Patient preferences for adjuvant radiotherapy in early breast cancer are strongly influenced by treatment received through random assignment

Objective: TARGIT‐A randomised women with early breast cancer to receive external beam radiotherapy (EBRT) or intraoperative radiotherapy (TARGIT‐IORT). This study aimed to identify what extra risk of recurrence patients would accept for per‐ ceived benefits and risks of different radiotherapy treatments. Methods: Patient preferences were determined by self‐rated trade‐off question‐ naires in two studies: Stage (1) 209 TARGIT‐A participants (TARGIT‐IORT n = 108, EBRT n = 101); Stage (2) 123 non‐trial patients yet to receive radiotherapy (pre‐treat‐ ment group), with 85 also surveyed post‐radiotherapy. Patients traded‐off risks of local recurrence in preference selection between TARGIT‐IORT and EBRT. Results: TARGIT‐IORT patients were more accepting of IORT than EBRT patients with 60% accepting the highest increased risk presented (4%–6%) compared to 12% of EBRT patients, and 2% not accepting IORT at all compared to 43% of EBRT pa‐ tients. Pre‐treatment patients were more accepting of IORT than post‐treatment pa‐ tients with 23% accepting the highest increased risk presented compared to 15% of post‐treatment patients, and 15% not accepting IORT at all compared to 41% of pre‐ treatment patients. Conclusions: Breast cancer patients yet to receive radiotherapy accept a higher recurrence risk than the actual risk found in TARGIT‐A. Measured patient preferences are highly influenced by experience of treatment received. This finding challenges the validity of post‐treatment preference studies

Modelling and optimisation of the operation of a radiant warmer

This paper presents numerical calculations of the temperature field obtained for the case of a neonate placed under a radiant warmer. The results of the simulations show a very non-uniform temperature distribution on the skin of the neonate, which may cause increased evaporation leading to severe dehydration. For this reason, we propose some modifications on the geometry and operation of the radiant warmer, in order to make the temperature distribution more uniform and prevent the high temperature gradients observed on the surface of the neonate. It is concluded that placing a high conductivity blanket over the neonate and introducing additional screens along the side of the mattress, thus recovering the radiation heat escaping through the side boundaries, helped providing more uniform temperature fields.The European Union for the Marie Curie Fellowship grant awarded to the Centre for CFD, University of Leeds

A feasibility, safety, and efficacy evaluation of supervised aerobic and resistance exercise for patients with glioblastoma undertaking adjuvant chemoradiotherapy

Background: While therapeutically effective, chemoradiotherapy treatment for high-grade glioma (glioblastoma) is often accompanied by side effects. Exercise has been demonstrated to alleviate the adverse effects of such treatments in other cancers. We aimed to evaluate the feasibility and preliminary efficacy of supervised exercise incorporating autoregulation. Methods: Thirty glioblastoma patients were recruited, five declined exercise and 25 were provided with a multimodal exercise intervention for the duration of their chemoradiotherapy treatment. Patient recruitment, retention, adherence to training sessions and safety were evaluated throughout the study. Physical function, body composition, fatigue, sleep quality, and quality of life were evaluated before and after the exercise intervention. Results: Eight of the 25 participants commencing exercise withdrew prior to completion of the study (32%). Seventeen patients (68%) demonstrated low to high adherence (33%–100%) and exercise dosage compliance (24%–83%). There were no reported adverse events. Significant improvements were observed for all trained exercises and lower limb muscle strength and function with no significant changes observed for any other physical function, body composition, fatigue, sleep, or quality of life outcomes. Conclusions: Only half of glioblastoma patients recruited were willing or able to commence, complete or meet minimum dose compliance for the exercise intervention during chemoradiotherapy indicating the intervention evaluated may not be feasible for part of this patient cohort. For those who were able to complete the exercise program, supervised, autoregulated, multimodal exercise was safe and significantly improved strength and function and may have prevented deterioration in body composition and quality of life

Cancer chemotherapy: insights into cellular and tumor microenvironmental mechanisms of action

Chemotherapy has historically been the mainstay of cancer treatment, but our understanding of what drives a successful therapeutic response remains limited. The diverse response of cancer patients to chemotherapy has been attributed principally to differences in the proliferation rate of the tumor cells, but there is actually very little experimental data supporting this hypothesis. Instead, other mechanisms at the cellular level and the composition of the tumor microenvironment appear to drive chemotherapy sensitivity. In particular, the immune system is a critical determinant of chemotherapy response with the depletion or knock-out of key immune cell populations or immunological mediators completely abrogating the benefits of chemotherapy in pre-clinical models. In this perspective, we review the literature regarding the known mechanisms of action of cytotoxic chemotherapy agents and the determinants of response to chemotherapy from the level of individual cells to the composition of the tumor microenvironment. We then summarize current work toward the development of dynamic biomarkers for response and propose a model for a chemotherapy sensitive tumor microenvironment

Observing changes in human functioning during induced sleep deficiency and recovery periods

Prolonged periods of sleep restriction seem to be common in the contemporary world. Sleep loss causes perturbations of circadian rhythmicity and degradation of waking alertness as reflected in attention, cognitive efficiency and memory. Understanding whether and how the human brain recovers from chronic sleep loss is important not only from a scientific but also from a public health perspective. In this work we report on behavioral, motor, and neurophysiological correlates of sleep loss in healthy adults in an unprecedented study conducted in natural conditions and comprising 21 consecutive days divided into periods of 4 days of regular life (a baseline), 10 days of chronic partial sleep restriction (30% reduction relative to individual sleep need) and 7 days of recovery. Throughout the whole experiment we continuously measured the spontaneous locomotor activity by means of actigraphy with 1-minute resolution. On a daily basis the subjects were undergoing EEG measurements (64-electrodes with 500 Hz sampling frequency): resting state with eyes open and closed (8 minutes long each) followed by Stroop task lasting 22 minutes. Altogether we analyzed actigraphy (distributions of rest and activity durations), behavioral measures (reaction times and accuracy from Stroop task) and EEG (amplitudes, latencies and scalp maps of event-related potentials from Stroop task and power spectra from resting states). We observed unanimous deterioration in all the measures during sleep restriction. Further results indicate that a week of recovery subsequent to prolonged periods of sleep restriction is insufficient to recover fully. Only one measure (mean reaction time in Stroop task) reverted to baseline values, while the others did not.Fil: Ochab, Jeremi K.. Jagiellonian University. Marian Smoluchowski Institute of Physics; Polonia. Jagiellonian University. Mark Kac Complex Systems Research Centre; PoloniaFil: Szwed, Jerzy. Jagiellonian University. Marian Smoluchowski Institute of Physics; Polonia. Jagiellonian University. Mark Kac Complex Systems Research Centre; PoloniaFil: Oles, Katarzyna. Jagiellonian University. Marian Smoluchowski Institute of Physics; PoloniaFil: Beres, Anna. Jagiellonian University. Department of Cognitive Neuroscience and Neuroergonomics; PoloniaFil: Chialvo, Dante Renato. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de San Martin. Escuela de Ciencia y Tecnologia. Centro de Estudios Multidisciplinarios En Sistemas Complejos y Ciencias del Cerebro.; ArgentinaFil: Domagalik, Aleksandra. Jagiellonian University. Department of Cognitive Neuroscience and Neuroergonomics; PoloniaFil: Frafrowicz, Magdalena. Jagiellonian University. Department of Cognitive Neuroscience and Neuroergonomics; PoloniaFil: Oginska, Halszka. Jagiellonian University. Department of Cognitive Neuroscience and Neuroergonomics; PoloniaFil: Gudowska-Nowak, Ewa. Jagiellonian University. Marian Smoluchowski Institute of Physics; Polonia. Jagiellonian University. Małopolska Center of Biotechnology ; PoloniaFil: Marek, Tadeusz. Jagiellonian University. Department of Cognitive Neuroscience and Neuroergonomic; Polonia. Jagiellonian University. Małopolska Center of Biotechnology; ArgentinaFil: Nowak, Maciej A.. Jagiellonian University. Marian Smoluchowski Institute of Physics; Polonia. Jagiellonian University. Mark Kac Complex Systems Research Centre; Poloni

NIPU: a randomised, open-label, phase II study evaluating nivolumab and ipilimumab combined with UV1 vaccination as second line treatment in patients with malignant mesothelioma

Ipilimumab; Mesotelioma pleural maligne; Vacuna telomerasaIpilimumab; Mesotelioma pleural maligno; Vacuna de telomerasaIpilimumab; Malignant pleural mesothelioma; Telomerase vaccineBackground Malignant pleural mesothelioma (MPM) is a rare and aggressive tumour. For patients with inoperable disease, few treatment options are available after first line chemotherapy. The combination of ipilimumab and nivolumab has recently shown increased survival compared to standard chemotherapy, but most patients do not respond and improvements are called for. Telomerase is expressed in mesothelioma cells, but only sparsely in normal tissues and is therefore an attractive target for therapeutic vaccination. Vaccination against telomerase is tolerable and has shown to induce immune responses associated with increased survival in other cancer types. There is a well-founded scientific rationale for the combination of a telomerase vaccine and checkpoint inhibition to improve treatment response in MPM patients. Methods NIPU is a randomized, multi-centre, open-label, phase II study comparing the efficacy and safety of nivolumab and ipilimumab with or without telomerase vaccine in patients with inoperable malignant pleural mesothelioma after first-line platinum-based chemotherapy. Participants (n = 118) are randomized 1:1 into two treatment arms. All participants receive treatment with nivolumab (240 mg every 2 weeks) and ipilimumab (1 mg/kg every 6 weeks) until disease progression, unacceptable toxicity or for a maximum of 2 years. Patients randomised to the experimental arm receive 8 intradermal injections of UV1 vaccine during the first three months of treatment. Tumour tissue, blood, urine, faeces and imaging will be collected for biomarker analyses and exploration of mechanisms for response and resistance to therapy. Discussion Checkpoint inhibition is used for treatment of mesothelioma, but many patients still do not respond. Increasing therapy response to immunotherapy is an important goal. Possible approaches include combination with chemotherapy, radiotherapy, targeted therapy and other immunotherapeutic agents. Predictive biomarkers are necessary to ensure optimal treatment for each patient and to prevent unnecessary side effects. This trial seeks to improve treatment response by combining checkpoint inhibition with a telomerase vaccine and also to explore mechanisms for treatment response and resistance. Knowledge gained in the NIPU study may be transferred to the first line setting and to other cancers with limited benefit from immunotherapy.Ultimovacs provides UV1 vaccine and sargramostin for patients treated in arm A and some funding for the clinical trial. BMS provides ipilimumab and nivolumab for all patients. The South-Eastern Norway regional health authority has provided support for the clinical trial, PhD students and research analyses (Grant nos. 2021083 and 2020077)

Cosmetic outcome as rated by patients, doctors, nurses and BCCT.core software assessed over 5 years in a subset of patients in the TARGIT-A trial

Background: The purpose of this research was to assess agreement between four rating systems of cosmetic outcome measured in a subset of patients with early breast cancer participating in the randomised TARGIT-A trial. TARGIT-A compared risk-adapted single-dose intra-operative radiotherapy (TARGIT-IORT) to whole breast external beam radiotherapy (EBRT). Methods: Patients, their Radiation Oncologist and Research Nurse completed a subjective cosmetic assessment questionnaire before radiotherapy and annually thereafter for five years. Objective data previously calculated by the validated BCCT.core software which utilizes digital photographs to score symmetry, colour and scar was also used. Agreement was assessed by the Kappa statistic and longitudinal changes were assessed by generalized estimating equations. Results: Overall, an Excellent-Good (EG) cosmetic result was scored more often than a Fair-Poor (FP) result for both treatment groups across all time points, with patients who received TARGIT-IORT scoring EG more often than those who received EBRT however this was statistically significant at Year 5 only. There was modest agreement between the four rating systems with the highest Kappa score being moderate agreement which was between nurse and doctor scores at Year 1 with Kappa = 0.46 (p \u3c 0.001), 95% CI (0.24, 0.68). Conclusion: Despite similar overall findings between treatment groups and rating systems, the inter-rater agreement was only modest. This suggests that the four rating systems utilized may not necessarily be used interchangeably and it is arguable that for an outcome such as cosmetic appearance, the patient’s point of view is the most important. Trial Registration: TARGIT-A ISRCTN34086741, Registered 21 July 2004, retrospectively registered

Imaging in pleural mesothelioma: a review of the 13th International Conference of the International Mesothelioma Interest Group

Imaging plays an important role in the detection, diagnosis, staging, response assessment, and surveillance of malignant pleural mesothelioma. The etiology, biology, and growth pattern of mesothelioma present unique challenges for each modality used to capture various aspects of this disease. Clinical implementation of imaging techniques and information derived from images continue to evolve based on active research in this field worldwide. This paper summarizes the imaging-based research presented orally at the 2016 International Conference of the International Mesothelioma Interest Group (iMig) in Birmingham, United Kingdom, held May 1–4, 2016. Presented topics included intraoperative near-infrared imaging of mesothelioma to aid the assessment of resection completeness, an evaluation of tumor enhancement improvement with increased time delay between contrast injection and image acquisition in standard clinical magnetic resonance imaging (MRI) scans, the potential of early contrast enhancement analysis to provide MRI with a role in mesothelioma detection, the differentiation of short- and long-term survivors based on MRI tumor volume and histogram analysis, the response-assessment potential of hemodynamic parameters derived from dynamic contrast-enhanced computed tomography (DCE-CT) scans, the correlation of CT-based tumor volume with post-surgical tumor specimen weight, and consideration of the need to update the mesothelioma tumor response assessment paradigm

Tumour-infiltrating regulatory T cell density before neoadjuvant chemoradiotherapy for rectal cancer does not predict treatment response

Neoadjuvant (preoperative) chemoradiotherapy (CRT) decreases the risk of rectal cancer recurrence and reduces tumour volume prior to surgery. However, response to CRT varies considerably between individuals and factors associated with response are poorly understood. Foxp3+ regulatory T cells (Tregs) inhibit anti-tumour immunity and may limit any response to chemotherapy and radiotherapy. We have previously reported that a low density of Tregs in the tumour stroma following neoadjuvant CRT for rectal cancer is associated with improved tumour regression. Here we have examined the association between Treg density in pre-treatment diagnostic biopsy specimens and treatment response, in this same patient cohort. We aimed to determine whether pre-treatment tumour-infiltrating Treg density predicts subsequent response to neoadjuvant CRT. Foxp3+, CD8+ and CD3+ cell densities in biopsy samples from 106 patients were assessed by standard immunohistochemistry (IHC) and evaluated for their association with tumour regression grade and survival. We found no association between the density of any T cell subset pre-treatment and clinical outcome, indicating that tumour-infiltrating Treg density does not predict response to neoadjuvant CRT in rectal cancer. Taken together with the findings of the previous study, these data suggest that in the context of neoadjuvant CRT for rectal cancer, the impact of chemotherapy and/or radiotherapy on anti-tumour immunity may be more important than the state of the pre-existing local immune response

LUMOS - Low and Intermediate Grade Glioma Umbrella Study of Molecular Guided TherapieS at relapse: Protocol for a pilot study

Grades 2 and 3 gliomas (G2/3 gliomas), when combined, are the second largest group of malignant brain tumours in adults. The outcomes for G2/3 gliomas at progression approach the dismal outcomes for glioblastoma (GBM), yet there is a paucity of trials for Australian patients with relapsed G2/3 gliomas compared with patients with GBM. LUMOS will be a pilot umbrella study for patients with relapsed G2/3 gliomas that aims to match patients to targeted therapies based on molecular screening with contemporaneous tumour tissue. Participants in whom no actionable or no druggable mutation is found, or in whom the matching drug is not available, will form a comparator arm and receive standard of care chemotherapy. The objective of the LUMOS trial is to assess the feasibility of this approach in a multicentre study across five sites in Australia, with a view to establishing a national molecular screening platform for patient treatment guided by the mutational analysis of contemporaneous tissue biopsies