A Non-Canonical Role for the Glycosyltransferase Enzyme UGT2B17 as a Novel Constituent of the B Cell Receptor Signalosome.

In chronic lymphocytic leukemia (CLL), an elevated glycosyltransferase UGT2B17 expression (UGT2B17HI) identifies a subgroup of patients with shorter survival and poor drug response. We uncovered a mechanism, possibly independent of its enzymatic function, characterized by an enhanced expression and signaling of the proximal effectors of the pro-survival B cell receptor (BCR) pathway and elevated Bruton tyrosine kinase (BTK) phosphorylation in B-CLL cells from UGT2B17HI patients. A prominent feature of B-CLL cells is the strong correlation of UGT2B17 expression with the adverse marker ZAP70 encoding a tyrosine kinase that promotes B-CLL cell survival. Their combined high expression levels in the treatment of naïve patients further defined a prognostic group with the highest risk of poor survival. In leukemic cells, UGT2B17 knockout and repression of ZAP70 reduced proliferation, suggesting that the function of UGT2B17 might involve ZAP70. Mechanistically, UGT2B17 interacted with several kinases of the BCR pathway, including ZAP70, SYK, and BTK, revealing a potential therapeutic vulnerability. The dual SYK and JAK/STAT6 inhibitor cerdulatinib most effectively compromised the proliferative advantage conferred by UGT2B17 compared to the selective BTK inhibitor ibrutinib. Findings point to an oncogenic role for UGT2B17 as a novel constituent of BCR signalosome also connected with microenvironmental signaling.

UGT2B28 accelerates prostate cancer progression through stabilization of the endocytic adaptor protein HIP1 regulating AR and EGFR pathways.

The androgen inactivating UGT2B28 pathway emerges as a predictor of progression in prostate cancer (PCa). However, the clinical significance of UGT2B28 tumoral expression and its contribution to PCa progression remain unclear. Using the Canadian Prostate Cancer Biomarker Network biobank (CPCBN; n = 1512), we analyzed UGT2B28 tumor expression in relation to clinical outcomes in men with localized PCa. UGT2B28 was overexpressed in tumors compared to paired normal adjacent prostatic tissue and was associated with inferior outcomes. Functional analyses indicated that UGT2B28 promoted cell proliferation, and its expression was regulated by the androgen receptor (AR)/ARv7. Mechanistically, UGT2B28 was shown to be a protein partner of the endocytic adaptor protein huntingtin-interacting protein 1 (HIP1), increasing its stability and priming AR/epidermal growth factor receptor (EGFR) pathways, leading to ERK1/2 activation triggering cell proliferation and epithelial-to-mesenchymal transition (EMT). HIP1 knockdown in UGT2B28 positive cells, and dual pharmacological targeting of AR and EGFR pathways, abolished cell proliferative advantages conferred by UGT2B28. In conclusion, UGT2B28 is a prognosticator of progression in localized PCa, regulates both AR and EGFR oncogenic signaling pathways via HIP1, and therefore can be therapeutically targeted by using combination of existing AR/EGFR inhibitors.

A Truncated NRIP1 Mutant Amplifies Microsatellite Instability of Colorectal Cancer by Regulating MSH2/MSH6 Expression, and Is a Prognostic Marker of Stage III Tumors.

Microsatellite instability (MSI) is related to the alteration of mismatch repair (MMR) genes and plays a key role in colorectal cancer (CRC) pathogenesis. We previously reported that the transcription factor Nuclear Receptor Interacting Protein 1 (NRIP1) is involved in sporadic intestinal tumorigenesis. The aim of this study was to decipher its role in MSI CRC. By using different mouse models and engineered cell lines, we demonstrated that NRIP1 increased MSH2 and MSH6 MMR gene transcription and mRNA/protein levels. In human CRC cells, NRIP1 expression was associated with decreased MSI and the hypermutator phenotype, and with resistance to chemotherapy drugs. Using a cohort of 194 CRC patients, we detected in 22% of the cases a MSI-induced frameshift mutation in the NRIP1 coding sequence. This genetic alteration generates a truncated protein with a dominant negative activity that increased human CRC cell proliferation and impaired the regulation of MSH2 and MSH6 gene expression. Moreover, the NRIP1 mutant correlated with a decreased overall survival of patients with advanced CRC, especially when MLH1-deficient. By decreasing the expression of MSH2 and MSH6 gene expression, the NRIP1 variant may amplify MLH1-dependent CRC progression and behave as a new prognostic marker of advanced MSI CRC.

MR to CT synthesis with multicenter data in the pelvic area using a conditional generative adversarial network.

The establishment of an MRI-only workflow in radiotherapy depends on the ability to generate an accurate synthetic CT (sCT) for dose calculation. Previously proposed methods have used a Generative Adversarial Network (GAN) for fast sCT generation in order to simplify the clinical workflow and reduces uncertainties. In the current paper we use a conditional Generative Adversarial Network (cGAN) framework called pix2pixHD to create a robust model prone to multicenter data. This study included T2-weighted MR and CT images of 19 patients in treatment position from 3 different sites. The cGAN was trained on 2D transverse slices of 11 patients from 2 different sites. Once trained, the network was used to generate sCT images of 8 patients coming from a third site. The Mean Absolute Errors (MAE) for each patient were evaluated between real and synthetic CTs. A radiotherapy plan was optimized on the sCT series and re-calculated on CTs to assess the dose distribution in terms of voxel-wise dose difference and Dose Volume Histograms (DVH) analysis. It takes on average of [Formula: see text] to generate a complete sCT (88 slices) for a patient on our GPU. The average MAE in HU between the sCT and actual patient CT (within the body contour) is 48.5 ± 6 HU with our method. The maximum dose difference to the target is 1.3%. This study demonstrates that an sCT can be generated in a multicentric context, with fewer pre-processing steps while being fast and accurate.

Abstract ID: 222 Clinical implementation of a Monte Carlo based QA platform for validation of Tomotherapy and Cyberknife treatment plans.

INTRODUCTION: This work describes the clinical implementation of a Monte Carlo based platform for treatment plan validation for Tomotherapy and Cyberknife, including a semi-automatic plan evaluation module based on dose constraints for organs-at-risk (OAR). METHODS: The Monte Carlo-based platform Moderato [1] is based on BEAMnrc/DOSXYZnrc and allows for automated re-calculation of doses planned with Tomotherapy and Cyberknife techniques. The Prescription/Validation module generates a set of dose constraints based on the anatomical region and fractionation scheme considered. Upon achievement of the planning, dose results are displayed with visual warnings in case of constraint violation. The system was tested on 83 patient cases in order to evaluate the influence of difference in calculation algorithms on OAR constraints. RESULTS: The first results with the Tomotherapy plans allowed for detecting and correcting a problem with the CT Hounsfield units when using a large reconstruction diameter (a CT artifact that lead to air voxels with an overestimated density). The Cyberknife results also showed some dose differences associated with different energy thresholds between Moderato and the Monte Carlo algorithm used in the Treatment Planning Station. Regarding OAR constraints, re-calculation generated few violations in thoracic, pelvic and abdominal cases. However, in spinal and head cases, significant differences can appear (-11% to +6%) on optic pathways and spinal cord, leading to doses above the limits. CONCLUSIONS: The Moderato platform constitutes a promising tool for the validation of plan quality, offering both dose re-calculation and OAR constraints evaluation. First results show the importance of this verification for some specific regions. Further work is ongoing to optimize the quantity and relevance of the information displayed, before fully introducing the system in clinical routine.

Can We Spare the Pancreas and Other Abdominal Organs at Risk? A Comparison of Conformal Radiotherapy, Helical Tomotherapy and Proton Beam Therapy in Pediatric Irradiation.

OBJECTIVES: Late abdominal irradiation toxicity during childhood included renal damage, hepatic toxicity and secondary diabetes mellitus. We compared the potential of conformal radiotherapy (CRT), helical tomotherapy (HT) and proton beam therapy (PBT) to spare the abdominal organs at risk (pancreas, kidneys and liver- OAR) in children undergoing abdominal irradiation. METHODS: We selected children with abdominal tumors who received more than 10 Gy to the abdomen. Treatment plans were calculated in order to keep the dose to abdominal OAR as low as possible while maintaining the same planned target volume (PTV) coverage. Dosimetric values were compared using the Wilcoxon signed-rank test. RESULTS: The dose distribution of 20 clinical cases with a median age of 8 years (range 1-14) were calculated with different doses to the PTV: 5 medulloblastomas (36 Gy), 3 left-sided and 2 right-sided nephroblastomas (14.4 Gy to the tumor + 10.8 Gy boost to para-aortic lymphnodes), 1 left-sided and 4 right-sided or midline neuroblastomas (21 Gy) and 5 Hodgkin lymphomas (19.8 Gy to the para-aortic lymphnodes and spleen). HT significantly reduced the mean dose to the whole pancreas (WP), the pancreatic tail (PT) and to the ipsilateral kidney compared to CRT. PBT reduced the mean dose to the WP and PT compared to both CRT and HT especially in midline and right-sided tumors. PBT decreased the mean dose to the ispilateral kidney but also to the contralateral kidney and the liver compared to CRT. Low dose to normal tissue was similar or increased with HT whereas integral dose and the volume of normal tissue receiving at least 5 and 10 Gy were reduced with PBT compared to CRT and HT. CONCLUSION: In children undergoing abdominal irradiation therapy, proton beam therapy reduces the dose to abdominal OAR while sparing normal tissue by limiting low dose irradiation.

Characterization of recombination effects in a liquid ionization chamber used for the dosimetry of a radiosurgical accelerator.

Most modern radiation therapy devices allow the use of very small fields, either through beamlets in Intensity-Modulated Radiation Therapy (IMRT) or via stereotactic radiotherapy where positioning accuracy allows delivering very high doses per fraction in a small volume of the patient. Dosimetric measurements on medical accelerators are conventionally realized using air-filled ionization chambers. However, in small beams these are subject to nonnegligible perturbation effects. This study focuses on liquid ionization chambers, which offer advantages in terms of spatial resolution and low fluence perturbation. Ion recombination effects are investigated for the microLion detector (PTW) used with the Cyberknife system (Accuray). The method consists of performing a series of water tank measurements at different source-surface distances, and applying corrections to the liquid detector readings based on simultaneous gaseous detector measurements. This approach facilitates isolating the recombination effects arising from the high density of the liquid sensitive medium and obtaining correction factors to apply to the detector readings. The main difficulty resides in achieving a sufficient level of accuracy in the setup to be able to detect small changes in the chamber response.

[Radiotherapy promises: focus on lung cancer]. / Les promesses de la radiothérapie. Focus sur les tumeurs pulmonaires.

Radiotherapy is a key cancer treatment, which greatly modified its practice in recent years thanks to medical imaging and technical improvements. The systematic use of computed tomography (CT) for treatment planning, the imaging fusion/co-registration between CT/magnetic resonance imaging (MRI) or CT/positron emission tomography (PET) improve target identification/selection and delineation. New irradiation techniques such as image-guided radiotherapy (IGRT), stereotactic radiotherapy or hadron therapy offer a more diverse therapeutic armamentarium to patients together with lower toxicity. Radiotherapy, as well as medical oncology, tends to offer a personalized treatment to patients thanks to the IGRT, which takes into account the inter- or intra-fraction anatomic variations. IGRT leads to adaptive radiotherapy (ART) with a new planification in the treatment course in order to decrease toxicity and improve tumor control. The use of systemic therapies with radiations needs to be studied in order to improve efficiency without increasing toxicities from these multimodal approaches. Finally, radiotherapy advances were impacted by radiotherapy accidents like Epinal. They led to an increased quality control with the intensification of identity control, the emergence of in vivo dosimetry or the experience feedback committee in radiotherapy. We will illustrate through the example of lung cancer.

Lesion-based detection of early chemosensitivity using serial static FDG PET/CT in metastatic colorectal cancer.

PURPOSE: Medical oncology needs early identification of patients that are not responding to systemic therapy. (18)F-Fluorodeoxyglucose (FDG) positron emission tomography (PET) performed before and early during treatment has been proposed for this purpose. However, the best way to assess the change in FDG uptake between two scans has not been identified. We studied cutoff thresholds to identify responding tumours as a function of the method used to measure tumour uptake. METHODS: The study included 28 metastatic colorectal cancer (mCRC) patients who underwent 2 FDG PET/CT scans (baseline and at day 14 of the first course of polychemotherapy). For 78 tumour lesions, 4 standardized uptake value (SUV) indices were measured: maximum SUV (SUV(max)) and mean SUV in a region obtained using an isocontour (SUV(40 %)), with each of these SUV normalized either by the patient body weight (BW) or body surface area (BSA). The per cent change and absolute change in tumour uptake between the baseline and the early PET scans were measured based on these four indices. These changes were correlated to the RECIST 1.0-based response using contrast-enhanced CT at baseline and at 6-8 weeks on treatment. RESULTS: The 78 tumours were classified as non-responding (NRL, n = 58) and responding lesions (RL, n = 20). Receiver-operating characteristic (ROC) curves characterizing the performance in NRL/RL classification using early FDG PET uptake had areas under the curve between 0.75 and 0.84, without significant difference between the indices. The cutoff threshold in FDG uptake per cent change to get a 95 % sensitivity of RL detection depended on the way uptake was measured: -14 % (specificity of 53 %) and -22 % (specificity of 64 %) for SUV(max) and SUV(40 %), respectively. Thresholds expressed as absolute SUV decrease instead of per cent change were less sensitive to the SUV definition: an SUV decline by 1.2 yielded a sensitivity of RL detection of 95 % for SUV(max) and SUV(40 %). For a given cutoff threshold, the sensitivity was the same whatever the normalization (by BSA or BW). CONCLUSION: A 14 % drop of tumour FDG SUV(max), 22 % drop of SUV(40 %) or 1.2 drop of SUV(max) or SUV(mean) after one single course of polychemotherapy predicts objective response in mCRC lesions with a high sensitivity, potentially allowing the early identification of non-responding patients.

Detection and characterization of tumor changes in 18F-FDG PET patient monitoring using parametric imaging.

UNLABELLED: In PET-based patient monitoring, metabolic tumor changes occurring between PET scans are most often assessed visually or by measuring only a few parameters (tumor volume or uptake), neglecting most of the image content. We propose and evaluate a parametric imaging (PI) method to assess tumor changes at the voxel level. METHODS: Seventy-eight pairs of tumor images obtained from baseline and follow-up (18)F-FDG PET/CT for 28 patients with metastatic colorectal cancer were considered. For each pair, after CT-based registration of the PET volumes, the 2 PET datasets were subtracted. A biparametric graph of subtracted voxel values versus voxel values in the first PET scan was obtained. A model-based analysis of this graph was used to identify the tumor voxels in which significant changes occurred between the 2 scans and yielded indices characterizing these changes. The Response Evaluation Criteria in Solid Tumors (RECIST) based on the CT images obtained 5-8 wk after the second PET/CT scan were used to classify tumor masses as responding or progressive. On the basis of this classification, we compared the sensitivity and specificity of PI and an approach based on recommendations from the European Organization for Research and Treatment of Cancer (EORTC). RESULTS: For tumor-based classification, the EORTC-based approach had a sensitivity and specificity of 85% and 52%, respectively, for detecting responding lesions, whereas PI had a sensitivity and specificity of 100% and 53%, respectively. None of responding tumors using RECIST was classified as progressive with the PI or EORTC-based criteria. Among the 14 progressive lesions according to RECIST, 12 were identified as progressive with PI whereas EORTC-based criteria classified only 1 as progressive and 13 as stable tumors. Considering the patient-based classification, none of the responders according to RECIST was classified as having progressive disease with the PI and EORTC-based criteria. PI has the advantage of showing a parametric image of the patient response to therapy, indicating potential heterogeneity in tumor response. CONCLUSION: The PI method has been successfully applied to characterize early metabolic tumor changes in 78 lesions from (18)F-FDG PET/CT scans of patients with metastatic colorectal cancer during chemotherapy. The PI findings correlated well with the standard RECIST-based response assessment.