Notch: From fly wings to human hematological tumors

Notch history begins in 1919 with Thomas Hunt Morgan studies on fruit fly mutants. From then, this gene aroused lively interest in the scientific community since it is involved in a wide variety of processes, including morphogenesis, tissue homeostasis, and stem cell maintenance. Deregulation of Notch signaling characterizes several human tumors. Hematopoietic system is affected by mutations of Notch receptors, Notch ligands, and proteins controlling their stability. Approximately 60% T acute lymphoblastic leukemia (T-ALL) patients carry activating Notch1 mutations prompting blasts growth. In addition, multiple myeloma is characterized by Notch signaling hyper-activation due to an abnormal expression of the Jagged2 ligand; this affects not only myeloma cells, but also their interaction with bone marrow microenvironment, influencing tumor burden and bone disease. These findings make Notch a rational target of a therapeutic approach. Inhibitors of the Notch activating enzyme, ?-Secretase, have been successfully used in vitro and in vivo and are currently under clinical trials for T-ALL and breast cancer. Yet a wide use of these inhibitors is prevented by frequently occurring drug resistance. To elucidate the mechanism underlying this phenomenon, a number of pathways have been identified mediating Notch biological effects: AKT and c-Myc are frequently deregulated in leukemic patients and account for resistance to ?-Secretase inhibitors by acting downstream Notch receptor. Therefore, the interaction of Notch with other cancer-associated proteins should be clarified to predict the biological outcome of a Notch targeted therapy and possibly, to exploit combined treatments against the key deregulated elements in Notch-associated cancers

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

Localization of anatomical changes in patients during proton therapy with in-beam PET monitoring: a voxel-based morphometry approach exploiting Monte Carlo simulations

Purpose: In-beam positron emission tomography (PET) is one of the modalities that can be used for in vivo noninvasive treatment monitoring in proton therapy. Although PET monitoring has been frequently applied for this purpose, there is still no straightforward method to translate the information obtained from the PET images into easy-to-interpret information for clinical personnel. The purpose of this work is to propose a statistical method for analyzing in-beam PET monitoring images that can be used to locate, quantify, and visualize regions with possible morphological changes occurring over the course of treatment. Methods: We selected a patient treated for squamous cell carcinoma (SCC) with proton therapy, to perform multiple Monte Carlo (MC) simulations of the expected PET signal at the start of treatment, and to study how the PET signal may change along the treatment course due to morphological changes. We performed voxel-wise two-tailed statistical tests of the simulated PET images, resembling the voxel-based morphometry (VBM) method commonly used in neuroimaging data analysis, to locate regions with significant morphological changes and to quantify the change. Results: The VBM resembling method has been successfully applied to the simulated in-beam PET images, despite the fact that such images suffer from image artifacts and limited statistics. Three dimensional probability maps were obtained, that allowed to identify interfractional morphological changes and to visualize them superimposed on the computed tomography (CT) scan. In particular, the characteristic color patterns resulting from the two-tailed statistical tests lend themselves to trigger alarms in case of morphological changes along the course of treatment. Conclusions: The statistical method presented in this work is a promising method to apply to PET monitoring data to reveal interfractional morphological changes in patients, occurring over the course of treatment. Based on simulated in-beam PET treatment monitoring images, we showed that with our method it was possible to correctly identify the regions that changed. Moreover we could quantify the changes, and visualize them superimposed on the CT scan. The proposed method can possibly help clinical personnel in the replanning procedure in adaptive proton therapy treatments

In-vivo range verification analysis with in-beam PET data for patients treated with proton therapy at CNAO

Morphological changes that may arise through a treatment course are probably one of the most significant sources of range uncertainty in proton therapy. Non-invasive in-vivo treatment monitoring is useful to increase treatment quality. The INSIDE in-beam Positron Emission Tomography (PET) scanner performs in-vivo range monitoring in proton and carbon therapy treatments at the National Center of Oncological Hadrontherapy (CNAO). It is currently in a clinical trial (ID: NCT03662373) and has acquired in-beam PET data during the treatment of various patients. In this work we analyze the in-beam PET (IB-PET) data of eight patients treated with proton therapy at CNAO. The goal of the analysis is twofold. First, we assess the level of experimental fluctuations in inter-fractional range differences (sensitivity) of the INSIDE PET system by studying patients without morphological changes. Second, we use the obtained results to see whether we can observe anomalously large range variations in patients where morphological changes have occurred. The sensitivity of the INSIDE IB-PET scanner was quantified as the standard deviation of the range difference distributions observed for six patients that did not show morphological changes. Inter-fractional range variations with respect to a reference distribution were estimated using the Most-Likely-Shift (MLS) method. To establish the efficacy of this method, we made a comparison with the Beam's Eye View (BEV) method. For patients showing no morphological changes in the control CT the average range variation standard deviation was found to be 2.5 mm with the MLS method and 2.3 mm with the BEV method. On the other hand, for patients where some small anatomical changes occurred, we found larger standard deviation values. In these patients we evaluated where anomalous range differences were found and compared them with the CT. We found that the identified regions were mostly in agreement with the morphological changes seen in the CT scan

Monitoring Carbon Ion Beams Transverse Position Detecting Charged Secondary Fragments: Results From Patient Treatment Performed at CNAO

Particle therapy in which deep seated tumours are treated using 12C ions (Carbon Ions RadioTherapy or CIRT) exploits the high conformity in the dose release, the high relative biological effectiveness and low oxygen enhancement ratio of such projectiles. The advantages of CIRT are driving a rapid increase in the number of centres that are trying to implement such technique. To fully profit from the ballistic precision achievable in delivering the dose to the target volume an online range verification system would be needed, but currently missing. The 12C ions beams range could only be monitored by looking at the secondary radiation emitted by the primary beam interaction with the patient tissues and no technical solution capable of the needed precision has been adopted in the clinical centres yet. The detection of charged secondary fragments, mainly protons, emitted by the patient is a promising approach, and is currently being explored in clinical trials at CNAO. Charged particles are easy to detect and can be back-tracked to the emission point with high efficiency in an almost background-free environment. These fragments are the product of projectiles fragmentation, and are hence mainly produced along the beam path inside the patient. This experimental signature can be used to monitor the beam position in the plane orthogonal to its flight direction, providing an online feedback to the beam transverse position monitor chambers used in the clinical centres. This information could be used to cross-check, validate and calibrate, whenever needed, the information provided by the ion chambers already implemented in most clinical centres as beam control detectors. In this paper we study the feasibility of such strategy in the clinical routine, analysing the data collected during the clinical trial performed at the CNAO facility on patients treated using 12C ions and monitored using the Dose Profiler (DP) detector developed within the INSIDE project. On the basis of the data collected monitoring three patients, the technique potential and limitations will be discussed

Attivit\ue0 fisica e comportamento sedentario

Regular exercise significantly affects the quality of life, improving both the physical and psychological state of health and reducing the risk of general mortality. Regular exercise produces numerous physiological benefits, with the subsequent reduction in the risk of insurgence of serious pathologies, such as cardiovascular diseases, diabetes, obesity, some types of tumours and osteoarticular diseases. The literature advises children and adolescents to do from 30 to 60 minutes of moderate physical exercise for a few days a week and recommends avoiding long periods of inactivity. Results At the regional level: \u2022 the percentages of those who carry out exercise for at least one hour, 5 or more days a week, are similar, being 31% for the stratum of 11-year olds, 33% for that of 13-year olds, and about 27% for the stratum of 15-year olds; \u2022 in general, the analysis of data has found that 15-year olds are less active, and gender comparison has shown that the most inactive are girls in all three strata. Nonetheless, among girls, those who report doing physical exercise most regularly are the 13-year-olds (39%); \u2022 during school days 12% of 11-year olds, 20.3% of 13-year olds and 19% of 15- year olds watch television for more than 4 hours a day. The numbers increase if weekends are taken into account; in relation to the gender difference, only in the 11-year old stratum does the phenomenon have a strictly male tendency - in the other two strata there are no significantly statistical differences; \u2022 the largest percentage of 15-year olds report doing homework during the week (35.4%), followed by 13-year olds (32.5%) and 11-year olds (30.7%); those who spend 3 or more hours doing this type of sedentary activity are notably girls, and the rather large gap between boys and girls tends to increase with age; at weekends, the estimates decrease in all three strata of the sample. Comments Data comparing exercise carried out in the last 7 days and during a normal week show little variation, and this indicates reliable answers to the questionnaires. In relation to sedentary activity in front of the TV, at weekends the rate increases more in the first two strata. Maybe 15-year olds have other things to do such as going to the discoteque on Sunday afternoon, or other forms of enjoyment which do not involve huge amounts of time in front of the TV screen. Girls are more interested in homework than boys, in particular 13-year old and 15-year olds

Adapted Physical Activity Protocol for Lower Limb Functional and Strength Recovery in a Young Athlete with Cutaneous Melanoma: Feasibility and Efficacy during COVID-19 Pandemic

Adapted physical activity (APA) can improve psychophysical wellbeing and quality of life (QoL) in cancer survivors, a vulnerable population requiring a global management, especially during the recent pandemic. On this basis, we investigated for the first time the impact of a tailored APA intervention on a melanoma-affected 18-year-old female athlete to counteract treatment sequelae and promote lower limb functional and strength recovery. Patient was evaluated at baseline and post-protocol by a test battery focusing on mobility, muscle strength measured by dynamometry, and lower limb girths assessed at specific anatomical points. Moreover, health-related QoL, depression/anxiety, psychological distress and pain intensity were evaluated by Functional Assessment of Cancer Therapy–Melanoma (FACT-M), Hospital Anxiety and Depression Scale (HADS), distress thermometer, and numerical rating scale (NRS) questionnaires, respectively. An almost doubled up increase in lower limb strength, along with hip mobility improvement, and post-surgical edema and pain reduction were observed following the protocol. Concerning the QoL assessment, a moderate post-intervention improvement in physical and emotional wellbeing was detected, while depression state worsened though remaining within the normality range. Our findings show that a specialist-supervised structured APA protocol based on a patient-centered multidisciplinary approach may represent an effective strategy to recover functional and psychophysical efficiency, thus promoting a quick return to daily life activities and offering a concrete chance of resuming competitive sport practice

BRCA test: what is the correct timing for surgery?

[not available

Breast cancer and gastrointestinal metastasis. A case report and review of the literature

Introduction: Invasive lobular cancer (ILC) is the second most common type of a heterogeneous group of different histological types of invasive breast carcinoma. Breast cancer can metastatize anywhere, the most common sites are bones, liver, lungs and brain. Gastrointestinal tract (GI) metastases observed in autopsy studies account for about 6% to 18% of the overall metastases from breast cancer. Objective: We describe a 54-year old woman with recurrent ILC in the contralateral breast. She underwent right mastectomy 16 years before. After symptomatic presentation a duodenal invasion was found and subjected to diagnostic scrutiny (FDG PET/CT, diagnostic CT, MR, EGDS). In particular, we analyse if FDG PET/CT is enough accurate in the restaging of the patient. A review of our database and of the literature of similar cases were made. Results: In this patient CT and RM were suspicious for a slow developing process of the duodenum but FDG PET/CT did not show pathological uptake in the affected duodenal tract. A highly intense focus was described in a cervical lymph node, that there isn't metastatic lesion, whereas the recurrent breast lesion had only slight increased glycolytic activity. CONCLUSION: Metastatic lobular carcinoma of the breast is a rare entity with a heterogeneous range of clinical presentations. Detection of eventual gastrointestinal metastases are complicated to assess. ILC has various scale of glycolytic activity both in the primary lesion as well in the metastatic foci. When the level of suspicion is high and there is no uptake of FDG, further investigations are necessary