FLASH Proton Radiation Therapy Mitigates Inflammatory and Fibrotic Pathways and Preserves Cardiac Function in a Preclinical Mouse Model of Radiation-Induced Heart Disease.

PURPOSE: Studies during the past 9 years suggest that delivering radiation at dose rates exceeding 40 Gy/s, known as "FLASH" radiation therapy, enhances the therapeutic index of radiation therapy (RT) by decreasing normal tissue damage while maintaining tumor response compared with conventional (or standard) RT. This study demonstrates the cardioprotective benefits of FLASH proton RT (F-PRT) compared with standard (conventional) proton RT (S-PRT), as evidenced by reduced acute and chronic cardiac toxicities. METHODS AND MATERIALS: Mice were imaged using cone beam computed tomography to precisely determine the heart's apex as the beam isocenter. Irradiation was conducted using a shoot-through technique with a 5-mm diameter circular collimator. Bulk RNA-sequencing was performed on nonirradiated samples, as well as apexes treated with F-PRT or S-PRT, at 2 weeks after a single 40 Gy dose. Inflammatory responses were assessed through multiplex cytokine/chemokine microbead assay and immunofluorescence analyses. Levels of perivascular fibrosis were quantified using Masson's Trichrome and Picrosirius red staining. Additionally, cardiac tissue functionality was evaluated by 2-dimensional echocardiograms at 8- and 30-weeks post-PRT. RESULTS: Radiation damage was specifically localized to the heart's apex. RNA profiling of cardiac tissues treated with PRT revealed that S-PRT uniquely upregulated pathways associated with DNA damage response, induction of tumor necrosis factor superfamily, and inflammatory response, and F-PRT primarily affected cytoplasmic translation, mitochondrion organization, and adenosine triphosphate synthesis. Notably, F-PRT led to a milder inflammatory response, accompanied by significantly attenuated changes in transforming growth factor ß1 and α smooth muscle actin levels. Critically, F-PRT decreased collagen deposition and better preserved cardiac functionality compared with S-PRT. CONCLUSIONS: This study demonstrated that F-PRT reduces the induction of an inflammatory environment with lower expression of inflammatory cytokines and profibrotic factors. Importantly, the results indicate that F-PRT better preserves cardiac functionality, as confirmed by echocardiography analysis, while also mitigating the development of long-term fibrosis.

Growth differentiation factor 11 mitigates cardiac radiotoxicity via activating AMPKα.

Cardiac radiotoxicity largely impedes the therapeutic benefits of radiotherapy to malignancies. Growth differentiation factor 11 (GDF11) is implicated in the pathogenesis of cardiac diseases under different pathological conditions. This study aims to investigate the role and underlying mechanisms of GDF11 on cardiac radiotoxicity. Mice were injected with cardiotropic adeno-associated virus 9 carrying the full-length mouse GDF11 gene or negative control under a cTnT promoter from the tail vein, and then received a single dose of 20 Gray (Gy) whole-heart irradiation (WHI) for 16 weeks to imitate cardiac radiotoxicity. Compound C (CC, 20 mg/kg) was intraperitoneally injected every two days at 1 week before WHI stimulation to inhibit 5' AMP-activated protein kinase α (AMPKα). Cardiac GDF11 expression was significantly suppressed at both the protein and mRNA levels. GDF11 overexpression decreased oxidative stress, apoptosis, and fibrosis in radiated hearts, thereby mitigating cardiac radiotoxicity, and dysfunction. Further detection revealed that GDF11 activated AMPKα to reduce radiation-induced oxidative damage and that AMPKα inhibition by CC offset the cardioprotective effects by GDF11. GDF11 mitigates cardiac radiotoxicity via activating AMPKα and it is a promising candidate to treat cardiac radiotoxicity.

MEDiastinal Irradiation and CArdio-Toxic Effects (MEDICATE): Exploring the Relationship between Cardiac Irradiation and High Sensitivity Troponins.

AIMS: Radiation-induced heart disease is a late effect of cardiac irradiation and has been shown in patients with lymphoma and thoracic cancers. There is no established measurement tool to detect acute cardiac damage. However, high sensitivity troponin I and T (HsTnI and HsTnT) and echocardiograms have shown promise in some studies. A pilot trial was conducted to characterise whether these instruments may detect subclinical radiotherapy-induced cardiac damage. MATERIALS AND METHODS: Eligible patients received high cardiac doses defined by either at least 30 Gy to 5% of cardiac volume or a mean dose of 4 Gy. HsTnI and HsTnT were measured before radiotherapy and after 2 and 4 weeks of radiotherapy; three-dimensional echocardiograms were completed before and 1 year after radiotherapy. RESULTS: Of 19 patients, the median 'mean left ventricular dose' was 3.1 Gy and the 'mean cardiac dose' was 8.6 Gy. Significant positive associations between HsTnI and HsTnT were observed at all time points, but there was no significant association with cardiac dose. The mean left ventricular dose and the maximum left ventricular dose were, however, associated with a decrease in ejection fraction (P = 0.054, 0.043) as well as an increase in left ventricular strain (P = 0.058). CONCLUSION: This study suggests that HsTnI and HsTnT are intimately related, but detection of acute cardiac damage was not shown, potentially due to limitations of these markers or low radiotherapy doses using conformal techniques. Our results also suggest subacute damage at 1 year may depend on the dose to the left ventricle. Further studies are needed, as identification of early damage could facilitate the ability to closely monitor and intervene in patients at risk for radiation-induced heart disease.

Dosimetric study to assess the feasibility of intraoperative radiotherapy with electrons (ELIOT) as partial breast irradiation for patients with cardiac implantable electronic device (CIED).

PURPOSE: To report in-vivo dosimetry in the infraclavicular region, a potential site of a cardiac implantable electronic device (CIED) and to evaluate the absorbed dose from intraoperative radiotherapy with electrons (ELIOT). METHODS: 27 non-cardiopathic breast cancer (BC) patients without CIED received quadrantectomy and ELIOT as partial breast irradiation. Before delivering ELIOT, two catheters, each containing eight thermoluminescent dosimeters (TLDs), were positioned in the infraclavicular region. TLDs internal catheter was located deep in the tumor bed while the external catheter was placed on patient's skin. RESULTS: Data were available for 24/27 patients. The absorbed doses were referred to the dose of 21 Gy. Values measured by the external catheter were low, although statistically significant higher doses were found close to the applicator (mean values 0.26-0.49 Gy). External TLD doses in proximity of the applicator were lower than those detected by their internal counterparts. Values measured by the internal catheter TLDs varied according to the distance from the applicator while no correlation with tumor site and beam energy was found. The distance from the applicator to deliver < 2 Gy to a CIED was 2 cm, while from 2.5 cm the dose measured in all the patients became negligible. CONCLUSIONS: This dosimetric study provided data to support the clinical use of ELIOT in BC patients having CIEDs as long as the suggested minimum safe distance of 2.5 cm is taken from the RT field in case of ELIOT single dose of 21 Gy, in the energy range of 6-10 MeV.

An intrapericardial ectopic thyroid mimicking metastasis in a patient with papillary thyroid cancer: Localization, differential diagnosis by 18F-FDG PET/CT and ablation by 131I.

We report a very rare case of incidental intrapericardial thyroid in a papillary thyroid cancer patient. Post ablation scan revealed iodine-131 (131I) uptake in the mid-chest. Fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) was performed and showed a 18F-FDG avid lesion between the right atrium and the ascending aorta, (which was) shown to be an ectopic thyroid and not metastasis. The lesion disappeared on a 6 month follow-up 123I whole body scan while serum thyroglobulin was negative. Although intrapericardial ectopic thyroid is reported to show high iodine uptake, low 18F-FDG avidity of the lesion could be helpful in the exclusion of metastases.

Method for Correction of Consequences of Radiation-Induced Heart Disease using Low-Intensity Electromagnetic Emission under Experimental Conditions.

Effects of successive exposure to ionizing irradiation and low-intensity broadband red light on electrical activity of the heart and myocardium microstructure were studied in rats. Lowintensity red light corrected some ECG parameters, in particular, it normalized QT and QTc intervals and voltage of R and T waves. Changes in ECG parameters were followed by alterations in microstructure of muscle fi laments in the myocardium of treatment group animals comparing to control group.

Estudo dos efeitos da radioterapia no tecido cardíaco e sua associação com o metabolismo energético / Study of the effects of radiation therapy in cardiac tissue and its association with energy metabolism

Durante o tratamento radioterápico para tumores localizados na região torácica, parte do coração frequentemente é incluída no campo de tratamento e pode receber doses de radiação ionizante, significativas em relação à terapêutica. A irradiação do coração é capaz de causar importantes complicações cardíacas ao paciente, caracterizadas por alterações funcionais progressivas cerca de 10 a 20 anos após a exposição do órgão. Devido ao seu alto grau de contração e grande consumo energético, o tecido cardíaco é altamente dependente do metabolismo oxidativo que ocorre nas mitocôndrias. Danos as estas organelas podem levar ao decréscimo da produção de energia, tendo um impacto direto sobre a performance cardíaca. Ainda, ao interagir com as células, a radiação ionizante pode gerar uma série de eventos bioquímicos que conduzem a uma resposta celular complexa, em que muitas proteínas parecem estar envolvidas. Tendo em vista tais conhecimentos, o objetivo do estudo foi avaliar o aspecto ultraestrutural do tecido cardíaco, a bioenergética mitocondrial e a expressão diferencial de proteínas após irradiação. Os ensaios foram realizados em amostras de tecido cardíaco de ratos Wistar irradiados com dose única de 20 Gy direcionada ao coração. As análise tiveram início 4 e 32 semanas após irradiação. A análise ultraestrutural foi realizada através de microscopia eletrônica de transmissão. A respiração mitocondrial foi mensurada em oxígrafo, a partir das taxas de consumo de oxigênio pelas fibras cardíacas. A identificação de proteínas diferencialmente expressas foi investigada através de duas técnicas proteômicas: 2D-DIGE (2-D Fluorescence Difference Gel Electrophoresis) e uma abordagem label-free seguida de espectrometria de massas. Os resultados mostraram que os efeitos tardios da radiação incluem a degeneração das mitocôndrias e das unidades contráteis do tecido cardíaco, disfunções na cadeia respiratória mitocondrial e expressão diferencial de proteínas...

During radiotherapy for tumors located at toracic region, part of the heart is often included in the treatment field and may receive a significant ionizing radiation dose comparing to the therapeutics. Heart irradiation is able to cause substantial cardiac complications to patient, characterized by functional progressive changes from 10 to 20 years after the exposure of the organ. Because of its high level of contraction and large energetic consumption, cardiac tissue is highly depending on oxidative metabolism which happens at mitochondrias. Damage to these organelles can lead to decreased energy production, having a direct impact on cardiac performance. Even when interacting with cells, ionizing radiation can generate a series of biochemical events that lead to a complex cellular response, in many proteins seem to be involved. Given this knowledge, the aim of the study was to evaluate the ultrastructural appearance of cardiac tissue, mitochondrial bioenergetics and differential expression of proteins after irradiation. The tests were performed on samples of cardiac tissue of rats irradiated with single dose of 20 Gy directed to the heart. The analysis started 4 to 32 weeks after irradiation. The ultrastructural analysis was performed by transmission electron microscopy. Mitochondrial respiration was measured in oxigraph from rates of oxygen consumption by cardiac fibers. The identification of differentially expressed proteins was investigated using two proteomic techniques: 2D-DIGE (2-D Fluorescence Difference Gel Electrophoresis) and a label-free approach followed by mass spectrometry. The results showed that the late effects of radiation include degeneration of mitochondria and contractile units of cardiac tissue, dysfunction in the mitochondrial respiratory chain and differential expression of proteins involved in energy metabolism of carbohydrates, lipids and phosphocreatine. In general, the study showed that the cardiac irradiation damages...

Helical tomotherapy for extramedullary hematopoiesis involving the pericardium in a patient with chronic myeloid leukemia.

Extramedullary hematopoiesis (EMH) refers to the development of foci of hematopoiesis outside its normal location in the bone marrow. This occurs normally during fetal development but is abnormal postpartum. The most common sites of EMH are the spleen and liver. The phenomenon occurs in a number of disease states, notably in myelofibrosis, thalassemia, immune thrombocytopenic purpura, sickle cell anemia, polycythemia vera, and myelodysplastic syndrome. Affected patients often develop symptoms related to the location of the EMH. Reported treatments include red blood cell transfusions, surgical excision, decompressive laminectomy in cases of cord compression, chemotherapy, and irradiation. Radiation therapy is highly effective for treating hematopoietic tissue because such tissues are extremely radiosensitive. Megavoltage helical tomotherapy is a technical advance in the delivery of radiation therapy, allowing more conformal and precise treatments. The present case report describes a patient with the diagnosis of atypical chronic myeloid leukemia and myelofibrosis who subsequently developed EMH of the pericardium with effusion and tamponade. By utilizing tomotherapy we were able to treat the pericardium while sparing much of the myocardium. The patient tolerated treatment well without acute adverse effects. His symptoms were alleviated, but he died approximately 1 year later.

Análisis cuantitativo de la función ventricular izquierda como herramienta para la investigación clínica. Fundamentos y metodología / Quantitative analysis of left ventricular function as a tool in clinical research. Theoretical basis and methodology

La utilización de la fracción de eyección del ventrículo izquierdo como objetivo subrogado en los ensayos clínicos está avalada por numerosos estudios. Para que el rendimiento de este objetivo sea aceptable, es esencial ser muy rigurosos en la adquisición de las imágenes y es conveniente utilizar unidades específicamente dedicadas a analizar cuantitativamente parámetros de imagen con las diversas técnicas disponibles. A continuación se expone la evidencia disponible en relación con la fracción de eyección y los volúmenes del ventrículo izquierdo, la importancia de las unidades de análisis de imagen y las distintas técnicas disponibles. Finalmente, se comenta sobre las técnicas de imagen de elección según el contexto clínico (AU)

The usefulness the left ventricular ejection fraction as a surrogate endpoint in clinical trials has been confirmed by numerous studies. However, if this approach is to be applied successfully, images must be acquired in a rigorously controlled manner, and it is advisable to use measurement units that have been specifically developed for quantitative analysis of the imaging parameters obtained with current imaging techniques. This review summarizes what is now known about the left ventricular ejection fraction and left ventricular volumes, discusses the importance of measurement units in image analysis, and describes the different imaging techniques available. Finally, there is a discussion of how to select the best imaging technique for specific clinical applications (AU)

[Clinical development of cardiac CT diagnostics: clinical and scientific applications from the cardiologist's point of view]. / Entwicklung der kardialen CT-Diagnostik: Klinische und wissenschaftliche Anwendungen aus der Sicht des Kardiologen.

The development of cardiac CT imaging has been extraordinary in the last few years. Due to excellent cooperation with our radiology departments we have been able to gain a very close insight into the newest clinical and technical improvements made in this field. The following article aims to highlight the relevant, practically orientated indications and applications of cardiac CT. Furthermore you will find a summary of clinically driven multicenter and interdisciplinary scientific work using this fascinating imaging modality.

Protocolos de estudio de perfusión miocárdica con radioisotopos en evaluación de cardiopatía coronaria / Studies of myocardial perfusion using radioisotopes in the coronary heart disease

Se revisan los principales protocolos actuales de perfusión miocárdica con técnica isotópica, sus indicaciones, requerimientos y nuevas aplicaciones. Se da especial énfasis a la técnica de SPECT gatillado que agrega parámetros de función a las imágenes tomográficas con mayor valor diagnóstico y pronóstico y también a la introducción de positrones mediante fluordeoxiglucosa en la detección de viabilidad miocárdica.

Short communication: Practical aspects for the evaluation of skin doses in interventional cardiology using a new slow film.

Mapping skin doses in complex fluoroscopy interventions is useful to determine the probability of a possible injury, to detect areas of overlapping irradiation fields and to obtain a permanent register of the most exposed patient skin areas. To fulfil this task, large films with slow X-ray response can be used. Recently, Kodak has introduced a new radiotherapy verification film, named EDR2 (Extended Dose Range). The aim of this paper is to analyse the possibilities of using this new film for estimating skin dose distributions in interventions with potentially higher doses, such as complex percutaneous transluminal coronary angioplasty (PTCA), intravascular brachytherapy procedures (IVB) or cardiac ablations. The EDR2 film by Kodak is an improved option to be used in interventional cardiology to obtain maps of patient skin doses and to estimate maximum skin doses up to 1400 mGy. Film kVp dependence is negligible and the processor conditions can be standardized to obtain skin dose estimations. The linear range for accurate dose measurements is from 50 mGy to 500 mGy.

Nuclear cardiology in the UK: activity and practice 1997.

A questionnaire was sent to 251 nuclear medicine centres asking for details of nuclear medicine activity, and nuclear cardiology activity and practice in 1997. One hundred and seventy-one (68%) centres replied. Nuclear medicine activity was estimated at 11.8 studies/1,000 population/year, and 9.5% of these studies were within cardiology (1.12 studies/1,000/year). Myocardial perfusion imaging (MPI) studies accounted for 77% and radionuclide ventriculography (RNV) for 22% of all nuclear cardiology. On a national basis this represents activity levels of 0.86 and 0.25 studies/1,000/year for MPI and RNV, respectively. Of the 171 responding centres, 102 (60%) performed MPI studies and 81 (79%) of these reported that activity was increasing. However, MPI activity was unevenly distributed between hospitals. Two centres accounted for 13% of total MPI; others had far lower activity rates, and 51/102 (50%) centres performed less than 200 MPI studies/year. Comparison with previous surveys showed that nuclear medicine activity had almost doubled since 1990 (it was 6.0 studies/1,000 population in 1990, 9.3 studies/1,000 in 1994 and 11.8 studies/1,000 in 1997). Over the same period, nuclear cardiology activity had also risen, the greatest increase being seen for the last 3 years (it was 0.7 studies/1,000 population in 1990, 0.82 studies/1,000 in 1994 and 1.12 studies/1,000 in 1997). Despite these encouraging figures, MPI activity for 1997 remained well below that recommended by the British Cardiac Society in 1994 (2.6 studies/1,000/year) as adequate to serve the needs of patients with cardiac disease in the UK; it was also below the European average activity for the same year (2.2 studies/1,000/year). The anticipated increased workload for nuclear cardiology is encouraging despite the wide and varied practice of nuclear cardiology around the UK. The nuclear medicine community now needs to address the issues that will prevent it keeping up with demand, such as restricted camera time, excessive waiting lists and outdated equipment, but also to standardise acquisition and reporting techniques so that all studies, wherever performed, will be of a uniformly high standard.

Geographical miss during catheter-based intracoronary beta-radiation: incidence and implications in the BRIE study. Beta-Radiation In Europe.

OBJECTIVES: We sought to determine the incidence and causes of geographical miss (GM) and to evaluate its impact on edge restenosis after intracoronary beta-radiation therapy. BACKGROUND: Edge restenosis is a limitation of intracoronary beta-radiation therapy. Geographical miss is the situation in which the radiation source does not fully cover the injured segment and may lead to edge restenosis. METHODS: We analyzed 175 vessels treated according to the Beta-Radiation In Europe (BRIE) study protocol. The effective irradiated segment (EIRS) and both edges were studied with quantitative coronary angiography. The edges of the EIRS that were injured constituted the GM edges. Restenosis was defined as diameter stenosis >50% at follow-up. Geographical miss was determined by simultaneous electrocardiographic-matched, side-by-side projection of the source and balloons deflated at the injury site, in identical angiographic projections surrounded by contrast. RESULTS: Geographical miss affected 41.2% of the edges and increased edge restenosis significantly compared with non-GM edges (16.3% vs. 4.3%, respectively, p = 0.004). Restenosis was increased both in the proximal (p = 0.05) and distal (p = 0.02) GM edges compared with noninjured edges. Geographical miss associated with stent injury significantly increased edge restenosis (p = 0.006), whereas GM related to balloon injury did not significantly increase edge restenosis (p = 0.35). The restenosis in the EIRS was similar between vessels with and without GM (24.3% and 21.6%, respectively, p = 0.8). CONCLUSIONS: Geographical miss is strongly associated with restenosis at the edges of the EIRS. This effect is more prominent when caused by stenting. Geographical miss does not increase restenosis in the EIRS.

[Laser therapy in diabetes mellitus]. / Lazeroterapiia pry tsukrovomu diabeti.

Diabetic patients have been shown to derive great benefit from treatment with laser therapy as evidenced by experience gained with its use over many years. Laser therapy promotes compensation, has an antiatherogenic, antioxidant, immunomodulating effects, improves microcirculation, myocardial contractility and performance capability.

Preservation of atrioventricular nodal conduction during radiofrequency current catheter ablation of midseptal accessory pathways.

BACKGROUND: Septal accessory atrioventricular (AV) pathways may be located in close vicinity of the His bundle-AV nodal conduction system. Attempts at surgical or electrical interruption of these pathways may therefore result in impairment of normal AV conduction. This study focuses on a subset of septal pathways with an atrial insertion located inside the triangle of Koch. In this study, they were called "midseptal." METHODS AND RESULTS: Six patients with a midseptal accessory pathway (mean +/- SD age, 40 +/- 12 years; five with Wolff-Parkinson-White syndrome and one with a concealed accessory pathway) underwent attempts at ablation of their pathway using 500-kHz radiofrequency current applied to the atrial insertion of the accessory connection. Guided by the recording of accessory pathway activation potentials, the ablation catheter was positioned in all patients in an area bounded anteriorly by the tip electrode of the His bundle catheter and posteriorly by the coronary sinus ostium. All pathways were successfully ablated without the induction of complete heart block. First-degree AV conduction block occurred in one patient in whom a concealed accessory connection was located closer to the AV node than to the coronary sinus ostium. CONCLUSIONS: Radiofrequency current catheter ablation may be used effectively for midseptal accessory pathways and should be preferred in experienced centers as a safe alternative to surgical therapy.