One-class Gaussian process regressor for quality assessment of transperineal ultrasound images

The use of ultrasound guidance in prostate cancer radiotherapy workflows is not widespread. This can be partially attributed to the need for image interpretation by a trained operator during ultrasound image acquisition. In this work, a one-class regressor, based on DenseNet and Gaussian processes, was implemented to assess automatically the quality of transperineal ultrasound images of the male pelvic region. The implemented deep learning approach achieved a scoring accuracy of 94%, a specificity of 95% and a sensitivity of 93% with respect to the majority vote of three experts, which was comparable with the results of these experts. This is the first step towards a fully automatic workflow, which could potentially remove the need for image interpretation and thereby make the use of ultrasound imaging, which allows real-time volumetric organ tracking in the RT environment, more appealing for hospitals

A Deep Learning Approach Validates Genetic Risk Factors for Late Toxicity After Prostate Cancer Radiotherapy in a REQUITE Multi-National Cohort.

Background: REQUITE (validating pREdictive models and biomarkers of radiotherapy toxicity to reduce side effects and improve QUalITy of lifE in cancer survivors) is an international prospective cohort study. The purpose of this project was to analyse a cohort of patients recruited into REQUITE using a deep learning algorithm to identify patient-specific features associated with the development of toxicity, and test the approach by attempting to validate previously published genetic risk factors. Methods: The study involved REQUITE prostate cancer patients treated with external beam radiotherapy who had complete 2-year follow-up. We used five separate late toxicity endpoints: ≥grade 1 late rectal bleeding, ≥grade 2 urinary frequency, ≥grade 1 haematuria, ≥ grade 2 nocturia, ≥ grade 1 decreased urinary stream. Forty-three single nucleotide polymorphisms (SNPs) already reported in the literature to be associated with the toxicity endpoints were included in the analysis. No SNP had been studied before in the REQUITE cohort. Deep Sparse AutoEncoders (DSAE) were trained to recognize features (SNPs) identifying patients with no toxicity and tested on a different independent mixed population including patients without and with toxicity. Results: One thousand, four hundred and one patients were included, and toxicity rates were: rectal bleeding 11.7%, urinary frequency 4%, haematuria 5.5%, nocturia 7.8%, decreased urinary stream 17.1%. Twenty-four of the 43 SNPs that were associated with the toxicity endpoints were validated as identifying patients with toxicity. Twenty of the 24 SNPs were associated with the same toxicity endpoint as reported in the literature: 9 SNPs for urinary symptoms and 11 SNPs for overall toxicity. The other 4 SNPs were associated with a different endpoint. Conclusion: Deep learning algorithms can validate SNPs associated with toxicity after radiotherapy for prostate cancer. The method should be studied further to identify polygenic SNP risk signatures for radiotherapy toxicity. The signatures could then be included in integrated normal tissue complication probability models and tested for their ability to personalize radiotherapy treatment planning

De Moleculaire Pathogenese van Hoofd en Hals Kanker: de rol van Tyrosine Kinasen en HPV.

Head-and-neck squamous cell carcinoma (HNSCC) is the fifth most common malignancy worldwide, responsible for approximately half a millionnew cases every year. The treatment of this disease is challenging and characterized by high rates of therapy failure and toxicity, stressing the need for new innovative treatment strategies. In this work we primarily aimed to identify potential starting points for new therapeutic targeting strategies. We therefore performed a high throughput shRNAmir based screen on HNSCC cells with the aim to identify tyrosine kinases that are mediating radiotherapy resistance. Using this screen setup we identified the receptor tyrosine kinase FLT1 (VEGFR1) as an important driver of cell survival and radioresistance, and demonstrate receptoractivation through autocrine production of FLT1 ligands. Immunohistochemistry on HNSCC patient samples demonstrated FLT1 and ligands to be uniformly expressed. Interestingly, FLT1 was selectively overexpressed in tumour tissue as compared to non-cancerous epithelium. Remarkably, we found only membrane permeable FLT1 kinase inhibitors to be effective, which was in agreement with the intracellular localization of FLT1. Taken together, we document expression of FLT1 in HNSCC and demonstrate this kinase to modulate radioresistance and cancer cell survival. Given the fact that FLT1 kinase is selectively upregulated in tumour tissue and that itskinase function seems expendable for normal life and development, this kinase holds great promise as a new potential therapeutic target. Nonetheless several scientific questions still need to be resolved before FLT1targeted therapy can be transferred from bench to bedside. Most crucialis the development of a good FLT1 targeting drug, which is able to shutdown FLT1 activity at concentrations which are maintainable in a clinical setting. Also further validation of such a FLT1 targeting strategy isrecommended in different patient derived HNSCC xenograft models to evaluate therapy responses as well as to validate prognostic biomarkers likefor example (semi)quantitative VEGFA expression or Human Papilloma Virus (HPV) status. A subgroup of HNSCC is etiologically related to HPV infection. These HPV related tumors show an intriguing clinicalbehavior as compared to classical HPV-unrelated HNSCC: they tend to have a better prognosis and show a better response to radio/chemotherapy although these tumors are undifferentiated and present themselves at more advanced clinical stages. Additionally, in contrast to HPV unrelated HNSCC they seem not responsive to hypoxia targeted therapy although the level of hypoxia between these tumors is comparable. To date these characteristics are unexplained on a molecular level. As a starting point to shed light on this remarkable behavior, we started from observations done on breast cancer cells where it was shown that p16 suppresses the expression of VEGFA (a FLT1 activating ligand), through inhibition of HIF1a, the key regulator of hypoxic metabolism. If we could show that p16 is suppressing HIF1a in HPV positive HNSCC, a resulting reduction of VEGFA expression could maybe explain part of the increased radiosensitivity through impaired FLT1 activity. Additionally, an impaired HIF1a function couldlead to hypoxia intolerance, owing to impaired adaptation to cellular hypoxia related metabolic stress. This hypoxia intolerance could then severely impact cellular survival under oxygen deprivation. This would thenlead to increased radiosensitivity in vivo, since these cells would be unable to rely on hypoxic niches within a tumor to protect them from radiation. We clearly demonstrated p16 related HIF1a suppressive activity in HPV positive HNSCC resulting in suppressed VEGFA expression. However we also showed that this suppressive activity did not suffice to prevent a HIF1a mediated metabolic shift nor to induce hypoxia intolerance in these cells. The reason why HPV positive HNSCC is not responsive on hypoxia targeted therapy therefore remains elusive. HPV associated HNSCC is currently becoming a global epidemic. According to American SEER data, the incidence of this type of cancer is increasing with 2-3% each year. American studies have shown that 40 to 65% of HNSCC arising from the base of tongue or tonsils could be attributed to HPV16. As already mentioned these tumors are more radiocurable but not responsive to hypoxia targeted therapy. These factors could probably have an impact on treatment selection. Currently, locally advanced stage oropharyngeal cancers are being treated in the same way as the classical HNSCC with radio-chemotherapy schedules. These intense treatment regimens come however at the cost of severe acute and late toxicity (like dysphagia and PEG-tube dependency). Patients with HPV-associated HNSCC might not need these intense treatment regimens, and perhaps more function sparing therapies would lead to equal survival numbers in this population. To set up new clinical studies, we needed to have an idea about the prevalence of HPV in oropharyngeal cancer in our Flemish (Belgian) patient population, certainly because large geographical differences are existing. Therefore a multicenter cooperative study was undertaken between the radiation-oncology departments of the Flemish universities. We found indeed an increasing incidence of oropharyngeal carcinoma in males as well as females. The prevalence of HPV(+) oropharyngeal carcinoma was found to be 24.78% (19.93-30.36%). HPV status remained a strong predictor of better locoregional control after multivariate analysis. Regarding locoregional control we found the addition of concurrent chemotherapy to be of equal benefit in HPV(+) and HPV(-) patients suggesting that treatment de-escalation by omitting concurrent chemotherapy is probably not a good idea.status: publishe

Result of the STAMPEDE trial; :plausibility and practical consequences

Recently, the results of the STAMPEDE trial arm H were reported. This trial investigated the effect of radiotherapy to the prostate only on the overall survival of patients with metastatic prostate cancer. Although on the whole the findings of the trial were negative, a significant increase in survival was noted in the prespecified subgroup of patients with a low metastatic burden. As only a few analyses were prespecified, the direction of the subgroup effect was prespecified and consistent with previous observations from the separate but comparable HORRAD trial. The subgroup effect was large and independent of other subgroup variables, and as there is a solid biological rationale for these results, they are to be considered trustworthy, and are likely to change clinical practice. Further research should focus on better specification of the low metastatic burden subgroup, if other locally ablative treatments such as surgery are equivalent, and if ablation of all metastatic lesions would give additional benefit