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Introduction: Treatment of men with metastatic prostate cancer can be difficult due to the heterogeneity of response of lesions. [ 68 Ga]Ga-PSMA-11 (PSMA) PET/CT assists with monitoring and directing clinical intervention; however, the impact of response heterogeneity has yet to be related to outcome measures. The aim of this study was to assess the impact of quantitative imaging information on the value of PSMA PET/CT to assess patient outcomes in response evaluation., Patients and Methods: Baseline and follow-up (6 months) PSMA PET/CT of 162 men with oligometastatic PC treated with standard clinical care were acquired between 2015 and 2016 for analysis. An augmentative software medical device was used to track lesions between scans and quantify lesion change to categorize them as either new, increasing, stable, decreasing, or disappeared. Quantitative imaging features describing the size, intensity, extent, change, and heterogeneity of change (based on percent change in SUV total ) among lesions were extracted and evaluated for association with overall survival (OS) using Cox regression models. Model performance was evaluated using the c-index., Results: Forty-one (25%) of subjects demonstrated heterogeneous response at follow-up, defined as having at least 1 new or increasing lesion and at least 1 decreasing or disappeared lesion. Subjects with heterogeneous response demonstrated significantly shorter OS than subjects without (median OS = 76.6 months vs. median OS not reached, P < .05, c-index = 0.61). In univariate analyses, SUV total at follow-up was most strongly associated with OS (HR = 1.29 [1.19, 1.40], P < .001, c-index = 0.73). Multivariable models applied using heterogeneity of change features demonstrated higher performance (c-index = 0.79) than models without (c-index = 0.71-0.76, P < .05)., Conclusion: Augmentative software tools enhance the evaluation change on serial PSMA PET scans and can facilitate lesional evaluation between timepoints. This study demonstrates that a heterogeneous response at a lesional level may impact adversely on patient outcomes and supports further investigation to evaluate the role of imaging to guide individualized patient management to improve clinical outcomes., Competing Interests: Disclosure Financial interests: Author M.D. is supported by an AIQ Research Fellowship, a joint program established by AIQ Australia Pty. Ltd. and the University of Western Australia. Authors D.H., O.L., R.G., and T.P. are employees of AIQ Solutions. Nonfinancial interests: Author R.F. is a scientific advisory board member of AIQ Solutions., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Tumour repopulation during treatment is a well acknowledged yet still challenging aspect of cancer management. The latest research results show clear evidence towards the existence of cancer stem cells (CSCs) that are responsible for tumour repopulation, dissemination, and distant metastases in most solid cancers. Cancer stem cell quiescence and the loss of asymmetrical division are two powerful mechanisms behind repopulation. Another important aspect in the context of cancer stem cells is cell plasticity, which was shown to be triggered during fractionated radiotherapy, leading to cell dedifferentiation and thus reactivation of stem-like properties. Repopulation during treatment is not limited to radiotherapy, as there is clinical proof for repopulation mechanisms to be activated through other conventional treatment techniques, such as chemotherapy. The dynamic nature of stem-like cancer cells often elicits resistance to treatment by escaping drug-induced cell death. The aims of this scoping review are (1) to describe the main mechanisms used by cancer stem cells to initiate tumour repopulation during therapy; (2) to present clinical evidence for tumour repopulation during radio- and chemotherapy; (3) to illustrate current trends in the identification of CSCs using specific imaging techniques; and (4) to highlight novel technologies that show potential in the eradication of CSCs.

Objective: Radiobiological modelling the risks of second primary cancer (SPC) after proton therapy (PT) for childhood cranial cancer remains largely unknown. Organ-specific dose-response risk factors such as radiosensitivity require exploration. This study compared the influence of radiosensitivity data (slope of β EAR ) on children's lifetime attributable risks (LAR) of SPC development in out-of-field organs following cranial scattering and scanning PT., Methods: Out-of-field radiosensitivity parameter estimates for organs (α/β and β EAR ) were sourced from literature. Physical distances for 13 out-of-field organs were measured and input into Schneider's SPC model. Sensitivity analyses were performed as a function of radiosensitivity (α/β of 1-10 Gy) and initial slope (β EAR ) from Japanese/UK data to estimate the influence on the risk of radiation-induced SPC following scattering and scanning PT., Results: Models showed similar LAR of SPC estimates for age and sex-matched paediatric phantoms, however, for breast there was a significant increase using Japanese β EAR data. For most organs, scattering PT demonstrated a larger risk of LAR for SPC which increased with α/β., Conclusion: Breast tissue exhibited the highest susceptibility in calculated LAR risk, demonstrating the importance for accurate data input when estimating LAR of SPC., Advances in Knowledge: The findings of this study demonstrated younger female patients undergoing cranial proton therapy have a higher risk of developing second primary cancer of the breast tissue. Long-term multicenter registries are important to improve predictive radiobiological modelling studies of side effects., Competing Interests: Competing interestsNone. This work was performed while Mikaela Dell’Oro was a PhD student supported through Australian Government Research Training Program (RTP) Scholarship.

Proton-to-photon comparative treatment planning is a current requirement of Australian Government funding for patients to receive proton beam therapy (PBT) overseas, and a future requirement for Medicare funding of PBT in Australia. Because of the fundamental differences in treatment plan creation and evaluation between PBT and conventional radiation therapy with x-rays (XRT), there is the potential for a lack of consistency in the process of comparing PBT and XRT treatment plans. This may have an impact on patient eligibility assessment for PBT. The objective of these guidelines is to provide a practical reference document for centres performing proton-to-photon comparative planning and thereby facilitate national uniformity., (© 2023 The Authors. Journal of Medical Imaging and Radiation Oncology published by John Wiley & Sons Australia, Ltd on behalf of Royal Australian and New Zealand College of Radiologists.)

This study aimed at comparing the nutrient supply and dietary behaviors during a plant-based diet (PBD) combined with time-restricted eating (TRE) to standard dietary recommendations in rheumatoid arthritis patients. In this open-label, randomized, controlled clinical trial, patients were assigned to either a 7-day fast followed by an 11-week PBD including TRE (A) or a 12-week anti-inflammatory diet following official German guidelines (German Nutrition Society, DGE) (B). Dietary habits were assessed by 3-day food records at weeks -1, 4 and 9 and food frequency questionnaires. 41 out of 53 participants were included in a post-hoc per protocol analysis. Both groups had similar energy, carbohydrate, sugar, fiber and protein intake at week 4. Group A consumed significantly less total saturated fat than group B (15.9 ± 7.7 vs. 23.2 ± 10.3 g/day; p = 0.02). Regarding micronutrients, group B consumed more vitamin A, B 12 , D, riboflavin and calcium (each p ≤ 0.02). Zinc and calcium were below recommended intakes in both groups. Cluster analysis did not show clear group allocation after three months. Hence, dietary counselling for a PBD combined with TRE compared to a standard anti-inflammatory diet does not seem to lead to two different dietary clusters, i.e., actual different dietary behaviors as expected. Larger confirmatory studies are warranted to further define dietary recommendations for RA.

Background: Patients with atopic dermatitis (AD) frequently use healthy lifestyle behaviors, although their benefits are unclear. This study's aim was to investigate the effectiveness of hypnotherapy, fasting with diet adjustments, and exercise in AD patients. Methods: In a four-armed randomized controlled monocenter open explorative clinical trial, adult patients with mild-to-moderate severe AD underwent, over 16 weeks, a five-session hypnotherapy group program (HTP), a five-session intermittent fasting with diet adjustment group program (IFDP), a five-session exercise group program (EP), or no study intervention (control) as add-on to topical corticosteroid use if required. Endpoints included subjectively perceived itching on a visual analogue scale (VAS, 0-100 mm); disease severity by SCORing Atopic Dermatitis (SCORAD); and adverse events (AEs). Endpoints were analyzed descriptively in the Full Analysis Set (FAS). Due to the coronavirus disease 2019 (COVID-19) pandemic, relevant changes to the study protocol included online in addition to "in-presence" group interventions, closing the study arm EP and premature trial termination before randomization of 120 intended patients. Results: During the COVID-19 pandemic, study recruitment was poor. The FAS included 20 patients (17 female) with 35.0 ± 12.1 (mean ± standard deviation [SD]) years of age. At baseline, mean ± SD for HTP ( n  = 6), IFDP ( n  = 4), EP ( n  = 1), and control ( n  = 9) were VAS itching 63.2 ± 18.0, 65.0 ± 13.9, 43.0 mm, 62.1 ± 17.3; SCORAD 43.0 ± 13.6, 47.0 ± 21.0, 60.3, 39.1 ± 15.6. After 16 weeks, endpoints were VAS itching 26.0 ± 16.4, 31.7 ± 9.9, 23.0 mm, 39.3 ± 27.0; SCORAD 24.1 ± 12.2, 29.1 ± 19.1, 49.1, 25.5 ± 14.4. No serious AEs related to the interventions were observed. Conclusion: Despite very small groups, study results indicated potential beneficial changes to baseline in perceived itching intensity, disease severity, and disease-specific quality of life for HTP and IFDP. Therefore, further clinical trials should be performed investigating the effectiveness and safety of all interventions. Clinical Trial Registration: January 31, 2020 German Clinical Trials Register (DRKS): DRKS00020557, Universal Trial Number (UTN): U1111-1247-1512.

Background: Fasting is beneficial in many diseases, including rheumatoid arthritis (RA), with lasting effects for up to 1 year. However, existing data dates back several decades before the introduction of modern therapeutic modalities., Objective: This exploratory RCT compares the effects of a 7-day fast followed by a plant-based diet (PBD) to the effects of the dietary recommendations of the German society for nutrition (Deutsche Gesellschaft für Ernährung, DGE) on RA disease activity, cardiovascular (CV) risk factors, and well-being., Methods: In this RCT we randomly assigned 53 RA patients to either a 7-day fast followed by an 11-week PBD or a 12-week standard DGE diet. The primary endpoint was the group change from baseline to 12 weeks on the Health Assessment Questionnaire Disability Index (HAQ-DI). Further outcomes included other disease activity scores, body composition, and quality of life., Results: Of 53 RA patients enrolled, 50 participants (25 per group) completed the trial and were included into the per-protocol analysis. The primary endpoint was not statistically significant. However, HAQ-DI improved rapidly in the fasting group by day 7 and remained stable over 12 weeks (Δ-0.29, p = 0.001), while the DGE group improved later at 6 and 12 weeks (Δ-0.23, p = 0.032). DAS28 ameliorated in both groups by week 12 (Δ-0.97, p < 0.001 and Δ-1.14, p < 0.001; respectively), with 9 patients in the fasting but only 3 in the DGE group achieving ACR50 or higher. CV risk factors including weight improved stronger in the fasting group than in the DGE group (Δ-3.9 kg, p < 0.001 and Δ-0.7 kg, p = 0.146)., Conclusions: Compared with a guideline-based anti-inflammatory diet, fasting followed by a plant-based diet showed no benefit in terms of function and disability after 12 weeks. Both dietary approaches had a positive effect on RA disease activity and cardiovascular risk factors in patients with RA., Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT03856190, identifier: NCT03856190., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hartmann, Dell'Oro, Spoo, Fischer, Steckhan, Jeitler, Häupl, Kandil, Michalsen, Koppold-Liebscher and Kessler.)

Background and Purpose: Proton therapy (PT) can reduce side effects for paediatric cranial malignancies. Despite the high number of paediatric patients treated with PT, radiation induced risk factors for second primary cancer (SPC) in out-of-field organs are unknown. This study estimated lifetime attributable risk (LAR) of SPC as a function of age and sex for out-of-field organs following passive scattering and scanning beam PT in paediatric brain tumours., Materials and Methods: Measured neutron dose equivalent spectra for scattered and scanning PT were sourced from literature. The physical distance of 12 measured organs from paediatric CT dataset-based phantoms (5, 9 and 13 years-of-age) were applied to Schneider et al.'s analytical model using MATLAB (R2020B) to calculate the organ-specific LAR of SPC., Results: Scanning beam PT demonstrated smaller LAR (per 10,000 person years) of SPC compared to scattering. This was prominent for more radiosensitive organs, including the lung (320 vs 50), breast (1000 vs 150) and thyroid (350 vs 75), but not for all (i.e., rectum and reproductive organs were <10). For most organs, LAR was highest for 5-year-old females (i.e., breast LAR was 1,000 higher than for 13-year-olds), however, outliers existed for distal organs (i.e., stomach and lung)., Conclusion: There was large variation in LAR estimates of out-of-field organs based on measured neutron dose equivalents. Younger female cranial paediatric patients were found at higher risk compared to males, especially for passive scattering PT. Not all organs had improved LAR using scanning beam PT for younger age groups., Competing Interests: Conflict of interest None., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Purpose: Proton therapy (PT) is broadly accepted as the gold standard of care for pediatric patients with cranial cancer. The superior dose distribution of PT compared to photon radiotherapy reduces normal tissue complication probability (NTCP) for organs at risk. As NTCPs for pediatric organs are not well understood, clinics generally base radiation response on adult data. However, there is evidence that radiation response strongly depends on the age and even sex of a patient. Furthermore, questions surround the influence of individual intrinsic radiosensitivity (α/β ratio) on pediatric NTCP. While the clinical pediatric NTCP data is scarce, radiobiological modeling and sensitivity analyses can be used to investigate the NTCP trends and its dependence on individual modeling parameters. The purpose of this study was to perform sensitivity analyses of NTCP models to ascertain the dependence of radiosensitivity, sex, and age of a child and predict cranial side-effects following intensity-modulated proton therapy (IMPT) and intensity-modulated radiotherapy (IMRT)., Methods: Previously, six sex-matched pediatric cranial datasets (5, 9, and 13 years old) were planned in Varian Eclipse treatment planning system (13.7). Up to 108 scanning beam IMPT plans and 108 IMRT plans were retrospectively optimized for a range of simulated target volumes and locations. In this work, dose-volume histograms were extracted and imported into BioSuite Software for radiobiological modeling. Relative-Seriality and Lyman-Kutcher-Burman models were used to calculate NTCP values for toxicity endpoints, where TD50, (based on reported adult clinical data) was varied to simulate sex dependence of NTCP. Plausible parameter ranges, based on published literature for adults, were used in modeling. In addition to sensitivity analyses, a 20% difference in TD50 was used to represent the radiosensitivity between the sexes (with females considered more radiosensitive) for ease of data comparison as a function of parameters such as α/β ratio., Results: IMPT plans resulted in lower NTCP compared to IMRT across all models (p < 0.0001). For medulloblastoma treatment, the risk of brainstem necrosis (> 10%) and cochlea tinnitus (> 20%) among females could potentially be underestimated considering a lower TD50 value for females. Sensitivity analyses show that the difference in NTCP between sexes was significant (p < 0.0001). Similarly, both brainstem necrosis and cochlea tinnitus NTCP varied significantly (p < 0.0001) across tested α/β as a function of TD50 values (assumption being that TD50 values are 20% lower in females). If the true α/β of these pediatric tissues is higher than expected (α/β ∼ 3), the risk of tinnitus for IMRT can significantly increase (p < 0.0001)., Conclusion: Due to the scarcity of pediatric NTCP data available, sensitivity analyses were performed using plausible ranges based on published adult data. In the clinical scenario where, if female pediatric patients were 20% more radiosensitive (lower TD50 value), they could be up to twice as likely to experience side-effects of brainstem necrosis and cochlea tinnitus compared to males, highlighting the need for considering the sex in NTCP models. Based on our sensitivity analyses, age and sex of a pediatric patient could significantly affect the resultant NTCP from cranial radiotherapy, especially at higher α/β values., (© 2021 American Association of Physicists in Medicine.)

Background: Previous studies have shown beneficial effects of therapeutic fasting and plant-based dietary interventions on disease activity in patients with rheumatoid arthritis (RA) for a duration of up to 1 year. To date, the effects of such interventions on the gut microbiome and on modern diagnostic markers in patients with RA have not been studied. This trial aims to investigate the clinical effects of therapeutic fasting and a plant-based diet in patients with RA, additionally considering current immunological diagnostic tools and microbiome analyses., Methods/design: This trial is an open-label, single-centre, randomised, controlled, parallel-group clinical trial. We will randomly assign 84 patients with RA under a stable standard therapy to either (1) therapeutic fasting followed by a plant-based dietary intervention or (2) to a conventional nutritional counselling focusing on an anti-inflammatory dietary pattern according to the recommendations of the Deutsche Gesellschaft für Ernährung (German society for nutrition). Primary outcome parameter is the group difference from baseline to 12 weeks on the Health Assessment Questionnaire (HAQ). Other secondary outcomes include established clinical criteria for disease activity and treatment response in RA (Disease Activity Score 28, Simple Disease Activity Index, ACR-Response Criteria), changes in self-reported health and physical functional ability, mood, stress, quality of life, dietary behaviour via 3-day food records and a modified Food Frequency Questionnaire, body composition, changes in the gut microbiome, metabolomics and cytometric parameters. Outcomes will be assessed at baseline and day 7, after 6 weeks, 12 weeks and after 6 months., Ethics and Dissemination: Ethical approval to process and analyse data, and to publish the results was obtained through the institutional review board of Charité-Universitätsmedizin Berlin. Results of this trial will be disseminated through peer-reviewed publications and scientific presentations., Trial Registration Number: NCT03856190., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Proton radiotherapy (PT) is used increasingly for paediatric brain cancer patients. However, as demonstrated here, the knowledge on normal tissue dose constraints, to minimize side-effects, for this cohort is limited., Methods: A search strategy was systematically conducted on MEDLINE® database. 65 papers were evaluated ranging from 2013 to 2021., Results: Large variations in normal tissue tolerance and toxicity reporting across PT studies makes estimation of normal tissue dose constraints difficult, with the potential for significant late effects to go unmeasured. Mean dose delivered to the pituitary gland varies from 20 to 30 Gy across literature. Similarly, the hypothalamic dose delivery ranges from 20 to 54.6 Gy for paediatric patients., Conclusion: There is a significant lack of radiobiological data for paediatric brain cancer patients undergoing proton therapy, often using data from x-ray radiotherapy and adult populations. The way forward is through standardisation of reporting in order to validate relevant dose constraints., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Proton radiotherapy produces superior dose distributions compared to photon radiotherapy, reducing side effects. Differences between the two modalities are not fully quantified in paediatric patients for various intracranial tumour sites or age. Understanding these differences may help clinicians estimate the benefit and improve referral across available centres. Our aim was to compare intensity-modulated proton therapy (IMPT) and intensity-modulated photon radiotherapy (IMRT) radiation doses for select paediatric intracranial tumours., Methods: IMPT and IMRT dose distributions for gender-matched paediatric cranial CT-datasets (ages 5, 9 and 13 years) were retrospectively calculated to simulate irradiation of supratentorial (ependymoma) and infratentorial (medulloblastoma) target volumes diameters (1-3 cm) and position (central and 1-2 cm shifts)., Results: Clinical dosimetric objectives were achieved for all 216 treatment plans. Whilst infratentorial IMPT plans achieved greater maximum dose sparing to optic structures (4.8-12.6 Gy optic chiasm), brainstem sparing was limited (~0.5 Gy). Mean dose difference for optic chiasm was associated with medulloblastoma target position ( p < 0.0197). Supratentorial IMPT plans demonstrated greater dose reduction for the youngest patients (pituitary gland p < 0.001)., Conclusions: Normal tissue sparing was achieved regardless of patient age for infratentorial tumours. However, for supratentorial tumours, there was a dosimetric advantage of IMPT across 9 vs. 13-year-old patients.

Introduction: Despite improvements in radiation therapy, chemotherapy and surgical procedures over the last 30 years, pancreatic cancer 5-year survival rate remains at 9%. Reduced stroma permeability and heterogeneous blood supply to the tumour prevent chemoradiation from making a meaningful impact on overall survival. Hypoxia-activated prodrugs are the latest strategy to reintroduce oxygenation to radioresistant cells harbouring in pancreatic cancer. This paper reviews the current status of photon and particle radiation therapy for pancreatic cancer in combination with systemic therapies and hypoxia activators., Methods: The current effectiveness of management of pancreatic cancer was systematically evaluated from MEDLINE ® database search in April 2019., Results: Limited published data suggest pancreatic cancer patients undergoing carbon ion therapy and proton therapy achieve a comparable median survival time (25.1 months and 25.6 months, respectively) and 1-year overall survival rate (84% and 77.8%). Inconsistencies in methodology, recording parameters and protocols have prevented the safety and technical aspects of particle therapy to be fully defined yet., Conclusion: There is an increasing requirement to tackle unmet clinical demands of pancreatic cancer, particularly the lack of synergistic therapies in the advancing space of radiation oncology., Competing Interests: The authors declare no conflict of interest

Background: Several studies have investigated cardiac dose reduction when utilizing the deep inspiration breath hold (DIBH) technique in patients undergoing radiotherapy for left-sided breast cancer. This paper aims to recommend potential selection criteria based on a retrospective single institute study of free breathing (FB) and DIBH computed tomography (CT) simulation planning scans., Methods: Dosimetric comparisons were performed retrospectively for 20 patients correlating the dose reduction and patient anatomical factors (anatomical variation of chest shape, chest wall separation, total lung volume (TLV) and others)., Results: Paired t-tests demonstrated significant cardiac dose reduction for most patients but not all. Minimal cardiac dose reduction was observed for three patients using their DIBH plan, with one patient receiving a higher dose. Linear regression analysis identified a positive correlation between the patient's TLV (on the FB CT simulation scan) and the magnitude of dosimetric benefit received (0.4045 R²)., Conclusion: The TLV measured on a FB plan could potentially be utilised to predict cardiac exposure and assist with patient selection for DIBH. This is important in resource allocation, as DIBH may be unnecessarily recommended for some patients with little dosimetric benefit.

Pentraxin-3 (PTX3) is a member of the long pentraxin superfamily and has a nonredundant role in mediating resistance to fungal pathogens. Serial monitoring of PTX3 plasmatic levels was performed in 10 pediatric leukemia patients affected by pulmonary fungal infections. When compared with values of a control pediatric cohort, PTX3 showed significantly higher plasmatic values. Moreover, the response to the antifungal therapy correlated with normalization of PTX3 values. PTX3 may represent a useful tool for the diagnosis and monitoring of fungal infections in immuno-compromised children.