpara™ software was used to obtain total breast volume (cm3), absolute breast dense volume (DV, cm3) and volumetric percent density (VPD, %) from the first available FFDM (average 5.3 years from FU). Multivariable linear regression models were applied to evaluate the associations between smoking habits and VPD or DV.ResultsAn inverse association between smoking exposure and VPD emerged (Diff% -7.96%, p

PurposeMagnetic resonance imaging (MRI)-guided radiotherapy enables adaptive treatment plans based on daily anatomical changes and accurate organ visualization. However, the bias field artifact can compromise image quality, affecting diagnostic accuracy and quantitative analyses. This study aims to assess the impact of bias field correction on 0.35 T pelvis MRIs by evaluating clinical anatomy visualization and generative adversarial network (GAN) auto-segmentation performance.Materials and methods3D simulation MRIs from 60 prostate cancer patients treated on MR-Linac (0.35 T) were collected and preprocessed with the N4ITK algorithm for bias field correction. A 3D GAN architecture was trained, validated, and tested on 40, 10, and 10 patients, respectively, to auto-segment the organs at risk (OARs) rectum and bladder. The GAN was trained and evaluated either with the original or the bias-corrected MRIs. The Dice similarity coefficient (DSC) and 95th percentile Hausdorff distance (HD95th) were computed for the segmented volumes of each patient. The Wilcoxon signed-rank test assessed the statistical difference of the metrics within OARs, both with and without bias field correction. Five radiation oncologists blindly scored 22 randomly chosen patients in terms of overall image quality and visibility of boundaries (prostate, rectum, bladder, seminal vesicles) of the original and bias-corrected MRIs. Bennett’s S score and Fleiss’ kappa were used to assess the pairwise interrater agreement and the interrater agreement among all the observers, respectively.ResultsIn the test set, the GAN trained and evaluated on original and bias-corrected MRIs showed DSC/HD95th of 0.92/5.63 mm and 0.92/5.91 mm for the bladder and 0.84/10.61 mm and 0.83/9.71 mm for the rectum. No statistical differences in the distribution of the evaluation metrics were found neither for the bladder (DSC: p = 0.07; HD95th: p = 0.35) nor for the rectum (DSC: p = 0.32; HD95th: p = 0.63). From the clinical visual grading assessment, the bias-corrected MRI resulted mostly in either no change or an improvement of the image quality and visualization of the organs’ boundaries compared with the original MRI.ConclusionThe bias field correction did not improve the anatomy visualization from a clinical point of view and the OARs’ auto-segmentation outputs generated by the GAN.

The increased availability of genetic technologies has significantly improved the detection of novel germline variants conferring a predisposition to tumor development in patients with malignant disease. The identification of variants of uncertain significance (VUS) represents a challenge for the clinician, leading to difficulties in decision-making regarding medical management, the surveillance program, and genetic counseling. Moreover, it can generate confusion and anxiety for patients and their family members. Herein, we report a 5-year-old girl carrying a VUS in the Succinate Dehydrogenase Complex Subunit C (SHDC) gene who had been previously treated for high-risk neuroblastoma and subsequently followed by the development of secondary acute myeloid leukemia. In this context, we describe how functional studies can provide additional insight on gene function determining whether the variant interferes with normal protein function or stability.

IntroductionContouring of gas pockets is a time consuming step in the workflow of adaptive radiotherapy. We would like to better understand which gas pockets electronic densitiy should be used and the dosimetric impact on adaptive MRgRT treatment.Materials and methods21 CT scans of patients undergoing SBRT were retrospectively evaluated. Anatomical structures were contoured: Gross Tumour Volume (GTV), stomach (ST), small bowel (SB), large bowel (LB), gas pockets (GAS) and gas in each organ respectively STG, SBG, LBG. Average HU in GAS was converted in RED, the obtained value has been named as Gastrointestinal Gas RED (GIGED). Differences of average HU in GAS, STG, SBG and LBG were computed. Three treatment plans were calculated editing the GAS volume RED that was overwritten with: air RED (0.0012), water RED (1.000), GIGED, generating respectively APLAN, WPLAN and the GPLAN. 2-D dose distributions were analyzed by gamma analysis. Parameter called active gas volume (AGV) was calculated as the intersection of GAS with the isodose of 5% of prescription dose.ResultsAverage HU value contained in GAS results to be equal to -620. No significative difference was noted between the average HU of gas in different organ at risk. Value of Gamma Passing Rate (GPR) anticorrelates with the AGV for each plan comparison and the threshold value for GPR to fall below 90% is 41, 60 and 139 cc for WPLANvsAPLAN, GPLANvsAPLAN and WPLANvsGPLAN respectively.DiscussionsGIGED is the right RED for Gastrointestinal Gas. Novel AGV is a useful parameter to evaluate the effect of gas pocket on dose distribution.

BackgroundGerm cell tumors (GCT) account for a minority of central nervous system (CNS) malignancies, highly prevalent in adolescents and young adults. Despite their aggressive biological behavior, prognosis is excellent in most cases with risk stratified treatment, consisting in a combination of chemotherapy and radiotherapy. Whole ventricular irradiation (WVI) and craniospinal irradiation, the treatment of choice for localized and metastatic disease, pose significant risk of collateral effects, therefore proton beam radiation (PBT) has been recently proposed for its steep dose fallout.Materials and methodsWe report our experience in a consecutive series of 17 patients treated for CNS GCT at our Institution from 2015 to 2021.ResultsMost frequent lesion location were sellar/suprasellar (35%) and bifocal germinoma (35%), followed by pineal (18%) and thalamic (12%). Two patients (12%), had evidence of disseminated disease at the time of diagnosis. At the latest follow-up all but one patient showed complete response to treatment. The only relapse was successfully rescued by additional chemotherapy and PBT. PBT was well tolerated in all cases. No visual, neurological or endocrinological worsening was documented during and after treatment. Neuropsychological evaluation demonstrated preservation of cognitive performance after PBT treatment.ConclusionsOur data, albeit preliminary, strongly support the favourable therapeutic profile of PBT for the treatment of CNS germ cell tumors.

IntroductionNew oral tyrosine kinase inhibitors (TKIs) are approved for metastatic colorectal cancer (mCRC). The aim of this study was to assess the neuropsychiatric adverse drug reactions (ADRs) of these drugs reported in the FDA Adverse Event Reporting System (FAERS) database.MethodsAll reports with regorafenib (REG) and encorafenib (ENC) as the primary suspect, and reported in the FAERS between 2012 and 2022, were collected. A descriptive and disproportionality analyses were conducted.ResultsOut of 4,984 cases, 1,357 (30.2%) reported at least one neuropsychiatric ADR. New potential signals for REG included neuropathy peripheral (n = 265; reporting odds ratio, ROR = 19.48, 95% confidence interval, CI 95% = 17.52-22.47; information component, IC = 2.89, IC025-IC075 = 2.77-3.02), hyperesthesia (n = 18; ROR = 12.56, CI 95% = 7.90-19.96; IC = 2.25, IC025-IC075 = 1.79-2.72), taste disorder (n = 41; ROR = 9.91, CI 95% = 7.29-13.49; IC = 2.18, IC025-IC075 = 1.88-2.49), poor quality sleep (n = 18; ROR = 6.56, CI 95% = 4.13-10.42; IC = 1.74, IC025-IC075 = 1.27-2.20), altered state of consciousness (n = 15; ROR = 5.50, CI 95% = 3.31-9.14; IC = 1.57, IC025-IC075 = 1.06-2.07), depressed mood (n = 13; ROR = 1.85, CI 95% = 1.07-3.19; IC = 0.58, IC025-IC075 = 0.04-1.13) and insomnia (n = 63; ROR = 1.48, CI 95% = 1.15-1.89; IC = 0.38, IC025-IC075 = 0.13-0.63). For ENC comprised depressed mood (n = 4; ROR = 5.75, CI 95% = 2.15-15.39; IC = 1.74, IC025-IC075 = 0.76-2.73) and cognitive disorders (n = 3; ROR = 4.71, CI 95% = 1.51-14.66; IC = 1.54, IC025-IC075 = 0.41-2.68).DiscussionThis study identified new unknown potential neuropsychiatric ADRs. Further investigations are required to better define the neurotoxicity of TKIs in mCRC patients.

In the era of evidence-based medicine, several clinical guidelines were developed, supporting cancer management from diagnosis to treatment and aiming to optimize patient care and hospital resources. Nevertheless, individual patient characteristics and organizational factors may lead to deviations from these standard recommendations during clinical practice. In this context, process mining in healthcare constitutes a valid tool to evaluate conformance of real treatment pathways, extracted from hospital data warehouses as event log, to standard clinical guidelines, translated into computer-interpretable formats. In this study we translate the European Society of Medical Oncology guidelines for rectal cancer treatment into a computer-interpretable format using Pseudo-Workflow formalism (PWF), a language already employed in pMineR software library for Process Mining in Healthcare. We investigate the adherence of a real-world cohort of rectal cancer patients treated at Fondazione Policlinico Universitario A. Gemelli IRCCS, data associated with cancer diagnosis and treatment are extracted from hospital databases in 453 patients diagnosed with rectal cancer. PWF enables the easy implementation of guidelines in a computer-interpretable format and visualizations that can improve understandability and interpretability of physicians. Results of the conformance checking analysis on our cohort identify a subgroup of patients receiving a long course treatment that deviates from guidelines due to a moderate increase in radiotherapy dose and an addition of oxaliplatin during chemotherapy treatment. This study demonstrates the importance of PWF to evaluate clinical guidelines adherence and to identify reasons of deviations during a treatment process in a real-world and multidisciplinary setting.

Cholangiocarcinoma is a rare group of tumors that involve the hepatic biliary tree. Prognosis for patients with cholangiocarcinoma remains dismal. Herein, we present survival trends over a long time period spanning almost 20 years in patients with advanced cholangiocarcinoma receiving systemic chemotherapy. We retrospectively analyzed a large multicenter dataset of cholangiocarcinoma outpatients evaluated in 14 centers within the Cholangiocarcinoma Italian Group Onlus (Gruppo Italiano Colangiocarcinoma Onlus, G.I.C.O.) between 2000 and 2017 (first-line), and 2002 and 2017 (second-line). Three time periods were considered: 2000-2009, 2010-2013, and 2014-2017. A total of 922 patients (51.19% male) with cholangiocarcinoma undergoing first-line therapy were evaluated. The median durations of follow-up for progression-free survival (PFS) and overall survival (OS) were 37 and 57 months, respectively. PFS at 12 months in the three periods of starting first-line therapy was similar, ranging from 11.71% to 15.25%. OS at 12 months progressively improved (38.30%, 44.61% and 49.52%, respectively), although the differences were not statistically significant after adjusting for age, disease status, and primary tumor site. A total of 410 patients (48.5% male) underwent second-line chemotherapy. The median durations of follow-up for PFS and OS were 47.6 and 41.90 months, respectively. An OS of 24.3%, 32.3%, and 33.1% was observed in 2002-2009, 2010-2013, and 2014-2017, respectively. Despite incremental benefits across years, our clinical experience confirms that modest overall advances have been achieved with first- and second-line chemotherapy in advanced cholangiocarcinoma. Efforts should focus on the identification of patients who derive the greatest benefit from treatment.

IntroductionNon-small cell lung cancer (NSCLC) is often caused by molecular alterations that can be detected by predictive biomarkers including mutations or amplifications of several genes. Several tyrosine kinase inhibitors (TKIs) have been approved in Europe by the European Medicines Agency (EMA) for NSCLC. The aim of this study was to analyze the onset of adverse drug reactions (ADRs) related to TKIs in NSCLC through a spontaneous reporting system (SRS) database.MethodsAll ADR reports having as suspected drug afatinib (AFT), alectinib (ALEC), brigatinib (BRG), ceritinib (CER), crizotinib (CRIZ), erlotinib (ERL), gefitinib (GEF), lorlatinib (LORL), nintedanib (NTB), and osimertinib (OSI) recorded into the Report Reazioni Avverse dei Medicinali (RAM) system database for national data and into the Italian SRS database for Sicilian data and collected from 2006 to 2021 have been evaluated. A descriptive analysis of basal demographic and drug-related characteristics was performed. A case-by-case methodology was conducted paying particular attention to all serious ADR reports collected in Sicily, focusing on type of seriousness, age, sex, concomitant drugs, and comorbidities.ResultsOf the 3,048 Italian reports, most of ADRs were related to ERL (n = 1,448), followed by AFT (n = 435) and GEF (n = 366). ADR reports were slightly more frequent in females (52.2%) and in the age group >65 years (53.0%). A higher number of cases were related to skin disorders (n = 1,766; 57.9%), followed by gastrointestinal disorders (n = 1,024; 33.6%), general disorders and administration site conditions (n = 536; 17.6%), and infections (n = 483; 15.8%). The case-by-case assessment of Sicilian ADRs showed that 33 cases were serious (12.5%) and mainly involved ERL (n = 17; 51.5%), occurring in males with a higher onset of respiratory diseases (30.3%) such as respiratory failure, interstitial lung disease and dyspnea.DiscussionThe analysis of spontaneous ADR reports of TKIs confirmed, in general, well-known risks, which often include skin, gastrointestinal, general, liver, and respiratory diseases as well as infections. However, more attention should be paid to the occurrence of serious life-threatening ADRs including respiratory failure, interstitial lung disease, and cardiogenic shock, especially in young patients.

AimThe aim of the current study is to investigate the impact of primary compared to secondary chemotherapy-induced nausea and vomiting (CINV) prophylaxis with NK1 receptor antagonists (NK1-RA) in patients affected by gastrointestinal malignancies and treated with oxaliplatin- and/or irinotecan-based doublet or triplet regimens.Study design and methodsClinical data of patients affected by gastrointestinal malignancies, treated with an oxaliplatin and/or irinotecan-based doublet or triplet regimen as neo/adjuvant or advanced-line treatment, and who received NK1-RA as primary (from the first cycle of treatment) or secondary (after the onset of CINV with a previous regimen with 5HT3-RA and dexamethasone) prophylaxis for CINV, were retrospectively collected in an observational study involving 16 Italian centers. A propensity score matching was performed by taking into account the following stratification factors: sex (male vs. female), age (< vs. ≥70 years old), overweight (body mass index, BMI < vs. ≥25), underweight (BMI < vs. ≥19), disease spread (early vs. advanced/metastatic), tumor type (esophagogastric cancer vs. the rest, hepatobiliary tumor vs. the rest, colorectal cancer vs. the rest), type of NK1-RA used as primary/secondary prophylaxis (netupitant-palonosetron vs. fosaprepitant/aprepitant), concomitant use of opioids (yes vs. no), concomitant use of antidepressant/antipsychotic drugs (yes vs. no), Eastern Cooperative Oncology Group (ECOG) performance status at the start of NK1-RA treatment (0 vs. 1–2), and intensity of chemotherapy regimen (doublet vs. triplet).ResultsAmong 409 patients included from January 2015 to January 2022 and eligible for analysis, 284 (69%) and 125 (31%) were treated with NK1-RA as primary and secondary antiemetic prophylaxis, respectively. After matching, primary NK1-RA use was not associated with higher rates of protection from emesis regardless the emesis phase (acute phase, p = 0.34; delayed phase, p = 0.14; overall phase, p = 0.80). On the other hand, a lower rate of relevant nausea (p = 0.02) and need for rescue antiemetic therapy (p = 0.000007) in the overall phase was found in primary NK1-RA users. Furthermore, a higher rate of both complete antiemetic response (p = 0.00001) and complete antiemetic protection (p = 0.00007) in the overall phase was more frequently observed in primary NK1-RA users. Finally, chemotherapy delays (p = 0.000009) and chemotherapy dose reductions (p = 0.0000006) were less frequently observed in primary NK1-RA users.ConclusionIn patients affected by gastrointestinal malignancies, a primary CINV prophylaxis with NK1-RA, 5HT3-RA, and dexamethasone might be appropriate, particularly in those situations at higher risk of emesis and in which it is important to avoid dose delays and/or dose reductions, keeping a proper dose intensity of chemotherapy drugs.

Central nervous system localization of multiple myeloma (CNS-MM) accounts for about 1% of all MM during disease course or even rarer at diagnosis. A difference in the origin, i.e., osteodural or primary dural vs leptomeningeal/intraparenchymal, seems to define two distinct types of intracranial myeloma, with different clinical behavior. CNS-MM may occur also as a presentation of MM. Treatment is still unsatisfactory and many treatments have been reported: chemotherapy, intrathecal therapy, and radiotherapy, with dismal prognosis. Other sites of myeloma localization could be also of interest and deserve description. Because of the rarity and aggressiveness of the disease clinicians are often doubtful on how to treat it since there is no general agreement. Moreover, recent drugs such as the anti CD38 monoclonal antibody, immunomodulatory drugs, and proteasome inhibitors have changed the treatment of patients with MM with a significant improvement in overall response and survival. The role of novel agents in CNS MM management and unusual presentations will be discussed as well as the potential role of other new immunomodulatory drugs and proteasome inhibitors that seem to cross the blood-brain barrier. The purpose of this review is to increase awareness of the clinical unusual presentation and neuroradiological findings, give practical diagnostic advice and treatment options algorithm.

Aim of this study was to analyze the efficacy and tolerability of simultaneous integrated boost volumetric modulated arc therapy (SIB-VMAT) associated with cisplatin-based chemotherapy in preoperative setting of patients with locally advanced cervical cancer (LACC). From June 2013 to September 2019, we analyzed patients with LACC who had undergone neoadjuvant chemoradiation (CRT). A radiation dose of 39.6 Gy, 1.8 Gy/fraction was delivered to the pelvis plus a radiation dose to the primary tumor delivered with SIB-VMAT strategy for a total of 50.6Gy, 2.3Gy/fraction in 25 fractions. Cisplatin-based chemotherapy was delivered combined with radiotherapy. Radical hysterectomy plus pelvic with or without aortic lymphadenectomy was performed within 7 to 8 weeks from CRT. One hundred forty-eight patients (median age: 49.5 years; FIGO stage IB2: 7, IIA: 8, IIB: 106, IIIA: 5; IIIB: 16; IVA: 5, IVB: 1; N0: 56, N1: 92) were analyzed. The treatment was well tolerated with good compliance: no grade 3/4 gastrointestinal or genitourinary toxicity was reported; grade 3 neutropenia was described in five cases. Pathological complete response (pCR) was documented in 68 cases (46%) and 32 patients (21.6%) had microscopic residual disease. Pathological nodal involvement was observed in 23 patients (15.5%). At median follow-up of 59 months (range: 27-100), the 3-year local control was 78.5%, whereas the 3-year metastasis-free survival was 70.5%. The 3-year overall survival rate was 89.0%. Neoadjuvant CRT with SIB-VMAT followed by radical surgery results in a high rate of pathologically assessed complete response and a very encouraging local control rate, with acceptable toxicity.

PurposeDistant metastasis is the main cause of treatment failure in locally advanced rectal cancer (LARC) patients, despite the recent improvement in treatment strategies. This study aims to evaluate the “delta radiomics” approach in patients undergoing neoadjuvant chemoradiotherapy (nCRT) treated with 0.35-T magnetic resonance-guided radiotherapy (MRgRT), developing a logistic regression model able to predict 2-year disease-free-survival (2yDFS).MethodsPatients affected by LARC were enrolled in this multi-institutional study. A predictive model of 2yDFS was developed taking into account both clinical and radiomics variables. Gross tumour volume (GTV) was delineated on the magnetic resonance (MR) images acquired during MRgRT, and 1,067 radiomic features (RF) were extracted using the MODDICOM platform. The performance of RF in predicting 2yDFS was investigated in terms of the Wilcoxon–Mann–Whitney test and area under receiver operating characteristic (ROC) curve (AUC).Results48 patients have been retrospectively enrolled, with 8 patients (16.7%) developing distant metastases at the 2-year follow-up. A total of 1,099 variables (1,067 RF and 32 clinical variables) were evaluated in two different models: radiomics and radiomics/clinical. The best-performing 2yDFS predictive model was a delta radiomics one, based on the variation in terms of area/surface ratio between biologically effective doses (BED) at 54 Gy and simulation (AUC of 0.92).ConclusionsThe results of this study suggest a promising role of delta radiomics analysis on 0.35-T MR images in predicting 2yDFS for LARC patients. Further analyses including larger cohorts of patients and an external validation are needed to confirm these preliminary results.

AimThe first prototype of the “Multidisciplinary Tumor Board Smart Virtual Assistant” is presented, aimed to (i) Automated classification of clinical stage starting from different free-text diagnostic reports; (ii) Resolution of inconsistencies by identifying controversial cases drawing the clinician’s attention to particular cases worthy for multi-disciplinary discussion; (iii) Support environment for education and knowledge transfer to junior staff; (iv) Integrated data-driven decision making and standardized language and interpretation.Patients and MethodData from patients affected by Locally Advanced Cervical Cancer (LACC), FIGO stage IB2-IVa, treated between 2015 and 2018 were extracted. Magnetic Resonance (MR), Gynecologic examination under general anesthesia (EAU), and Positron Emission Tomography–Computed Tomography (PET-CT) performed at the time of diagnosis were the items from the Electronic Health Records (eHRs) considered for analysis. An automated extraction of eHR that capture the patient’s data before the diagnosis and then, through Natural Language Processing (NLP), analysis and categorization of all data to transform source information into structured data has been performed.ResultsIn the first round, the system has been used to retrieve all the eHR for the 96 patients with LACC. The system has been able to classify all patients belonging to the training set and - through the NLP procedures - the clinical features were analyzed and classified for each patient. A second important result was the setup of a predictive model to evaluate the patient’s staging (accuracy of 94%). Lastly, we created a user-oriented operational tool targeting the MTB who are confronted with the challenge of large volumes of patients to be diagnosed in the most accurate way.ConclusionThis is the first proof of concept concerning the possibility of creating a smart virtual assistant for the MTB. A significant benefit could come from the integration of these automated methods in the collaborative, crucial decision stages.

Prostate cancer (PCa) is the most frequent male malignancy and the assessment of PCa aggressiveness, for which a biopsy is required, is fundamental for patient management. Currently, multiparametric (mp) MRI is strongly recommended before biopsy. Quantitative assessment of mpMRI might provide the radiologist with an objective and noninvasive tool for supporting the decision-making in clinical practice and decreasing intra- and inter-reader variability. In this view, high dimensional radiomics features and Machine Learning (ML) techniques, along with Deep Learning (DL) methods working on raw images directly, could assist the radiologist in the clinical workflow. The aim of this study was to develop and validate ML/DL frameworks on mpMRI data to characterize PCas according to their aggressiveness. We optimized several ML/DL frameworks on T2w, ADC and T2w+ADC data, using a patient-based nested validation scheme. The dataset was composed of 112 patients (132 peripheral lesions with Prostate Imaging Reporting and Data System (PI-RADS) score ≥ 3) acquired following both PI-RADS 2.0 and 2.1 guidelines. Firstly, ML/DL frameworks trained and validated on PI-RADS 2.0 data were tested on both PI-RADS 2.0 and 2.1 data. Then, we trained, validated and tested ML/DL frameworks on a multi PI-RADS dataset. We reported the performances in terms of Area Under the Receiver Operating curve (AUROC), specificity and sensitivity. The ML/DL frameworks trained on T2w data achieved the overall best performance. Notably, ML and DL frameworks trained and validated on PI-RADS 2.0 data obtained median AUROC values equal to 0.750 and 0.875, respectively, on unseen PI-RADS 2.0 test set. Similarly, ML/DL frameworks trained and validated on multi PI-RADS T2w data showed median AUROC values equal to 0.795 and 0.750, respectively, on unseen multi PI-RADS test set. Conversely, all the ML/DL frameworks trained and validated on PI-RADS 2.0 data, achieved AUROC values no better than the chance level when tested on PI-RADS 2.1 data. Both ML/DL techniques applied on mpMRI seem to be a valid aid in predicting PCa aggressiveness. In particular, ML/DL frameworks fed with T2w images data (objective, fast and non-invasive) show good performances and might support decision-making in patient diagnostic and therapeutic management, reducing intra- and inter-reader variability.

Langerhans cell histiocytosis (LCH) is due to aberrant monoclonal proliferation and accumulation of dendritic cells, ranging from a self-limiting local condition to a rapidly progressive multisystem disease with poor prognosis. Pathogenic cells originate from a myeloid-derived precursor characterized by an activation of the MAPK/ERK signaling pathway in about 70% of cases. In particular, BRAF V600E mutation is usually associated with a more severe clinical course and poor response to chemotherapy. We report on a newborn with multisystem LCH in life-threatening medical conditions. At diagnosis, the patient was successfully treated with the early association of BRAF inhibitor Vemurafenib to standard chemotherapy representing a new approach in first-line treatment. A rapid clinical improvement with a prompt fever regression from day 2 and complete resolution of skin lesions by week 2 were observed; laboratory data normalized as well. Vemurafenib was discontinued after 12 months of treatment. No signs of relapse occurred after 12 months of discontinuation. This case indicates that early combination of target therapy with standard treatment may induce rapid response and prolonged disease remission without significant toxicities in infants. This approach represents a valid and safe option as first-line treatment in multisystem disease, especially in high-risk patients.

IntroductionThe aim of this study was to create a radiomic model able to calculate the probability of 5-year disease-free survival (5yDFS) when oxaliplatin (OXA) is or not administered in patients with locally advanced rectal cancer (LARC) and treated with neoadjuvant chemoradiotherapy (nCRT), allowing physicians to choose the best chemotherapy (CT) regimen.MethodsLARC patients with cT3–4 cN0 or cT1–4 cN1–2 were treated according to an nCRT protocol that included concomitant CT schedules with or without OXA and radiotherapy dose of 55 Gy in 25 fractions. Radiomic analysis was performed on the T2-weighted (T2-w) MR images acquired during the initial tumor staging. Statistical analysis was performed separately for the cohort of patients treated with and without OXA. The ability of every single radiomic feature in predicting 5yDFS as a univariate analysis was assessed using the Wilcoxon–Mann–Whitney (WMW) test or t-test. Two logistic models (one for each cohort) were calculated, and their performance was assessed using the area under the receiver operating characteristic (ROC) curve (AUC).ResultsA total of 176 image features belonging to four families (morphological, statistical, textural, and fractal) were calculated for each patient. At the univariate analysis, the only feature showing significance in predicting 5yDFS was the maximum fractal dimension of the subpopulation identified considering 30% and 50% as threshold levels (maxFD30–50). Once the models were developed using this feature, an AUC of 0.67 (0.57–0.77) and 0.75 (0.56–0.95) was obtained for patients treated with and without OXA, respectively. A maxFD30–50 >1.6 was correlated to a higher 5yDFS probability in patients treated with OXA.ConclusionThis study suggests that radiomic analysis of MR T2-w images can be used to define the optimal concomitant CT regimen for stage III LARC cancer patients. In particular, by providing an indication of the gross tumor volume (GTV) spatial heterogeneity at initial staging, maxFD30–50 seems to be able to predict the probability of 5yDFS. New studies including a larger cohort of patients and external validation sets are recommended to verify the results of this hypothesis-generating study.

BackgroundAdult body fatness is a convincing risk factor for postmenopausal breast cancer. With the aim to compare the different breast cancer (BC) features in Northern and Southern Italy, we investigated the relationship between BMI and BC characteristic in two groups of patients referred in the Modena and Lecce breast units.Materials and MethodsA retrospective analysis of a continuous series of BC patients referred to the Città di Lecce Hospital and the Modena Cancer Center, from January 2019 to December 2020 was performed. We identified four groups of BMI at BC diagnosis: underweight, BMI

BackgroundCutaneous melanoma (CM) is one of the most aggressive types of skin cancer. Currently, innovative approaches such as target therapies and immunotherapies have been introduced in clinical practice. Data of clinical trials and real life studies that evaluate the outcomes of these therapeutic associations are necessary to establish their clinical utility. The aim of this study is to investigate the types of oncological treatments employed in the real-life clinical management of patients with advanced CM in several Italian centers, which are part of the Clinical National Melanoma Registry (CNMR).MethodsMelanoma-specific survival and overall survival were calculated. Multivariate Cox regression models were used to estimate the hazard ratios adjusting for confounders and other prognostic factors.ResultsThe median follow-up time was 36 months (range 1.2-185.1). 787 CM were included in the analysis with completed information about therapies. All types of immunotherapy showed a significant improved survival compared with all other therapies (p=0.001). 75% was the highest reduction of death reached by anti-PD-1 (HR=0.25), globally immunotherapy was significantly associated with improved survival, either for anti-CTLA4 monotherapy or combined with anti-PD-1 (HR=0.47 and 0.26, respectively) and BRAFI+MEKI (HR=0.62).ConclusionsThe nivolumab/pembrolizumab in combination of ipilimumab and the addition of ant-MEK to the BRAFi can be considered the best therapies to improve survival in a real-world-population. The CNMR can complement clinical registries with the intent of improving cancer management and standardizing cancer treatment.

Hereditary Breast and Ovarian Cancer (HBOC) syndrome is a condition in which the risk of breast and ovarian cancer is higher than in the general population. The prevalent pathogenesis is attributable to inactivating variants of the BRCA1-2 highly penetrant genes, however, other cancer susceptibility genes may also be involved. By Exome Sequencing (ES) we analyzed a series of 200 individuals selected for genetic testing in BRCA1-2 genes according to the updated National Comprehensive Cancer Network (NCCN) guidelines. Analysis by MLPA was performed to detect large BRCA1-2 deletions/duplications. Focusing on BRCA1-2 genes, data analysis identified 11 cases with pathogenic variants (4 in BRCA1 and 7 in BRCA1-2) and 12 with uncertain variants (7 in BRCA1 and 5 in BRCA2). Only one case was found with a large BRCA1 deletion. Exome analysis allowed to characterize pathogenic variants in 21 additional genes: 10 genes more traditionally associated to breast and ovarian cancer (ATM, BRIP1, CDH1, PALB2, PTEN, RAD51C, and TP53) (5% diagnostic yield) and 11 in candidate cancer susceptibility genes (DPYD, ERBB3, ERCC2, MUTYH, NQO2, NTHL1, PARK2, RAD54L, and RNASEL). In conclusion, this study allowed a personalized risk assessment and clinical surveillance in an increased number of HBOC families and to broaden the spectrum of causative variants also to candidate “non-canonical” genes.

Aims: Pediatric patients may experience considerable distress during radiotherapy. Combining psychological interventions with standard therapies can reduce the need for sedation. The RADAR Project aims to use a systematic method of recording data that can reveal patients' difficulties and fragility during treatment.In this context, the aim of our study was to investigate the ability of a multidimensional assessment tool (M.A.P.-RT schedule) to predict the need for sedation during radiotherapy. The schedule, which is administered during the first evaluation, was created to collect information on patients and their families in a standardized way.Materials and Methods: The study enrolled pediatric patients (aged 0–18 years or 18–21 with cognitive impairment). Data were collected by means of the M.A.P.-RT module; this explores various thematic areas, and is completed by the radiation oncologist, psychologist and nurse during their first evaluation. Features were selected by means of the Boruta method (random forest classifier), and the totals of the significant partial scores on each subsection of the module were inserted into a logistic model in order to test for their correlation with the use of anesthesia and with the frequency of psychological support. The results of logistic regression (LR) were used to identify the best predictors. The AUC was used to identify the best threshold for the scores in the evaluation.Results: A total of 99 patients were considered for this analysis. The feature that best predicted both the need for anesthesia and the frequency of psychological support was the total score (TS), the AUC of the ROC being 0.9875 for anesthesia and 0.8866 for psychological support.Conclusion: During the first evaluation, the M.A.P.-RT form can predict the need for anesthesia in pediatric patients, and is a potential tool for personalizing therapeutic and management procedures.

DICER1 syndrome is a rare genetic condition predisposing to hereditary cancer and caused by variants in the DICER1 gene. The risk to present a neoplasm before the age of 10 years is 5.3 and 31.5% before the age of 60. DICER1 variants have been associated with a syndrome involving familial pleuropulmonary blastoma (PPB), a rare malignant tumor of the lung, which occurs primarily in children under the age of 6 years and represents the most common life-threatening manifestation of DICER1 syndrome. Type I, II, III, and Ir (type I regressed) PPB are reported with a 5-year overall survival ranging from 53 to 100% (for type Ir). DICER1 gene should be screened in all patients with PPB and considered in other tumors mainly in thyroid neoplasms (multinodular goiter, thyroid cancer, adenomas), ovarian tumors (Sertoli-Leydig cell tumor, sarcoma, and gynandroblastoma), and cystic nephroma. A prompt identification of this syndrome is necessary to plan a correct follow-up and screening during lifetime.

PurposeDistant metastases are currently the main cause of treatment failure in locally advanced rectal cancer (LARC) patients. The aim of this research is to investigate a correlation between the variation of radiomics features using pre- and post-neoadjuvant chemoradiation (nCRT) magnetic resonance imaging (MRI) with 2 years distant metastasis (2yDM) rate in LARC patients.Methods and MaterialsDiagnostic pre- and post- nCRT MRI of LARC patients, treated in a single institution from May 2008 to June 2015 with an adequate follow-up time, were retrospectively collected. Gross tumor volumes (GTV) were contoured by an abdominal radiologist and blindly reviewed by a radiation oncologist expert in rectal cancer. The dataset was firstly randomly split into 90% training data, for features selection, and 10% testing data, for the validation. The final set of features after the selection was used to train 15 different classifiers using accuracy as target metric. The models’ performance was then assessed on the testing data and the best performing classifier was then selected, maximising the confusion matrix balanced accuracy (BA).ResultsData regarding 213 LARC patients (36% female, 64% male) were collected. Overall 2yDM was 17%. A total of 2,606 features extracted from the pre- and post- nCRT GTV were tested and 4 features were selected after features selection process. Among the 15 tested classifiers, logistic regression proved to be the best performing one with a testing set BA, sensitivity and specificity of 78.5%, 71.4% and 85.7%, respectively.ConclusionsThis study supports a possible role of delta radiomics in predicting following occurrence of distant metastasis. Further studies including a consistent external validation are needed to confirm these results and allows to translate radiomics model in clinical practice. Future integration with clinical and molecular data will be mandatory to fully personalized treatment and follow-up approaches.

Peritoneal carcinosis (PC) is characterized by poor prognosis. PC is currently treated as a locoregional disease and the possibility to perform very precise treatments such as stereotactic body radiation therapy (SBRT) has opened up new therapeutic perspectives. More recently, the introduction of Magnetic Resonance-guided Radiation Therapy (MRgRT) allowed online adaptation (OA) of treatment plan to optimize daily dose distribution based on patient’s anatomy. The aim of this study is the evaluation of the effectiveness of SBRT OA workflow in an oligometastatic patient affected by PC. We report the clinical case of a patient affected by PC originating from colon cancer, previously treated with chemotherapy and surgery, addressed to OA SBRT treatment on a single chemoresistant PC nodule, delivered with a 0.35 T MR Linac. Treatment was delivered using gating approach in deep inspiration breath hold condition in order to reduce intrafraction variability. Prescription dose was 35 Gy in 5 fractions. The PTV V95% of the original plan was 96.6%, while the predicted values for the following fractions were 11.9, 56.4, 0, 0, and 61%. Similarly, the small bowel V19.5 Gy of the original plan was 4.63 cc, while the predicted values for the following fractions were 3.7, 8.6, 10.7, 1.96, 3.7 cc. Thanks to the OA approach, the re-optimized PTV V95% coverage improved to 96.1, 89.0, 85.5, 94.5, and 94%; while the small bowel V19.5 Gy to 3.36; 3.28; 1.84; 2.62; 2.6 cc respectively. After the end of RT, the patient was addressed to follow-up, and the re-evaluation 18F-FDG PET-CT was performed after 10 months from irradiation showed complete response. No acute or late toxicities were recorded. MRgRT with OA approach in PC patients is technically and clinically feasible with clean toxicity result. Online adaptive SBRT for oligometastases opens up new therapeutic scenarios in the management of this category of patients.

Malignant ovarian germ cell tumors (MOGCTs) are neoplasms of the ovary, of which, due to their rarity and heterogeneity, few is reported about genetic background and development. Here, we report a 18-years old patient diagnosed with an ovarian mixed germ cell tumor, without any previous history of malignancies, who has been treated with surgery and chemotherapy and died 4 years later due to peritoneal metastasis complications. Patient's blood DNA was screened for a panel of 52 cancer-related genes in order to identify predisposing aberrations to this rare cancer. The analysis discovered the uncharacterized c.2393G>A variant in RB1, the retinoblastoma gene, leading both to a missense change and a splicing perturbation of the RB1 transcript. The variant was found to be hypomorphic, damaging the C-terminal domain with a partially impaired protein function. The variant is inherited from the unaffected mother. Due to an imprinting mechanism, the maternal allele is ~3-fold more expressed than the paternal one. The parent-of-origin effect combined with the hypomorphic impact of the variant determines a rescue of sufficient tumor-suppressor activity to prevent retinoblastoma development but can predispose to other cancers in the adult age. In order to understand the somatic events acting on the germline predisposition we used the NGS-liquid biopsy covering 77 cancer driver genes. Using this approach, we detected deleterious mutations in TP53, SMAD4, FGFR3, and MSH2, indicative of a dis-regulation of cell cycle and DNA repair mechanisms pathways. In conclusion, we have pinpointed for the first time that an RB1 leaky variant, not leading to retinoblastoma because of its maternal origin, can predispose in adults to a very rare form of ovarian cancer and that the somatic disruption of few genes contributes to the tumor progression and aggressiveness.

The contribution of cell-extrinsic factors in Acute Myeloid Leukemia (AML) generation and persistence has gained interest. Bitter taste receptors (TAS2Rs) are G protein-coupled receptors known for their primary role as a central warning signal to induce aversion toward noxious or harmful substances. Nevertheless, the increasing amount of evidence about their extra-oral localization has suggested a wider function in sensing microenvironment, also in cancer settings. In this study, we found that AML cells express functional TAS2Rs. We also highlighted a significant association between the modulation of some TAS2Rs and the poor-prognosis AML groups, i.e., TP53- and TET2-mutated, supporting a potential role of TAS2Rs in AML cell biology. Gene expression profile analysis showed that TAS2R activation with the prototypical agonist, denatonium benzoate, significantly modulated a number of genes involved in relevant AML cellular processes. Functional assay substantiated molecular data and indicated that denatonium reduced AML cell proliferation by inducing cell cycle arrest in G0/G1 phase or induced apoptosis via caspase cascade activation. Moreover, denatonium exposure impaired AML cell motility and migratory capacity, and inhibited cellular respiration by decreasing glucose uptake and oxidative phosphorylation. In conclusion, our results in AML cells expand the observation of cancer TAS2R expression to the setting of hematological neoplasms and shed light on a role of TAS2Rs in the extrinsic regulation of leukemia cell functions.

Primary cutaneous B-cell lymphomas (PCBCL) are rare types of extranodal non-Hodgkin's lymphoma. The choice of treatment usually depends on the variant of PCBCL, number, size, and location of the lesions, involved body surface area as well as patient's age and health condition. The efficacy of radiotherapy (RT) in the treatment of PCBCL has been widely reported conversely, data about the acute and late skin toxicity, patient's treatment satisfaction and quality of life are scarce. A systematic search using PubMed, Scopus, and Cochrane library was performed to identify full original articles analyzing the safety of RT in patients with PCBCL with the primary outcome to assess the acute and late skin toxicity. Secondary outcomes were complete remission, disease free survival, and overall survival. The literature search resulted in 276 articles including eight studies assessing the safety of RT for the treatment of PCBCL. Most patients (median 73%, range 11.9–99.9%) were recorded as having acute skin toxicity of grade 1–2, while acute grade 3–4 toxicity occurred in a median of 8% (range 4–23%) of patients. A median of 20% (range 4–54%) of patients had late skin toxicity of grade 1–2. No late grade 3–4 toxicity was reported. Only one study evaluated patient's satisfaction showing that the 97% of patients were satisfied with radiation therapy. This systematic review confirms the safety of RT in the treatment of PCBCL. Patients with a PCBCL should be managed in highly specialized centers in the context of a multidisciplinary team including dermatologist, hematologist, pathologist, and radiation oncologist.

Ectopic ACTH syndrome is rare in pediatric age. Sarcomas that cause Ectopic ACTH Syndrome (EAS) are even more uncommon. Currently, only three cases of EAS caused by Ewing' sarcoma have been reported. We detail a 10-year-old boy with Cushing's syndrome symptoms caused by ectopic ACTH production by a metastatic Ewing's sarcoma of the right ischio-pubic and ileo-pubic branches. The rapid appearance of cushingoid symptoms, with significant weight gain, acne, hirsutism, and hypercortisolism were implications of ectopic ACTH production as paraneoplastic Cushing's Syndrome. The very high levels of ACTH and non-suppression at the high dose dexamethasone test confirmed the clinical suspicion. We underline the possibility EAS was caused by an ACTH-secreting tumor, including soft tissue sarcomas.

The immune escape mechanisms at the base of tumor progression in endometrial cancer mimic immune tolerance mechanisms occurring at the maternal–fetal interface. The biological and immunological processes behind the maternal–fetal interface are finely tuned in time and space during embryo implantation and subsequent pregnancy stages; conversely, those behind cancer progression are often aberrant. The environment composition at the maternal–fetal interface parallels the pro-tumor microenvironment identified in many cancers, pointing to the possibility for the use of the maternal–fetal interface as a model to depict immune therapeutic targets in cancer. The framework of cancer environment signatures involved in immune adaptations, precisely timed in cancer progression, could reveal a specific “immune clock” in endometrial cancer, which might guide clinicians in patient risk class assessment, diagnostic workup, management, surgical and therapeutic approach, and surveillance strategies. Here, we review studies approaching this hypothesis, focusing on what is known so far about oncofetal similarities in immunity with the idea to individualize personalized immunotherapy targets, through the downregulation of the immune escape stage or the reactivation of the pro-inflammatory processes suppressed by the tumor.

Conjunctival melanoma is a rare primary ocular tumor. So far, no standard treatment exists for metastatic disease. Similarly to cutaneous melanoma, up to 50% of conjunctival melanomas harbor BRAF mutations. The most common is represented by V600E. Combined therapy with BRAF and MEK inhibitors is approved for BRAF mutant cutaneous metastatic melanomas. Herein, we report a case of a 70-years old patient with a metastatic conjunctival melanoma harboring V600E BRAF mutation successfully treated with dabrafenib and trametinib.

Background: Most of the patients with Pancreatic Ductal Adenocarcinoma (PDA) are not eligible for a curative surgical resection. For this reason there is an urgent need for personalized therapies. PDA is the result of complex interactions between tumor molecular profile and metabolites produced by its microenvironment. Despite recent studies identified PDA molecular subtypes, its metabolic classification is still lacking.Methods: We applied an integrative analysis on transcriptomic and genomic data of glycolytic genes in PDA. Data were collected from public datasets and molecular glycolytic subtypes were defined using hierarchical clustering. The grade of purity of the cancer samples was assessed estimating the different amount of stromal and immunological infiltrate among the identified PDA subtypes. Analyses of metabolomic data from a subset of PDA cell lines allowed us to identify the different metabolites produced by the metabolic subtypes. Sera of a cohort of 31 PDA patients were analyzed using Q-TOF mass spectrometer to measure the amount of metabolic circulating proteins present before and after chemotherapy.Results: Our integrative analysis of glycolytic genes identified two glycolytic and two non-glycolytic metabolic PDA subtypes. Glycolytic patients develop disease earlier, have poor prognosis, low immune-infiltrated tumors, and are characterized by a gain in chr12p13 genomic region. This gain results in the over-expression of GAPDH, TPI1, and FOXM1. PDA cell lines with the gain of chr12p13 are characterized by an higher lipid uptake and sensitivity to drug targeting the fatty acid metabolism. Our sera proteomic analysis confirms that TPI1 serum levels increase in poor prognosis gemcitabine-treated patients.Conclusions: We identify four metabolic PDA subtypes with different prognosis outcomes which may have pivotal role in setting personalized treatments. Moreover, our data suggest TPI1 as putative prognostic PDA biomarker.

Cyclic AMP response element binding (CREB) protein is a member of the CREB/activating transcription factor (ATF) family of transcription factors that play an important role in the cell response to different environmental stimuli leading to proliferation, differentiation, apoptosis, and survival. A number of studies highlight the involvement of CREB in the resistance to ionizing radiation (IR) therapy, demonstrating a relationship between IR-induced CREB family members’ activation and cell survival. Consistent with these observations, we have recently demonstrated that CREB and ATF-1 are expressed in leukemia cell lines and that low-dose radiation treatment can trigger CREB activation, leading to survival of erythro-leukemia cells (K562). On the other hand, a number of evidences highlight a proapoptotic role of CREB following IR treatment of cancer cells. Since the development of multiple mechanisms of resistance is one key problem of most malignancies, including those of hematological origin, it is highly desirable to identify biological markers of responsiveness/unresponsiveness useful to follow-up the individual response and to adjust anticancer treatments. Taking into account all these considerations, this mini-review will be focused on the involvement of CREB/ATF family members in response to IR therapy, to deepen our knowledge of this topic, and to pave the way to translation into a therapeutic context.