No abstract

Gastrointestinal stromal tumors (GISTs) are the most common human sarcoma. Most of the data available on GISTs derive from retrospective studies of patients referred to oncology centers. The MolecGIST study sought to determine and correlate clinicopathological and molecular characteristics of GISTs. Tumor samples and clinical records were prospectively obtained and reviewed for patients diagnosed in France during a 24-month period. Five hundred and ninety-six patients were included, of whom 10% had synchronous metastases. GISTs originated from the stomach, small bowel or other site in 56.4, 30.2 and 13.4% of cases, respectively. The main prognostic markers, tumor localization, size and mitotic index were not independent variables (P < 0.0001). Mutational status was determined in 492 (83%) patients, and 138 different mutations were identified. KIT and PDGFRA mutations were detected in 348 (71%) and 74 (15%) patients, respectively, contrasting with 82.8 and 2.1% in patients with advanced GIST (MetaGIST) (P < 0.0001). Further comparison of localized GISTs in the MolecGIST cohort with advanced GISTs from previous clinical trials showed that the mutations of PDGFRA exon18 (D842V and others) as well as KIT exon11 substitutions (W557R and V559D) were more likely to be seen in patients with localized GISTs (odds ratio 7.9, 3.1, 2.7 and 2.5, respectively), while KIT exon 9 502_503dup and KIT exon 11 557_559del were more frequent in metastatic GISTs (odds ratio of 0.3 and 0.5, respectively). These data suggest that KIT and PDGFRA mutations and standardized mitotic count deserve to be investigated to evaluate the relapse risk of GISTs.

Background Since 2010, nationwide networks of reference centers for sarcomas (RREPS/NETSARC/RESOS) collected and prospectively reviewed all cases of sarcomas and connective tumors of intermediate malignancy (TIM) in France. Methods The nationwide incidence of sarcoma or TIM (2013–2016) was measured using the 2013 WHO classification and confirmed by a second independent review by expert pathologists. Simple clinical characteristics, yearly variations and correlation of incidence with published clinical trials are presented and analyzed. Results Over 150 different histological subtypes are reported from the 25172 patients with sarcomas (n = 18712, 74,3%) or TIM (n = 6460, 25.7%), with n = 5838, n = 6153, n = 6654, and n = 6527 yearly cases from 2013 to 2016. Over these 4 years, the yearly incidence of sarcomas and TIM was therefore 70.7 and 24.4 respectively, with a combined incidence of 95.1/106/year, higher than previously reported. GIST, liposarcoma, leiomyosarcomas, undifferentiated sarcomas represented 13%, 13%, 11% and 11% of tumors. Only GIST, as a single entity had a yearly incidence above 10/106/year. There were respectively 30, 64 and 66 different histological subtypes of sarcomas or TIM with an incidence ranging from 10 to 1/106, 1–0.1/106, or < 0.1/106/year respectively. The 2 latter incidence groups represented 21% of the patients with 130 histotypes. Published phase III and phase II clinical trials (p<10−6) are significantly higher with sarcomas subtypes with an incidence above 1/106 per. Conclusions This nationwide registry of sarcoma patients, with exhaustive histology review by sarcoma experts, shows that the incidence of sarcoma and TIM is higher than reported, and that tumors with a very low incidence (1<106/year) are less likely to be included in clinical trials.

Adjuvant radiotherapy after prostatectomy was recently challenged by early salvage radiotherapy, which highlighted the need for biomarkers to improve risk stratification. Therefore, we developed an MRI ADC map-derived radiomics model to predict biochemical recurrence (BCR) and BCR-free survival (bRFS) after surgery. Our goal in this work was to externally validate this radiomics-based prediction model. Experimental Design: A total of 195 patients with a high recurrence risk of prostate cancer (pT3-4 and/or R1 and/or Gleason’s score > 7) were retrospectively included in two institutions. Patients with postoperative PSA (Prostate Specific Antigen) > 0.04 ng/mL or lymph node involvement were excluded. Radiomics features were extracted from T2 and ADC delineated tumors. A total of 107 patients from Institution 1 were used to retrain the previously published model. The retrained model was then applied to 88 patients from Institution 2 for external validation. BCR predictions were evaluated using AUC (Area Under the Curve), accuracy, and bRFS using Kaplan–Meier curves. Results: With a median follow-up of 46.3 months, 52/195 patients experienced BCR. In the retraining cohort, the clinical prediction model (combining the number of risk factors and postoperative PSA) demonstrated moderate predictive power (accuracy of 63%). The radiomics model (ADC-based SZEGLSZM) predicted BCR with an accuracy of 78% and allowed for significant stratification of patients for bRFS (p < 0.0001). In Institution 2, this radiomics model remained predictive of BCR (accuracy of 0.76%) contrary to the clinical model (accuracy of 0.56%). Conclusions: The recently developed MRI ADC map-based radiomics model was validated in terms of its predictive accuracy of BCR and bRFS after prostatectomy in an external cohort.

Several studies have demonstrated that intravenous administration of DNA complexed with cationic lipid vectors induces the production of large quantities of proinflammatory cytokines. In this study we confirm these observations, using cationic lipid DOTAP and cationic phospholipid compounds. Moreover, we demonstrate that although intravenous administration of lipid-DNA complexes does not induce toxic effects in the lung, high transgene expression in lung correlates with histopathological lesions in liver, this fact being documented by high transaminase levels in serum of treated mice. We examine the contribution of various components of the lipoplexes in this observed liver toxicity, as well as in the increasing level of transaminases, and more particularly the role of nonmethylated CpG sequences of plasmid DNA. We show that blood samples from animals treated either with cationic lipid alone, or with cationic lipid complexed with methylated plasmid DNA, contain low levels of transaminases. The significant decrease in transaminase levels after injection of cationic lipid-methylated pDNA complexes leads us to believe that nonmethylated CpG sequences could play a major role in this hepatoxicity. Similar results were observed when using a vector that did not encode a transgene, demonstrating that the expression of luciferase in lung was not responsible for this liver toxicity. All these observations suggest that significant work should be devoted to understand more clearly the mechanism of cationic lipid-DNA complex toxicity, and to overcome the problems subsequent to administration of non-methylated CpG sequences of plasmid DNA.

In kidney transplantation, the composition of the B-cell compartment is increasingly identified as an important determinant for graft outcome. Whereas naive and transitional B cells have been associated with long-term allograft survival and operational tolerance, memory B cells have been linked to graft rejection and graft loss. Chronic antibody-mediated rejection now represents a major complication in transplantation and is a challenge in current therapeutics. Here, we show that patients with chronic antibody-mediated rejection display a unique B-cell phenotype with a reduced ratio of activated to memory B cells associated with an impaired immunosuppressive activity. The regulatory functions of the B cells depended on their maturation status. Thus, phenotypic and functional analyses of the B-cell compartment may be indicated for appropriate follow-up after transplantation and drive therapy in the establishment of transplant tolerance processes.

Transplant recipients receiving a kidney from an extended-criteria donor (ECD) are exposed to calcineurin inhibitor (CNI) nephrotoxicity, as demonstrated by severe delayed graft function and/or a low GFR. Belatacept is a nonnephrotoxic drug that is indicated as an alternative to CNIs. We reported 25 cases of conversion from a CNI to belatacept due to CNI intolerance within the first 6 mo after transplantation. The mean age of the recipients was 59 years, and 24 of 25 patients received ECD kidneys. At the date of the medication switch, 12 of 25 patients displayed a calculated GFR (cGFR) <15 mL/min, six patients remained on dialysis, and the biopsies showed evidence of acute tubular damage associated with severe vascular or tubulointerstitial chronic lesions. Three patients did not recover renal function, and three patients died during the follow-up period. Among the remaining patients, renal function improved: The cGFR was 18.28 AE 12.3 mL/min before the medication switch compared with 34.9 AE 14.5 mL/min at 1 year after conversion to belatacept (p = 0.002). Tolerance of and compliance with belatacept were good, and only one patient experienced acute rejection. Belatacept is an effective therapy that preserves renal function in kidney transplant patients who are intolerant of CNIs.

Purpose: Prostatectomy is one of the main therapeutic options for prostate cancer (PCa). Studies proved the benefit of adjuvant radiotherapy (aRT) on clinical outcomes, with more toxicities when compared to salvage radiotherapy. A better assessment of the likelihood of biochemical recurrence (BCR) would rationalize performing aRT. Our goal was to assess the prognostic value of MRI-derived radiomics on BCR for PCa with high recurrence risk. Methods: We retrospectively selected patients with a high recurrence risk (T3a/b or T4 and/or R1 and/or Gleason score>7) and excluded patients with a post-operative PSA > 0.04 ng/mL or a lymph-node involvement. We extracted IBSI-compliant radiomic features (shape and first order intensity metrics, as well as second and third order textural features) from tumors delineated in T2 and ADC sequences. After random division (training and testing sets) and machine learning based feature reduction, a univariate and multivariate Cox regression analysis was performed to identify independent factors. The correlation with BCR was assessed using AUC and prediction of biochemical relapse free survival (bRFS) with a Kaplan-Meier analysis. Results: One hundred seven patients were included. With a median follow-up of 52.0 months, 17 experienced BCR. In the training set, no clinical feature was correlated with BCR. One feature from ADC (SZE GLSZM ) outperformed with an AUC of 0.79 and a HR 17.9 ( p = 0.0001). Lower values of SZE GLSZM are associated with more heterogeneous tumors. In the testing set, this feature remained predictive of BCR and bRFS (AUC 0.76, p = 0.0236). Conclusion: One radiomic feature was predictive of BCR and bRFS after prostatectomy helping to guide post-operative management.