FFCD 1709-SIRTCI phase II trial: Selective internal radiation therapy plus Xelox, Bevacizumab and Atezolizumab in liver-dominant metastatic colorectal cancer.

Immune checkpoint inhibitors (ICI) have high efficacy in metastatic colorectal cancer (mCRC) with microsatellite instability (MSI) but not in microsatellite stable (MSS) tumour due to the low tumour mutational burden. Selective internal radiation therapy (SIRT) could enhance neoantigen production thus triggering systemic anti-tumoral immune response (abscopal effect). In addition, Oxalipatin can induce immunogenic cell death and Bevacizumab can decrease the exhaustion of tumour infiltrating lymphocyte. In combination, these treatments could act synergistically to sensitize MSS mCRCs to ICI SIRTCI is a prospective, multicentre, open-label, phase II, non-comparative single-arm study evaluating the efficacy and safety of SIRT plus Xelox, Bevacizumab and Atezolizumab (anti-programmed death-ligand 1) in patients with liver-dominant MSS mCRC. The primary objective is progression-free survival at 9 months. The main inclusion criteria are patients with MSS mCRC with liver-dominant disease, initially unresectable disease and with no prior oncologic treatment for metastatic disease. The trial started in November 2020 and has included 10 out of the 52 planned patients.

Qualitative and quantitative reproducibility of [18]fluoromethycholine PET/computed tomography in prostate cancer.

BACKGROUND: Recurrence occurs in more than 50% of prostate cancer. To be effective, treatments require precise localization of tumor cells. [F]fluoromethylcholine ([18F]FCH) PET/computed tomography (CT) is currently used to restage disease in cases of biochemical relapse. To be used for therapy response as has been suggested, repeatability limits of PET derived indices need to be established. OBJECTIVE: The aim of our study was to prospectively assess the qualitative and quantitative reproducibility [18F]FCH PET/CT in prostate cancer. METHODS: Patients with histologically proven prostate cancer referred for initial staging or restaging were prospectively included. All patients underwent two [18F]FCH PET/CTs in the same conditions within a maximum of 3 weeks' time. We studied the repeatability of the visual report and the repeatability of SUVmax and its evolution over the acquisition time in lesions, liver and vascular background. Statistical analysis was performed using the Bland-Altman approach. RESULTS: Twenty-one patients were included. Reporting repeatability was excellent with 97.8% of concordance. Mean repeatability of SUVmax considering all times and all lesions was 2.2% ± 20. Evolution of SUVmax was unpredictable, either increasing or decreasing over the acquisition time, both for lesions and for physiological activity. CONCLUSION: Our study demonstrated that visual report of [18F]FCH PET/CT was very reproducible and that the repeatability limits of SUVmax was similar to those of other PET radiotracers. An SUVmax difference of more than 40% should be considered as representing a treatment response effect. Change of SUVmax during the acquisition time varied and should not be considered as an interpretation criterion.

Use of baseline 18F-FDG PET scan to identify initial sub-volumes with local failure after concomitant radio-chemotherapy in head and neck cancer.

INTRODUCTION: Head and neck squamous cell carcinoma (HNSCC) treated by radio-chemotherapy have a significant local recurrence rate. It has been previously suggested that 18F-FDG PET could identify the high uptake areas that can be potential targets for dose boosting. The purpose of this study was to compare the location of initial hypermetabolic regions on baseline scans with the metabolic relapse sites after radio-chemotherapy in HNSCC. RESULTS: The initial functional tumor volume was significantly higher for patients with proven local recurrence or residual disease (23.5 cc vs. 8.9 cc; p = 0.0005). The overlap between baseline and follow-up sub-volumes were moderate with an overlap fraction ranging from 0.52 to 0.39 between R40 and I30 to I60. CONCLUSION: In our study the overlap between baseline and post-therapeutic metabolic tumor sub-volumes was only moderate. These results need to be investigated in a larger cohort acquired with a more standardized patient repositioning protocol for sequential PET imaging. METHODS: Pre and post treatment PET/CT scans of ninety four HNSCC patients treated with radio-chemotherapy were retrospectively reviewed. Follow-up 18F-FDG PET/CT images were registered to baseline scans using a rigid body transformation. Seven metabolic tumor sub-volumes were obtained on the baseline scans using a fixed percentage of SUVmax (I30, I40, I50, I60, I70, I80, and I90) and were subsequently compared with two post-treatment sub-volumes (R40, R90) in 38 cases of local recurrence or residual metabolic disease. Overlap fraction, Dice and Jaccard indices, common volume/baseline volume and common volume/recurrent volume were used to determine the overlap of the different estimated sub-volumes.

Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial.

BACKGROUND: Sorafenib is the recommended treatment for patients with advanced hepatocellular carcinoma. We aimed to compare the efficacy and safety of sorafenib to that of selective internal radiotherapy (SIRT) with yttrium-90 (90Y) resin microspheres in patients with hepatocellular carcinoma. METHODS: SARAH was a multicentre, open-label, randomised, controlled, investigator-initiated, phase 3 trial done at 25 centres specialising in liver diseases in France. Patients were eligible if they were aged at least 18 years with a life expectancy greater than 3 months, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, Child-Pugh liver function class A or B score of 7 or lower, and locally advanced hepatocellular carcinoma (Barcelona Clinic Liver Cancer [BCLC] stage C), or new hepatocellular carcinoma not eligible for surgical resection, liver transplantation, or thermal ablation after a previously cured hepatocellular carcinoma (cured by surgery or thermoablative therapy), or hepatocellular carcinoma with two unsuccessful rounds of transarterial chemoembolisation. Patients were randomly assigned (1:1) by a permutated block method with block sizes two and four to receive continuous oral sorafenib (400 mg twice daily) or SIRT with 90Y-loaded resin microspheres 2-5 weeks after randomisation. Patients were stratified according to randomising centre, ECOG performance status, previous transarterial chemoembolisation, and presence of macroscopic vascular invasion. The primary endpoint was overall survival. Analyses were done on the intention-to-treat population; safety was assessed in all patients who received at least one dose of sorafenib or underwent at least one of the SIRT work-up exams. This study has been completed and the final results are reported here. The trial is registered with ClinicalTrials.gov, number NCT01482442. FINDINGS: Between Dec 5, 2011, and March 12, 2015, 467 patients were randomly assigned; after eight patients withdrew consent, 237 were assigned to SIRT and 222 to sorafenib. In the SIRT group, 53 (22%) of 237 patients did not receive SIRT; 26 (49%) of these 53 patients were treated with sorafenib. Median follow-up was 27·9 months (IQR 21·9-33·6) in the SIRT group and 28·1 months (20·0-35·3) in the sorafenib group. Median overall survival was 8·0 months (95% CI 6·7-9·9) in the SIRT group versus 9·9 months (8·7-11·4) in the sorafenib group (hazard ratio 1·15 [95% CI 0·94-1·41] for SIRT vs sorafenib; p=0·18). In the safety population, at least one serious adverse event was reported in 174 (77%) of 226 patients in the SIRT group and in 176 (82%) of 216 in the sorafenib group. The most frequent grade 3 or worse treatment-related adverse events were fatigue (20 [9%] vs 41 [19%]), liver dysfunction (25 [11%] vs 27 [13%]), increased laboratory liver values (20 [9%] vs 16 [7%]), haematological abnormalities (23 [10%] vs 30 [14%]), diarrhoea (three [1%] vs 30 [14%]), abdominal pain (six [3%] vs 14 [6%]), increased creatinine (four [2%] vs 12 [6%]), and hand-foot skin reaction (one [<1%] vs 12 [6%]). 19 deaths in the SIRT group and 12 in the sorafenib group were deemed to be treatment related. INTERPRETATION: In patients with locally advanced or intermediate-stage hepatocellular carcinoma after unsuccessful transarterial chemoembolisation, overall survival did not significantly differ between the two groups. Quality of life and tolerance might help when choosing between the two treatments. FUNDING: Sirtex Medical Inc.

Development of a nomogram combining clinical staging with (18)F-FDG PET/CT image features in non-small-cell lung cancer stage I-III.

PURPOSE: Our goal was to develop a nomogram by exploiting intratumour heterogeneity on CT and PET images from routine (18)F-FDG PET/CT acquisitions to identify patients with the poorest prognosis. METHODS: This retrospective study included 116 patients with NSCLC stage I, II or III and with staging (18)F-FDG PET/CT imaging. Primary tumour volumes were delineated using the FLAB algorithm and 3D Slicer™ on PET and CT images, respectively. PET and CT heterogeneities were quantified using texture analysis. The reproducibility of the CT features was assessed on a separate test-retest dataset. The stratification power of the PET/CT features was evaluated using the Kaplan-Meier method and the log-rank test. The best standard metric (functional volume) was combined with the least redundant and most prognostic PET/CT heterogeneity features to build the nomogram. RESULTS: PET entropy and CT zone percentage had the highest complementary values with clinical stage and functional volume. The nomogram improved stratification amongst patients with stage II and III disease, allowing identification of patients with the poorest prognosis (clinical stage III, large tumour volume, high PET heterogeneity and low CT heterogeneity). CONCLUSION: Intratumour heterogeneity quantified using textural features on both CT and PET images from routine staging (18)F-FDG PET/CT acquisitions can be used to create a nomogram with higher stratification power than staging alone.

18F-FDG PET uptake characterization through texture analysis: investigating the complementary nature of heterogeneity and functional tumor volume in a multi-cancer site patient cohort.

UNLABELLED: Intratumoral uptake heterogeneity in (18)F-FDG PET has been associated with patient treatment outcomes in several cancer types. Textural feature analysis is a promising method for its quantification. An open issue associated with textural features for the quantification of intratumoral heterogeneity concerns its added contribution and dependence on the metabolically active tumor volume (MATV), which has already been shown to be a significant predictive and prognostic parameter. Our objective was to address this question using a larger cohort of patients covering different cancer types. METHODS: A single database of 555 pretreatment (18)F-FDG PET images (breast, cervix, esophageal, head and neck, and lung cancer tumors) was assembled. Four robust and reproducible textural feature-derived parameters were considered. The issues associated with the calculation of textural features using co-occurrence matrices (such as the quantization and spatial directionality relationships) were also investigated. The relationship between these features and MATV, as well as among the features themselves, was investigated using Spearman rank coefficients for different volume ranges. The complementary prognostic value of MATV and textural features was assessed through multivariate Cox analysis in the esophageal and non-small cell lung cancer (NSCLC) cohorts. RESULTS: A large range of MATVs was included in the population considered (3-415 cm(3); mean, 35; median, 19; SD, 50). The correlation between MATV and textural features varied greatly depending on the MATVs, with reduced correlation for increasing volumes. These findings were reproducible across the different cancer types. The quantization and calculation methods both had an impact on the correlation. Volume and heterogeneity were independent prognostic factors (P = 0.0053 and 0.0093, respectively) along with stage (P = 0.002) in non-small cell lung cancer, but in the esophageal tumors, volume and heterogeneity had less complementary value because of smaller overall volumes. CONCLUSION: Our results suggest that heterogeneity quantification and volume may provide valuable complementary information for volumes above 10 cm(3), although the complementary information increases substantially with larger volumes.

Visual versus quantitative assessment of intratumor 18F-FDG PET uptake heterogeneity: prognostic value in non-small cell lung cancer.

UNLABELLED: The goal of this study was to compare visual assessment of intratumor (18)F-FDG PET uptake distribution with a textural-features (TF) automated quantification and to establish their respective prognostic value in non-small cell lung cancer (NSCLC). METHODS: The study retrospectively included 102 consecutive patients. Only primary tumors were considered. Intratumor heterogeneity was visually scored (3-level scale [Hvisu]) by 2 nuclear medicine physicians. Tumor volumes were automatically delineated, and heterogeneity was quantified with TF. Mean and maximum standardized uptake value were also included. Visual interobserver agreement and correlations with quantitative assessment were evaluated using the κ test and Spearman rank (ρ) coefficient, respectively. Association with overall survival and recurrence-free survival was investigated using the Kaplan-Meier method and Cox regression models. RESULTS: Moderate correlations (0.4 < ρ < 0.6) between TF parameters and Hvisu were observed. Interobserver agreement for Hvisu was moderate (κ = 0.64, discrepancies in 27% of the cases). High standardized uptake value, large metabolic volumes, and high heterogeneity according to TF were associated with poorer overall survival and recurrence-free survival and remained an independent prognostic factor of overall survival with respect to clinical variables. CONCLUSION: Quantification of (18)F-FDG uptake heterogeneity in NSCLC through TF was correlated with visual assessment by experts. However, TF also constitutes an objective heterogeneity quantification, with reduced interobserver variability, and independent prognostic value potentially useful for patient stratification and management.

Influence of temperature on the radiochemical purity of 99mTc-colloidal rhenium sulfide for use in sentinel node localization.

BACKGROUND: Some preparations of 99mTc-colloidal rhenium sulfide (Nanocis) contain excess free pertechnetate (99mTcO4) impurity (>5%). OBJECTIVES: To improve the radiochemical purity of Nanocis preparations and the quality of preoperative lymphoscintigraphy in sentinel node localization of breast cancer patients, we investigated the effects of temperature on the presence of free 99mTcO4 and nanocolloid size modification. METHODS: A Nanocis kit was reconstituted with sodium pertechnetate (650-850 MBq) in a final volume of 3.5 ml and heated for 30 min at 100, 115, or 130 degrees C. The radiochemical purity was determined by paper chromatography, in triplicate. The particle size was evaluated by membrane filtration through a 200-nm and 100-nm filter. The preoperative lymphoscintigraphy images were acquired about 2 h after tracer administration. RESULTS: Significantly higher radiochemical purity values were observed with 28 Nanocis preparations heated at 130 degrees C (median: 99.8%, min-max: 97.0-99.9%) compared with values from 37 Nanocis preparations heated at 100 degrees C (median: 96.3%, min-max: 85.2-99.5%) or 26 Nanocis preparations heated at 115 degrees C (median: 95.1%, min-max: 85.7-99.8%). The interbatch variations of the radiochemical purity were reduced at 130 degrees C. A high temperature level (130 degrees C) did not modify the particle size. In lymphoscintigraphy, free 99mTcO4 uptake by the thyroid or stomach, which was sometimes observed with a Nanocis preparation heated at 100 or 115 degrees C, was never visualized with a Nanocis preparation heated at 130 degrees C. CONCLUSION: These results indicate that increasing temperature from 100 to 130 degrees C can be used in routine clinical practice to improve the radiochemical purity of the Nanocis preparation.

Coronary spasm after an adenosine stress test: an adverse effect of a vasodilator.

The occurrence of a coronary spasm after an adenosine stress test is an exceptional event. We report a vasospasm in a patient with normal coronary angiography. The spasm occurred shortly after termination of adenosine infusion on abrupt withdrawal of vasodilation. Ischaemia induced ventricular arrhythmia (bursts of polymorphous tachycardia) that responded well to antispastic therapy. The main identified predisposing factor for coronary spasm was vasospastic angina and adenosine acted as a revealing factor of this unsuspected diagnosis.

Immunohistochemical detection, regulation and antiproliferative function of G-protein-coupled receptor kinase 2 in thyroid carcinomas.

TSH, via its G-protein-coupled receptor, activates cell growth of both benign and malignant thyroid tumors. G-protein-coupled receptors (GR) kinase 2 (GRK2) has been reported to regulate the TSH receptor but its role in cancer is unknown. To determine a possible function for GRK2 in the growth process of thyroid cancers, we analysed its expression in normal and tumoral thyroid tissues and studied thyroid cancer cell line proliferation after GRK2 overexpression. Thirty one thyroid tissues, including 16 non-medullary thyroid cancers and 15 adjacent normal tissues, were analysed by immunohistochemistry. Five paired tissues were also studied by western blotting for the GRK2 enzymatic activity. Immunohistochemical staining showed an increase in GRK2 in thyroid cancers including papillary, follicular, and anaplastic types, compared with their adjacent normal tissues. Immunoblot analysis and GRK2 enzymatic activity measurement confirmed immunohistochemical study. TSH and TSH in association with insulin or IGF-I stimulated GRK2 protein accumulation in normal human thyroid cells in primary culture. The TSH effect on the GRK2 expression was mimicked by forskolin. After GRK2 overexpression in two poorly differentiated thyroid cell lines, all the clones showed a significant reduction in cell proliferation, ranging from 28 to 65% inhibition compared with vector alone after 96-h culture. In conclusion, thyroid mitogenic factor-stimulated GRK2 accumulation may explain, in part, high GRK2 levels in differentiated carcinoma, because TSH, insulin, or IGF-I is known to be involved in the thyroid cancer progression. Surprisingly, instead of stimulating, GRK2 reduced cell proliferation revealing a new role for this kinase in the growth of thyroid cancers.

Pathophysiological roles of G-protein-coupled receptor kinases.

G-protein-coupled receptor kinases (GRKs) interact with the agonist-activated form of G-protein-coupled receptors (GPCRs) to effect receptor phosphorylation and to initiate profound impairment of receptor signalling, or desensitization. GPCRs form the largest family of cell surface receptors known and defects in GRK function have the potential consequence to affect GPCR-stimulated biological responses in many pathological situations. This review focuses on the physiological role of GRKs revealed by genetically modified animals but also develops the involvement of GRKs in human diseases as, Oguchi disease, heart failure, hypertension or rhumatoid arthritis. Furthermore, the regulation of GRK levels in opiate addiction, cancers, psychiatric diseases, cystic fibrosis and cardiac diseases is discussed. Both transgenic mice and human pathologies have demonstrated the importance of GRKs in the signalling pathways of rhodopsin, beta-adrenergic and dopamine-1 receptors. The modulation of GRK activity in animal models of cardiac diseases can be effective to restore cardiac function in heart failure and opens a novel therapeutic strategy in diseases with GPCR dysregulation.