Sunitinib for metastatic progressive phaeochromocytomas and paragangliomas: results from FIRSTMAPPP, an academic, multicentre, international, randomised, placebo-controlled, double-blind, phase 2 trial.

BACKGROUND: No randomised controlled trial has ever been done in patients with metastatic phaeochromocytomas and paragangliomas. Preclinical and first clinical evidence suggested beneficial effects of sunitinib. We aimed to evaluate the safety and efficacy of sunitinib in patients with metastatic phaeochromocytomas and paragangliomas. METHODS: FIRSTMAPPP is a multicentre, international, randomised, placebo-controlled, double-blind, phase 2 trial done at 14 academic centres across four European countries. Eligible participants were adults (aged ≥18 years) with sporadic or inherited progressive metastatic phaeochromocytomas and paragangliomas. Patients were randomly assigned (1:1) to receive either oral sunitinib (37·5 mg per day) or placebo. Randomisation was stratified according to SDHB status (mutation present vs wild type) and number of previous systemic therapies (0 vs ≥1). Primary endpoint was the rate of progression-free survival at 12 months according to real-time central review (Response Evaluation Criteria in Solid Tumours version 1.1). On the basis of a two-step Simon model, we aimed for the accrual of 78 patients, assuming a 20% improvement of the 12-month progression-free survival rate from 20% to 40%, to conclude that sunitinib is effective. Crossover from the placebo group was allowed. This trial is registered with ClinicalTrials.gov, number NCT01371201, and is closed for enrolment. FINDINGS: From Dec 1, 2011, to Jan 31, 2019, a total of 78 patients with progressive metastatic phaeochromocytomas and paragangliomas were enrolled (39 patients per group). 25 (32%) of 78 patients had germline SDHx variants and 54 (69%) had used previous therapies. The primary endpoint was met, with a 12-month progression-free survival in 14 of 39 patients (36% [90% CI 23-50]) in the sunitinib group. In the placebo group, the 12-month progression-free survival in seven of 39 patients was 19% (90% CI 11-31), validating the hypotheses of our study design. The most frequent grade 3 or 4 adverse events were asthenia (seven [18%] of 39 and one [3%] of 39), hypertension (five [13%] and four [10%]), and back or bone pain (one [3%] and three [8%]) in the sunitinib and placebo groups, respectively. Three deaths occurred in the sunitinib group: these deaths were due to respiratory insufficiency, amyotrophic lateral sclerosis, and rectal bleeding. Only the latter event was considered drug related. Two deaths occurred in the placebo group due to aspiration pneumonia and septic shock. INTERPRETATION: This first randomised trial supports the use of sunitinib as the medical option with the highest level of evidence for anti-tumour efficacy in progressive metastatic phaeochromocytomas and paragangliomas. FUNDING: French Ministry of Health, through the National Institute for Cancer, German Ministry of Education and Research, and the German Research Foundation within the CRC/Transregio 205/2, EU Seventh Framework Programme, and a private donator grant.

Indeterminate pulmonary nodules in non-rhabdomyosarcoma soft tissue sarcoma: A study of the European paediatric Soft Tissue Sarcoma Study Group.

BACKGROUND: The aim of this study was to assess the clinical impact of indeterminate pulmonary nodules (no more than four pulmonary nodules of less than 5 mm or one nodule measuring between 5 and less than 10 mm by computed tomography [CT]) in children and adolescents with adult-type non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) at diagnosis. METHODS: Patients with NRSTS treated in 11 centers as part of the European paediatric Soft Tissue Sarcoma Study Group (EpSSG) were retrospectively assessed. Local radiologists, blinded to clinical information except for patients' age and tumor histotype, reviewed the chest CT at diagnosis and filled out a case report form. Because patients with or without indeterminate nodules in the EpSSG NRSTS 2005 study received the same type of treatment, event-free survival (EFS) and overall survival (OS) between groups by log-rank test were compared. RESULTS: Overall, 206 patients were examined: 109 (52.9%) were without any nodules, 78 (38%) had at least one indeterminate nodule, and 19 (9.2%) had nodules meeting the definition of metastases, which were then considered to be misclassified and were excluded from further analyses. Five-year EFS was 78.5% (95% CI, 69.4%-85.1%) for patients without nodules and 69.6% (95% CI, 57.9%-78.7%) for patients with indeterminate nodules (p = .135); 5-year OS was 87.4% (95% CI, 79.3%-92.5%) and 79.0% (95% CI, 67.5%-86.8%), respectively (p = .086). CONCLUSIONS: This study suggests that survival does not differ in otherwise nonmetastatic patients with indeterminate pulmonary nodules compared to nonmetastatic patients without pulmonary nodules. PLAIN LANGUAGE SUMMARY: Radiologists should be aware of the classification of indeterminate pulmonary nodules in non-rhabdomyosarcoma soft tissue sarcomas and use it in their reports. More than a third of patients with non-rhabdomyosarcoma soft tissue sarcoma can be affected by indeterminate pulmonary nodules. Indeterminate pulmonary nodules do not significantly affect the overall survival of pediatric patients with non-rhabdomyosarcoma soft tissue sarcoma.

Quantitative diffusion-weighted MRI response assessment in rhabdomyosarcoma: an international retrospective study on behalf of the European paediatric Soft tissue sarcoma Study Group Imaging Committee.

OBJECTIVE: To investigate the feasibility of diffusion-weighted magnetic resonance imaging (DW-MRI) as a predictive imaging marker after neoadjuvant chemotherapy in patients with rhabdomyosarcoma. MATERIAL AND METHODS: We performed a multicenter retrospective study including pediatric, adolescent and young adult patients with rhabdomyosarcoma, Intergroup Rhabdomyosarcoma Study group III/IV, treated according to the European paediatric Soft tissue sarcoma Study Group (EpSSG) RMS2005 or MTS2008 studies. DW-MRI was performed according to institutional protocols. We performed two-dimensional single-slice tumor delineation. Areas of necrosis or hemorrhage were delineated to be excluded in the primary analysis. Mean, median and 5th and 95th apparent diffusion coefficient (ADC) were extracted. RESULTS: Of 134 included patients, 82 had measurable tumor at diagnosis and response and DW-MRI scans of adequate quality and were included in the analysis. Technical heterogeneity in scan acquisition protocols and scanners was observed. Mean ADC at diagnosis was 1.1 (95% confidence interval [CI]: 1.1-1.2) (all ADC expressed in * 10-3 mm2/s), versus 1.6 (1.5-1.6) at response assessment. The 5th percentile ADC was 0.8 (0.7-0.9) at diagnosis and 1.1 (1.0-1.2) at response. Absolute change in mean ADC after neoadjuvant chemotherapy was 0.4 (0.3-0.5). Exploratory analyses for association between ADC and clinical parameters showed a significant difference in mean ADC at diagnosis for alveolar versus embryonal histology. Landmark analysis at nine weeks after the date of diagnosis showed no significant association (hazard ratio 1.3 [0.6-3.2]) between the mean ADC change and event-free survival. CONCLUSION: A significant change in the 5th percentile and the mean ADC after chemotherapy was observed. Strong heterogeneity was identified in DW-MRI acquisition protocols between centers and in individual patients.

Clinical, pathologic, and molecular features of inflammatory myofibroblastic tumors in children and adolescents.

BACKGROUND: Inflammatory myofibroblastic tumors (IMT) are rare, intermediate malignant tumors harboring frequent somatic molecular rearrangements. The management of IMT has not been standardized. METHODS: A retrospective multicenter study was conducted on all pediatric patients treated for IMT between 2000 and 2019. RESULTS: This series included 39 cases of IMT, with a median age at diagnosis of 7 years (range 20 days to 16 years). Tumor location included pelvis-abdomen (n = 16), thorax (n = 14), head and neck (n = 7), and limbs (n = 2). One patient had metastatic disease. Immunochemistry showed 21/39 (54%) anaplastic lymphoma kinase (ALK)-positive tumors. Somatic tyrosine kinase rearrangement was present in 31/36 (86%) of the tumors analyzed: 21 ALK, five ROS1, and five NTRK. Immediate surgery was performed in 24 patients (62%), with adjuvant therapy for three patients. Delayed surgery after neoadjuvant therapy was possible in 10 cases. Exclusive systemic therapy was delivered to four patients; one patient with orbital IMT was managed by watchful waiting. After a median follow-up of 33 months (range 5-124), eight (20%) recurrences/progressions occurred after surgery (seven after primary surgery and one after delayed surgery), after a median interval of 7 months (range 2-21), all in thoracic locations. The 3-year overall and disease-free survivals were 96.8% (95% CI: 79.2%-94.0%) and 77.4% (95% CI: 59.6%-88.1%), respectively. Relapses/progressions were more common in patients with a thoracic primary (p < .001) or after incomplete surgery with no adjuvant therapy (p = .027). CONCLUSION: Surgery is effective in most cases of pediatric IMT. Systematic analysis of tyrosine kinase rearrangement is recommended. When the tumor is deemed only partially resectable to preserve organs and function, neoadjuvant therapy may be proposed to allow adequate conservative surgery.

PAX3-NCOA1 alveolar rhabdomyosarcoma of the tongue: A rare entity with challenging diagnosis and management.

Alveolar rhabdomyosarcoma (ARMS) is associated with PAX3/PAX7-FOXO1 fusion, which confers specific clinic and biologic characteristics with inferior outcomes. A minority of tumors still histologically classified as "true" ARMS lack the canonical PAX-FOXO1 fusion but have new molecular alterations. We present the first case of PAX3-NCOA1 ARMS with clinical data and follow-up in a two-year-old girl with ARMS of the tongue and nodal extension, treated with chemotherapy, hemi glossectomy, lymph node dissection, and brachytherapy to conserve oral function and limit long-term sequelae. Given the rarity of such variant fusion in ARMS, international collaboration is required to evaluate its prognostic value.

Early detection with MRI of incomplete treatment of spine metastases after percutaneous cryoablation.

OBJECTIVES: To evaluate post-ablation MRI for the detection of incompletely treated spinal osseous metastases (SOM) after cryoablation and to propose a post-ablation imaging classification. METHODS: After IRB consent, all patients treated with cryoablation of SOM between 2011 and 2017 having at least 1-year minimum follow-up and a spine MRI within 4 months after cryoablation were retrospectively included. A classification of MRI images into four types was set up. The primary endpoint of our study was to assess the diagnostic performance of the post-ablation MRI. The secondary endpoints were the 1-year complete treatment rate (CTR) and complications. RESULTS: Fifty-four SOMs in 39 patients were evaluated. Post-ablation MRI was performed with a median delay of 25 days after cryoablation. Images were evaluated by two independent readers according to the pre-established image classification. Sensitivity and specificity for the detection of residual tumor were 77.3% (95%CI = 62.2-88.5) and 85.9% (95%CI = 75.0-93.4), respectively. Types I, II, III, and IV of the classification were associated with a 1-year complete treatment in 100%, 83.3%, 35.7%, and 10% of cases, respectively. The 1-year CTR was 59.3% for all 54 metastases, and 95.8% for metastases measuring less than 25 mm and at least 2 mm or more away from the spinal canal. Two grade 3 and two grade 2 adverse events according to the CTCAE were reported. CONCLUSIONS: MRI after cryoablation is useful for the evaluation of the ablation efficacy. The classification of post-cryoablation MRI provides reliable clues for the prediction of complete treatment at 1 year. KEY POINTS: • MRI performed 25 days after cryoablation is useful to evaluate the efficacy. • The proposed classification provides a reliable clue for complete cryoablation. • Percutaneous cryoablation of spinal metastases is highly effective for lesions less than 25 mm in diameter and of at least 2 mm away from the spinal canal.

Image-guided lung metastasis ablation: a literature review.

Purpose: To review the available options of percutaneous ablation of lung metastasis. Methods: General indications, prognostic factors, and image guidance of percutaneous lung ablations were reviewed. Specificities, technical aspects, advantages and limitations of each technic were highlighted. Complications and follow up where also reviewed. Results: Image-guided, percutaneous ablation is of interest for patients with a limit number (<3-5) small metastases (<2-3 cm). Other predictive factors have been reported such as the disease-free interval, the primary tumor, or the proximity with large vessels or bronchus. Radiofrequency ablation (RFA) is the most reported technic, with local control rate >90% for small tumors, and a very low complication rate. Microwave (MWA) and cryoablation are alternative technics developed in the last 15 years to overcome RFA limitations, with encouraging results. Larger ablations zones and less heat sink effect have been described with MWA. On the other hand, cryoablation allows painless treatments under conscious sedation and/or local anesthesia, high accessibility of difficult locations and promising results on prospective multicenter series. Although irreversible electroporation (IRE) could be used for lesions close to main blood vessels as it is not limited by the heat sink effect and does not have significant effects on connective tissue, allowing to treat lesions near to vital organs, preliminary results for lung metastasis are disappointing. Conclusion: Percutaneous ablation of lung metastases, whatever technic is used, is feasible, with high local control rate, and acceptable complication rate. Although indications seem clear enough, validation through controlled trials is mandatory.

Imaging characterization of paediatric tumours with the neurotrophic tyrosine receptor kinase fusion transcript.

OBJECTIVES: The neurotrophic tyrosine receptor kinase (NTRK) fusion transcript (FT) is a major genetic landmark of infantile fibrosarcoma (IFS) and cellular congenital mesoblastic nephroma (cCMN) but is also described in other tumours. The recent availability of NTRK-targeted drugs enhances the need for better identification. We aimed to describe the anatomic locations and imaging features of tumours with NTRK-FT in children. CASE SERIES: Imaging characteristics of NTRK-FT tumours of 41 children (median age: 4 months; 63% <1 year old; range: 0-188) managed between 2001 and 2019 were retrospectively analysed. The tumours were located in the soft tissues (n = 24, including 19 IFS), kidneys (n = 9, including 8 cCMN), central nervous system (CNS) (n = 5), lung (n = 2), and bone (n = 1). The tumours were frequently deep-located (93%) and heterogeneous (71%) with necrotic (53%) or haemorrhagic components (29%). Although inconstant, enlarged intratumoural vessels were a recurrent finding (70%) with an irregular distribution (63%) in the most frequent anatomical locations. CONCLUSION: Paediatric NTRK-FT tumours mainly occur in infants with very variable histotypes and locations. Rich and irregular intra-tumoural vascularization are recurrent findings. ADVANCES IN KNOWLEDGE: Apart from IFS of soft tissues and cCMN of the kidneys, others NTRK-FT tumours locations have to be known, as CNS tumours. Better knowledge of the imaging characteristics may help guide the pathological and biological identification.

Brachytherapy for Pediatric Patients at Gustave Roussy Cancer Campus: A Model of International Cooperation for Highly Specialized Treatments.

PURPOSE: Childhood cancer is rare, and treatment is frequently associated with long-term morbidity. Disparities in survival and long-term side effects encourage the establishment of networks to increase access to complex organ-conservative strategies, such as brachytherapy. We report our experience of an international cooperation model in childhood cancers. METHODS AND MATERIALS: We examined the outcome of all children referred to our center from national or international networks to be treated according to a multimodal organ-conservative approach, including brachytherapy. RESULTS: We identified 305 patients whose median age at diagnosis was 2.2 years (range, 1.4 months to 17.2 years). Among these patients, 99 (32.4%) were treated between 2015 and 2020; 172 (56.4%) were referred from national centers; and 133 (43.6%) were international patients from 31 countries (mainly Europe). Also, 263 patients were referred for primary treatment and 42 patients were referred for salvage treatment. Genitourinary tumors were the most frequent sites, with 56.4% bladder/prostate rhabdomyosarcoma and 28.5% gynecologic tumors. In addition to brachytherapy, local treatment consisted of partial tumor resection in 207 patients (67.9%), and 39 patients (13%) had additional external radiation therapy. Median follow-up was 58 months (range, 1 month to 48 years), 93 months for national patients, and 37 months for international patients (P < .0001). Five-year local control, disease-free survival, and overall survival rates were 90.8% (95% confidence interval [CI], 87.3%-94.4%), 84.4% (95% CI, 80.1%-89.0%), and 93.3% (95% CI, 90.1%-96.5%), respectively. Patients referred for salvage treatment had poorer disease-free survival (P < .01). Implementation of image guided pulse-dose-rate brachytherapy was associated with better local control among patients with rhabdomyosarcoma referred for primary treatment (hazard ratio, 9.72; 95% CI, 1.24-71.0). At last follow-up, 16.7% patients had long-term severe treatment-related complications, and 2 patients (0.7%) had developed second malignancy. CONCLUSIONS: This retrospective series shows the feasibility of a multinational referral network for brachytherapy allowing high patient numbers in rare pediatric cancers. High local control probability and acceptable late severe complication probability could be achieved despite very challenging situations. This cooperation model could serve as a basis for generating international reference networks for high-tech radiation such as brachytherapy to increase treatment care opportunities and cure probability.

Development and characterization of chitosan films carrying Artemisia campestris antioxidants for potential use as active food packaging materials.

Active food packaging films based on chitosan and enriched with Artemisia campestris hydroalcoholic extract (ACHE), aqueous extract (ACAE) and essential oil (ACEO) were developed. The effects of incorporating A. campestris were investigated on the physical, mechanical, thermal and antioxidant characteristics of the films. The structural properties of the films were evaluated using Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD) and scanning electron microscopy (SEM). The results showed that adding ACHE and ACEO improved the water resistance of chitosan films. The FTIR spectroscopy analysis revealed covalent interaction and hydrogen bonding between chitosan and ACHE. The XRD and SEM analyses indicated that interactions occurred between the film matrix and A. campestris active compounds, which could be reflected by the physical and mechanical properties of composite films. Incorporating ACHE and ACAE in the chitosan matrix decreased the tensile strength. The film extensibility was reduced when ACHE and ACEO were added. All films exhibited great thermal stability as the degradation occurred above 300 °C. The addition of A. campestris active compounds, particularly extracts, to chitosan films notably increased the antioxidant and UV-Vis barrier properties. Chitosan films enriched with the A. campestris antioxidant compounds could be applied as food packaging alternatives.

Machine-Learning-Based Radiomics MRI Model for Survival Prediction of Recurrent Glioblastomas Treated with Bevacizumab.

Anti-angiogenic therapy with bevacizumab is a widely used therapeutic option for recurrent glioblastoma (GBM). Nevertheless, the therapeutic response remains highly heterogeneous among GBM patients with discordant outcomes. Recent data have shown that radiomics, an advanced recent imaging analysis method, can help to predict both prognosis and therapy in a multitude of solid tumours. The objective of this study was to identify novel biomarkers, extracted from MRI and clinical data, which could predict overall survival (OS) and progression-free survival (PFS) in GBM patients treated with bevacizumab using machine-learning algorithms. In a cohort of 194 recurrent GBM patients (age range 18-80), radiomics data from pre-treatment T2 FLAIR and gadolinium-injected MRI images along with clinical features were analysed. Binary classification models for OS at 9, 12, and 15 months were evaluated. Our classification models successfully stratified the OS. The AUCs were equal to 0.78, 0.85, and 0.76 on the test sets (0.79, 0.82, and 0.87 on the training sets) for the 9-, 12-, and 15-month endpoints, respectively. Regressions yielded a C-index of 0.64 (0.74) for OS and 0.57 (0.69) for PFS. These results suggest that radiomics could assist in the elaboration of a predictive model for treatment selection in recurrent GBM patients.

Methodological Study to Investigate the Potential of Ultrasound-Based Elastography and Texture as Biomarkers to Monitor Liver Tumors.

AIMS AND OBJECTIVES: In order to evaluate the responses of hepatic lesions to treatment in terms of tissue stiffness and heterogeneity, this work investigated the robustness of 2D shear-wave elastography (2D SWE) stiffness measurements and texture analyses in vitro and in vivo in terms of repeatability and variability. METHODS AND MATERIALS: A multioperator (n = 5) study was performed with an ultrasonic elastography device on two sets of phantoms. For the first set of phantoms, 10 measurements for each of the eight inclusions were performed by each observer, whereas the second set of phantoms was used to evaluate the influence of depth on the stiffness measurements. Variability of the stiffness measurements was evaluated in vivo on 10 healthy livers, with 10 measurements for each hepatic segment. Texture analyses were performed in B-mode, obtaining elastography images for every hepatic segment. RESULTS: Stiffness measurements were influenced by depth, particularly when exceeding 7 cm. In vivo measurements demonstrated that measurements of segments I, VII, and VIII were less reliable, mainly due to their deeper locations. The protocols used were more flexible in terms of acquisition setup and probe placement than those currently used with Fibroscan®. For texture analysis on the B-mode images, 12 features showed low variability regardless of the evaluated hepatic segment. On elastogram, only two features showed low variability, but not in every segment. CONCLUSION: We demonstrated the robustness of two methodologies for the quantification of liver stiffness and heterogeneity. Further clinical studies should evaluate whether these techniques can assess tumor responses to treatment and, therefore, have the potential to be used as imaging biomarkers.

Influence of Magnetic Field Strength on Magnetic Resonance Imaging Radiomics Features in Brain Imaging, an In Vitro and In Vivo Study.

BACKGROUND: The development and clinical adoption of quantitative imaging biomarkers (radiomics) has established the need for the identification of parameters altering radiomics reproducibility. The aim of this study was to assess the impact of magnetic field strength on magnetic resonance imaging (MRI) radiomics features in neuroradiology clinical practice. METHODS: T1 3D SPGR sequence was acquired on two phantoms and 10 healthy volunteers with two clinical MR devices from the same manufacturer using two different magnetic fields (1.5 and 3T). Phantoms varied in terms of gadolinium concentrations and textural heterogeneity. 27 regions of interest were segmented (phantom: 21, volunteers: 6) using the LIFEX software. 34 features were analyzed. RESULTS: In the phantom dataset, 10 (67%) out of 15 radiomics features were significantly different when measured at 1.5T or 3T (student's t-test, p < 0.05). Gray levels resampling, and pixel size also influence part of texture features. These findings were validated in healthy volunteers. CONCLUSIONS: According to daily used protocols for clinical examinations, radiomic features extracted on 1.5T should not be used interchangeably with 3T when evaluating texture features. Such confounding factor should be adjusted when adapting the results of a study to a different platform, or when designing a multicentric trial.

Constitutional mismatch repair deficiency-associated brain tumors: report from the European C4CMMRD consortium.

BACKGROUND: Malignant brain tumors (BT) are among the cancers most frequently associated with constitutional mismatch repair deficiency (CMMRD), a rare childhood cancer predisposition syndrome resulting from biallelic germline mutations in mismatch repair genes. This study analyzed data from the European "Care for CMMRD" (C4CMMRD) database to describe their clinical characteristics, treatments, and outcome with the aim of improving its diagnosis/treatment. METHODS: Retrospective analysis of data on patients with CMMRD and malignant BT from the C4CMMRD database up to July 2017. RESULTS: Among the 87 registered patients, 49 developed 56 malignant BTs: 50 high-grade gliomas (HGG) (with giant multinucleated cells in 16/21 histologically reviewed tumors) and 6 embryonal tumors. The median age at first BT was 9.2 years [1.1-40.6], with nine patients older than 18. Twenty-seven patients developed multiple malignancies (including16 before the BT). Most patients received standard treatment, and eight patients immunotherapy for relapsed HGG. The 3- and 5-year overall survival (OS) rates were 30% (95% CI: 19-45) and 22% (95% CI: 12-37) after the first BT, with worse prognosis for HGG (3-year OS = 20.5%). Six patients were alive (median follow-up 2.5 years) and 43 dead (38 deaths, 88%, were BT-related). Other CMMRD-specific features were café-au-lait macules (40/41), multiple BTs (5/15), developmental brain anomalies (11/15), and consanguinity (20/38 families). CONCLUSIONS: Several characteristics could help suspecting CMMRD in pediatric malignant BTs: giant cells on histology, previous malignancies, parental consanguinity, café-au-lait macules, multiple BTs, and developmental brain anomalies. The prognosis of CMMRD-associated BT treated with standard therapies is poor requiring new therapeutic up-front approaches.

Tumor Growth Rate as a Validated Early Radiological Biomarker Able to Reflect Treatment-Induced Changes in Neuroendocrine Tumors: The GREPONET-2 Study.

PURPOSE: Tumor growth rate (TGR) represents the percentage change in tumor volume per month (%/m). Previous results from the GREPONET study showed that TGR measured after 3 months (TGR3m) of starting systemic treatment (ST) or watch and wait (WW) was an early biomarker predicting progression-free survival (PFS) in neuroendocrine tumors (NET). EXPERIMENTAL DESIGN: Patients from 7 centers with advanced grade (G) 1/2 NETs from the pancreas (P)/small bowel (SB) initiating ST/WW were eligible. Computed tomography (CT)/MRI performed at prebaseline, baseline, and 3(±1) months of study entry were retrospectively reviewed. Aim-1: explore treatment-induced changes in TGR (ΔTGR3m-BL; paired T test), and Aim-2: validate TGR3m (<0.8%/m vs. ≥0.8%/m) as an early biomarker in an independent cohort (Kaplan-Meier/Cox regression). RESULTS: Of 785 patients screened, 127 were eligible. Mean (SD) TGR0 and TGR3m were 5.4%/m (14.9) and -1.4%/m (11.8), respectively. Mean (SD) ΔTGR3m-BL paired-difference was -6.8%/m (19.3; P < 0.001). Most marked ΔTGR3m-BL [mean (SD)] were identified with targeted therapies [-11.3%/m (4.7); P = 0.0237] and chemotherapy [-7.9%/m (3.4); P = 0.0261]. Multivariable analysis confirmed the absence of previous treatment (OR = 4.65; 95% CI, 1.31-16.52; P = 0.018) and low TGR3m (continuous variable; OR 1.09; 95% CI, 1.01-1.19; P = 0.042) to be independent predictors of radiologic objective response. When the multivariable survival analysis for PFS (Cox regression) was adjusted to grade (P = 0.004) and stage (P = 0.017), TGR3m ≥ 0.8 (vs. <0.8) maintained its significance as a prognostic factor (P < 0.001), whereas TGR0 and ΔTGR3m-BL did not. TGR3m ≥ 0.8%/m was confirmed as an independent prognostic factor for PFS [external validation; Aim-2; multivariable HR 2.21 (95% CI, 1.21-3.70; P = 0.003)]. CONCLUSIONS: TGR has a role as a biomarker for monitoring response to therapy for early identification of treatment-induced changes and for early prediction of PFS and radiologic objective response.

Are we reproducible in measurement of NET liver metastasis?

Accurate measurement of well-differentiated neuroendocrine tumours (NET) liver metastases is critical to determine tumour slope and to assess treatment efficacy. Our objectives were to determine which CT or MRI sequence is the most reproducible to measure NET liver metastases and to assess the percentage of variability of measurements. Intra and inter-observer variability were studied on triphasic abdominal CT or liver MRI in 22 and 32 NET patients respectively. Patients were treatment-naïve or under somatostatin analogues. A maximum of 5 liver target lesions per patient was defined and three radiologists measured them on each sequence. Reproducibility were analysed by calculating the relative variation (RV) as defined by RECIST criteria. We analysed 1656 target measurements for CT and 3384 for MRI. Intra-observers RV were better than inter-observers. T2 for MRI and portal-phase for CT were associated with the lowest measurement variability. The MRI sequence offering the best intra and inter-observer reproducibility is the T2W-sequence. MRI allows more reproducible measurement than CT (inter-observer RV <20% in 96.8% for MRI and 81% for CT). Our study demonstrates intermediate to high imaging reproducibility of liver metastases measurements in NET patients. Non-enhanced MRI should be preferred to triphasic-CT for follow-up, assessment of treatment and trials.