The p16INK4a protein is a principal cyclin-dependent kinase inhibitor that decelerates the cell cycle. Abnormally high levels of p16INK4a are commonly observed in human papillomavirus (HPV)-positive head and neck squamous cell carcinomas (HNSCC). We and others found that p16INK4a overexpression is associated with improved therapy response and survival of patients with HNSCC treated with radiotherapy. However, the functional role of p16INK4a in HNSCC remains unexplored. Our results implicate p16INK4a in regulation of homologous recombination-mediated DNA damage response independently from its role in control of the cell cycle. We found that expression of p16INK4a dramatically affects radiation sensitivity of HNSCC cells. p16INK4a overexpression impairs the recruitment of RAD51 to the site of DNA damage in HPV-positive cells by downregulating of cyclin D1 protein expression. Consistent with the in vitro findings, immunostaining of HNSCC patient samples revealed that high levels p16INK4a expression significantly correlated with decreased cyclin D1 expression. In summary, these findings reveal an unexpected function of p16INK4a in homologous recombination-mediated DNA repair response and imply p16INK4a status as an independent marker to predict response of patients with HNSCC to radiotherapy. Cancer Res; 74(6);

ObjectiveThe purpose of this study was to give an overview of the measures used to prevent chronic radiation proctitis (CRP) and to provide an algorithm for the treatment of CRP.MethodsMedical literature databases including PubMed and Medline were screened and critically analyzed for relevance in the scope of our purpose.ResultsCRP is a relatively frequent late side effect (5–20%) and mainly dependent on the dose and volume of irradiated rectum. Radiation treatment (RT) techniques to prevent CRP are constantly improving thanks to image-guided RT and intensity-modulated RT. Also, newer techniques like protons and new devices such as rectum spacers and balloons have been developed to spare rectal structures. Biopsies do not contribute to diagnosing CRP and should be avoided because of the risk of severe rectal wall damage, such as necrosis and fistulas. There is no consensus on the optimal treatment of CRP. A variety of possibilities is available and includes topical and oral agents, hyperbaric oxygen therapy, and endoscopic interventions.ConclusionsCRP has a natural history of improving over time, even without treatment. This is important to take into account when considering these treatments: first be conservative (topical and oral agents) and be aware that invasive treatments can be very toxic.

A paradigm shift from current population based medicine to personalized and participative medicine is underway. This transition is being supported by the development of clinical decision support systems based on prediction models of treatment outcome. In radiation oncology, these models 'learn' using advanced and innovative information technologies (ideally in a distributed fashion - please watch the animation: http://youtu.be/ZDJFOxpwqEA) from all available/appropriate medical data (clinical, treatment, imaging, biological/genetic, etc.) to achieve the highest possible accuracy with respect to prediction of tumor response and normal tissue toxicity. In this position paper, we deliver an overview of the factors that are associated with outcome in radiation oncology and discuss the methodology behind the development of accurate prediction models, which is a multi-faceted process. Subsequent to initial development/validation and clinical introduction, decision support systems should be constantly re-evaluated (through quality assurance procedures) in different patient datasets in order to refine and re-optimize the models, ensuring the continuous utility of the models. In the reasonably near future, decision support systems will be fully integrated within the clinic, with data and knowledge being shared in a standardized, dynamic, and potentially global manner enabling truly personalized and participative medicine.

The advent of immunotherapy is currently revolutionizing the field of oncology, where different drugs are used to stimulate different steps in a failing cancer immune response chain. This review gives a basic overview of the immune response against cancer, as well as the historical and current evidence on the interaction of radiotherapy with the immune system and the different forms of immunotherapy. Furthermore the review elaborates on the many open questions on how to exploit this interaction to the full extent in clinical practice.

Brachytherapy is employed to treat a wide variety of cancers. However, an accurate treatment verification method is currently not available. This study describes a pre-treatment verification system that uses an imaging panel (IP) to verify important aspects of the treatment plan. A detailed modelling of the IP was only possible with an extensive calibration performed using a robotic arm. Irradiations were performed with a high dose rate (HDR) Ir source within a water phantom. An empirical fit was applied to measure the distance between the source and the detector so 3D Cartesian coordinates of the dwell positions can be obtained using a single panel. The IP acquires 7.14 fps to verify the dwell times, dwell positions and air kerma strength (Sk). A gynecological applicator was used to create a treatment plan that was registered with a CT image of the water phantom used during the experiments for verification purposes. Errors (shifts, exchanged connections and wrong dwell times) were simulated to verify the proposed verification system. Cartesian source positions (panel measurement plane) have a standard deviation of about 0.02 cm. The measured distance between the source and the panel (z-coordinate) have a standard deviation up to 0.16 cm and maximum absolute error of  ≈0.6 cm if the signal is close to sensitive limit of the panel. The average response of the panel is very linear with Sk. Therefore, Sk measurements can be performed with relatively small errors. The measured dwell times show a maximum error of 0.2 s which is consistent with the acquisition rate of the panel. All simulated errors were clearly identified by the proposed system. The use of IPs is not common in brachytherapy, however, it provides considerable advantages. It was demonstrated that the IP can accurately measure Sk, dwell times and dwell positions.

Radiotherapy (RT) for prostate cancer (PC) has steadily evolved over the last decades, with improving biochemical disease-free survival. Recently population based research also revealed an association between overall survival and doses ≥ 75.6 Gray (Gy) in men with intermediate- and high-risk PC. Examples of improved RT techniques are image-guided RT, intensity-modulated RT, volumetric modulated arc therapy, and stereotactic ablative body RT, which could facilitate further dose escalation. Brachytherapy is an internal form of RT that also developed substantially. New devices such as rectum spacers and balloons have been developed to spare rectal structures. Newer techniques like protons and carbon ions have the intrinsic characteristics maximising the dose on the tumour while minimising the effect on the surrounding healthy tissue, but clinical data are needed for confirmation in randomised phase III trials. Furthermore, it provides an overview of an important discussion issue in PC treatment between urologists and radiation oncologists: the comparison between radical prostatectomy and RT. Current literature reveals that all possible treatment modalities have the same cure rate, but a different toxicity pattern. We recommend proposing the possible different treatment modalities with their own advantages and side-effects to the individual patient. Clinicians and patients should make treatment decisions together (shared decision-making) while using patient decision aids.

Recently, we have shown that the administration of the tumour-targeted antibody-based immunocytokine L19-IL2 after radiotherapy (RT) resulted in synergistic anti-tumour effect. Here we show that RT and L19-IL2 can activate a curative abscopal effect, with a long-lasting immunological memory. Ionizing radiation (single dose of 15Gy, 5 × 2Gy or 5 × 5Gy) was delivered to primary C51 colon tumour-bearing immunocompetent mice in combination with L19-IL2 and response of secondary non-irradiated C51 or CT26 colon tumours was evaluated. 15Gy + L19-IL2 triggered a curative (20%) abscopal effect, which was T cell dependent. Moreover, 10Gy + L19-IL2 treated and cured mice were re-injected after 150 days with C51 tumour cells and tumour uptake was assessed. Age-matched controls (matrigel injected mice treated with 10Gy + L19-IL2, mice cured after treatment with surgery + L19-IL2 and mice cured after high dose RT 40Gy + vehicle) were included. Several immunological parameters in blood, tumours, lymph nodes and spleens were investigated. Treatment with 10Gy + L19-IL2 resulted in long-lasting immunological memory, associated with CD44+CD127+ expression on circulating T cells. This combination treatment can induce long-lasting curative abscopal responses, and therefore it has also great potential for treatment of metastatic disease. Preclinical findings have led to the initiation of a phase I clinical trial (NCT02086721) in our institute investigating stereotactic ablative radiotherapy with L19-IL2 in patients with oligometastatic solid tumours.

Background: About 50% of non-small cell lung cancer (NSCLC) patients have metastatic disease at initial diagnosis, which limits their treatment options and, consequently, the 5-year survival rate (15%). Immune checkpoint inhibitors (ICI), either alone or in combination with chemotherapy, have become standard of care (SOC) for most good performance status patients. However, most patients will not obtain long-term benefit and new treatment strategies are therefore needed. We previously demonstrated clinical safety of the tumour-selective immunocytokine L19-IL2, consisting of the anti-ED-B scFv L19 antibody coupled to IL2, combined with stereotactic ablative radiotherapy (SABR).