Pulse Dose Research Articles

Toxicity assessment following conventional radiation therapy and pulsed low dose rate radiation therapy: an in vivo animal study

Abstract Background Pulsed low dose rate radiotherapy (PLDR) is a new radiation delivery method, in which the fractional dose is divided into sub-fractional doses with periodical time breaks in between. The goal of our study is to assess the toxicity on healthy tissues resulting from PLDR as compared to conventional radiotherapy (CRT) using the same physical X-ray dose. Methods We analyzed the weight and survival time for CRT and PLDR groups and studied the inflammatory cytokine transforming Growth Factor-β (TGF-β), usually released following irradiation. Histopathological and immunohistochemical analyses were conducted for intestinal and bone marrow tissues from rats subjected to 8 Gy whole- body irradiation using CRT and PLDR techniques. We investigated genotoxicity by performing a comet assay (CA) in splenic tissues. Results Our findings showed an improvement in survival time with PLDR versus CRT by 82%.The mean survival time for CRT rats’ group was 6.3 days, while it was 35.9 days for PLDR group.The weight of CRT group decreased gradually by 3.7%, while weight of PLDR group increased gradually by 2.4%.CRT resulted in more cellular atrophy in bone marrow and intestinal tissues than in PLDR treatments as shown by hematoxylin and eosin staining analysis. In addition, the transforming growth factor-β (TGF-β) expression in bone marrow and intestinal tissues of CRT was higher than those expressed in tissues from PLDR as demonstrated by the Immuno reactive score (IRS). It was10(0.53) and 9.8(0.55) for BM and intestinal tissues, respectively from CRT group and 5.8(0.63) for PLDR for both tissues. The measured CA parameters were larger with CRT compared to PLDR, where the Tail Length (TL), Tail DNA % (TD%) and Tail Moment (TM) measurements were 25.4(3.4), 56.5(7.6) % and 20.5(3.5) for CRT, 7.3(1.9), 30.0(7.2) % and 5.7(1.8) for PLDR, with P value 0.000064, 0.0004 and 0.00017, respectively. Conclusion This study indicates that PLDR can reduce the toxicity on normal tissues compared to CRT.

Abstract 4124120: Rare but Deadly - Eosinophilic Myocarditis in a Patient with Eosinophilic Granulomatosis Polyangiitis

Eosinophilic myocarditis (EM) is a rare inflammatory myocarditis characterized by eosinophilic infiltration of myocardial tissue. Despite the high mortality rate, EM is frequently underdiagnosed and is often first identified in postmortem studies. We share a case of EM as an early manifestation of newly diagnosed eosinophilic granulomatosis polyangiitis (EGPA). The patient is a 46-year-old female with a past medical history of ulcerative colitis and adult-onset asthma who presented to the emergency department with a 2–3-week history of worsening positional chest pain radiating to the left upper extremity. Associated symptoms include 3 months of fatigue, headaches, right foot neuropathy, urticaria, and B-symptoms. Prior to admission, the patient was started on empiric prednisone for presumed EGPA. Initial lab work on admission was notable for elevated troponin (602 ng/L), hyper-eosinophilia (19.5%), thrombocytosis (680K/uL), and elevated ESR (42 mm/h) that have improved since initiation of prednisone. Transthoracic echocardiogram revealed a newly reduced LVEF of 40% with basal and mid-septal wall motion abnormalities. Cardiac catheterization showed normal coronaries confirming the diagnosis of non-ischemic cardiomyopathy. Late gadolinium enhancement in cardiac MRI was seen in basal to mid segments with patchy pericardial enhancement, meeting the Lake Louise criteria for myocarditis. An endomyocardial biopsy showed substantial myocardial infiltration with lymphocytes, histiocytes and eosinophils, confirming the diagnosis of EM. After multidisciplinary team discussion with cardiology and rheumatology, the patient was started on guideline-directed medical therapy for her HFrEF and pulse dose steroids with a prolonged taper and cyclophosphamide. She is tolerating her treatment well. This case highlights the importance of early recognition, comprehensive assessment and targeted treatment for EM depending on its underlying etiology. In the case of autoimmune dysfunction, it involves a combination of immunosuppressive and symptomatic therapy. Ongoing research is crucial to enhance our understanding and improve clinical outcomes, like arrhythmias and cardiogenic shock, for this complex condition.

Delayed vascular occlusion following hyaluronic acid-based skin booster – A rare case report

Hyaluronic acid (HA) based skin boosters used for treating fine lines and for enhancing the quality of skin are quite popular as they help by drawing water under the dermis (hydrofilling effect), helping in prolonged hydration of the skin. They are also considered safe due to the superficial plane of injection and low volumes injected. The patient came to the clinic for skin hydration and rejuvenation treatment. After detailed discussion and informed consent, a non-animal origin HA-based skin booster with a concentration of 20 mg/mL was chosen for facial rejuvenation. As per protocol, 2 mL of the product was injected by micropuncture technique with the automated click technology, delivering 0.01 mL per point in the mid dermis all over the cheeks, chin, and forehead. The patient tolerated the procedure well and presented to us 48 hours post-injection with persisting redness and pain on the central forehead. The redness appeared to be in a triangular pattern, with the apex at the left eyebrow and the base toward the hairline. Diagnosis of vascular compromise was made, and the patient was immediately treated with pulsed doses of hyaluronidase. The entire area healed without any sequelae. We hereby report a rare case of delayed vascular occlusion following skin booster treatment, which was successfully managed by hyaluronidase treatment. Skin boosters are the most sought after treatments for skin hydration and are generally considered safe; this is the first case report with delayed vascular occlusion reported following skin booster injections. Because of the high risk associated with glabella and forehead areas for fillers, one should be mindful in this area even with the skin boosters.

Rheumatoid arthritis: a rare cause of pachymeningitis and optic neuritis

Introduction: Rheumatoid pachymeningitis and optic neuritis are rare complications of rheumatoid arthritis (RA) and are a diagnosis of exclusion. Case description: A 75-year-old male with a history of seronegative RA presented to the emergency department with left eye pain and blurry vision lasting two days. He had been diagnosed with seronegative RA around nine months previously. His blood pressure was elevated at 204/75 mmHg upon arrival. Physical examination revealed left conjunctival injection, mild ptosis, painful extraocular movements and tenderness over the orbit and sinuses. Initial treatments included painkillers and intravenous labetalol, which alleviated his symptoms and decreased his blood pressure. Laboratory tests showed a C-reactive protein of 2.5 mg/dl and an erythrocyte sedimentation rate of 32 mm/h, with other blood work unremarkable. A computed tomography (CT) angiogram of the head and neck showed no high-grade stenosis. Given his RA history, initial concerns included scleritis. A magnetic resonance imaging (MRI) of the brain and orbit revealed inflammation around the left optic nerve, and pachymeningitis at the left cerebral convexity and interhemispheric fissure, suggesting hypertrophic pachymeningitis. An ophthalmologic examination was unremarkable. Treatment was adjusted to include pulse doses of intravenous methylprednisolone for optic neuritis, resulting in significant pain relief. Though inadequate for complete testing, a lumbar puncture indicated an inflammatory disorder with elevated glucose (199 mg/dl), protein (109 mg/dl), and unremarkable WBC/RBC and Gram staining. Cytology and culture were unremarkable. The most likely diagnosis at this point was rheumatological meningitis and rheumatological optic neuritis. The patient improved markedly with high-dose steroids over four days and was discharged on prednisone. Conclusion: In cases of optic neuritis and pachymeningitis, RA should remain on the differential in patients with or without a prior diagnosis.

PO0115: Validation of Scintillator-Based In Vivo Dosimetry for Pulsed Dose Rate Brachytherapy with Tandem Ring Applicators for Cervical Cancer

PO0115: Validation of Scintillator-Based In Vivo Dosimetry for Pulsed Dose Rate Brachytherapy with Tandem Ring Applicators for Cervical Cancer

7137 The Sugar Saga: A Profound Case Of Diabetic Ketoacidosis Due To Enfortumab Vedotin

Abstract Disclosure: P. Aron: None. B. Connell: None. R. Longo: None. J. Upadhyay: None. This is a case of severe hyperglycemia with the use of Enfortumab Vedotin (EV) in the setting of advanced urothelial cancer. EV is a nectin-4-directed antibody-drug conjugate with a microtubule inhibitor approved for treating advanced/recurrent disease. It is the first of its class that is an antibody-drug conjugate (ADC), targeting nectin, but not the first ADC to cause hyperglycemia. Here we present a case of severe insulin resistance requiring insulin infusion at 50 units/hour in addition to subcutaneous insulin all in the setting of EV use.74 year old male with BMI of 28 and HbA1c of 7.5%, managed only with diet was started on EV for metastatic urothelial cancer. Patient received one cycle (3 doses) of EV (on days 1, 8, 15) and thereafter noticed worsening of hyperglycemia with blood glucose of 533 mg/dL, requiring subcutaneous insulin. Patient’s blood glucose readings remained elevated and he was admitted to the hospital as he was found to be in DKA with a pH of 7.2, bicarbonate 14 mmol/L, anion gap of 16 mmol/L and a glucose of 558 mg/dL. The patient was started on intravenous insulin (IV) infusion using insulin infusion protocol titrated up to 14 units an hour with an additional 30 units of glargine. Patients’ clinical condition continued to worsen and he was in septic shock with pressors and on insulin infusion exceeding 55 units/hour, NPH at 50 units, and regular insulin 30 units with glucose persistently above 400 mg/dL. Patient was started on hydrocortisone 50mg every 6h and his blood glucose readings eventually normalized over a span of 1 week. Patient eventually was able to be discharged to rehabilitation with just a correctional humalog insulin. Our case demonstrates DKA as a consequence of severe insulin resistance seen as a side effect of EV. Hyperglycemia is seen in 8% of patients using this medication, but severe cases are mostly seen with high BMI and uncontrolled diabetes. This case illustrates the fact that one needs to be cautious in ALL patients with diabetes when using this drug and warrants screening for DKA/severe insulin resistance if blood glucose is running >250mg/dL. The exact mechanism for hyperglycemia is unknown but it is likely immunomodulatory and therefore treatment with pulse dose steroids may help with overcoming insulin resistance in this setting like in our patient. More research needs to be done to understand mechanisms and establish treatment guidelines for severe insulin resistance and hyperglycemia caused by this medication. Presentation: 6/1/2024

Definitive treatment for primary urethral cancer: A single institution's experience with organ-preserving brachytherapy

BackgroundRadical urethectomy ± cystectomy has long represented the standard of care for rare primary urethral cancer (PUC). With our analysis, we want to demonstrate the efficacy and safety of brachytherapy (BT) of urethra for organ preservation. Materials and methodsWe analyzed treatment procedures and results of three patients with PUC, which have been treated in our department between 2011 - 2020 with brachytherapy. One male patient underwent brachytherapy with chemoradiotherapy after transurethral resection (TUR). Brachytherapy has been performed as high-dose-rate (HDR) boost with a cumulative dose of 8 Gy (9.3 Gy EQD2-α/β = 10Gy). The two further female patients have been treated with sole pulsed-dose-rate (PDR) brachytherapy with a total dose of 49.9 Gy (50.3 Gy EQD2-α/β = 10Gy) and 62.2 Gy (64.6 Gy EQD2-α/β = 10Gy). ResultsMedian follow-up was 103 months (41-153). No local recurrence occurred and all patients are still alive. For the male patient we documented Grade 3 cystitis. As late side effects the pre-existing Grade 2 incontinence worsened to Grade 3. Among female patients one developed Grade 3 vaginal synechiae. There was no Grade ≥4 toxicity. ConclusionBrachytherapy in PUC is a feasible and promising option with high local control rate and tolerable toxicity. It provides a good alternative to surgery for organ preservation in selected patients.

Efficacy of Methylprednisolone in Acute Respiratory Distress Syndrome- COVID-19 Middle Euphrates Patients

Background: The coronavirus disease 2019 was initially identified in Wuhan, the Chinese province of Hubei, in December 2019, and it quickly spread to other parts of the world. Objective: To assess the efficacy of MP in ARDS COVID-19 patients who admitted to ICU. Patients and Methods: Prospective cohort study, the data collection was among COVID 19 positive patients with severe acute respiratory syndrome attending the Intensive care unit One-hundred patients were included in this study: MP treated group included forty patients who exposed to high doses of MP 1 gm first day then 500 mg for other 4 days with standard treatment for COVID 19.Non MP treated group included sixty patients with standard care for COVID 19 alone. Results: A total of 100 patients with ARDS-COVID 19 positive were included in this study (40 MP treated and 60 non MP treated control group). The outcome for both group after 5 days has shown that; in exposed group: (27) 67.5 % of patients were improved, (7) 17.5 %of patients were worsen and (6) 15 %of patients died. In non MP treated group: 21.7 %of patients were improved, ( 40) 66.7 %of patients were worsen and(7) 11.7 %of patients were died and there were a significant association in the outcome and MP expose. Conclusion: In patients with ARDS COVID 19 positive, early administration of pulse dose of methylprednisolone was associated with remarkable improvement of general condition, vital signs and SPO2 ,and inflammatory markers .

Investigation of the linear accelerator low dose rate mode for pulsed low-dose-rate radiotherapy delivery

Purpose. Pulsed volumetric modulated arc therapy (VMAT) was proposed as an advanced treatment that combines the biological benefits of pulsed low dose rate (PLDR) and the dosimetric benefits of the intensity-modulated beams. In our conventional pulsed VMAT technique, a daily fractional dose of 200 cGy is delivered in 10 arcs with 3 min intervals between the arcs. In this study, we are testing the feasibility of pulsed VMAT that omits the need to split into ten arcs and excludes any beam-off gaps. Methods. The study was conducted using computed tomographic images of 24 patients previously treated at our institution with the conventional PLDR technique. Our newly installed Elekta machine has a low dose rate option on the order of 25 MU min−1. PLDR requires an effective dose rate of 6.7 cGy min−1 with attention being paid to the maximum dose received within any point within the target not to exceed 13 cGy min−1. The quality of treatment plans was judged based on dose-volume histograms, isodose distribution, dose conformality to the target, and target dose homogeneity. The dose delivery accuracy was assessed by measurements using the MatriXX Evolution 2D array system. Results. All cases were normalized to cover 95% of the target volume with 100% of the prescription dose. The average conformity index was 1.03 ± 0.08 while the average homogeneity index was 1.05 ± 0.02. The maximum reported dose rate at any point within the target was 10.44 cGy min−1. The mean dose rate for all pulsed VMAT plans was 6.88 ± 0.1 cGy min−1. All cases passed our gamma analysis with an average passing rate of 99.00% ± 0.48%. Conclusion. The study showed the applicability of planning pulsed VMAT using Eclipse and its successful delivery on our Elekta linac. Pulsed VMAT using the machine’s low dose rate mode is more efficient than our previous pulsed VMAT delivery.

Image-guided brachytherapy for pediatric bladder and/or prostate rhabdomyosarcoma: toward an increased personalization of treatment.: Brachytherapy in uro-pediatric rhabdomyosarcoma

IntroductionRhabdomyosarcoma (RMS) is the most common soft tissue cancer in children. Around 15% of RMS involve the bladder and/or prostate (BP). Overall survival is around 85%. After chemotherapy, patients receive local treatment based on surgery and/or radiotherapy. In recent decades, image guidance and pulsed dose-rate (PDR) brachytherapy have made it possible to personalize treatment, reduce radiation-related toxicity, while maintaining a good tumor control. We report one of the largest series of image-guided brachytherapy for pediatric RMS BP. Material and methodsThe clinical and dosimetric parameters of children treated with brachytherapy for BP RMS between July 2014 and September 2020 were retrospectively reviewed. Patients were treated with a multimodal conservative approach, combining partial conservative surgery (preservation of the bladder neck and urethra), followed by an interstitial brachytherapy procedure. Iridium-192 PDR treatment was administered on the basis of CT and MRI planning. Toxicities were reported according to version 4.0 of the Common Terminology Criteria for Adverse Events. ResultsA total of 75 patients were identified, with a median age of 29 months (range 2–84) at diagnosis. The median brachytherapy dose was 60.06 Gy (143 pulses, 0.42 Gy/pulse). With a median follow-up of 44.1 months (range 0.7–90), the 5-year OS and PFS rates were 97.3% and 92% respectively. Median D50% for the bladder and D1cc for the rectum were 38.6 Gy and 49 Gy respectively. The 5-year probability of survival without severe late urinary toxicity (grade 3 or higher) was estimated at 78.8% (CI95%: 68.1–91.1). A total of 9.3% of children experienced grade 2 or 3 late rectal toxicity. ConclusionsImage-guided PDR brachytherapy offers a personalized treatment for pediatric BP RMS, with a favorable therapeutic index. No prognostic factors for urinary toxicity have been identified. Multicenter studies with larger numbers of patients are needed to clarify these data.

A case of MERS presenting with acute motor aphasia and tetraparesis and literature review

BackgroundMild encephalopathy wıth reversible splenial lesions (MERS) are a clinical–radiological diagnosis that can be diagnosed with radiological imaging and can be accompanied by impaired consciousness, aphasia, headache, and paralysis. MERS can be divided into two different types based on radiological findings; Involvement of the splenium is seen in type 1, and involvement of the splenium and deep white matter is seen in type 2. MERS Type 2 is very rare in adults. Here, we describe a patient diagnosed with MERS Type 2 and our therapeutic intervention.Case presentationA 22-year-old woman presented with slurred speech, weakness in the extremities and headache that started 14 h ago. The patient had sore throat and fever of 37.6 °C for 2 days, and medical history or family history were unremarkable. Neurological examination revealed that she was conscious, cooperative, with no signs of meningeal irritation. Speech comprehension, naming, and repetition were preserved, motor examination revealed 5/5 left upper extremity strength, 4/5 right upper extremity strength, and 2/5 bilateral lower extremity strength. Diffusion-weighted magnetic resonance imaging (MRI-DWI) revealed bilateral deep white matter and splenium symmetrical diffusion restriction. Blood tests showed high C-reactive protein (CRP) and no leukocytosis. No cells were detected in the cerebrospinal fluid (CSF), protein was 151 mg/dl, glucose was within normal limits. The patient, who developed quadriparesis during follow-up, was started on pulse dose steroids. Neurological examination improved to patient’s baseline at the 12th hour of treatment. In the 72nd hour control MRI-DWI, it was seen that the lesions had regressed. Culture/Polymerase chain reaction (PCR) for bacterial/viral infection agents came back negative. After steroids were given for 5 days, patient was discharged at her baseline.ConclusionsMERS is a rare diagnosis in adults and can be radiologically confused with acute toxic leukoencephalopathy. It can be distinguished clinically by the absence of prior infection, fever, and toxic agent exposure. Although there is no consensus in the literature regarding the treatment, the clinical picture improved rapidly after steroid in our case. Despite being rare, it should be considered in the differential diagnosis of patients with deep white matter lesions in adults.

Ruminal passage rate and digestibility of fiber from dairy cows consuming diets containing alfalfa and orchardgrass hays with different concentrations of undegradable neutral detergent fiber (uNDF)

This study aimed to evaluate the effect of feeding diets with different fractions of undegraded NDF (uNDF) and potentially degradable (pdNDF) on ruminal NDF degradation and passage kinetics of lactating dairy cows. Six rumen-cannulated (533 ± 43 kg BW and 122 ± 15 DIM) and 6 non-cannulated (558 ± 62 kg BW and 126 ± 16 DIM) primiparous Holstein dairy cows were randomly assigned to 1 of 2 experimental diets in a crossover design with 2 28-d periods. The experimental diets were formulated to include either alfalfa hay (ALFA) or orchardgrass hay (ORCH) in addition to corn silage. Rations were formulated to contain 30% NDF (DM basis), where the concentrate, corn silage, and each of the hays provided one third of the dietary NDF. The marker dilution technique was used to measure the passage rate utilizing a pulse dose of marked corn silage fiber. On d 17 and 24 of each period, ruminal contents were evacuated to determine ruminal pool size. Following the return of the ruminal contents containing the pulse dose of marked corn silage to the rumen, ruminal grab samples were collected at 0, 3, 6, 9, 12, 24, 36, 48, 60, and 72 h. Samples from each time point were separated into solids and liquid, and the solids were analyzed for NDF, uNDF, and marker concentration. Alfalfa hay had a higher concentration of CP (16.4 vs. 10.7%) and a lower concentration of NDF (38.0 vs. 63.2) than orchardgrass hay. Alfalfa hay had a greater concentration of uNDF than orchardgrass hay (36.5 vs. 32.8% uNDF; NDF basis). Cows consuming the ALFA diet had similar milk yield (39.1 kg/d) and similar milk fat and protein concentrations (3.72% fat and 3.24% protein, respectively) than cows consuming the ORCH diet. Cows consuming the ALFA diet consumed more DM (26.7 vs. 24.6 kg/d) and uNDF (2.7 vs. 2.3 kg/d), than cows consuming the ORCH diet. Cows consuming the ALFA diet digested more NDF and pdNDF than cows consuming the ORCH diet (3.3 vs. 2.8 kg/d). Even though cows consuming the ALFA diet had a smaller pool size of NDF than cows consuming the ORCH diet (5.4 vs. 6.7 kg), the pool size of uNDF did not differ between groups (2.4 kg). Cows consuming the ALFA diet had a faster rate of passage of uNDF than cows consuming the ORCH diet (5.02 vs. 4.03%/h). This translated into a shorter mean retention time of uNDF for cows consuming the ALFA diet relative to cows consuming the ORCH diet (21.0 vs. 26.2 h). In conclusion, cows consuming diets containing alfalfa hay had a faster ruminal passage rate and a shorter mean retention time of uNDF than cows consuming diets containing orchardgrass hay, and this occurred despite the greater concentrations of dietary uNDF in the alfalfa-based diet. These findings suggest that the kinetics of ruminal digestion and passage influence NDF degradation in ways beyond uNDF concentration or forage quality.

Model based analysis of trace metal dosing strategies to improve methane yield in anaerobic digestion systems

Favourable effects of trace metals (TMs) on regulating anaerobic digestion (AD) performance are extensively utilised to improve methane yield. This study discusses a model-based approach to find out the best TM dosing strategies. The model has been applied to compare continuous, preloading, pulse dosing and in-situ loading. Simulations were also carried out to comprehend appropriate dosing form, dosing time and quantity of metals to be dosed. Model results show that the best way to dose TMs is repeated pulse dosing at low concentration levels in the optimum range with high frequency. Best dosing strategy for the system in this study was found to be 5 µM pulse loading at 5 days intervals as it gave maximum methane production and low effluent metal loss. Preferable dosing form depends on reactor configuration and this has been verified after model calibration with experimental data. Easily dissociable metal chlorides are ideal for continuous reactors.

MOSkin dosimetry for an ultra-high dose-rate, very high-energy electron irradiation environment at PEER

FLASH radiotherapy, which refers to the delivery of radiation at ultra-high dose-rates (UHDRs), has been demonstrated with various forms of radiation and is the subject of intense research and development recently, including the use of very high-energy electrons (VHEEs) to treat deep-seated tumors. Delivering FLASH radiotherapy in a clinical setting is expected to place high demands on real-time quality assurance and dosimetry systems. Furthermore, very high-energy electron research currently requires the transformation of existing non-medical accelerators into radiotherapy research environments. Accurate dosimetry is crucial for any such transformation. In this article, we assess the response of the MOSkin, developed by the Center for Medical Radiation Physics, which is designed for on-patient, real-time skin dose measurements during radiotherapy, and whether it exhibits dose-rate independence when exposed to 100 MeV electron beams at the Pulsed Energetic Electrons for Research (PEER) end-station. PEER utilizes the electron beam from a 100 MeV linear accelerator when it is not used as the injector for the ANSTO Australian Synchrotron. With the estimated pulse dose-rates ranging from (7.84±0.21)×105 Gy/s to (1.28±0.03)×107 Gy/s and an estimated peak bunch dose-rate of (2.55±0.06)×108 Gy/s, MOSkin measurements were verified against a scintillating screen to confirm that the MOSkin responds proportionally to the charge delivered and, therefore, exhibits dose-rate independence in this irradiation environment.

Individualized 3D-printed applicators for magnetic resonance imaging-guided brachytherapy in nasal vestibule cancer

Background and purposeBrachytherapy is treatment of choice for early stage nasal vestibule cancer. Over the years improvements were achieved by means of image guided target definition, interstitial implant techniques and also individual mold techniques. The aim of this study was to improve the technique of the implant so that the need for interstitial catheters can be limited by making use of patient individualized 3D-printed applicators. Materials and MethodsIn 19 patients 3D-printed applicators were used to deliver pulse dose rate (PDR) brachytherapy. All patients underwent computed tomography (CT) and magnetic resonance imaging (MRI). A pre-plan with tumor delineation and manually optimized catheter positions to achieve tumor coverage was made. Based on the pre-plan a 3D-printed applicator was manufactured. Dose was evaluated by several indices: Conformity Index, Healthy Tissues Conformity Index, Dose Homogeneity Index, Dose non-uniformity ratio, Conformal index and high dose (HD) index. ResultsA high target coverage was achieved, with a median V100%CTV of 99.1 % (range, 81.8–100 %) and median CI of 0.99 (range, 0.82–1.00), as well as a median V0.7GyGTV of 100 % (range, 93.0–100 %). The median HD was 0.39 (range, 0.20–0.83). Interstitial catheters were needed in 12 patients. None of the patients developed grade ≥ II toxicity within the median follow up of 18 months. ConclusionsThis study shows that using 3D-printed applicators limits the need for interstitial catheters and also limits the high doses in normal tissue.

ETV6::RUNX1 Acute Lymphoblastic Leukemia: how much therapy is needed for cure?

Recent trials show 5-year survival rates >95% for ETV6::RUNX1 Acute Lymphoblastic Leukemia (ALL). Since treatment has many side effects, an overview of cumulative drug doses and intensities between eight international trials is presented to characterize therapy needed for cure. A meta-analysis was performed as a comprehensive summary of survival outcomes at 5 and 10 years. For drug dose comparison in non-high risk trial arms, risk group distribution was applied to split the trials into two groups: trial group A with ~70% (range: 63.5–75%) of patients in low risk (LR) (CCLSG ALL2004, CoALL 07-03, NOPHO ALL2008, UKALL2003) and trial group B with ~45% (range: 38.7–52.7%) in LR (AIEOP-BFM ALL 2000, ALL-IC BFM ALL 2002, DCOG ALL10, JACLS ALL-02). Meta-analysis did not show evidence of heterogeneity between studies in trial group A LR and medium risk (MR) despite differences in treatment intensity. Statistical heterogeneity was present in trial group B LR and MR. Trials using higher cumulative dose and intensity of asparaginase and pulses of glucocorticoids and vincristine showed better 5-year event-free survival but similar overall survival. Based on similar outcomes between trials despite differences in therapy intensity, future trials should investigate, to what extent de-escalation is feasible for ETV6::RUNX1 ALL.

Average dose rate is the primary determinant of lipid peroxidation in liposome membranes exposed to pulsed electron FLASH beam

BackgroundLipid peroxidation, a self-propagating chain reaction that oxydates lipid molecules, contributes to harmful effects of ionizing radiation. A decrease in peroxidation at higher dose rates could play a role in the FLASH sparing effect. PurposeWe explored how lipid peroxidation induced by FLASH (>100 Gy/s) and conventional (CONV, <0.2 Gy/s) radiation depends on lipid concentration and content of polyunsaturated fatty acids (PUFA). Additionally, we investigated the correlation between the lipid peroxidation and the main beam parameters characterizing pulsed electron beams, namely the dose per pulse (DRp) and the average dose rate (DRav). MethodsWe employed phosphatidylcholine (PC) liposomes as a model of biological membranes. Suspensions of liposomes containing different proportions of linoleic acid (LA) were prepared at various concentrations and irradiated at FLASH and CONV dose rates. Additionally, the liposomes were exposed to beams characterized by diverse combinations of DRp and DRav. The extent of lipid peroxidation was assessed by monitoring oxygen consumption (ΔpO2) and measuring the yield of malondialdehyde (MDA), and in certain instances, of lipid peroxides (LOOH). ResultsRegardless of the radiation dose, liposome concentration or LA content, ΔpO2 and the yield of MDA were significantly lower for FLASH than for CONV irradiation. Increase in the proportion of readily oxidizable LA in the lipid had negative effect on the MDA yield but correlated positively with ΔpO2 and LOOH yield. Exposing liposomes to beams operating at different pulse repetition frequencies, while keeping the total dose and DRp constant, resulted in markedly different ΔpO2 and MDA yields. In contrast, DRav was found to exhibit stable correlation with both MDA yield and ΔpO2. ConclusionsIrradiation at FLASH dose rates produces lower yield of lipid peroxidation in PUFA-containing artificial PC membranes than CONV irradiation under all tested conditions. Time-averaged dose rate, in contrast to pulse dose rate, was the critical parameter determining the level of lipid peroxidation induced by pulsed electron beams.

Acute intracardiac electrogram changes and their relation to pulsed field ablation dose in porcine left ventricle

Abstract Background Pulsed field ablation (PFA) is an emerging cardiac ablation modality based on irreversible electroporation with promising preclinical and clinical results. Acute reduction of intracardiac electrograms (bipolar iEGMs) is consistently observed, similar to other ablation modalities, e.g. radiofrequency ablation. We and others have previously reported lesion size dependence on PFA dosing. However, the relevance of iEGM changes and their dependence on the PFA dose is not established. Furthermore, our study shows that unipolar iEGM signals may contain additional information about the effects of PFA in cardiac tissue. Purpose To quantify the effect of different PFA dosing on changes observed in bipolar and unipolar iEGMs within 5 minutes after the ablation. Methods In total, PFA was applied endocardially at 40 sites in the left ventricles of 8 pigs via a 5 mm tip catheter using a modified decapolar catheter in the inferior vena cava for current return (all electrodes). The following PFA doses (voltage and number of pulse trains) were used: 1000 V, 4 trains; 1300 V, 4 trains; 1500 V, 1 train; 1500 V, 4 trains; 1500 V, 8 trains; and 1500 V, 16 trains. For standard bipolar iEGMs (30 Hz – 500 Hz) the reduction in peak-to-peak amplitude after PFA was considered as a measure of the effect. In addition, unipolar iEGMs (0.5 Hz – 500 Hz) were decomposed into non-overlapping frequency sub-bands with Daubechies order 6 discrete wavelet transform (Figure 1A) allowing separate analysis in high-frequency (HF) and low-frequency (LF) ranges (63 Hz – 500 Hz and 0.5 Hz – 8 Hz, respectively). Results In total, 30 standard bipolar and 35 unipolar iEGMs (with at least 3.5 minutes of artefact-free post-ablation duration) were analysed. No dose dependency was observed for standard bipolar iEGMs within 5 minutes post-ablation (data not shown). However, the HF and LF content of unipolar iEGMs revealed opposing effects: a decrease in the HF and an increase in the LF content. Correlation with the dose was clearer in the LF content 3.5 minutes post-ablation, the difference being significant (p&amp;lt;0.05) between the lowest and the highest doses (Figure 1B and C). Discussion The decrease in HF content could reflect electrical silencing, ie. stunning of locally affected cardiomyocytes, most likely caused by irreversibly electroporated (ablated) cells located close to the catheter tip and by reversibly electroporated or otherwise temporarily silenced cells in adjacent tissue. The increase in LF content could reflect the current-of-injury effect, which is a broader area phenomenon derived from electrical potential differences between affected (reversibly and irreversibly electroporated) and non-affected regions. Conclusion Unipolar iEGMs acquired with a broadened frequency range and decomposed into HF and LF content provide new insight into the effects of PFA and correlate with PFA dosing in this pre-clinical porcine model.

First comparison of single-tip versus single-shot pulsed field ablation for pulmonary vein isolation in paroxysmal atrial fibrillation: interim analysis of a randomized trial

Abstract Background Non-thermal pulsed field ablation (PFA) is an emerging technology to perform pulmonary vein isolation (PVI) for atrial fibrillation (AF). Different PFA systems are available, but no comparative data exist. Purpose Randomized trial to compare single-tip versus single-shot PFA for initial PVI in paroxysmal AF patients. Methods In this single-center trial, paroxysmal AF patients are prospectively enrolled and 1:1 randomized in the single-tip or single-shot PFA group. Single-tip PVI is performed using a PFA generator and a 3.5mm contact-force enabled ablation catheter guided by 3D mapping system. The pulsed electric field dosing is 25 Ampere (A) (anterior) and 22 A (posterior), respectively. In the single-shot PVI group, a 31 or 35mm pentaspline PFA catheter is used for fluoroscopy-guided PVI. Eight PFA applications (2.0 kV) are applied per PV. In this interim analysis, acute efficacy, safety and short term clinical outcome within the 3 months blanking period were assessed. A subset of patients underwent cerebral MRI to detect silent lesions. Results To date, 50 patients were enrolled and underwent PVI in conscious sedation (25 single-tip, 25 single-shot, 63 ± 5 years, 42% female, CHA2DS2-VASc 2 [1-3]). There were no differences in baseline characteristics. Acute PVI was achieved in 100%. In the single-tip group, total procedure time was significantly longer (125 ± 31 min vs. 44 ± 12 min, p &amp;lt;0.001) and fluoroscopy time was significantly shorter (4 ± 2 min vs. 15 ± 6 min, p &amp;lt;0.001) as compared to the single-shot group. One groin hematoma was noted in the single-shot group. In the single-tip group, 1 aneurysm spurium was detected and 1 pericardial tamponade requiring drainage resulted from coughing during single-tip PFA while no real-time visualization of the catheter was available. No permanent sequelae occurred. There were no PFA specific complications and no cerebral embolisms were detected in all 14 MRI scans. At 3 months, 92% (single-shot group) and 80% in the single-tip group were free from arrhythmia (p=0.42). AF recurrences in the blanking period occurred in 2 patients in the single-shot group and in 5 patients in the single-tip group after a median of 2 [1-5] days following the procedure. Conclusions In this interim analysis of a randomized trial, single-shot or single-tip PFA for PVI both demonstrated high acute efficacy and a favourable 3 months clinical outcome. Procedural time was significantly longer in the single-tip PFA group. No silent lesions were detected in cerebral MRI. Non-availability of real-time visualization and contact-force information of the single-tip ablation catheter during energy application is a current technical limitation that could be associated with complications.

The impact of clinical audits on patient radiation exposure for device procedures

Abstract Background Clinical audits aim to ensure ideal use of ionizing radiation in clinical practice. Since it became mandatory by Swiss law in 2018, such an audit also took place in our Cardiac Pacing and Electrophysiology Division at the University Heart Center. Purpose To establish local diagnostic reference levels (DRLs) for specific procedures and to examine if patient radiation exposure was reduced after the clinical audit. Methods Retrospective cohort study including patients from October 2018 to October 2020 who underwent device implantation, including pacemakers, implantable cardioverter defibrillators (ICD), cardiac resynchronization therapy (CRT), or lead extraction / device explantation. Main measures to reduce radiation exposure after the audit were lower pulsed fluoroscopy frame rates and dose characteristics at baseline. Patient radiation exposure was evaluated with the dose-area product (DAP), cumulative dose, fluoroscopy time, and the number of cine acquisitions. Secondary endpoints included the effective dose, the acute procedural success rate and 30-day complications. Data were collected from a dose management system and cross-checked for accuracy with the patient information system. The third quartiles were set as local DRLs. Data before and after the clinical audit were compared. Results A total of 541 patients (45.7 % before the audit, 54.3% after the audit) were included. 28.3% had a conventional pacemaker, 22.0% a leadless pacemaker, 21.1% an ICD, and 17.2% a CRT implantation. Lead extraction / device explantation was undergone by 11.5% of patients. The local DRLs (including all procedures before and after the audit) for the DAP were significantly lower as compared to national DRLs (6.2 dGy.cm2 versus 300 dGy.cm2 for conventional pacemakers; 7.6 dGy.cm2 versus 200 dGy.cm2 for ICDs, 203 dGy.cm2 versus 570 dGy.cm2 for CRTs). After the audit, DAP (Figure 1), cumulative dose, effective dose and the number of cine acquisition significantly decreased for conventional pacemakers (p-value ≤ 0.04), whereas no significant differences were observed for the other procedures. The acute procedural success rate (98.4 vs 98.9%) and the 30-day complications (4.0 vs 7.8%) were not significantly different before and after the audit. Conclusions The clinical audit in our institution led to a significant reduction of radiation exposure for patients during pacemaker implantations. Regarding DRLs, local values were far below national DRLs, which suggests that national DRLs need to be updated more regularly. Our study highlights the importance of clinical audits and the need for more research in this field.