Modelling a new approach for radio-ablation after resection of breast ductal carcinoma in-situ based on the BAT-90 medical device

The majority of local recurrences, after conservative surgery of breast cancer, occurs in the same anatomical area where the tumour was originally located. For the treatment of ductal carcinoma in situ (DCIS), a new medical device, named BAT-90, (BetaGlue Technologies SpA) has been proposed. BAT-90 is based on the administration of 90Y β-emitting microspheres, embedded in a bio-compatible matrix. In this work, the Geant4 simulation toolkit is used to simulate BAT-90 as a homogenous cylindrical 90Y layer placed in the middle of a bulk material. The activity needed to deliver a 20 Gy isodose at a given distance z from the BAT-90 layer is calculated for different device thicknesses, tumour bed sizes and for water and adipose bulk materials. A radiobiological analysis has been performed using both the Poisson and logistic Tumour Control Probability (TCP) models. A range of radiobiological parameters (α and β), target sizes, and densities of tumour cells were considered. Increasing α values, TCP increases too, while, for a fixed α value, TCP decreases as a function of clonogenic cell density. The models predict very solid results in case of limited tumour burden while the activity/dose ratio could be further optimized in case of larger tumour beds.

Radiation-induced neuroinflammation – a potential protective role for PARP (poly ADP ribose polymerase) inhibitors?

Radiotherapy (RT) plays a fundamental role in the treatment of glioblastoma (GBM). GBM are notoriously invasive and harbour a subpopulation of cells with stem-like features which exhibit upregulation of the DNA damage response and are radioresistant. High radiation doses are therefore delivered to large brain volumes and are known to extend survival but also cause delayed toxicity with 50-90% of patients developing neurocognitive dysfunction. Emerging evidence identifies neuroinflammation as a critical mediator of the adverse effects of RT on cognitive function. In addition to its well-established role in promoting repair of radiation induced DNA damage, activation of poly(ADP-ribose) polymerase (PARP) can exacerbate neuroinflammation by promoting secretion of inflammatory mediators. Therefore, PARP represents an intriguing mechanistic link between radiation-induced activation of the DNA damage response and subsequent neuroinflammation. PARP inhibitors have emerged as promising new agents for GBM when given in combination with RT, with multiple preclinical studies demonstrating radiosensitizing effects and at least three compounds being evaluated in clinical trials. We propose that concomitant use of PARP inhibitors could reduce radiation-induced neuroinflammation and reduce the severity of radiation-induced cognitive dysfunction while at the same time improving tumour control by enhancing radiosensitivity.

Optimisation of the Chicken Chorioallantoic Membrane Assay in Uveal Melanoma Research

The treatment of uveal melanoma and its metastases has not evolved sufficiently over the last decades in comparison to other tumour entities, posing a great challenge in the field of ocular oncology. Despite improvements in the conventional treatment regime and new discoveries about the genetic and molecular background of the primary tumour, effective treatment strategies to either prevent tumours or treat patients with advanced or metastatic disease are still lacking. New therapeutic options are necessary in order to achieve satisfactory local tumour control, reduce the risk of metastasis development, and preserve the eyeball and possibly the visual function of the eye. The development of in vivo model systems remains crucial for the identification and investigation of potential novel treatment modalities. The aim of this study was the optimisation of the chorioallantoic membrane (CAM) model for uveal melanoma research. We analysed the established CAM assay and its modification after the implantation of three-dimensional spheroids. The chorioallantoic membrane of a chick embryo was used to implant uveal melanoma-cell-line-derived spheroids in order to study their growth rate, angiogenic potential, and metastatic capability. Using the UM 92.1, UPMD2, UPMM3, and Mel270 cell lines, we were able to improve the viability of the embryos from 20% to >80% and to achieve up to a fourfold volume increase of the transplanted spheroid masses. The results point to the value of an optimised chicken embryo assay as an in vivo model for testing novel therapies for uveal melanoma by simplifying the research conditions and by contributing to a considerable reduction in animal experiments.

Clinical Outcomes after International Referral of Uveal Melanoma Patients for Proton Therapy

Objective: To assess oncological and ophthalmological outcomes after international referral of uveal melanoma patients for proton therapy. Materials and Methods: This is a retrospective study among Dutch uveal melanoma patients who were treated in Switzerland with 60.0 CGE proton therapy (in 4 fractions) from 1987 to 2019. All patients were ineligible for brachytherapy due to tumour size and/or proximity to the optic nerve. Time-to-event analyses were performed using Kaplan–Meier’s methodology and Cox proportional hazards models. Results: There were 103 patients (104 eyes) with a median largest tumour diameter of 19 mm (range 6–26 mm). Tumours were localised centrally (11%), mid-peripherally (65%) or peripherally (34%). Median follow-up was 7 years. Five-year local control, distant metastasis-free survival and eye preservation rates were 94%, 70% and 81% respectively. At five years, severe, moderate and mild visual impairment was observed in respectively 79%, 4% and 6% of the patients. Larger tumour volumes and more central tumour localisation were associated with severe visual impairment. After correction for these factors, dose to the macula, optic disc and retina, but not optic nerve was significantly associated with severe visual impairment. Conclusion: International referral for proton therapy yielded good tumour control and eye preservation rates, but risk of distant metastasis and severe visual impairment were substantial, possibly due to the selection of advanced tumour stages and/or central localisation. Dose to the macula may be more relevant than dose to the optic nerve for preservation of visual acuity, which is relevant for the treatment planning of proton therapy.

Nanomedicine in Pancreatic Cancer: Current Status and Future Opportunities for Overcoming Therapy Resistance

The development of drug resistance remains one of the greatest clinical oncology challenges that can radically dampen the prospect of achieving complete and durable tumour control. Efforts to mitigate drug resistance are therefore of utmost importance, and nanotechnology is rapidly emerging for its potential to overcome such issues. Studies have showcased the ability of nanomedicines to bypass drug efflux pumps, counteract immune suppression, serve as radioenhancers, correct metabolic disturbances and elicit numerous other effects that collectively alleviate various mechanisms of tumour resistance. Much of this progress can be attributed to the remarkable benefits that nanoparticles offer as drug delivery vehicles, such as improvements in pharmacokinetics, protection against degradation and spatiotemporally controlled release kinetics. These attributes provide scope for precision targeting of drugs to tumours that can enhance sensitivity to treatment and have formed the basis for the successful clinical translation of multiple nanoformulations to date. In this review, we focus on the longstanding reputation of pancreatic cancer as one of the most difficult-to-treat malignancies where resistance plays a dominant role in therapy failure. We outline the mechanisms that contribute to the treatment-refractory nature of these tumours, and how they may be effectively addressed by harnessing the unique capabilities of nanomedicines. Moreover, we include a brief perspective on the likely future direction of nanotechnology in pancreatic cancer, discussing how efforts to develop multidrug formulations will guide the field further towards a therapeutic solution for these highly intractable tumours.

Proton beam radiation for iris melanoma: case series and review of literature

ObjectivePurpose of this study is to analyse the visual outcomes, the complication and eye retention rate as well as tumour control data of patients treated with proton beam radiation therapy (PBRT) for iris melanoma.MethodsRetrospective case series and review based on patients’ records. All tumours were categorised according to the American Joint Committee of Cancer staging criteria for primary iris melanoma und underwent either sectorial or whole anterior segment PBRT.ResultsThirteen cases were identified of which five received PBRT of the whole anterior segment and eight received sectorial PBRT. Local tumour control after a mean follow-up of 25 months was 92%. Complications after PBRT included cataract (46%), secondary glaucoma (31%), superficial keratitis (15%) and madarosis (8%). Complications were more common in patients necessitating irradiation of the entire anterior segment than in patients which received sectorial irradiation. Eye retention was achieved in all cases. No statistically significant difference in the mean best corrected visual acuity (BCVA) and intraocular pressure (IOP) was found before and after treatment. Comparison of mean BCVA and IOP between different treatment groups (complete anterior segment vs sectorial irradiation) at the last follow-up visit were also not significantly different. No patient developed metastatic disease during follow-up.ConclusionPBRT is a safe and vision preserving therapeutic modality for iris melanoma. Complete irradiation of the anterior segment is associated with higher complication rates.

Combination of brachytherapy and intravitreal chemotherapy in the treatment of retinoblastoma with vitreous seeding

Purpose: To report the efficacy of combined intravitreal chemotherapy (IVC) and ruthenium-106 brachytherapy in retinoblastoma, either as first line or second line treatment following systemic chemoreduction or intraarterial chemotherapy. Methods: Retrospective data collection of 18 eyes from 18 patients treated with IVC and brachytherapy from August 2014 to December 2019. Results: The method described was our first line therapy in 6 patients, whereas it was used as second line treatment after chemoreduction in the remaining 12 patients. The eyes showed the following classification at initial presentation: 2 group B eyes, 3 group C eyes and 13 group D eyes. The mean follow-up was 19.5 months (range 2 – 53 months). Mean patient age at brachytherapy was 34.0 months (range 15 – 83 months). Median prescribed dose at the tumour base and apex was 574.5 ± 306.7Gy and 88.5 ± 12.2Gy, respectively. The ocular retention rate was 66.7%. Six eyes had to be enucleated due to uncontrollable subretinal and recurrent vitreous seeding, tumour relapse, recurrence of a solid tumour elsewhere in the eye and persistent vitreous bleeding with loss of tumour control. The mean number of intravitreal injections of Melphalan was 5.0. Two patients received a simultaneous injection of Topotecan for insufficient therapeutic response. With regard to radiogenic complications, we could observe temporary retinal and vitreous bleeding (27.8%), serous retinal detachment (44.4%) and radiogenic maculopathy and retinopathy (11.1%). None of the children showed metastatic disease during follow up. Conclusion: Ruthenium-106 plaque therapy in combination with intravitreal chemotherapy is an effective local therapy with good tumour control rates even in advanced eyes. Overall, the analysed therapeutic approach shows an acceptable side effect profile, especially when considering that EBRT and systemic polychemotherapy, or at least the number of cycles needed, with their increased incidence of adverse events can thus be avoided.

Oxygen Depletion in Proton Spot Scanning: A Tool for Exploring the Conditions Needed for FLASH

FLASH radiotherapy is a rapidly developing field which promises improved normal tissue protection compared to conventional irradiation and no compromise on tumour control. The transient hypoxic state induced by the depletion of oxygen at high dose rates provides one possible explanation. However, studies have mostly focused on uniform fields of dose and there is a lack of investigation into the spatial and temporal variation of dose from proton pencil-beam scanning (PBS). A model of oxygen reaction and diffusion in tissue has been extended to simulate proton PBS delivery and its impact on oxygen levels. This provides a tool to predict oxygen effects from various PBS treatments, and explore potential delivery strategies. Here we present a number of case applications to demonstrate the use of this tool for FLASH-related investigations. We show that levels of oxygen depletion could vary significantly across a large parameter space for PBS treatments, and highlight the need for in silico models such as this to aid in the development and optimisation of FLASH radiotherapy.

What is the effectiveness of radiofrequency ablation in the management of patients with spinal metastases? A systematic review and meta-analysis

Purpose Spinal metastases are indicative of progressive cancer which can lead to vertebral body fractures and spinal cord compression. Radiofrequency ablation (RFA) treatment is infrequently used in patients with refractory pain. The aim of this systematic review is to determine the clinical efficacy of RFA, with the scope of using it as front-line management of spinal metastases. Methods Electronic databases were searched (to July 2020) for studies evaluating RFA treatment for spinal metastases in adults. Measured outcomes were pain (primary), disability, health-related quality of life (HRQOL), complications, tumour control and mortality. Study inclusion, data extraction and risk of bias using the ROBIN-I tool were assessed. Meta-analysis was conducted for pooled results with homogeneity, and narrative synthesis was conducted otherwise. Results 15 studies were included. RFA reduces pain scores at 3–5 weeks [standardised mean difference (SMD 2.24, 95% confidence intervals (CI) 1.55–2.93], 3–4 months (SMD 3.00, 95% CI 1.11–4.90) and 5–6 months (SMD 3.54, 95% CI 1.96–5.11). RFA is effective in reducing disability/improving HRQOL in the short-term but longer-term efficacy remains unclear. 13.2% cases reported local tumour control failure (2.5 months–5 year follow-up) whereas mortality was 23.6% (follow-up of up to 1 year). Conclusion Low quality evidence has proven RFA to be safe and effective in reducing pain and disability, especially in the short-term. RFA may be routinely implemented in all cases involving refractory pain or radiotherapy-resistant tumours but controlled trials are required to compare the efficacy of RFA to current frontline treatments. PROSPERO protocol registration number: CRD42020202377.

Tumor irradiation combined with minimally invasive surgery (vascular-targeted photodynamic therapy) enhances anti-tumour effects in preclinical prostate cancer

Hanna T Sjoberg, Yiannis Philippou, Anette L Magnussen, Iain DC Tullis, Esther Bridges, Andrea Chatrian, Joel Loefebvre, Ka Ho Tam, Emma A Murphy, Jens Rittscher, Dina Preise, Lilach Agemy, Tamar Yechezkel, Sean C Smart, Paul Kinchesh, Stuart Gilchrist, Danny P Allen, David A Scheiblin, Stephen J Lockett, David A Wink, Alastair D Lamb, Ian G Mills, Adrian Harris, Ruth J Muschel, Boris Vojnovic, Avigdor Scherz, Freddie C Hamdy, Richard J Bryant. Introduction There is an important clinical need to improve the treatment of high risk localised and locally advanced prostate cancer (PCa), and to reduce the side effects of these treatments. We hypothesised that multi-modality therapy combining radiotherapy and vascular-targeted photodynamic therapy (VTP) could PCa tumour control compared against monotherapy with each of these treatments alone. This could provide proof-of-concept to take to the clinic. VTP is a minimally invasive focal surgical therapy for localised PCa, which rapidly destroys targeted tumours through vascular disruption. Tumour vasculature is characterised by vessel immaturity, increased permeability, aberrant branching and inefficient flow. Fractionated radiotherapy (FRT) alters the tumour microenvironment and promotes transient vascular normalisation. Materials and Methods We investigated whether sequential delivery of FRT followed by VTP 7 days later improves PCa tumour control compared to monotherapy with FRT or VTP alone. Results FRT induced vascular normalisation changes in PCa flank tumour allografts, improving vascular function as demonstrated using dynamic contrast enhanced magnetic resonance imaging. FRT followed by VTP significantly delayed tumour growth in flank PCa allograft pre-clinical models, compared with monotherapy with FRT or VTP alone, and improved overall survival. Conclusion Taken together, these results suggest that combining FRT and VTP could become a promising multimodal clinical strategy in PCa therapy. This provides proof-of-concept for this multi-modality therapy approach to take forward to early phase clinical trials.