Dose and DNA damage modelling of diffusing alpha-emitters radiation therapy using Geant4.

PURPOSE: Diffusing alpha-emitters radiation therapy (DaRT) is a brachytherapy technique using α-particles to treat solid tumours. The high linear energy transfer (LET) and short range of α-particles make them good candidates for the targeted treatment of cancer. Treatment planning of DaRT requires a good understanding of the dose from α-particles and the other particles released in the 224Ra decay chain. METHODS: The Geant4 Monte Carlo toolkit has been used to simulate a DaRT seed to better understand the dose contribution from all particles and simulate the DNA damage due to this treatment. RESULTS: Close to the seed α-particles deliver the majority of dose, however at radial distances greater than 4 mm, the contribution of ß-particles is greater. The RBE has been estimated as a function of number of double strand breaks (DSBs) and complex DSBs. A maximum seed spacing of 5.5 mm and 6.5 mm was found to deliver at least 20 Gy RBE weighted dose between the seeds for RBEDSB and RBEcDSB respectively. CONCLUSIONS: The DNA damage changes with radial distance from the seed and has been found to become less complex with distance, which is potentially easier for the cell to repair. Close to the seed α-particles contribute the majority of dose, however the contribution from other particles cannot be neglected and may influence the choice of seed spacing.

Electron contamination suppression in transmission detectors for radiotherapy.

Objective.Higher energy and intensity radiotherapy beams are being used, in part, due to the increased spatial accuracy of treatments. However, higher intensity beams can result in a larger total dose error, motivating the increasing need for real-time dose monitoring. We are developing a thin, real-time upstream monolithic active pixel sensor based system for beam monitoring with excellent precision on measuring the beam shape. Here we present a method to additionally provide dosimetry by adding thin conversion material in strips to the surface of the detector, a grating structure.Approach.By modulating the thickness of the conversion material to minimally disturb the contamination electron signal while enhancing the photon signal, the difference in these signals can be used to extract a photon-only signal, and hence dose. The simulation software Gate, based on Geant4, is utilised to study whether well functioning gratings can be better made from aluminium or copper and to optimise the thickness of a copper grating.Main results.It is possible to enhance the photon signal by a factor 6.7 (7.7) compared to the bare sensor for a 5.8 (6.7) MV beam, without modulation of the signal due to beam electrons.Significance.The grating can be used to perform dosimetry in real-time using a thin upstream detector.

In-silico calculations of DNA damage induced by α-particles in the 224Ra DaRT decay chain for a better understanding of the radiobiological effectiveness of this treatment.

Diffusing alpha-emitters radiation Therapy (DaRT) is an interstitial brachytherapy technique using 224Ra seeds. For accurate treatment planning a good understanding of the early DNA damage due to α-particles is required. Geant4-DNA was used to calculate the initial DNA damage and radiobiological effectiveness due to α-particles with linear energy transfer (LET) values in the range 57.5-225.9 keV/µm from the 224Ra decay chain. The impact of DNA base pair density on DNA damage has been modelled, as this parameter varies between human cell lines. Results show that the quantity and complexity of DNA damage changes with LET as expected. Indirect damage, due to water radical reactions with the DNA, decreases and becomes less significant at higher LET values as shown in previous studies. As expected, the yield of complex double strand breaks (DSBs), which are harder for a cell to repair, increases approximately linearly with LET. The level of complexity of DSBs and radiobiological effectiveness have been found to increase with LET as expected. The quantity of DNA damage has been shown to increase for increased DNA density in the expected base pair density range of human cells. The change in damage yield as a function of base pair density is largest for higher LET α-particles, an increase of over 50% for individual strand breaks between 62.7 and 127.4 keV/µm. This change in yield shows that the DNA base pair density is an important parameter for modelling DNA damage particularly at higher LET where the DNA damage is greatest and most complex.

Performance of a Full-Scale Upstream MAPS-Based Verification Device for Radiotherapy.

Intensity-modulated radiotherapy is a widely used technique for accurately targeting cancerous tumours in difficult locations using dynamically shaped beams. This is ideally accompanied by real-time independent verification. Monolithic active pixel sensors are a viable candidate for providing upstream beam monitoring during treatment. We have already demonstrated that a Monolithic Active Pixel Sensor (MAPS)-based system can fulfill all clinical requirements except for the minimum required size. Here, we report the performance of a large-scale demonstrator system consisting of a matrix of 2 × 2 sensors, which is large enough to cover almost all radiotherapy treatment fields when affixed to the shadow tray of the LINAC head. When building a matrix structure, a small dead area is inevitable. Here, we report that with a newly developed position algorithm, leaf positions can be reconstructed over the entire range with a position resolution of below ∼200 µm in the centre of the sensor, which worsens to just below 300 µm in the middle of the gap between two sensors. A leaf position resolution below 300 µm results in a dose error below 2%, which is good enough for clinical deployment.

"Starry liver" - Von Meyenburg complex clinical case presentation and differential diagnosis discussion: A case report.

BACKGROUND: Von Meyenburg complex (VMC) (i.e., biliary hamartoma) is a rare congenital disorder characterized by multiple dilated cystic bile ducts, without clear trends in sex or age predominance. Due to the low number of published cases and the lack of recognized guidelines, the management of such patients remains a clinical challenge. CASE SUMMARY: We present a case of symptomatic VMC that was diagnosed after imaging and histopathological examinations. Considering the patient's condition, a conservative treatment strategy was chosen. Instrumental, laboratory, and clinical follow-up demonstrated the stable condition of the patient receiving conservative treatment. CONCLUSION: VMC is a potentially non-life threatening condition, but its recognition is crucial for the management of patients.

Bedside ultrasound as a screening test for the diagnosis of catheter-related bloodstream infection (CRBI).

PURPOSE: Between 15 and 30% of all nosocomial bacteremias and sepsis are associated with the use of intravascular devices. Catheter-related bloodstream infections (CRBI) are infections in which the organism identified in the blood is also present on the tip of the catheter itself or in a blood sample taken through it. The aim of the study was to evaluate the role of ultrasound in the diagnosis of infections related to the use of central catheters. METHODS: Between January 2018 and June 2019, we carried out a prospective study on 36 patients with a central catheter, such as a central venous catheter (CVC), a central catheter with peripheral insertion (PICC), or a fully implanted central venous catheter (PORT-a-cath) and who had signs and symptoms of infection. These patients were submitted to an ultrasound of the catheter upon arrival in the ward in case of suspected infection, or at the time of the onset of signs and symptoms of infection (if these arose during hospitalization). Patients with a central catheter but without signs and symptoms of infection were not included in the study. The end point of the study was to evaluate sensitivity (SENS), specificity (SPEC), positive and negative predictive value (PPV-NPV) and overall diagnostic accuracy (ODA) of ultrasound in the diagnosis of CRBI through Receiver Operating Characteristic (ROC) curve analysis. RESULTS: US showed a SENS of 94%, a SPEC of 84%, a PPV of 84%, an NPV of 94% and an ODA of 88.8% for the diagnosis of CRBI. CONCLUSIONS: Preliminary data from our study show that US of intravascular devices has a high SENS and SPEC in the diagnosis of CRBI, and can, therefore, be used as a valid tool to decide whether to remove the device early or leave it in place.

Lung ultrasound as diagnostic tool for SARS-CoV-2 infection.

The aim of this study was to explore the role of lung ultrasound (LUS) in the diagnosis of SARS-CoV-2 infection and to verify its utility in the prediction of lung disease's severity and outcome. Fifty-three consecutive patients presenting to the Emergency Department of Santa Maria delle Grazie Hospital with high suspicion of SARS-CoV-2 infection underwent diagnostic test for SARS-CoV-2 on samples obtained from nasopharyngeal swab as well as complete proper diagnostic work-up that included clinical evaluation, laboratory tests, blood gas analyses, chest CT and LUS. A semiquantitative analysis of B-lines distribution was performed to calculate the LUS score. Patients were divided into two groups according to the results of both SARS-CoV-2 diagnostic test and other exams (Group A = pneumonia due to SARS-CoV2 infection vs Group B = no SARS-CoV2 infection and another definite diagnosis). LUS showed an excellent accuracy in predicting the diagnosis of SARS-CoV-2 infection (area under the ROC curve of 0.92 with a sensibility of 73% and a specificity of 89% a the cut-off of 12.5). LUS score was more impaired in SARS-CoV-2 patients (18.1 ± 6.0 vs 7.6 ± 5.9, p < 0.00001) and it is significantly negatively correlated with PF ratio values (r = - 0.719, p < 0.0001). An intrahospital mortality rate of 46% was found; patients with adverse outcome had significant higher value of LUS, PF, LDH, and APACHE II score. None of these parameters was predictive of mortality. LUS is a useful tool for the early detection of SARS-CoV-2 infection and for the evaluation of the disease severity, but does not predict mortality. Further studies with repeated evaluations of LUS score are needed to further explore the role of LUS in the assessment of severity in SARS-CoV-2 disease and in the monitoring of the response to treatments.

Aspirin in a diabetic retinopathy setting: Insights from NO BLIND study.

BACKGROUND AND AIMS: Diabetic retinopathy (DR) is the most common microvascular complication of diabetes. Diabetic macroangiopathies, particularly cardiovascular (CV) diseases, seem closely related to diabetes microvascular complications. Aspirin represents the most prescribed compound in CV prevention. Aspirin impact on DR is still object of debate. As it is already recommended among diabetics at high CV risk, aim of this study was to assess a potential relationship between DR and aspirin therapy, in a type 2 diabetes cohort of patients screened through telemedicine. METHODS AND RESULTS: NO Blind is a cross-sectional, multicenter, observational study, which involved nine Italian outpatient clinics. Primary endpoint was the assessment of the relationship between aspirin treatment and DR. 2068 patients were enrolled in the study, subsequently split in two subpopulations according to either the presence or absence of DR. Overall, 995 subjects were under aspirin therapy. After adjusting for most common potential confounders, age and gender, aspirin reveals significantly associated with DR (OR: 1.72, 95%CI: 1.58-2.89, p = 0.002) and proliferative DR (PDR) (OR: 1.89, 95%CI: 1.24-2.84, p = 0.003). Association comes lost further adjusting for MACEs (OR: 1.28, 95%CI: 0.85-1.42, p = 0.157) (Model 4) and eGFR (OR: 0.93; 95%CI: 0.71-1.22; p = 0.591) (Model 5). CONCLUSION: In this multicenter cross-sectional study including a large sample of outpatients with T2DM, we showed that aspirin was not associated with DR after adjustment for several cardio-metabolic confounders. However, as partially confirmed by our findings, and related to the well-known pro-hemorrhagic effect of aspirin, its use should be individually tailored, even by telemedicine tools.

First muography of Stromboli volcano.

Muography consists in observing the differential absorption of muons - elementary particles produced through cosmic-ray interactions in the Earth atmosphere - going through the volcano and can attain a spatial resolution of tens of meters. We present here the first experiment of nuclear emulsion muography at the Stromboli volcano. Muons have been recorded during a period of five months by a detector of 0.96 m2 area. The emulsion films were prepared at the Gran Sasso underground laboratory and were analyzed at Napoli, Salerno and Tokyo scanning laboratories. Our results highlight a significant low-density zone at the summit of the volcano with density contrast of 30-40% with respect to bedrock. The structural setting of this part of the volcanic edifice controls the eruptive dynamics and the stability of the "Sciara del Fuoco" slope, which is affected by recurrent tsunamigenic landslides. Periodical imaging of the summit of the Stromboli volcano such as that provided by muography can become a useful method for studying the evolution of the internal structure of the volcanic edifice.

High HDL cholesterol: A risk factor for diabetic retinopathy? Findings from NO BLIND study.

AIMS: To assess the correlation between diabetic retinopathy (DR) and potential risk factors, as well as the relationship between DR and the other complications of diabetes, in a real-life population of type 2 diabetes patients recruited in several centres in Italy. METHODS: The NO BLIND is a cross-sectional, multicentre, observational study, which involved nine public outpatient clinics in Italy. The patients were assessed for eligibility from November 2016 till November 2017. Those enrolled underwent standard fundus oculi exam. Clinical and laboratory data were also collected. RESULTS: 2068 T2DM underwent fundus oculi exam. 435 received diagnosis of diabetic retinopathy (21%). Diabetic retinopathy was independently associated with HDL cholesterol (O.R.: 1.042; 95% C.I.: 1.012-1.109; p = 0.004), Albumin Excretion Rate (AER) (O.R.: 1.001; 95% C.I.: 1.000-1.002; p = 0.034) and GFR (O.R.: 1.159; 95% C.I.: 1.039-1.294; p = 0.008). HDL cholesterol values were hence split in two classes according to a potential cut-off (40 mg/dL), as defined by the ROC curve. Following analysis confirmed the association between DR and high HDL values (p = 0.032). Somatic neuropathy and diabetic ulcer were independently related with DR (p < 0.001 and p = 0.012, respectively). CONCLUSIONS: A novel relationship between high HDL cholesterol and DR was observed.

Telemedicine for screening diabetic retinopathy: The NO BLIND Italian multicenter study.

AIMS: Diabetic retinopathy (DR) represents the main cause of blindness among adults in the industrialized Countries. Use of telemedicine could offer an easy, smart specialist fundus oculi examination, as well as putting in a screening programme many patients who otherwise would be excluded. MATERIALS AND METHODS: The NO BLIND is a transversal, multicentre, observational study. Its pilot phase involved nine public outpatient clinics for 6 months. As endpoint of the study, we assessed the prevalence of DR by retinography in a subset of the Italian population. Patients' fundus oculi photos were performed by trained diabetologists through a digital smart ophthalmoscope. RESULTS: According to our endpoint, in the final study population (n = 1461), obtained excluding patients for whom retinography was not able to provide any diagnosis, DR prevalence was equal to 15.5%. According to the receiver operating characteristic (ROC) curve performed, we can observe how retinography appears a highly accurate method to detect DR (AUROC 0.971, 95% confidence interval, 0.954-0.989), with a specificity of the 100% and a sensitivity of the 94.3%. CONCLUSIONS: Our findings, in an Italian setting, confirm main data in the literature about DR prevalence. Hence, telemedicine could represent an accurate, fast, and cheap method for screening of DR.

Atrial fibrillation following therapy with high-dose i.v. methylprednisolone: A brief case-based review.

Atrial fibrillation following high-dose i.v. steroids for treatment of severe immune-mediated diseases has been rarely reported in the literature. Here we report a further case of atrial fibrillation following high-dose i.v. methylprednisolone (HDIVMP) therapy of severe thrombocytopenia in a female patient with a flare-up of systemic lupus erythematosus (SLE). The available literature on this topic is reviewed as well.

Optimized contrast-enhanced ultrasonography for characterization of focal liver lesions in cirrhosis: A single-center retrospective study.

BACKGROUND: Hepatocellular carcinoma (HCC) is the leading cause of death amongst cirrhotic patients. Its diagnosis and discrimination from non-HCC malignant lesions in cirrhosis includes contrast enhanced computed tomography (CECT), contrast enhanced magnetic resonance imaging (CEMRI), or, in selected cases, liver biopsy. The role of contrast-enhanced ultrasonography (CEUS) is still controversial. AIMS: To evaluate whether, by selecting an appropriate 'time to wash-out' cut-off value, CEUS capability of discriminating between HCC and non-HCC malignancies in cirrhotic patients may be enhanced. METHODS: We enrolled 282 cirrhotic patients who underwent CEUS at our institute, from January 2008 to January 2012, for focal liver lesions (FLLs) detected at ultrasound (US). We used liver biopsy and subsequent histological evaluation as the gold standard for correct classification of FLLs. We calculated the area under receiver operator characteristic curves for CEUS to distinguish patients with HCC from those with non-HCC malignancies. The best 'time to wash-out' cut-off values were selected. RESULTS: HISTOLOGICAL DIAGNOSIS OF FLLS WAS AS FOLLOWS: 34 benign lesions (i.e. 25 regenerative nodules and 9 dysplastic nodules) and 248 malignant lesions (223 well-to-moderately differentiated HCCs; 7 poorly-differentiated HCCs; 5 intrahepatic colangiocellular carcinomas (ICCs); 5 primary non-Hodgkin B-cell lymphomas (NHBLs); and 8 metastatic liver tumors). A time to wash-out > 55 s identified patients with HCC with the highest level of accuracy (92.7%). Similarly, a time to wash-out ≤ 55 s correctly identified the vast majority of the non-HCC malignancies (100% sensitivity, 98.2% specificity and diagnostic accuracy of 98.3%). CONCLUSIONS: CEUS is an accurate and safe procedure for discriminating FLLs in cirrhotic patients, especially when a cut-off time to wash-out of 55 s is chosen as a reference value.

Liver failure in an obese middle-aged woman after biliointestinal bypass.

Obesity is considered an emerging epidemic that is often associated with non-alcoholic fatty liver disease. Among the therapeutic options for morbid obesity, bariatric surgery plays an important role when conventional therapies fail. The effects of bariatric surgery on liver function and morphology are controversial in the literature. Liver failure has been reported after jejunoileal bypass (JIB), biliopancreatic diversion and gastric bypass. Biliointestinal bypass (BIB) is considered an effective procedure among recently introduced bariatric surgery techniques. It is a clinically safe, purely malabsorptive operation in which the blind intestinal loop of the JIB is anastomosed to the gallbladder, allowing a portion of bile to transit into excluded intestinal tract. BIB is the only procedure, to our knowledge, to have no liver side effects reported in the literature. We report the case of a young obese woman who developed liver failure 8 mo after BIB. She had a rapid weight loss (70 kg) with a reduction in body mass index of 41% from January to September 2012. Because of a severe hepatic decompensation, she was referred to a transplantation centre. We strongly believe that the most important pathogenetic mechanism involved in the development of liver injury is the rapid weight loss that produced a significant fatty liver infiltration.