Quantifying societal burden of radiation-induced small bowel toxicity in patients with rectal cancer.

Introduction: Advancements in rectal cancer (RC) treatment not only led to an increase in lives saved but also improved quality of life (QoL). Notwithstanding these benefits, RC treatment comes at the price of gastrointestinal morbidity in many patients. Health economic modelling poses an opportunity to explore the societal burden of such side-effects. This study aims to quantify radiation-induced late small bowel (SB) toxicity in survivors of RC for Three-Dimensional Conformal Radiation Therapy (3D-CRT), Intensity Modulated Radiation Therapy (IMRT) and Intensity Modulated Radiation Therapy - Image Guided Radiation Therapy (IMRT/IGRT). Materials and methods: Materials and A model-based health economic evaluation was performed. The theoretical cohort consists of a case-mix of survivors of RC aged 25-99 years according to Belgian age-specific incidence rates. A societal perspective was adopted. The base case analysis was complemented with one-way deterministic analyses, deterministic scenario analyses and probabilistic sensitivity analysis (1,000 iterations). Results were presented as mean lifetime incremental cost (€) and utility (QALYs) per patient. Results: The analyses showed that the use of innovative radiotherapy (RT) improves lifetime QoL in survivors of RC by 0.11 QALYs and 0.05 QALYs by preferring IMRT/IGRT and IMRT over 3D-CRT, respectively. The use of IMRT/IGRT and IMRT results in an incremental cost-saving of €3,820 and €1,863 per patient, solely by radiation-induced SB toxicity, compared to 3D-CRT. Discussion and conclusion: It is important to consider late toxicity effects in decisions regarding investments and reimbursement as our analysis highlighted the potential long-term cost-savings and improved QoL of novel RT techniques in patients with rectal cancer.

Compartmentalized role of xCT in supporting pancreatic tumor growth, inflammation and mood disturbance in mice.

xCT (Slc7a11), the specific subunit of the cystine/glutamate antiporter system xc-, is present in the brain and on immune cells, where it is known to modulate behavior and inflammatory responses. In a variety of cancers -including pancreatic ductal adenocarcinoma (PDAC)-, xCT is upregulated by tumor cells to support their growth and spread. Therefore, we studied the impact of xCT deletion in pancreatic tumor cells (Panc02) and/or the host (xCT-/- mice) on tumor burden, inflammation, cachexia and mood disturbances. Deletion of xCT in the tumor strongly reduced tumor growth. Targeting xCT in the host and not the tumor resulted only in a partial reduction of tumor burden, while it did attenuate tumor-related systemic inflammation and prevented an increase in immunosuppressive regulatory T cells. The latter effect could be replicated by specific xCT deletion in immune cells. xCT deletion in the host or the tumor differentially modulated neuroinflammation. When mice were grafted with xCT-deleted tumor cells, hypothalamic inflammation was reduced and, accordingly, food intake improved. Tumor bearing xCT-/- mice showed a trend of reduced hippocampal neuroinflammation with less anxiety- and depressive-like behavior. Taken together, targeting xCT may have beneficial effects on pancreatic cancer-related comorbidities, beyond reducing tumor burden. The search for novel and specific xCT inhibitors is warranted as they may represent a holistic therapy in pancreatic cancer.

Introduction of ultra-hypofractionation in breast cancer: Implications for costs and resource use.

PURPOSE: A shift towards (ultra-)hypofractionated breast irradiation can have important implications for the practice of contemporary radiation oncology. This paper presents a systematic analysis of the impact of different fractionation schedules on multiple key performance indicators, namely resource use, costs, work times, throughput and waiting times. MATERIALS AND METHODS: Time-driven activity-based costing (TD-ABC) is applied to calculate the costs and resources consumed where the perspective of the radiotherapy department in adopted. Three fractionation regimens are considered: ultra-hypofractionation (5 x 5.2 Gy, UHF), moderate hypofractionation (15 x 2.67 Gy, HF) and conventional fractionation (25 x 2 Gy, CF). Subsequently, a discrete event simulation (DES) model of the radiotherapy care pathway is developed and scenarios are compared in which the following factors are varied: distribution of fractionation regimens, patient volume and operating hours. RESULTS: The application of (U)HF can permit radiotherapy departments to reduce the use of scarce resources, realise work time and cost savings, increase throughput and reduce waiting times. The financial advantages of (U)HF are, however, reduced in cases of excess capacity and cost savings may therefore be limited in the short-term. Moreover, although an extension of operating hours has favourable effects on throughput and waiting times, it may also reduce cost differences between fractionation schedules by increasing the capacity of resources. CONCLUSION: By providing an in-depth analysis of the consequences associated with a shift towards (U)HF in breast cancer, the present study demonstrates how a DES model based on TD-ABC costing can assist radiotherapy professionals in making data-driven decisions.

Nanobody-mediated SPECT/CT imaging reveals the spatiotemporal expression of programmed death-ligand 1 in response to a CD8+ T cell and iNKT cell activating mRNA vaccine.

Rationale: Although promising responses are obtained in patients treated with immune checkpoint inhibitors targeting programmed death ligand 1 (PD-L1) and its receptor programmed death-1 (PD-1), only a fraction of patients benefits from this immunotherapy. Cancer vaccination may be an effective approach to improve the response to immune checkpoint inhibitors anti-PD-L1/PD-1 therapy. However, there is a lack of research on the dynamics of PD-L1 expression in response to cancer vaccination. Methods: We performed non-invasive whole-body imaging to visualize PD-L1 expression at different timepoints after vaccination of melanoma-bearing mice. Mice bearing ovalbumin (OVA) expressing B16 tumors were i.v. injected with the Galsome mRNA vaccine: OVA encoding mRNA lipoplexes co-encapsulating a low or a high dose of the atypical adjuvant α-galactosylceramide (αGC) to activate invariant natural killer T (iNKT) cells. Serial non-invasive whole-body immune imaging was performed using a technetium-99m (99mTc)-labeled anti-PD-L1 nanobody, single-photon emission computerized tomography (SPECT) and X-ray computed tomography (CT) images were quantified. Additionally, cellular expression of PD-L1 was evaluated with flow cytometry. Results: SPECT/CT-imaging showed a rapid and systemic upregulation of PD-L1 after vaccination. PD-L1 expression could not be correlated to the αGC-dose, although we observed a dose-dependent iNKT cell activation. Dynamics of PD-L1 expression were organ-dependent and most pronounced in lungs and liver, organs to which the vaccine was distributed. PD-L1 expression in lungs increased immediately after vaccination and gradually decreased over time, whereas in liver, vaccination-induced PD-L1 upregulation was short-lived. Flow cytometric analysis of these organs further showed myeloid cells as well as non-immune cells with elevated PD-L1 expression in response to vaccination. SPECT/CT imaging of the tumor demonstrated that the expression of PD-L1 remained stable over time and was overall not affected by vaccination although flow cytometric analysis at the cellular level demonstrated changes in PD-L1 expression in various immune cell populations following vaccination. Conclusion: Repeated non-invasive whole-body imaging using 99mTc-labeled anti-PD-L1 nanobodies allows to document the dynamic nature of PD-L1 expression upon vaccination. Galsome vaccination rapidly induced systemic upregulation of PD-L1 expression with the most pronounced upregulation in lungs and liver while flow cytometry analysis showed upregulation of PD-L1 in the tumor microenvironment. This study shows that imaging using nanobodies may be useful for monitoring vaccine-mediated PD-L1 modulation in patients and could provide a rationale for combination therapy. To the best of our knowledge, this is the first report that visualizes PD-L1 expression upon cancer vaccination.

Neuromuscular end-point predictive capability of published rocuronium pharmacokinetic/pharmacodynamic models: An observational trial.

BACKGROUND: Objective neuromuscular monitoring remains the single most reliable method to ensure optimal perioperative neuromuscular management. Nevertheless, the prediction of clinical neuromuscular endpoints by means of Pharmacokinetic (PK) and Pharmacodynamic (PD) modelling has the potential to complement monitoring and improve perioperative neuromuscular management.s STUDY OBJECTIVE: The present study aims to assess the performance of published Rocuronium PK/PD models in predicting intraoperative Train-of-four (TOF) ratios when benchmarked against electromyographic TOF measurements. DESIGN: Observational trial. SETTING: Tertiary Belgian hospital, from August 2020 up to September 2021. PATIENTS AND INTERVENTIONS: Seventy-four patients undergoing general anaesthesia for elective surgery requiring the administration of rocuronium and subject to continuous EMG neuromuscular monitoring were included. PK/PD-simulated TOF ratios were plotted and synchronised with their measured electromyographic counterparts and their differences analysed by means of Predictive Error derivatives (Varvel criteria). MAIN RESULTS: Published rocuronium PK/PD models overestimated clinically registered TOF ratios. The models of Wierda, Szenohradszky, Cooper, Alvarez-Gomez and McCoy showed significant predictive consistency between themselves, displaying Median Absolute Performance Errors between 38% and 41%, and intra-individual differences (Wobble) between 14 and 15%. The Kleijn model outperformed the former with a lower Median Absolute Performance Error (16%, 95%CI [0.01; 57]) and Wobble (11%, 95%CI [0.01; 34]). All models displayed considerably wide 95% confidence intervals for all performance metrics, suggesting a significantly variable performance. CONCLUSIONS: Simulated TOF ratios based on published PK/PD models do not accurately predict real intraoperative TOF ratio dynamics. TRIAL REGISTRATION: NCT04518761 (clinicaltrials.gov), registered on 19 August 2020.

Lifespan extension with preservation of hippocampal function in aged system xc--deficient male mice.

The cystine/glutamate antiporter system xc- has been identified as the major source of extracellular glutamate in several brain regions as well as a modulator of neuroinflammation, and genetic deletion of its specific subunit xCT (xCT-/-) is protective in mouse models for age-related neurological disorders. However, the previously observed oxidative shift in the plasma cystine/cysteine ratio of adult xCT-/- mice led to the hypothesis that system xc- deletion would negatively affect life- and healthspan. Still, till now the role of system xc- in physiological aging remains unexplored. We therefore studied the effect of xCT deletion on the aging process of mice, with a particular focus on the immune system, hippocampal function, and cognitive aging. We observed that male xCT-/- mice have an extended lifespan, despite an even more increased plasma cystine/cysteine ratio in aged compared to adult mice. This oxidative shift does not negatively impact the general health status of the mice. On the contrary, the age-related priming of the innate immune system, that manifested as increased LPS-induced cytokine levels and hypothermia in xCT+/+ mice, was attenuated in xCT-/- mice. While this was associated with only a very moderate shift towards a more anti-inflammatory state of the aged hippocampus, we observed changes in the hippocampal metabolome that were associated with a preserved hippocampal function and the retention of hippocampus-dependent memory in male aged xCT-/- mice. Targeting system xc- is thus not only a promising strategy to prevent cognitive decline, but also to promote healthy aging.

Estimating lung cancer and cardiovascular mortality in female breast cancer patients receiving radiotherapy.

By integrating data of the PLCO cancer screening trial, SCORE-risk charts and radiotherapy excess ratios, we were able to create risk charts estimating radiotherapy-induced lung cancer and cardiovascular mortality in female breast cancer patients. These risk models might be useful to individualize radiotherapy and optimize lung cancer and cardiovascular prevention and screening.

Predictors of dopamine agonist resistance in prolactinoma patients.

BACKGROUND: Surgical resection of prolactinomas resistant to dopamine agonists is frequently incomplete due to fibrotic changes of the tumour under pharmacological therapy. In order to identify a subgroup of patients who may benefit from early surgery, we thought to investigate possible predictive factors of pharmacological resistance of prolactinomas to dopamine agonists. METHODS: We retrospectively analyzed a database of a Belgian tertiary reference center for patients with pituitary tumours from 2014 to 2016. The groups of interest were patients with dopamine agonist responsive and resistant prolactinomas. The possible predictive factors, including MRI findings, endocrinological parameters, response of tumour and patient factors for dopamine agonist resistance were investigated. RESULTS: We included 69 patients of whom 52 were women (75,4%) and 17 were men (24,6%). Rate of dopamine agonist resistance was 15.9%. We identified four significant predictors of dopamine agonist resistance: male gender, a large tumour volume, prolonged time to prolactin normalization and presence of a cystic, hemorrhagic and/or necrotic component. In addition, symptoms due to mass effect, high baseline prolactin level and a high contrast capture on MRI are factors that can be taken into consideration. CONCLUSION: We identified predictive factors for pharmacological resistance and developed a scoring system for patient specific prediction of resistance to dopamine agonists. This scoring system may have impact on the timing and decision of surgery in prolactinoma patients after further prospective evaluation.

The METABANK score: A clinical tool to predict survival after stereotactic radiotherapy for oligometastatic disease.

BACKGROUND AND PURPOSE: Stereotactic radiotherapy (SRT, SBRT) is widely used in oligometastatic cancer, but the heterogeneity of the population complicates estimation of the prognosis. We investigated the role of different clinical and inflammatory parameters. MATERIALS AND METHODS: We included all patients treated with SRT for 1-5 oligometastases between 2003 and 2017 in our center. Patients were randomized between a model training set (2/3) and a separate validation set (1/3). A Cox regression model was built, validated and risk points were attributed to the resulting parameters. RESULTS: 403 patients received SRT for 760 metastases. Treated sites were mainly lung, liver, nodal areas, and brain. Most common primaries were colorectal and lung cancer. Median follow-up for living patients reached 42 months and median overall survival (MS) was 26.6 months (95% CI 23.8-29.3). Five independent adverse factors were discriminated: male sex, synchronous timing of oligometastases, brain metastasis, non-adenocarcinoma histology, KPS <80. A risk score is formed by summation of the points of each factor (M:4, T:2, B:7, N:7, K:8). Four risk groups were defined: (1) 0-2 points: MS 41.2 months (95% CI 30.2-52.3); (2) 3-8 points: 29.3 months (24.6-34.0); (3) 9-13 points: 17.4 months (10.1-24.7), and (4) 14-28 points: 7.9 months (5.5-10.3). CONCLUSION: We propose a prognostic score applicable in a variety of primary tumors and disease locations, including presence of brain metastases. The nomogram and risk groups can be used to stratify patients in new trials and to support individualized care for oligometastatic patients. An online calculator will become available at predictcancer.org.