Development of PSMA-PET-guided CT-based radiomic signature to predict biochemical recurrence after salvage radiotherapy.

PURPOSE: To develop a CT-based radiomic signature to predict biochemical recurrence (BCR) in prostate cancer patients after sRT guided by positron-emission tomography targeting prostate-specific membrane antigen (PSMA-PET). MATERIAL AND METHODS: Consecutive patients, who underwent 68Ga-PSMA11-PET/CT-guided sRT from three high-volume centers in Germany, were included in this retrospective multicenter study. Patients had PET-positive local recurrences and were treated with intensity-modulated sRT. Radiomic features were extracted from volumes of interests on CT guided by focal PSMA-PET uptakes. After preprocessing, clinical, radiomics, and combined clinical-radiomic models were developed combining different feature reduction techniques and Cox proportional hazard models within a nested cross validation approach. RESULTS: Among 99 patients, median interval until BCR was the radiomic models outperformed clinical models and combined clinical-radiomic models for prediction of BCR with a C-index of 0.71 compared to 0.53 and 0.63 in the test sets, respectively. In contrast to the other models, the radiomic model achieved significantly improved patient stratification in Kaplan-Meier analysis. The radiomic and clinical-radiomic model achieved a significantly better time-dependent net reclassification improvement index (0.392 and 0.762, respectively) compared to the clinical model. Decision curve analysis demonstrated a clinical net benefit for both models. Mean intensity was the most predictive radiomic feature. CONCLUSION: This is the first study to develop a PSMA-PET-guided CT-based radiomic model to predict BCR after sRT. The radiomic models outperformed clinical models and might contribute to guide personalized treatment decisions.

Tspan8 is expressed in breast cancer and regulates E-cadherin/catenin signalling and metastasis accompanied by increased circulating extracellular vesicles.

Tspan8 exhibits a functional role in many cancer types including pancreatic, colorectal, oesophagus carcinoma, and melanoma. We present a first study on the expression and function of Tspan8 in breast cancer. Tspan8 protein was present in the majority of human primary breast cancer lesions and metastases in the brain, bone, lung, and liver. In a syngeneic rat breast cancer model, Tspan8+ tumours formed multiple liver and spleen metastases, while Tspan8- tumours exhibited a significantly diminished ability to metastasise, indicating a role of Tspan8 in metastases. Addressing the underlying molecular mechanisms, we discovered that Tspan8 can mediate up-regulation of E-cadherin and down-regulation of Twist, p120-catenin, and ß-catenin target genes accompanied by the change of cell phenotype, resembling the mesenchymal-epithelial transition. Furthermore, Tspan8+ cells exhibited enhanced cell-cell adhesion, diminished motility, and decreased sensitivity to irradiation. As a regulator of the content and function of extracellular vesicles (EVs), Tspan8 mediated a several-fold increase in EV number in cell culture and the circulation of tumour-bearing animals. We observed increased protein levels of E-cadherin and p120-catenin in these EVs; furthermore, Tspan8 and p120-catenin were co-immunoprecipitated, indicating that they may interact with each other. Altogether, our findings show the presence of Tspan8 in breast cancer primary lesion and metastases and indicate its role as a regulator of cell behaviour and EV release in breast cancer. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.