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A one-year-old French Bulldog was referred for the management of a severe form of pulmonary valve stenosis (PS) complicated by right-sided congestive heart failure. Echocardiography showed severe valvular PS with right ventricular concentric hypertrophy, dilatation and severe right atrial enlargement. A pulmonary balloon valvuloplasty (PBV) was performed with a balloon-to-pulmonary annulus ratio of 1.36. Echocardiography immediately after PBV showed a significant reduction in right atrial and ventricular size, improved opening and mobility of the pulmonary valve leaflets, and a 75% reduction in the pulmonary pressure gradient from 158 mmHg pre-operative to 40 mmHg post-operative. The dog recovered well from anesthesia, but 2 h later, it suddenly showed severe respiratory distress. Focus cardiac ultrasound showed increased left cardiac size with echocardiographic signs of high left ventricular filling pressure. Bedside lung ultrasound showed diffuse numerous-to-confluent B lines, compatible with a severe alveolar-interstitial syndrome. The dog was treated with furosemide, helmet continuous positive airway pressure, and then mechanical ventilation but without success. At post-mortem evaluation, histological examination of the lung showed diffuse, severe broncho-alveolar edema with mixed leukocyte, fibrin, and red blood cell infiltrate. Moreover, severe congestion and multifocal alveolar hemorrhages were evident. All findings were compatible with fatal acute lung injury after PBV secondary to pulmonary reperfusion-ischemia injury and increased pulmonary capillary hydrostatic pressure. Based on the present case, acute lung injury should be considered as a rare but serious complication of PBV. [ABSTRACT FROM AUTHOR]

• The sensitivity to beam quality variations of a miniaturized TEPC is studied. • Microdosimetric spectra taken in two proton beams of similar quality are compared. • Microdosimetric mean values highlight changes in track- and dose-averaged LET. • The calibrated microdosimetric RBE is consistent with cell survival data. This work aims at studying the sensitivity of a miniaturized Tissue-Equivalent Proportional Counter to variations of beam quality in clinical radiation fields, to further investigate its performances as radiation quality monitor. Measurements were taken at the CATANA facility (INFN-LNS, Catania, Italy), in a monoenergetic and an energy-modulated proton beam with the same initial energy of 62 MeV. PMMA layers were placed in front of the detector to measure at different depths along the depth-dose profile. The frequency- and dose-mean lineal energy were compared to the track- and dose-averaged LET calculated by Monte Carlo simulations. A microdosimetric evaluation of the Relative Biological Effectiveness (RBE) was performed and compared with cell survival experiments. Microdosimetric distributions measured at identical depths in the two beams show spectral differences reflecting their different radiation quality. Discrepancies are most evident at depths corresponding to the Spread-Out Bragg Peak, while spectra at the entrance and in the dose fall-off regions are similar. This can be explained by the different energy components that compose the pristine and spread-out peaks at each depth. The trend of microdosimetric mean values matches that of calculated LET averages along the entire penetration depth, and the microdosimetric estimation of RBE is consistent with radiobiological data not only at 2 Gy but also at lower dose levels, such as those absorbed by healthy tissues. The mini-TEPC is sensitive to differences in radiation quality resulting from different modulations of the proton beam, confirming its potential for beam quality monitoring in proton therapy. [ABSTRACT FROM AUTHOR]

Highlights • Monte Carlo approaches to calculate the Survival Fraction in clinical proton beam. • Computational method based to coupling Geant4 and LEM-III. • Computational method based to a parametrized approach. • Comparison with experimental data of two cell lines acquired at LNS-INFN. Abstract Purpose The Geant4 Monte Carlo simulation toolkit was used to reproduce radiobiological parameters measured by irradiating three different cancerous cell lines with monochromatic and clinical proton beams. Methods The experimental set-up adopted for irradiations was fully simulated with a dedicated open-source Geant4 application. Cells survival fractions was calculated coupling the Geant4 simulations with two analytical radiobiological models: one based on the LEM (Local Effect Model) approach and the other on a semi-empirical parameterisation. Results was evaluated and compared with experimental data. Results and conclusions The results demonstrated the Geant4 ability to reproduce radiobiological quantities for different cell lines. [ABSTRACT FROM AUTHOR]

Highlights • Laser-driven beams as alternative source for hadrontherapy applications. • Monte Carlo simulations of the ELIMED beam line for optically accelerated beams. • Spatial dose distributions optimization at the irradiation point. • Calculation of dose delivered per shot for energies of clinical relevance. Abstract The main purpose of this paper is to quantitatively study the possibility of delivering dose distributions of clinical relevance with laser-driven proton beams. A Monte Carlo application has been developed with the Geant4 toolkit, simulating the ELIMED (MEDical and multidisciplinary application at ELI-Beamlines) transport and dosimetry beam line which is being currently installed at the ELI-Beamlines in Prague (CZ). The beam line will be used to perform irradiations for multidisciplinary studies, with the purpose of demonstrating the possible use of optically accelerated ion beams for therapeutic purposes. The ELIMED Geant4-based application, already validated against reference transport codes, accurately simulates each single element of the beam line, necessary to collect the accelerated beams and to select them in energy. Transversal dose distributions at the irradiation point have been studied and optimized to try to quantitatively answer the question if such kind of beam lines, and specifically the systems developed for ELIMED in Prague, will be actually able to transport ion beams not only for multidisciplinary applications, such as pitcher-catcher nuclear reactions (e.g. neutrons), PIXE analysis for cultural heritage and space radiation, but also for delivering dose patterns of clinical relevance in a future perspective of possible medical applications. [ABSTRACT FROM AUTHOR]

Highlights • The relative biological effectiveness along Bragg peak is not constant. • Our GEANT 4 application uses DICOM images to define target. • A GEANT 4 application to support future RBEin vivostudies was developed. • The mean linear energy transfer of each treatment configurations was studied. • Our approach is a good way to improve radiation protocols in animal science. Abstract Preclinical studies represent an important step towards a deep understanding of the biological response to ionizing radiations. The effectiveness of proton therapy is higher than photons and, for clinical purposes, a fixed value of 1.1 is used for the relative biological effectiveness (RBE) of protons considered 1.1. Recent in vitro studies have reported that the RBE along the spread-out Bragg peak (SOBP) is not constant and, in particular, the RBE value increases on the distal part of SOBP. The present work has been carried-out in the perspective of a preclinical hadrontherapy facility at LNS-INFN and was focused on the experimental preparation of an in vivo study concerning the RBE variation along the SOBP. The main purpose of this work was to determine, using GEANT4-based Monte Carlo simulations, the best configuration for small animal treatments. The developed GEANT4 application simulates the proton-therapy beam line of LNS-INFN (CATANA facility) and allows to import the DICOM-CT images as targets. The RBE will be evaluated using a deterministic radiation damage like myelopathy as end-point. In fact, the dose at which the 50 % of animals will show the myelopathy is supposed to be LET-dependent. In this work, we studied different treatment configurations in order to choose the best two that maximize the LET difference reducing as much as possible the dose released to healthy tissue. The results will be useful to plan hadrontherapy treatments for preclinical in vivo studies and, in particular, for the future in vivo RBE studies. [ABSTRACT FROM AUTHOR]

Summary Aim of the study Current criteria for hepatic resection in patients with hepatocellular carcinoma (HCC) according to Barcellona Clinic Liver Cancer (BCLC) classification is debated. Actually, patients with multinodular or large HCC > 5 cm are excluded from surgical treatment following the algorithm, but several studies from referral centers showed that such patients may benefit from surgical resection in the clinical practice. The aim of this study was to compare short- and long-term outcomes after liver resection for HCC in stage 0/A or B in a middle volume center. Patients and methods Patients were grouped according to BCLC classification. Postoperative mortality, morbidity, overall and disease-free survival, univariate analysis of prognostic factors on survival was analyzed. Results Among 66 surgical procedures in 64 patients included in the study, 41 were BCLC stage 0/A (62.1%) and 25 BCLC stage B (37.9%). The overall 30- and the 90-days mortality rates were 1.5% and 3%. Patients in BCLC stage B had higher transfusion rate ( P = 0.04) but similar morbidity and mortality compared to patients in BCLC stage 0/A. After a median follow-up of 35 months (range: 14–147), the overall survival at 1, 3 and 5 years resulted 95%, 61.1%, 46.2% for stage 0–A and 83.3%, 50%, 41.2% for stage B ( P = 0.73). Univariate analysis identified poorly differentiated tumors ( P = 0.02) and positive margin ( P = 0.02) as negative prognostic factors on survival. Conclusions Surgical treatment of HCC in BCLC stage B offers similar results than the ones in BCLC stage 0/A and consequently should not be considered contraindicated for such patients. [ABSTRACT FROM AUTHOR]

Purpose The aim of this paper is to investigate the limits of LET monitoring of therapeutic carbon ion beams with miniaturized microdosimetric detectors. Methods Four different miniaturized microdosimeters have been used at the 62 MeV/u 12 C beam of INFN Southern National Laboratory (LNS) of Catania for this purpose, i.e. a mini-TEPC and a GEM-microdosimeter, both filled with propane gas, and a silicon and a diamond microdosimeter. The y - D (dose-mean lineal energy) values, measured at different depths in a PMMA phantom, have been compared with LET ¯ D (dose-mean LET) values in water, calculated at the same water-equivalent depth with a Monte Carlo simulation setup based on the GEANT4 toolkit. Results In these first measurements, no detector was found to be significantly better than the others as a LET monitor. The y - D relative standard deviation has been assessed to be 13% for all the detectors. On average, the ratio between y - D and LET ¯ D values is 0.9 ± 0.3, spanning from 0.73 ± 0.08 (in the proximal edge and Bragg peak region) to 1.1 ± 0.3 at the distal edge. Conclusions All the four microdosimeters are able to monitor the dose-mean LET with the 11% precision up to the distal edge. In the distal edge region, the ratio of y - D to LET ¯ D changes. Such variability is possibly due to a dependence of the detector response on depth, since the particle mean-path length inside the detectors can vary, especially in the distal edge region. [ABSTRACT FROM AUTHOR]

Microvascular invasion(MVI) is the main risk factor for overall mortality and recurrence after surgery for hepatocellular carcinoma(HCC). Its diagnosis can be made only postoperatively on the histological specimen. to train machine-learning models to predict MVI on preoperative CT scan (fig.1). Clinical data and 3-phases CT scans were retrospectively collected among 4 Italian centres. After an initial manual segmentation, an algorithm was developed to automatically identify the liver and the tumor on CT scans. Radiomics features were automatically extracted from the tumoral, peritumoral and healthy liver areas in each phase. Principal component analysis (PCA) was performed to reduce the dimensions of the dataset. Data were divided between training (70%) and test (30%) sets. Random-Forest (RF), fully connected Artificial neural network (neuralnet) and extreme gradient boosting (XGB) models were fitted to predict MVI. Hyperparameters tuning was made to reduce the out-of-bag error. Between 2008 and 2022, 218 consecutive preoperative CT scans of patients affected by HCC and submitted to surgery were collected. At the histological specimen 33.02% patients had MVI. The Jaccard index between manual and algorithm segmentations was 90%. First and second order radiomics features were extracted, obtaining 672 variables per patient. PCA selected 58 dimensions explaining >95% of the variance. After standardization and normalization, RF, neuralnet and XGB were fitted to predict the presence of MVI. Tuning parameters were: 1) RF: n.tree=500, mtry=30; 2) Neuralnet: 2 hidden layer with 40 and 20 neurons, learning rate= 0.001, threshold for termination= 1%, activation function= sigmoid; 3) XGB: nrounds = 100, max_depth = 3, eta = 0.3. The models were then fitted in the testset to estimate prediction accuracy by confusion-matrix. RF was the best performer (Acc=98.4%, 95%CI: 0.91-0.99, Sens: 95.2%, Spec: 100%, PPV: 100% and NPV: 97.7%, fig.2). RF model predicted automatically MVI with a never-before reached accuracy [ABSTRACT FROM AUTHOR]

The 2022 version of the BCLC staging system recommends a treatment stage migration from liver transplantation (LT) directly to trans-arterial chemo-embolization (TACE) in patients with multinodular early stage HCC, when LT is not feasible. We sought to compare the effectiveness of liver resection (LR), percutaneous radiofrequency ablation (PRA), and TACE in patients with not transplantable but potentially resectable multinodular early HCC. Only multinodular not transplantable early stage (2 or 3 nodules ≤3 cm) HCC patients were considered. LR patients were obtained from the HE.RC.O.LE.S. register, whereas PRA and TACE patients were obtained from the ITA.LI.CA register. Since the aim of this study was to compare the effectiveness of three potential treatments in resectable patients, the statistical method "matching-adjusted indirect comparison" (MAIC) was used to match the PRA and TACE groups to the LR group. Between 2008 and 2020, 655 HCC cirrhotic patients were enrolled: 303 in LR, 204 in PRA, and 148 in TACE groups. Age, sex, Charlson Comorbidity index, Child-Pugh grade, MELD, platelets count, aetiology of cirrhosis, number and diameter of nodules, and alpha-fetoprotein were weighted by MAIC to create two PRA and TACE pseudo-populations balanced with the LR group. After MAIC, 1-3-5 years OS was 88%, 71%, 56% for LR (median survival 67 months), 97%, 63%, 22% for PRA (median survival 53 months), and 88%, 58%, 32% for TACE (median survival 41 months)(P < 0.001). At Cox multivariable weighted regression, the survival benefit of LR over alternative treatments was confirmed: LR group as reference; PRA (hazard ratio 1.44; 95% confidence interval 1.19-1.84; P = 0.0045); TACE (hazard ratio 1.70; 95% confidence interval 1.25-2.31; P = 0.0007). In multinodular early not transplantable HCC, LR should be the first option, followed by PRA and TACE only when LR is not feasible. [ABSTRACT FROM AUTHOR]

Abstract: Goal: Proton treatment monitoring with Positron-Emission-Tomography (PET) is based on comparing measured and Monte Carlo (MC) predicted β+ activity distributions. Here we present PET β+ activity data and MC predictions both during and after proton irradiation of homogeneous PMMA targets, where protons were extracted from a cyclotron. Methods and materials: PMMA phantoms were irradiated with 62 MeV protons extracted from the CATANA cyclotron. PET activity data were acquired with a 10 × 10 cm2 planar PET system and compared with predictions from the FLUKA MC generator. We investigated which isotopes are produced and decay during irradiation, and compared them to the situation after irradiation. For various irradiation conditions we compared one-dimensional activity distributions of MC and data, focussing on Δw50%, i.e., the distance between the 50% rise and 50% fall-off position. Results: The PET system is able to acquire data during and after cyclotron irradiation. For PMMA phantoms the difference between the FLUKA MC prediction and our data in Δw50% is less than 1 mm. The ratio of PET activity events during and after irradiation is about 1 in both data and FLUKA, when equal time-frames are considered. Some differences are observed in profile shape. Conclusion: We found a good agreement in Δw50% and in the ratio between beam-on and beam-off activity between the PET data and the FLUKA MC predictions in all irradiation conditions. [Copyright &y& Elsevier]

Abstract: A 57-year-old woman presented with fever, vomiting and arthralgia, with a history of rheumatoid arthritis. Laboratory tests showed leucocytes, anaemia and elevation of C-reactive-protein (CRP). Blood cultures were positive for Gram negative bacteria and Streptococcus viridans. Patient underwent abdominal Computed Tomography (CT) scan revealing sigmoid acute diverticulitis with peridiverticular abscesses and thrombophlebitis within the inferior mesenteric and portal veins. She started antibiotic and anticoagulant therapy. After 20 days, a second CT revealed a thrombosis involving the superior mesenteric vein also. After 22 days of therapy the patient was discharged with the resolution of the septic status. Two months after discharge the patient underwent left hemicolectomy for a histopathologically documented diverticulitis with an uneventful postoperative course. This is a description of a rare association of septic thrombosis within the portal, inferior mesenteric and superior mesenteric veins during acute sigmoid diverticulitis with abdominal abscesses. Our therapeutic strategy was a first line medical approach and delayed surgery. [Copyright &y& Elsevier]

• In real life, DMF reduced the annualized relapse rate (ARR) by 75% respect to the pre-treatment ARR. • Age of onset of MS was related with rate or relapses, with younger age being protective. • De-escalating from second-line therapies was associated to higher risk of relapsing. • Disease duration was associated with higher rate of NEDA-3 failure. • Higher pre-treatment EDSS was associated with DMF discontinuation. Dimethyl-fumarate (DMF) was effective and safe in relapsing–remitting multiple sclerosis (MS) in randomized clinical trials. We aimed to evaluate the efficacy and safety of DMF and factors related to drug response in real-life setting. We analysed prospectively collected demographic and clinical data for patients treated with DMF in six multiple sclerosis (MS) centers from 2015 to 2017 in Campania region, Italy. We performed univariate and multivariate analyses to assess relationships between baseline parameters and DMF efficacy outcomes, Annualized Relapse Rate (ARR), Expanded Disability Status Scale (EDSS) progression and No Evidence of Disease Activity (NEDA-3) status. we analyzed data of 456 patients (67% female subjects, mean age 40 ± 12 years, mean disease duration 9 ± 9 years, mean treatment duration 18 ± 11 months, median EDSS 2.5, 0–8). Proportion of Naïve versus pretreated with other DMTs patients was 149/307 (32.7%), with 122 patients switching to DMF for disease activity (26.7%) and 185 for safety and tolerability issues (40.6%). During treatment with DMF, the annualized relapse rate was reduced by 75% respect to the pre-treatment ARR [incidence-rate-ratio (IRR) = 0.25, p < 0.001, CI 0.18–0.33]. Factors influencing ARR rate while on DMF were relapsing remitting (RR) MS course (IRR = 2.0, p = <0.001, CI 1.51–2.73) and previous DMTs status: de-escalating from second-line therapies was associated to higher risk of relapsing (IRR = 1.8, p < 0.001, CI 1.39–2.31). At multivariable Cox proportional hazard model, only age of onset was related with rate or relapses, with younger age being protective (HR 0.96, p = 0,02). EDSS remained stable in 88% of patients. Disease duration was associated with higher rate of NEDA-3 failure, that was instead maintained in 65% of patients at 24 months. 109 patients (22%) discontinued therapy after a mean of 1.1 ±+ 0.7 years. Reasons for DMF discontinuation over time were lack of efficacy (50%), safety issues (30%), tolerability (7%), poor compliance (7%), and pregnancy (4%). Higher pre-treatment EDSS was associated with DMF discontinuation (p = 0.009). Only 33 patients dropped out due to safety reasons (7%), the most frequent safety issues driving to drop out being lymphopenia, liver/pancreatic enzymes increase, gatrointestinal severe tolerability issues. We recorded 95 cases (24%) of lymphopenia: 60 grade I (13%), 31 grade II (7%) and 4 grade III (1%). We confirm that DMF shows a good efficacy in both naïve patients and patients switching from other first-line DMTs, especially in patients with early onset of disease. Higher baseline EDSS was a risk factor for discontinuing DMF therapy, while shorter disease duration was protective for both EDSS progression and NEDA-3 status maintenance. [ABSTRACT FROM AUTHOR]

To evaluate the efficacy of a total surgical treatment of ectopic cervical pregnancy, with a minimally invasive approach performed by hysteroscopy. Step-by-step video demonstration of the surgical technique using 5 mm hysteroscopy followed by 10 mm resectoscopy. 41-year-old woman with an US diagnosis of ectopic cervical pregnancy at 6+6 weeks of gestation with β hCG serum level of 55.951 mUI/mL We performed a two steps technique using 5 and 10 mm hysteroscopy. The study was approved by the Institutional Review Board. During the first step a 5 mm Bettocchi hysteroscope (Storz) with 5 Fr bipolar electrode Versapoint Twizzle, (Gynecare) was used. In this phase, the gestational sac was identified in order to confirm the diagnosis and its site of implantation. Later the gestational sac was opened and the pregnancy terminated by cord section under embryoscopic view. Finally, was performed a partial vessels coagulation. Afterwards the cervix was dilated and a resectoscopy performed. During the second step, a 10 mm GYNECARE resectoscope with bipolar GYNECARE VERSAPOINT™ was used. In this phase as first the gestational sac with embryo was removed, subsequently, a complete chorial villi resection was achieved. At last, a coagulation of bleeding vessels on implantation site, in order to control the hemostasis, was performed. The patient was discharged 24 h after the procedure. The β hCG serum level became negative in 20 days. After 40 days ultrasound cervical findings were regular. After five months the patient was pregnant with regular intrauterine implantation. The total hysteroscopic approach with a two steps technique offers an effective, safe and minimally invasive surgical treatment to ectopic cervical pregnancy. Considering that this approach without any medical treatment is reported for the first time in literature, more clinical data are needed to confirm these findings. [ABSTRACT FROM AUTHOR]