Multi-institutional experimental validation of online adaptive proton therapy workflows.

OBJECTIVE: To experimentally validate two online adaptive proton therapy (APT) workflows using Gafchromic EBT3 films and optically stimulated luminescent dosimeters (OSLDs) in an anthropomorphic head-and-neck phantom. Approach: A three-field proton plan was optimized on the planning CT of the head-and-neck phantom with 2.0 Gy(RBE) per fraction prescribed to the clinical target volume. Four fractions were simulated by varying the internal anatomy of the phantom. Three distinct methods were delivered: daily adaptive proton therapy researched by the Paul Scherrer Institute (DAPT_PSI), online adaptation researched by the Massachusetts General Hospital (OA_MGH), and a non-adaptive (NA) workflow. All methods were implemented and measured at PSI. DAPT_PSI performed full online replanning based on analytical dose calculation, optimizing to the same objectives as the initial treatment plan. OA_MGH performed Monte-Carlo-based online plan adaptation by only changing the fluences of a subset of proton beamlets, mimicking the planned dose distribution. NA delivered the initial plan with a couch-shift correction based on in-room-imaging. For all 12 deliveries, two films and two sets of OSLDs were placed at different locations in the phantom. Main results: Both adaptive methods showed improved dosimetric results compared to NA. For film measurements in the presence of anatomical variations, the [min-max] gamma pass rates (3%/3 mm) between measured and clinically approved doses were [91.5%-96.1%], [94.0%-95.8%], and [67.2%-93.1%] for DAPT_PSI, OA_MGH, and NA, respectively. The OSLDs confirmed the dose calculations in terms of absolute dosimetry. Between the two adaptive workflows, OA_MGH showed improved target coverage, while DAPT_PSI showed improved normal tissue sparing, particularly relevant for the brainstem. Significance: This is the first multi-institutional study to experimentally validate two different concepts with respect to online adaptive proton therapy workflows. It highlights their respective dosimetric advantages, particularly in managing interfractional variations in patient anatomy that cannot be addressed by non-adaptive methods, such as internal anatomy changes.

Absence of Tissue-Sparing Effects in Partial Proton FLASH Irradiation in Murine Intestine.

Ultra-high dose rate irradiation has been reported to protect normal tissues more than conventional dose rate irradiation. This tissue sparing has been termed the FLASH effect. We investigated the FLASH effect of proton irradiation on the intestine as well as the hypothesis that lymphocyte depletion is a cause of the FLASH effect. A 16 × 12 mm2 elliptical field with a dose rate of ~120 Gy/s was provided by a 228 MeV proton pencil beam. Partial abdominal irradiation was delivered to C57BL/6j and immunodeficient Rag1-/-/C57 mice. Proliferating crypt cells were counted at 2 days post exposure, and the thickness of the muscularis externa was measured at 280 days following irradiation. FLASH irradiation did not reduce the morbidity or mortality of conventional irradiation in either strain of mice; in fact, a tendency for worse survival in FLASH-irradiated mice was observed. There were no significant differences in lymphocyte numbers between FLASH and conventional-dose-rate mice. A similar number of proliferating crypt cells and a similar thickness of the muscularis externa following FLASH and conventional dose rate irradiation were observed. Partial abdominal FLASH proton irradiation at 120 Gy/s did not spare normal intestinal tissue, and no difference in lymphocyte depletion was observed. This study suggests that the effect of FLASH irradiation may depend on multiple factors, and in some cases dose rates of over 100 Gy/s do not induce a FLASH effect and can even result in worse outcomes.

Proton FLASH effects on mouse skin at different oxygen tensions.

Objective. Irradiation at FLASH dose rates (>40 Gy s-1) has received great attention due to its reported normal tissue sparing effect. The FLASH effect was originally observed in electron irradiations but has since been shown to also occur with both photon and proton beams. Several mechanisms have been proposed to explain the tissue sparing at high dose rates, including effects involving oxygen, such as depletion of oxygen within the irradiated cells. In this study, we investigated the protective role of FLASH proton irradiation on the skin when varying the oxygen concentration.Approach. Our double scattering proton system provided a 1.2 × 1.6 cm2elliptical field at a dose rate of ∼130 Gy s-1. The conventional dose rate was ∼0.4 Gy s-1. The legs of the FVB/N mice were marked with two tattooed dots and fixed in a holder for exposure. To alter the skin oxygen concentration, the mice were breathing pure oxygen or had their legs tied to restrict blood flow. The distance between the two dots was measured to analyze skin contraction over time.Main results. FLASH irradiation mitigated skin contraction by 15% compared to conventional dose rate irradiation. The epidermis thickness and collagen deposition at 75 d following 25 to 30 Gy exposure suggested a long-term protective function in the skin from FLASH irradiation. Providing the mice with oxygen or reducing the skin oxygen concentration removed the dose-rate-dependent difference in response.Significance. FLASH proton irradiation decreased skin contraction, epidermis thickness and collagen deposition compared to standard dose rate irradiations. The observed oxygen-dependence of the FLASH effect is consistent with, but not conclusive of, fast oxygen depletion during the exposure.

Al2O3:C optically stimulated luminescence dosimeters (OSLDs) for ultra-high dose rate proton dosimetry.

The response of Al2O3:C optically stimulated luminescence detectors (OSLDs) was investigated in a 250 MeV pencil proton beam. The OSLD response was mapped for a wide range of average dose rates up to 9000 Gy s-1, corresponding to a ∼150 kGy s-1instantaneous dose rate in each pulse. Two setups for ultra-high dose rate (FLASH) experiments are presented, which enable OSLDs or biological samples to be irradiated in either water-filled vials or cylinders. The OSLDs were found to be dose rate independent for all dose rates, with an average deviation <1% relative to the nominal dose for average dose rates of (1-1000) Gy s-1when irradiated in the two setups. A third setup for irradiations in a 9000 Gy s-1pencil beam is presented, where OSLDs are distributed in a 3 × 4 grid. Calculations of the signal averaging of the beam over the OSLDs were in agreement with the measured response at 9000 Gy s-1. Furthermore, a new method was presented to extract the beam spot size of narrow pencil beams, which is in agreement within a standard deviation with results derived from radiochromic films. The Al2O3:C OSLDs were found applicable to support radiobiological experiments in proton beams at ultra-high dose rates.

Author Correction: Risk factors for serious morbidity, prolonged length of stay and hospital readmission after laparoscopic appendectomy - results from Pol-LA (Polish Laparoscopic Appendectomy) multicenter large cohort study.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Risk factors for serious morbidity, prolonged length of stay and hospital readmission after laparoscopic appendectomy - results from Pol-LA (Polish Laparoscopic Appendectomy) multicenter large cohort study.

Laparoscopic appendectomy (LA) for treatment of acute appendicitis has gained acceptance with its considerable benefits over open appendectomy. LA, however, can involve some adverse outcomes: morbidity, prolonged length of hospital stay (LOS) and hospital readmission. Identification of predictive factors may help to identify and tailor treatment for patients with higher risk of these adverse events. Our aim was to identify risk factors for serious morbidity, prolonged LOS and hospital readmission after LA. A database compiled information of patients admitted for acute appendicitis from eighteen Polish and German surgical centers. It included factors related to the patient characteristics, peri- and postoperative period. Univariate and multivariate logistic regression models were used to identify risk factors for serious perioperative complications, prolonged LOS, and hospital readmissions in acute appendicitis cases. 4618 laparoscopic appendectomy patients were included. First, although several risk factors for serious perioperative complications (C-D III-V) were found in the univariate analysis, in the multivariate model only the presence of intraoperative adverse events (OR 4.09, 95% CI 1.32-12.65, p = 0.014) and complicated appendicitis (OR 3.63, 95% CI 1.74-7.61, p = 0.001) was statistically significant. Second, prolonged LOS was associated with the presence of complicated appendicitis (OR 2.8, 95% CI: 1.53-5.12, p = 0.001), postoperative morbidity (OR 5.01, 95% CI: 2.33-10.75, p < 0.001), conversions (OR 6.48, 95% CI: 3.48-12.08, p < 0.001) and reinterventions after primary procedure (OR 8.79, 95% CI: 3.2-24.14, p < 0.001) in the multivariate model. Third, although several risk factors for hospital readmissions were found in univariate analysis, in the multivariate model only the presence of postoperative complications (OR 10.33, 95% CI: 4.27-25.00), reintervention after primary procedure (OR 5.62, 95% CI: 2.17-14.54), and LA performed by resident (OR 1.96, 95% CI: 1.03-3.70) remained significant. Laparoscopic appendectomy is a safe procedure associated with low rates of complications, prolonged LOS, and readmissions. Risk factors for these adverse events include complicated appendicitis, postoperative morbidity, conversion, and re-intervention after the primary procedure. Any occurrence of these factors during treatment should alert the healthcare team to identify the patients that require more customized treatment to minimize the risk for adverse outcomes.

The significant impact of age on the clinical outcomes of laparoscopic appendectomy: Results from the Polish Laparoscopic Appendectomy multicenter large cohort study.

Acute appendicitis (AA) is the most common surgical emergency and can occur at any age. Nearly all of the studies comparing outcomes of appendectomy between younger and older patients set cut-off point at 65 years. In this multicenter observational study, we aimed to compare laparoscopic appendectomy for AA in various groups of patients with particular interest in the elderly and very elderly in comparison to younger adults.Our multicenter observational study of 18 surgical units assessed the outcomes of 4618 laparoscopic appendectomies for AA. Patients were divided in 4 groups according to their age: Group 1-<40 years old; Group 2-between 40 and 64 years old; Group 3-between 65 and 74 years old; and Group 4-75 years old or older. Groups were compared in terms of peri- and postoperative outcomes.The ratio of complicated appendicitis grew with age (20.97% vs 37.50% vs 43.97% vs 56.84%, P < .001). Similarly, elderly patients more frequently suffered from perioperative complications (5.06% vs 9.3% vs 10.88% vs 13.68%, P < .001) and had the longest median length of stay (3 [Interquartile Range (IQR) 2-4] vs 3 [IQR 3-5], vs 4 [IQR 3-5], vs 5 [IQR 3-6], P < .001) as well as the rate of patients with prolonged length of hospital stay (LOS) >8 days. Logistic regression models comparing perioperative results of each of the 3 oldest groups compared with the youngest one showed significant differences in odds ratios of symptoms lasting >48 hours, presence of complicated appendicitis, perioperative morbidity, conversion rate, prolonged LOS (>8 days).The findings of this study confirm that the outcomes of laparoscopic approach to AA in different age groups are not the same regarding outcomes and the clinical picture. Older patients are at high risk both in the preoperative, intraoperative, and postoperative period. The differences are visible already at the age of 40 years old. Since delayed diagnosis and postponed surgery result in the development of complicated appendicitis, more effort should be placed in improving treatment patterns for the elderly and their clinical outcome.

Measurement of 43Sc and 44Sc production cross-section with an 18MeV medical PET cyclotron.

43Sc and 44Sc are positron emitter radionuclides that, in conjunction with the ß- emitter 47Sc, represent one of the most promising possibilities for theranostics in nuclear medicine. Their availability in suitable quantity and quality for medical applications is an open issue and their production with medical cyclotrons represents a scientific and technological challenge. For this purpose, an accurate knowledge of the production cross sections is mandatory. In this paper, we report on the cross section measurement of the reactions 43Ca(p,n)43Sc, 44Ca(p,2n) 43Sc, 46Ti(p,α)43Sc, and 44Ca(p,n)44Sc at the Bern University Hospital cyclotron. A study of the production yield and purity performed by using commercially available enriched target materials is also presented.