Dosimetric feasibility study ("proof of concept") of refractory ventricular tachycardia radioablation using proton minibeams.

PURPOSE: Preclinical data demonstrated that the use of proton minibeam radiotherapy reduces the risk of toxicity in healthy tissue. Ventricular tachycardia radioablation is an area under clinical investigation in proton beam therapy. We sought to simulate a ventricular tachycardia radioablation with proton minibeams and to demonstrate that it was possible to obtain a homogeneous coverage of an arrhythmogenic cardiac zone with this technique. MATERIAL AND METHODS: An arrhythmogenic target volume was defined on the simulation CT scan of a patient, localized in the lateral wall of the left ventricle. A dose of 25Gy was planned to be delivered by proton minibeam radiotherapy, simulated using a Monte Carlo code (TOPAS v.3.7) with a collimator of 19 0.4 mm-wide slits spaced 3mm apart. The main objective of the study was to obtain a plan ensuring at least 93% of the prescription dose in 93% of the planning target volume without exceeding 110% of the prescribed dose in the planning target volume. RESULTS: The average dose in the planning treatment volume in proton minibeam radiotherapy was 25.12Gy. The percentage of the planning target volume receiving 93% (V93%), 110% (V110%), and 95% (V95%) of the prescribed dose was 94.25%, 0%, and 92.6% respectively. The lateral penumbra was 6.6mm. The mean value of the peak-to-valley-dose ratio in the planning target volume was 1.06. The mean heart dose was 2.54Gy versus 5.95Gy with stereotactic photon beam irradiation. CONCLUSION: This proof-of-concept study shows that proton minibeam radiotherapy can achieve a homogeneous coverage of an arrhythmogenic cardiac zone, reducing the dose at the normal tissues. This technique, ensuring could theoretically reduce the risk of late pulmonary and breast fibrosis, as well as cardiac toxicity as seen in previous biological studies in proton minibeam radiotherapy.

Effects of magnetic shear on toroidal rotation in tokamak plasmas with lower hybrid current drive.

Application of lower hybrid (LH) current drive in tokamak plasmas can induce both co- and countercurrent directed changes in toroidal rotation, depending on the core q profile. For discharges with q(0) <1, rotation increments in the countercurrent direction are observed. If the LH-driven current is sufficient to suppress sawteeth and increase q(0) above unity, the core toroidal rotation change is in the cocurrent direction. This change in sign of the rotation increment is consistent with a change in sign of the residual stress (the divergence of which constitutes an intrinsic torque that drives the flow) through its dependence on magnetic shear.

Fusion product measurements by nuclear diagnostics in the Joint European Torus deuterium-tritium 2 campaign (invited).

A new deuterium-tritium experimental, DTE2, campaign has been conducted at the Joint European Torus (JET) between August 2021 and late December 2021. Motivated by significant enhancements in the past decade at JET, such as the ITER-like wall and enhanced auxiliary heating power, the campaign achieved a new fusion energy world record and performed a broad range of fundamental experiments to inform ITER physics scenarios and operations. New capabilities in the area of fusion product measurements by nuclear diagnostics were available as a result of a decade long enhancement program. These have been tested for the first time in DTE2 and a concise overview is provided here. Confined alpha particle measurements by gamma-ray spectroscopy were successfully demonstrated, albeit with limitations at neutron rates higher than some 1017 n/s. High resolution neutron spectroscopy measurements with the magnetic proton recoil instrument were complemented by novel data from a set of synthetic diamond detectors, which enabled studies of the supra-thermal contributions to the neutron emission. In the area of escaping fast ion diagnostics, a lost fast ion detector and a set of Faraday cups made it possible to determine information on the velocity space and poloidal distribution of the lost alpha particles for the first time. This extensive set of data provides unique information for fundamental physics studies and validation of the numerical models, which are key to inform the physics and scenarios of ITER.

Effects of airway occlusion on breathing muscle electromyogram signals, during isoflurane anaesthesia, with and without the effects of fentanyl and hypercapnia.

BACKGROUND: Expiratory muscle action is prominent during anaesthesia and can impair lung function. This activity is exaggerated by the use of opioids. Airway pressure during occlusion of expiration would be a valuable measure in the study of expiratory muscle activation. However, this would only be valid if the imposed occlusion did not itself alter muscle activation. This possibility can be checked by directly assessing muscle activity by electromyography; varying arterial carbon dioxide tensions and opioid action should be considered. METHODS: We studied seven spontaneously breathing patients, anaesthetized with nitrous oxide and isoflurane, in four conditions: during an infusion of fentanyl and after naloxone, breathing normally and with breathing stimulated with CO(2). We compared diaphragm and external oblique abdominal electromyogram (EMG) signals during normal and occluded breaths. We also measured chest wall volume and compared airway occlusion pressure, during inspiration and expiration, with the EMG results. RESULTS: Inspiratory occlusion increased the duration of inspiration during hypercapnia by 20%, but not the rate of electrical activation of the diaphragm, indicating that occlusion does not cause a reflex increase in diaphragm contraction. In contrast, expiratory occlusion did not affect either the duration of expiration or the electrical activity of the external oblique muscles. CONCLUSIONS: In these conditions, except for a change in inspiratory duration, respiratory muscle activity is unaffected by airway occlusion. Airway occlusion will permit valid measures of muscle activity in inspiration and expiration and provide simple measurements of respiratory muscle function during anaesthesia.

Clinical and dosimetric impact of totally implantable venous access devices in radiotherapy of supra diaphragmatic Hodgkin Lymphoma.

PURPOSE: To evaluate attenuation of the totally implantable vascular access device (TIVAD) and assess its clinical and dosimetric impact on radiotherapy (RT) of lymphoma patients. MATERIALS AND METHODS: The first part of the study consisted of an in vitro approach by irradiating the TIVAD with different electron and photon energies. The attenuation data measured were compared with data calculated by our treatment planning system. All patients treated by radiotherapy for Hodgkin's lymphoma with their TIVAD in the target volume were then reviewed to assess the clinical outcome and dosimetric comparison using different plan metrics. All patients were treated by 3D conformal radiotherapy (3DCRT) or intensity-modulated radiotherapy delivered by Helical Tomotherapy (HT). RESULTS: Nineteen patients treated for stage I-III HL were studied. Seven patients were treated exclusively on the side of TIVAD and 12 were treated bilaterally. Median prescription dose was 30Gy. No significant clinical or dosimetric differences were observed between the side of the TIVAD and the contralateral side in patients treated bilaterally. HT resulted in a significantly higher conformity index (P<0.0022) and a significantly lower healthy tissue coverage (P=0.0008) than 3DCRT. The observed attenuation was 79% for 6 MeV, 59% for 9 MeV, and 46% for 12 MeV for electrons and 9% for 4 MV, 8% for 6 MV, 5% for 10 MV and 15 MV and 3% for 20 MV for X photons. CONCLUSION: TIVADs induce significant beam attenuation when using electrons, which can be overcome by using high-energy photons or by creating an exclusion zone in when HT is used.

Dose-response effect of serum butyrylcholinesterase activity after clinical doses of pancuronium.

INTRODUCTION: Low-dose pancuronium is known to affect serum cholinesterase activity (BChE); however, the dose-response effect of clinical doses of pancuronium on BChE has not been investigated. METHODS: Thirteen ASA I-II patients scheduled for elective surgery requiring muscle relaxation were enrolled in this study. All patients had normal BChE before surgery. Incremental doses of pancuronium (10, 20, 50, and 100 microg/kg) were injected in accordance with surgical needs every 45 min. BChE was measured 3 min after injection by an automatic colorimetric method. RESULTS: BChE decreased significantly in all except one patient in comparison to the baseline (P < 0.05). However all values remained within normal clinical range. A dose of 100 microg/kg yielded significant decrease in comparison to 10 microg/kg but not to other dosages. Linear regression was not significant for the dose-response relationship (P = 0.05). CONCLUSION: After clinical incremental doses of pancuronium, BChE remained within clinical range.

Access to innovative medicines for metastatic melanoma worldwide: Melanoma World Society and European Association of Dermato-oncology survey in 34 countries.

According to data from recent studies from Europe, a large percentage of patients have restricted access to innovative medicines for metastatic melanoma. Melanoma World Society and European Association of Dermato-oncology conducted a Web-based survey on access to first-line recommended treatments for metastatic melanoma by current guidelines (National Comprehensive Center Network, European Society for Medical Oncology [ESMO] and European Organization for Research and Treatment of Cancer/European Association of Dermato-oncology/European dermatology Forum) among melanoma experts from 27 European countries, USA, China, Australia, Argentina, Brazil, Chile and Mexico from September 1st, 2017 to July 1st, 2018. Data on licencing and reimbursement of medicines and the number of patient treated were correlated with the data on health expenditure per capita (HEPC), Mackenbach score of health policy performance, health technology assessment (HTA), ASCO and ESMO Magnitude of clinical benefit scale (ESMO MCBS) scores of clinical benefit and market price of medicines. Regression analysis for evaluation of correlation between the parameters was carried out using SPSS software. The estimated number of patients without access in surveyed countries was 13768. The recommended BRAFi + MEKi combination and anti-PD1 immunotherapy were fully reimbursed/covered in 19 of 34 (55.8%) and 17 of 34 (50%) countries, and combination anti-CTLA4+anti-PD1 in was fully covered in 6 of 34 (17.6%) countries. Median delay in reimbursement was 991 days, and it was in significant correlation with ESMO MCBS (p = 0.02), median market price (p = 0.001), HEPC and Mackenbach scores (p < 0.01). Price negotiations or managed entry agreements (MEAs) with national authorities were necessary for reimbursement. In conclusion, great discrepancy exists in metastatic melanoma treatment globally. Access to innovative medicines is in correlation with economic parameters as well as with healthcare system performance parameters. Patient-oriented drug development, market access and reimbursement pathways must be urgently found.

More than 5000 patients with metastatic melanoma in Europe per year do not have access to recommended first-line innovative treatments.

BACKGROUND: Despite the efficacy of innovative treatments for metastatic melanoma, their high costs has led to disparities in cancer care among different European countries. We analysed the availability of these innovative therapies in Europe and estimated the number of patients without access to first-line recommended treatment per current guidelines of professional entities such as the European Society for Medical Oncology (ESMO), the European Organisation for Research and Treatment of Cancer (EORTC), the European Association of Dermato-Oncology (EADO), and European Dermatology Forum (EDF). MATERIALS AND METHODS: Web-based online survey was conducted in 30 European countries with questions about the treatment schedules from 1st May 2015 to 1st May 2016: number of metastatic melanoma patients, registration and reimbursement of innovative medicines (updated data, as of 1st October 2016), percentage of patients treated and availability of clinical studies and compassionate-use programmes. RESULTS: The recommended BRAF inhibitor (BRAFi) + MEK inhibitor (MEKi) combination was both registered and fully reimbursed in 9/30 (30%) countries, and in 13/30 (43%) (all from Eastern Europe) not reimbursed. First-line immunotherapy with anti-PD1 antibodies was registered and fully reimbursed in 14/30 (47%) countries, while in 13/30 (43%) (all from Eastern Europe) not reimbursed. It was estimated that in Europe 19,600 patients with metastatic melanoma are treated, and 5238 (27%) do not have access to recommended first-line therapy. Significant correlation was found between human development index (HDI, UNDP report 2015), (r = 0.662; p < 0.001), health expenditure per capita (r = 0.695; p < 0.001) and the Mackenbach score of health policy performance (r = 0.765; p < 0.001) with the percentage of patients treated with innovative medicines and a number of reimbursed medicines. CONCLUSIONS: Great discrepancy exists in metastatic melanoma treatment across Europe. It is crucial to increase the awareness of national and European policymakers, oncological societies, melanoma patients' associations and pharma industry.

Evaluation of delayed apoptotic response in lethally irradiated human melanoma cell lines.

To assess the lethal doses of gamma radiation and corresponding apoptotic response in new established human melanoma cell lines we exposed exponentially growing cultures to 8-100 Gy gamma radiation. The apoptosis and cell survival were determined by trypan blue exclusion, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) reaction, agarose gel electrophoresis, colony forming assay, and long-term survival assay. The maximal DNA fragmentation 3 days after irradiation was observed in cultures irradiated with 20 Gy (36.9% TUNEL positive cells). The cultures irradiated with 50 and 100 Gy contained 18.7% and 16.4% TUNEL positive cells, respectively. Cultures exposed to 8 and 20 Gy gamma radiation recovered by week 3-4. Lethally irradiated (50 and 100 Gy) cultures which contained less apoptotic cells by day 3 died by week 5. A detectable increase in melanoma cell pigmentation after irradiation was also observed. The survival of human melanoma cell cultures after exposure to gamma radiation does not correlate with the level of apoptotic cells by day 3. At high radiation doses (> 50 Gy) when the radiation induced cell pigmentation is not inhibited the processes of apoptotic DNA fragmentation might be preferentially inactivated.

[Effectiveness of low mivacurium if its injection is postponed by a non-invasive pressure determination on the homolateral arm]. / L'efficacité du mivacurium baisse si son injection est retardée par une prise de pression non-invasive sur le bras homolatéral.

OBJECTIVE: We assessed the neuromuscular characteristics of 0.2 mg.kg-1 of mivacurium while its injection was concomitant to a non invasive blood pressure measurement in the ipsilateral arm. PATIENTS: Thirty-one patients ASA I-II were randomized into two groups. Group cuff (n = 15) and Group control (n = 16). METHODS: General anaesthesia was induced with fentanyl, thiopentone and mivacurium in all patients, however in the cuff group, measurement of non invasive blood pressure was performed immediately after the injection of mivacurium. Comparison was made on neuromuscular blockade of the adductor pollicis (AP) by mechanomyography, and intubating conditions which were guided by the visual estimation of the orbicularis oculi's (OO) response. RESULTS: In the cuff group, six out of 15 patients did not have complete blockade at the OO against one out of 16 in the control group, (Fisher exact test p < 0.05). Intubation time was significantly delayed in the cuff group, 201 +/- 66 s versus 123 +/- 32 s in the control group, (t test p < 0.001). The maximum neuromuscular blocking effect at the AP was significantly greater in the control group 99 +/- 2% against 89 +/- 7% in the cuff group, (t test p < 0.01). The onset of maximum blockade at the AP was longer in the cuff group 294 +/- 40 s versus 179 +/- 92 s, (t test p < 0.001] in the control group. Time to 25% recovery was shorter in the cuff group 16 +/- 3 min versus 20 +/- 5 min, in the control group (t test p < 0.05). CONCLUSION: This study suggests that non invasive blood pressure measurement of the ipsilateral arm, concomitant to the injection of mivacurium decreases the potency of mivacurium. This finding is mostly explained by the early hydrolysis of mivacurium in the plasma of the excluded arm.

[Sensitivity to atracurium in the lateral abdominal muscles] . / Sensibilité à l'atracurium des muscles abdominaux latéraux.

OBJECTIVE: To study the effect of atracurium on the electromyographic activity of the lateral abdominal muscles and adductor pollicis in anaesthetized subjects. STUDY DESIGN: Prospective, comparative, open study. PATIENTS AND METHODS: Sixteen patients, ASA physical status 1 or 2, undergoing elective orthopaedic surgery under general anaesthesia were studied. Anaesthesia was induced with propofol/fentanyl and orotracheal intubation performed after glottic local anaesthesia without using muscle relaxant. Anaesthesia was maintained with isoflurane/nitrous oxide/oxygen and fentanyl reinjections. Supramaximal percutaneous stimulations in a simple twitch mode (0.1 Hz) were applied at the 9th-10th intercostal nerve on the posterior axillary line and at the ulnar nerve at the wrist. The electromyographic responses were registered using skin surface electrodes, placed on the D9-D10 dermatome in regard of the lateral abdominal muscles and of the thenar muscles. After a single bolus dose of atracurium 0.5 mg.kg-1, the following parameters were studied: the maximum effect (Emax), the time for obtaining Emax (Delay) and the recovery time of 5, 10, 25, 50, 75 and 100% of the control neuromuscular response (T5, T10, T25, T50, T75, T100). RESULTS: The dose of 0.5 mg.kg-1 of atracurium induced 100% block in both lateral abdominal muscles and adductor pollicis. Lateral abdominal muscles blockade had faster onset (136 +/- 4 s versus 205 +/- 29 s) and shorter recovery, T5, T10, T25, T50, T75 and T100 were significantly (p < 0.05) shorter than at the adductor pollicis. CONCLUSION: Lateral abdominal muscles blockade have faster onset and recovery than adductor pollicis.

[The case of diagnostic difficulties of submucous myoma in early pregnancy]. / Diagnostichni trudnosti pri ranna bremennost s nalichna submukozna mioma--kazus.

The authors describe observed case of pregnancy and degenerative submucous myoma. Diagnostic difficulties.

[Large uterine myoma during pregnancy and delivery - choice of management]. / Goliama mioma na matkata prez bremennostta i razhdaneto - izbor na povedenie.

There are scanty of available data about the management of myoma of the uterus during pregnancy and birth. The authors describe two cases of such a pathology--big myoma of the uterus > 10 sm diameter (d.), who were treated conservatively and ended successfully, without serious complications. The pregnant women were done cesarean section and during the operation the myomas were excisiert. There were no complications intra- and postoperationem. The authors suggest that myectomy during pregnancy and cesarean section must not be don routinely.

[The Joel-Cohen (Misgav Ladach) method--a new surgical technic for cesarean section and gynecological laparotomy]. / Joel-Cohen (Misgav Ladach)-metod--nova operativna tekhnika pri tsezarovo sechenie i ginekologichna laparotomiia.

The authors make a review on this problem for first time in Bulgarian literature and for the first time by us operated with the Misgav Ladach method--cesarean section. The authors describe 50 cases wit Ladach method and as control 20 with Pfannenstiel. The authors establish shorter duration of the operation-Si] and 56.3 min. respective in benefit for Misgav method; the babies were extracted at 5.5 and 12.3 min. respect. The mothers with Misgav had better prognosis at the time of dehospitalization.

An arc control and protection system for the JET lower hybrid antenna based on an imaging system.

Arcs are the potentially most dangerous events related to Lower Hybrid (LH) antenna operation. If left uncontrolled they can produce damage and cause plasma disruption by impurity influx. To address this issue an arc real time control and protection imaging system for the Joint European Torus (JET) LH antenna has been implemented. The LH system is one of the additional heating systems at JET. It comprises 24 microwave generators (klystrons, operating at 3.7 GHz) providing up to 5 MW of heating and current drive to the JET plasma. This is done through an antenna composed of an array of waveguides facing the plasma. The protection system presented here is based primarily on an imaging arc detection and real time control system. It has adapted the ITER like wall hotspot protection system using an identical CCD camera and real time image processing unit. A filter has been installed to avoid saturation and spurious system triggers caused by ionization light. The antenna is divided in 24 Regions Of Interest (ROIs) each one corresponding to one klystron. If an arc precursor is detected in a ROI, power is reduced locally with subsequent potential damage and plasma disruption avoided. The power is subsequently reinstated if, during a defined interval of time, arcing is confirmed not to be present by image analysis. This system was successfully commissioned during the restart phase and beginning of the 2013 scientific campaign. Since its installation and commissioning, arcs and related phenomena have been prevented. In this contribution we briefly describe the camera, image processing, and real time control systems. Most importantly, we demonstrate that an LH antenna arc protection system based on CCD camera imaging systems works. Examples of both controlled and uncontrolled LH arc events and their consequences are shown.

[Radiotherapy for breast cancer and pacemaker]. / Radiothérapie pour un cancer du sein et stimulateur cardiaque.

PURPOSE: Patients with permanent cardiac pacemakers occasionally require radiotherapy. Therapeutic irradiation may cause pacemakers to malfunction due to the effects of ionizing radiation or electromagnetic interference. We studied the breast cancer patients who needed breast and/or chest wall and lymph node irradiation to assess the feasibility and tolerance in this population of patients. PATIENTS AND METHODS: From November 2008 to December 2009, more than 900 patients received radiotherapy for their breast cancer in our department using megavoltage linear accelerator (X 4-6 MV and electrons). Among them, seven patients were with permanent pacemaker. All patients have been treated to the breast and chest wall and/or lymph nodes. Total dose to breast and/or chest wall was 50 Gy/25 fractions and 46 Gy/23 fractions to lymph nodes. Patients who underwent conserving surgery followed by breast irradiation were boosted when indicated to tumour bed with 16 Gy/8 fractions. All patients were monitored everyday in presence of radiation oncologist to follow the function of their pacemaker. All pacemakers were controlled before and after radiotherapy by the patients' cardiologist. RESULTS: Seven patients were referred in our department for postoperative breast cancer radiotherapy. Among them, only one patient was declined for radiotherapy and underwent mastectomy without radiotherapy. In four cases the pacemaker was repositioned before the beginning of radiotherapy. Six patients, aged between 48 and 84 years underwent irradiation for their breast cancer. Four patients were treated with conserving surgery followed by breast radiotherapy and two with mastectomy followed by chest wall and internal mammary chain, supra- and infra-clavicular lymph node irradiation. The dose to the pacemaker generator was kept below 2 Gy. There was no pacemaker dysfunction observed during the radiotherapy. CONCLUSION: The multidisciplinary work with position change of the pacemaker before radiotherapy and everyday monitoring permitted the safe treatment of our patients. Updated guidelines are definitely needed with more details about acceptable doses at the different parts of the pacemaker.

[Rare endocrine tumors of the pancreas with secretion of cortisol].

UNLABELLED: The endocrine part of the pancreas consist 2% from the mass of the gland and it is built from little cells with name Langerhan's islands. The increased secretion of cells provokes to appearance of classic clinical syndrome, which is conditioned by large quantity of hormone in circulation of the blood. The endocrine tumors of the pancreas (ETP) are arisen out of cells that have large quantity to APUD-system. MATERIAL AND METHOD: We present a case report of rare ETP with secretion of cortisol (MEN2 syndrome), which is of interest by reason of the fact that this case report is the first announce in Bulgaria about similar tumor. Corporocaudal resention of the pancreas with spleenectomy has been made. RESULTS: Tumor cells with highly expresion (+++) of hromogranin were determined. The histological conclusion was malignant ETP (APUD system tumor)with secretion of cortisol. A decrease of the level of glucose in blood circulation, a decrease of blood pressure and reduction of the body weight were determined with range of first three postoperative weeks. CONCLUSION: The aims of the surgical therapy are a control over the level of hormones, clear resection and maximal organ saving operation.

TOF count at corrugator supercilii reflects abdominal muscles relaxation better than at adductor pollicis.

BACKGROUND: A recovery profile from neuromuscular block similar to that of abdominal (AB) muscles, but different to that of the adductor pollicis (AP) muscle, has been demonstrated at the corrugator supercilii (CSC) muscle. We hypothesized that neuromuscular transmission (NMT) monitoring of CSC might provide useful information on AB relaxation compared with AP. We compared the visual estimation of NMT at CSC and AP with electromyographic measurements of AB during recovery from a vecuronium block. METHODS: Ten adult patients were studied during balanced anaesthesia. After induction of anaesthesia and tracheal intubation without neuromuscular blocking agents, supramaximal stimulations were applied to three nerves: left 10th intercostal, ulnar, and facial. Electromyographic activity (EMG) of AB was measured (ABemg). After a bolus dose of vecuronium 0.1 mg kg-1, an independent observer blinded to the EMG measurements counted visually detectable train-of-four (TOF) responses at CSC and AP. Values of ABemg associated with 1 to 4 TOF responses at CSC and AP were compared. Values are means (sd). RESULTS: Reappearance of the first and second TOF responses at CSC occurred significantly (P<0.05) earlier and at lower ABemg recovery than that of AP [35 (8) and 41 (9) min vs 51 (10) and 56 (12) min; and 17 (8) and 26 (9)% vs 56 (10) and 75 (11)%, respectively]. CONCLUSIONS: We demonstrated that the TOF response count at the CSC, compared with the AP, allowed a better quantification of the degree of AB muscle relaxation during recovery from vecuronium block.