Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis.

Production of amphiregulin (Areg) by regulatory T (Treg) cells promotes repair after acute tissue injury. Here, we examined the function of Treg cells in non-alcoholic steatohepatitis (NASH), a setting of chronic liver injury. Areg-producing Treg cells were enriched in the livers of mice and humans with NASH. Deletion of Areg in Treg cells, but not in myeloid cells, reduced NASH-induced liver fibrosis. Chronic liver damage induced transcriptional changes associated with Treg cell activation. Mechanistically, Treg cell-derived Areg activated pro-fibrotic transcriptional programs in hepatic stellate cells via epidermal growth factor receptor (EGFR) signaling. Deletion of Areg in Treg cells protected mice from NASH-dependent glucose intolerance, which also was dependent on EGFR signaling on hepatic stellate cells. Areg from Treg cells promoted hepatocyte gluconeogenesis through hepatocyte detection of hepatic stellate cell-derived interleukin-6. Our findings reveal a maladaptive role for Treg cell-mediated tissue repair functions in chronic liver disease and link liver damage to NASH-dependent glucose intolerance.

B cells are associated with survival and immunotherapy response in sarcoma.

Soft-tissue sarcomas represent a heterogeneous group of cancer, with more than 50 histological subtypes1,2. The clinical presentation of patients with different subtypes is often atypical, and responses to therapies such as immune checkpoint blockade vary widely3,4. To explain this clinical variability, here we study gene expression profiles in 608 tumours across subtypes of soft-tissue sarcoma. We establish an immune-based classification on the basis of the composition of the tumour microenvironment and identify five distinct phenotypes: immune-low (A and B), immune-high (D and E), and highly vascularized (C) groups. In situ analysis of an independent validation cohort shows that class E was characterized by the presence of tertiary lymphoid structures that contain T cells and follicular dendritic cells and are particularly rich in B cells. B cells are the strongest prognostic factor even in the context of high or low CD8+ T cells and cytotoxic contents. The class-E group demonstrated improved survival and a high response rate to PD1 blockade with pembrolizumab in a phase 2 clinical trial. Together, this work confirms the immune subtypes in patients with soft-tissue sarcoma, and unravels the potential of B-cell-rich tertiary lymphoid structures to guide clinical decision-making and treatments, which could have broader applications in other diseases.

Patient-derived organoids identify an apico-basolateral polarity switch associated with survival in colorectal cancer.

The metastatic progression of cancer remains a major issue in patient treatment. However, the molecular and cellular mechanisms underlying this process remain unclear. Here, we use primary explants and organoids from patients harboring mucinous colorectal carcinoma (MUC CRC), a poor-prognosis histological form of digestive cancer, to study the architecture, invasive behavior and chemoresistance of tumor cell intermediates. We report that these tumors maintain a robust apico-basolateral polarity as they spread in the peritumoral stroma or organotypic collagen-I gels. We identified two distinct topologies - MUC CRCs either display a conventional 'apical-in' polarity or, more frequently, harbor an inverted 'apical-out' topology. Transcriptomic analyses combined with interference experiments on organoids showed that TGFß and focal adhesion signaling pathways are the main drivers of polarity orientation. Finally, we show that the apical-out topology is associated with increased resistance to chemotherapeutic treatments in organoids and decreased patient survival in the clinic. Thus, studies on patient-derived organoids have the potential to bridge histological, cellular and molecular analyses to decrypt onco-morphogenic programs and stratify cancer patients. This article has an associated First Person interview with the first author of the paper.

ROCK2 inhibition triggers the collective invasion of colorectal adenocarcinomas.

The metastatic progression of cancer is a multi-step process initiated by the local invasion of the peritumoral stroma. To identify the mechanisms underlying colorectal carcinoma (CRC) invasion, we collected live human primary cancer specimens at the time of surgery and monitored them ex vivo. This revealed that conventional adenocarcinomas undergo collective invasion while retaining their epithelial glandular architecture with an inward apical pole delineating a luminal cavity. To identify the underlying mechanisms, we used microscopy-based assays on 3D organotypic cultures of Caco-2 cysts as a model system. We performed two siRNA screens targeting Rho-GTPases effectors and guanine nucleotide exchange factors. These screens revealed that ROCK2 inhibition triggers the initial leader/follower polarization of the CRC cell cohorts and induces collective invasion. We further identified FARP2 as the Rac1 GEF necessary for CRC collective invasion. However, FARP2 activation is not sufficient to trigger leader cell formation and the concomitant inhibition of Myosin-II is required to induce invasion downstream of ROCK2 inhibition. Our results contrast with ROCK pro-invasive function in other cancers, stressing that the molecular mechanism of metastatic spread likely depends on tumour types and invasion mode.

Multicenter Harmonization Study of Pan-Trk Immunohistochemistry for the Detection of NTRK3 Fusions.

Pan-Trk immunohistochemistry has been described as a screening test for the detection of NTRK fusions in a broad spectrum of tumor types. However, pan-Trk testing in the clinical setting may be limited by many factors, including analytical parameters such as clones, platforms, and protocols used. This study aimed to harmonize pan-Trk testing using various clones and immunohistochemical (IHC) platforms and to evaluate the level of analytical variability across pathology laboratories. We developed several IHC pan-Trk assays using clones EPR17341 (Abcam) and A7H6R (Cell Signaling Technology) on Ventana/Roche, Agilent, and Leica platforms. To compare them, we sent unstained sections of a tissue microarray containing 9 cases with NTRK3 fusions to participating laboratories, to perform staining on Ventana/Roche (10 centers), Agilent (4 centers), and Leica (3 centers) platforms. A ready-to-use pan-Trk IVD assay (Ventana/Roche) was also performed in 3 centers. All slides were centrally and blindly reviewed for the percentage of stained tumor cells. Laboratory-developed tests with clone EPR17341 were able to detect pan-Trk protein expression in all cases, whereas lower rates of positivity were observed with clone A7H6R. Moderate to strong variability of the positive cases rate was observed with both antibodies in each IHC platforms type and each of the positivity cut points evaluated (≥1%, ≥10%, and ≥50% of stained tumor cells). The rate of false-negative cases was lower when pan-Trk staining was assessed with the lowest positivity threshold (≥1%). In conclusion, most evaluated pan-Trk IHC laboratory-developed tests were able to detect NTRK3-fusion proteins; however, a significant analytical variability was observed between antibodies, platforms, and centers.

Harmonization of programmed death-ligand 1 immunohistochemistry and mRNA expression scoring in metastatic melanoma: a multicentre analysis.

AIMS: The aim of this multicentre study was to harmonize programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) and melanoma scoring. To provide a reference for PD-L1 expression independently of the IHC protocol, PD-L1 mRNA expression was compared with IHC. METHODS AND RESULTS: Standardized PD-L1 assays (22C3, 28-8, SP142, SP263) and laboratory-developed tests (QR1, 22C3) were evaluated on three IHC platforms with a training set (seven cases). mRNA expression was determined by RNAscope (CD274/PD-L1 probe) and analysed with image analysis. PD-L1 IHC findings were scored by seven blinded pathologists using the tumour proportion score (TPS), the combined positive score (CPS), and the MELscore. This method was validated by three blinded pathologists on 40 metastatic melanomas. Concordances among various antibody/platforms were high across antibodies [intraclass correlation coefficient (ICC) >0.80 for the CPS], except for SP142. Two levels of immunostaining intensity were observed: high (QR1 and SP263) and low (28-8, 22C3, and SP142). Reproducibilities across pathologists were higher for QR1 and SP263 (ICC ≥0.87 and ICC ≥0.85 for the TPS and the CPS, respectively). QR1, SP263 and 28-8 showed the highest concordance with mRNA expression. We developed a standardized method for PD-L1 immunodetection and scoring, tested on 40 metastatic melanomas. Concordances among antibodies were excellent for all criteria, and concordances among pathologists were better for the MELscore than for other scores. CONCLUSION: Harmonization of PD-L1 staining and scoring in melanomas with good concordance is achievable with the PD-L1 IHC protocols applied to other cancers; this reproducible approach can simplify daily practice.

PD-L1 testing in urothelial bladder cancer: essentials of clinical practice.

PURPOSE: While immunotherapy has become an increasingly attractive strategy in patients with urothelial bladder cancer, the need for a biomarker to identify patients whose cancer is the most likely to respond has never been more crucial. This review systematically evaluates evidence regarding PD-L1 as a predictive biomarker of response to anti-PD(L)1 monoclonal antibodies in patients with urothelial bladder carcinoma, and discusses its current limits in routine clinical practice. METHODS: We performed a critical review of PubMed/Medline according to the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) statement. Prospective clinical trials evaluating anti-PD(L)1 monoclonal antibodies in urothelial bladder carcinoma together with retrospective studies evaluating PD-L1 expression in patients with bladder cancer were included. RESULTS: Evidence data related to PD-L1 as a predictive biomarker of response to immune checkpoint blockade monotherapy across clinical trials are detailed in this review. The different companion diagnostic assays, and the methods for PD-L1 scoring in urothelial bladder carcinoma are reported. Additionally, the issues related to the implementation of PD-L1 testing in clinical practice are discussed. CONCLUSIONS: PD-(L)1 monoclonal antibodies atezolizumab and pembrolizumab are restricted to patients with PD-L1 positive status in the first-line setting in patients with advanced or metastatic urothelial bladder carcinoma who are ineligible to cisplatin-based chemotherapy. Importantly, the use of anti-PD(L)1 mAb in the other clinical settings is not based on PD-L1 status, but rather on patients' clinical characteristics. Further identification of biomarkers with high negative predictive value will also be of utmost importance to identify patients who may not respond to such immunotherapies.

Surgical management of soft tissue tumors of the abdominal wall: A retrospective study in a high-volume sarcoma center.

BACKGROUND: The aim of the study is to evaluate functional and oncological outcomes of patients undergoing abdominal wall soft tissue tumors (AWSTT) surgery. METHODS: All consecutive patients that underwent surgery for malignant and intermediate AWSTT from 1999 to 2019 were retrospectively analyzed. RESULTS: Ninety-two patients were identified, 20 (22%) operated on for a desmoid tumor and 72 (78%) for a soft tissue sarcoma (STS). Fifty-two patients (57%) had in toto resection of the abdominal wall (from the skin to the peritoneum) and 9 (10%) required simultaneous visceral resection. The closure was direct in 28 patients (30%) and requiring a mesh, a flap or a combination of the two in respectively 42, 16, and 6 patients (47%, 17%, 6%). The postoperative complications rate was 26%. Thirteen patients (14%) developed an incisional hernia after a median delay of 27 months. After a median follow-up of 40 months, out of the 72 patients operated on for STS, 7 (10%) developed local recurrence and 11 (15%) distant recurrence. The median recurrence-free and overall survivals were 61 and 116, months respectively. CONCLUSIONS: Management of AWSTT requires extensive surgery but allows good local control with an acceptable rate of incisional hernia.

The path to a better biomarker: application of a risk management framework for the implementation of PD-L1 and TILs as immuno-oncology biomarkers in breast cancer clinical trials and daily practice.

Immune checkpoint inhibitor therapies targeting PD-1/PD-L1 are now the standard of care in oncology across several hematologic and solid tumor types, including triple negative breast cancer (TNBC). Patients with metastatic or locally advanced TNBC with PD-L1 expression on immune cells occupying ≥1% of tumor area demonstrated survival benefit with the addition of atezolizumab to nab-paclitaxel. However, concerns regarding variability between immunohistochemical PD-L1 assay performance and inter-reader reproducibility have been raised. High tumor-infiltrating lymphocytes (TILs) have also been associated with response to PD-1/PD-L1 inhibitors in patients with breast cancer (BC). TILs can be easily assessed on hematoxylin and eosin-stained slides and have shown reliable inter-reader reproducibility. As an established prognostic factor in early stage TNBC, TILs are soon anticipated to be reported in daily practice in many pathology laboratories worldwide. Because TILs and PD-L1 are parts of an immunological spectrum in BC, we propose the systematic implementation of combined PD-L1 and TIL analyses as a more comprehensive immuno-oncological biomarker for patient selection for PD-1/PD-L1 inhibition-based therapy in patients with BC. Although practical and regulatory considerations differ by jurisdiction, the pathology community has the responsibility to patients to implement assays that lead to optimal patient selection. We propose herewith a risk-management framework that may help mitigate the risks of suboptimal patient selection for immuno-therapeutic approaches in clinical trials and daily practice based on combined TILs/PD-L1 assessment in BC. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

EWSR1-PATZ1 fusion sarcoma - A new case report and review of the literature / Sarcome avec transcrit de fusion EWSR1-PATZ1 - Une nouvelle observation avec revue de la littérature.

Sarcoma with EWSR1-PATZ1 gene fusion is an exceedingly rare and newly described Ewing-like sarcoma harboring EWSR1 rearrangements involving fusion partners other than ETS family genes. The clinical, histopathologic and immunophenotypic features of cases reported in literature are fairly diverse and not specific. We report a new case report posing real challenges for histological and molecular diagnosis.

[How to test for NTRK gene fusions: A practical approach for pathologists]. / Recherche de fusions des gènes NTRK : guide pratique pour les pathologistes.

The recent availability of targeted anti-TRK therapies represents a new opportunity to treat patients with advanced cancers harboring NTRK gene fusions. In this article, we present an update on the practical modalities of implementing a "NTRK testing" to search for these fusions in view of the performances and availability of the different testing methods and the epidemiological characteristics of the tumors liable to present the NTRK1, NTRK2 or NTRK3 gene fusions.

Systemic treatments in MDM2 positive intimal sarcoma: A multicentre experience with anthracycline, gemcitabine, and pazopanib within the World Sarcoma Network.

BACKGROUND: Intimal sarcoma (InS) is an exceedingly rare neoplasm with an unfavorable prognosis, for which new potentially active treatments are under development. We report on the activity of anthracycline-based regimens, gemcitabine-based regimens, and pazopanib in patients with InS. METHODS: Seventeen sarcoma reference centers in Europe, the United States, and Japan contributed data to this retrospective analysis. Patients with MDM2-positive InS who were treated with anthracycline-based regimens, gemcitabine-based regimens, or pazopanib between October 2001 and January 2018 were selected. Local pathological review was performed to confirm diagnosis. Response was assessed by RECIST1.1. Recurrence-free survival (RFS), progression-free survival (PFS) and overall survival were computed by Kaplan-Meier method. RESULTS: Seventy-two patients were included (66 anthracycline-based regimens; 26 gemcitabine-based regimens; 12 pazopanib). In the anthracycline-based group, 24 (36%) patients were treated for localized disease, and 42 (64%) patients were treated for advanced disease. The real-world overall response rate (rwORR) was 38%. For patients with localized disease, the median RFS was 14.6 months. For patients with advanced disease, the median PFS was 7.7 months. No anthracycline-related cardiac toxicity was reported in patients with cardiac InS (n = 26). For gemcitabine and pazopanib, the rwORR was 8%, and the median PFS was 3.2 and 3.7 months, respectively. CONCLUSION: This retrospective series shows the activity of anthracycline-based regimens in InS. Of note, anthracyclines were used in patients with cardiac InS with no significant cardiac toxicity. The prognosis in patients with InS remains poor, and new active drugs and treatment strategies are needed.

"Interchangeability" of PD-L1 immunohistochemistry assays: a meta-analysis of diagnostic accuracy.

Different clones, protocol conditions, instruments, and scoring/readout methods may pose challenges in introducing different PD-L1 assays for immunotherapy. The diagnostic accuracy of using different PD-L1 assays interchangeably for various purposes is unknown. The primary objective of this meta-analysis was to address PD-L1 assay interchangeability based on assay diagnostic accuracy for established clinical uses/purposes. A systematic search of the MEDLINE database using PubMed platform was conducted using "PD-L1" as a search term for 01/01/2015 to 31/08/2018, with limitations "English" and "human". 2,515 abstracts were reviewed to select for original contributions only. 57 studies on comparison of two or more PD-L1 assays were fully reviewed. 22 publications were selected for meta-analysis. Additional data were requested from authors of 20/22 studies in order to enable the meta-analysis. Modified GRADE and QUADAS-2 criteria were used for grading published evidence and designing data abstraction templates for extraction by reviewers. PRISMA was used to guide reporting of systematic review and meta-analysis and STARD 2015 for reporting diagnostic accuracy study. CLSI EP12-A2 was used to guide test comparisons. Data were pooled using random-effects model. The main outcome measure was diagnostic accuracy of various PD-L1 assays. The 22 included studies provided 376 2×2 contingency tables for analyses. Results of our study suggest that, when the testing laboratory is not able to use an Food and Drug Administration-approved companion diagnostic(s) for PD-L1 assessment for its specific clinical purpose(s), it is better to develop a properly validated laboratory developed test for the same purpose(s) as the original PD-L1 Food and Drug Administration-approved immunohistochemistry companion diagnostic, than to replace the original PD-L1 Food and Drug Administration-approved immunohistochemistry companion diagnostic with a another PD-L1 Food and Drug Administration-approved companion diagnostic that was developed for a different purpose.

Baseline metabolic tumor burden on FDG PET/CT scans predicts outcome in advanced NSCLC patients treated with immune checkpoint inhibitors.

PURPOSE: We aimed to evaluate if imaging biomarkers on FDG PET are associated with clinical outcomes in patients with advanced non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs). METHODS: In this retrospective monocentric study, we included 109 patients with advanced NSCLC who underwent baseline FDG PET/CT before ICI initiation between July 2013 and September 2018. Clinical, biological (including dNLR = neutrophils/[leukocytes minus neutrophils]), pathological and PET parameters (tumor SUVmax, total metabolic tumor volume [TMTV]) were evaluated. A multivariate prediction model was developed using Cox models for progression-free survival (PFS) and overall survival (OS). The association between biomarkers on FDG PET/CT and disease clinical benefit (DCB) was tested using logistic regression. RESULTS: Eighty patients were eligible. Median follow-up was 11.6 months (95%CI 7.7-15.5). Sixty-four and 52 patients experienced progression and death, respectively. DCB was 40%. In multivariate analyses, TMTV > 75 cm3 and dNLR > 3 were associated with shorter OS (HR 2.5, 95%CI 1.3-4.7 and HR 3.3, 95%CI 1.6-6.4) and absence of DCB (OR 0.3, 95%CI 0.1-0.9 and OR 0.4, 95%CI 0.2-0.9). Unlike TMTV, dNLR was a significant prognostic factor for PFS (HR 1.9, 95%CI 1.1-3.3) along with anemia (HR 1.9, 95%CI 1.2-3.8). No association was observed between tumor SUVmax and PFS or OS. CONCLUSION: Baseline tumor burden (TMTV) on FDG PET/CT scans and inflammatory status (dNLR) were associated with poor OS and absence of DCB for ICI treatment in advanced NSCLC patients, unlike tumor SUVmax, and may be used together to improve the selection of appropriate candidates.

Association of metastatic pattern and molecular status in stage IV non-small cell lung cancer adenocarcinoma.

OBJECTIVES: The aim of our study was to investigate the association between driver oncogene alterations and metastatic patterns on imaging assessment, in a large cohort of metastatic lung adenocarcinoma patients. METHODS: From January 2010 to May 2017, 550 patients with stage IV lung adenocarcinoma with molecular analysis were studied retrospectively including 135 EGFR-mutated, 81 ALK-rearrangement, 47 BRAF-mutated, 141 KRAS-mutated, and 146 negative tumors for these 4 mutations (4N). After review of the complete imaging report by two radiologists (junior and senior) to identify metastatic sites, univariate correlation analyzes were performed. RESULTS: We found differences in metastatic tropism depending on the molecular alteration type when compared with the non-mutated 4N group: in the EGFR group, pleural metastases were more frequent (32% versus 20%; p = 0.021), and adrenal and node metastases less common (6% versus 23%; p < 0.001 and 11% versus 23%; p = 0.011). In the ALK group, there were more brain and lung metastases (respectively 42% versus 29%; p = 0.043 and 37% versus 24%; p = 0.037). In the BRAF group, pleural and pericardial metastases were more common (respectively 47% versus 20%; p < 0.001 and 11% versus 3%; p = 0.04) and bone metastases were rarer (21% versus 42%; p = 0.011). Lymphangitis was more frequent in EGFR, ALK, and BRAF groups (respectively 6%, 7%, and 15% versus 1%); p = 0.016; p = 0.009; and p < 0.001. CONCLUSION: The application of these correlations between molecular status and metastatic tropism in clinical practice may lead to earlier and more accurate identification of patients for targeted therapy. KEY POINTS: • Bone and brain metastasis are the most common organs involved in lung adenocarcinoma but the relative incidence of each metastatic site depends on the molecular alteration. • EGFR-mutated tumors preferentially spread to the pleura and less commonly to adrenals, ALK-rearrangement tumors usually spread to the brain and the lungs, whereas BRAF-mutated tumors are unlikely to spread to bones and have a serous (pericardial ad pleural) tropism. • These correlations could help in the clinical management of patients with metastatic lung adenocarcinoma.

Lung microwave ablation - an in vivo swine tumor model experiment to evaluate ablation zones.

PURPOSE: To evaluate microwave ablation (MWA) algorithms, comparing pulsed and continuous mode in an in vivo lung tumor mimic model. MATERIALS AND METHODS: A total of 43 lung tumor-mimic models of 1, 2 or 3 cm were created in 11 pigs through an intra-pulmonary injection of contrast-enriched minced muscle. Tumors were ablated under fluoroscopic and 3D-CBCT-guidance using a single microwave antenna. Continuous (CM) and pulsed mode (PM) were used. According to tumor size, 3 different algorithms for both continuous and pulsed mode were used. The ablation zones were measured using post-procedural 3D-CBCT and on pathologic specimens. RESULTS: Two radiologists measured the ablation zones on CBCT and they significantly correlated with macroscopic and microscopic pathological findings: r = 0.75 and 0.74 respectively (p < 0.0001) (inter-observer correlation r = 0.9). For 1, 2 and 3 cm tumors mimics lesions (TMLs), mean maximal and transverse ablation diameters were 3.6 [Formula: see text] 0.3 × 2.2 [Formula: see text] 0.3 cm; 4.1 [Formula: see text] 0.5 × 2.6 [Formula: see text] 0.3 cm and 4.8 [Formula: see text] 0.3 × 3.2 [Formula: see text] 0.3 cm respectively using CM; And, 3.0 [Formula: see text] 0.2 × 2.1 [Formula: see text] 0.2 cm; 4.0 [Formula: see text] 0.4 × 2.7 [Formula: see text] 0.4 cm and 4.6 [Formula: see text] 0.4 × 3.2 [Formula: see text] 0.4 cm respectively for PM, without any significant difference except for 1 cm TMLs treated by PM ablation which were significantly smaller (p = 0.009) The sphericity index was 1.6, 1.6, 1.5 and 1.4, 1.5, 1.4 at 1, 2 and 3 cm for CM and PM respectively, p = 0.07, 0.14 and 0.13 for 1, 2 and 3 cm tumors mimics. CONCLUSION: Microwave ablation for 1-3 cm lung tumors were successfully realized but with a moderate reproducibility rate, using either CM or PM. Immediate post ablation CBCT can accurately evaluate ablation zones.

Sarcomas in patients over 90: Natural history and treatment-A nationwide study over 6 years.

Soft tissue sarcomas (STS) are rare tumors accounting for less than 1% of human cancers. While the highest incidence of sarcomas is observed in elderly, this population is often excluded or poorly represented in clinical trials. The present study reports on clinicopathological presentation, and outcome of sarcoma patients over 90 recorded in the Netsarc.org French national database. NETSARC (netsarc.org) is a network of 26 reference sarcoma centers with specialized multidisciplinary tumor board (MDTB), funded by the French National Cancer Institute to improve the outcome of sarcoma patients. Since 2010, presentation to an MDTB, second pathological review, and collection of sarcoma patient characteristics and follow-up are collected in a database Information of patients registered from January 1, 2010, to December 31, 2016, in NETSARC were collected, analyzed and compared to the younger population. Patients with sarcomas aged >90 have almost exclusively sarcomas with complex genomics (92.0% vs. 66.3%), are less frequently metastatic (5.3% vs. 14·7%) at diagnosis, have more often superficial tumors (39.8% vs. 14.7%), as well as limbs and head and neck sites (75.2% vs. 38.7%) (all p < 0.001). Optimal diagnostic procedures and surgery were less frequently performed in patients over 90 (p < 0.001). These patients were less frequently operated in NETSARC centers, as compared to those of younger age groups including aged 80-90. However, local relapse-free survival, metastatic relapse-free survival and relapse-free survival were not significantly different from those of younger patients, in the whole cohort, as well as in the subgroup of operated patients. As expected overall survival was worse in patients over 90 (p < 0.001). Patients over 90 who were not operated had worse overall survival than younger patients (9.9 vs. 27.3 months, p < 0.001). Patients with STS diagnosed after 90 have distinct clinicopathological features, but comparable relapse-free survival, unless clinical practice guidelines recommendations are not applied. Standard management should be proposed to these patients if oncogeriatric status allows.

Brain Metastases and Place of Antiangiogenic Therapies in Alveolar Soft Part Sarcoma: A Retrospective Analysis of the French Sarcoma Group.

BACKGROUND: Alveolar soft part sarcoma (ASPS) is a rare sarcoma characterized by a slow evolution, brain metastasis (BM), and resistance to doxorubicin. Antiangiogenic therapies (AAT) have shown clinical activity, but little is known about the optimal therapeutic strategy, specifically considering BM. SUBJECTS, MATERIALS, AND METHODS: We performed a retrospective analysis of all patients with ASPS treated in three referral centers of the French Sarcoma Group. We aimed to describe factors associated with overall survival (OS) and the impact of BM on outcome of patients treated by AAT. RESULTS: We identified 75 patients between 1971 and 2012 (median age = 23, range: 5-96 years). Median follow-up was 74 months. Patients with localized (n = 44, 59%) and metastatic (n = 31, 41%) diseases had a 10-year OS of 69% and 25%, respectively. Only surgical incomplete resection was associated with shorter OS in localized disease (hazard ratio [HR] = 5.2, 95% confidence interval [CI] 1.2-22.4, p = .02). Fifty-two (69%) patients developed lung metastasis (LM; baseline: n = 31, [41%]; de novo: n = 21, [28%]). Thirteen patients developed BM, all occurring after LM. Tumor size ≥5 cm was associated with poorer BM-free survival (HR = 8.4, 95% CI 2.1-33.9, p = .002). Median OS post-BM was 17 months (95% CI 15 to not assessable). Overall, 12 patients were treated with AAT (sunitinib n = 10): 5 patients had BM and achieved poor outcomes compared with patients without, with median progression-free-survivals of 2 versus 11 months, respectively. CONCLUSION: Baseline larger tumors were associated with increased risk of brain metastasis in patients with ASPS. Patients with BM seem to have little benefit from AAT, suggesting the need to develop antineoplastic agents with high central nervous system penetrance in this setting. IMPLICATIONS FOR PRACTICE: Alveolar soft part sarcoma (ASPS) is an extremely rare subtype of sarcoma that is particularly resistant to conventional therapies. Antiangiogenic therapies (AAT) have shown promising results. However, patients with ASPS still die of tumor evolution. This study highlights the prognostic shift induced by brain metastasis (BM), identifying this event as a major contributor to the death of patients with ASPS, and observes a striking lack of effectiveness of AAT in patients who had previously developed BM. This observation is of interest for the therapeutic development in ASPS, highlighting the need to develop strategies dedicated to BM, such as radiosurgery or high-central nervous system penetrance tyrosine kinase inhibitors.

High proportion of PD-1-expressing CD4+ T cells in adipose tissue constitutes an immunomodulatory microenvironment that may support HIV persistence.

We and others have demonstrated that adipose tissue is a reservoir for HIV. Evaluation of the mechanisms responsible for viral persistence may lead to ways of reducing these reservoirs. Here, we evaluated the immune characteristics of adipose tissue in HIV-infected patients receiving antiretroviral therapy (ART) and in non-HIV-infected patients. We notably sought to determine whether adipose tissue's intrinsic properties and/or HIV induced alteration of the tissue environment may favour viral persistence. ART-controlled HIV infection was associated with a difference in the CD4/CD8 T-cell ratio and an elevated proportion of Treg cells in subcutaneous adipose tissue. No changes in Th1, Th2 and Th17 cell proportions or activation markers expression on T cell (Ki-67, HLA-DR) could be detected, and the percentage of CD69-expressing resident memory CD4+ T cells was not affected. Overall, our results indicate that adipose-tissue-resident CD4+ T cells are not extensively activated during HIV infection. PD-1 was expressed by a high proportion of tissue-resident memory CD4+ T cells in both HIV-infected patients and non-HIV-infected patients. Our findings suggest that adipose tissue's intrinsic immunomodulatory properties may limit immune activation and thus may strongly contribute to viral persistence.

Refinement of high-risk endometrial cancer classification using DNA damage response biomarkers: a TransPORTEC initiative.

The TransPORTEC consortium previouslclassified high-risk endometrial cancer including poor-risk histologies such as clear cells, into four molecular subtypes "POLE mutated," "microsatellite unstable," "TP53 mutated," and "no specific molecular profile." We evaluated whether DNA damage response biomarkers could further refine this high-risk tumors classification, in particular the heterogeneous "no specific molecular profile" and "TP53 mutated" subsets recently qualified as poor prognosis in high-risk endometrial cancer. DNA damage response biomarkers including proteins involved in DNA damage (δ-H2AX), homologous recombination (RAD51), regulators of error-prone Non Homologous End-Joining (DNA-pk, FANCD2), and PARP-1 were evaluated in 116 high-risk tumors by immunohistochemistry. CD8 and PD-1 expression by immunochemistry and mutation analyses were performed previously. Survival outcome were calculated using Kaplan-Meier and Log-rank test. None of the DNA damage response biomarkers alone were prognostic. However markers were informative within molecular subsets. Among the "no specific molecular profile" subset, δ-H2AX+ was significantly predictive of poor disease free survival (Hazard Ratio = 2.56; p = 0.026), and among "TP53 mutated," a DNA-pk+/FANCD2- profile (favouring error-prone Non Homologous End-Joining) predicted worst disease free survival (Hazard Ratio = 4.95; p = 0.009) resulting in five distinct prognostic subgroups from best to worst prognosis: group1 "POLE mutated/Microsatellite unstable" > group2 "no specific molecular profile with no DNA damage" > group3 "TP53 mutated/Non Homologous End-Joining negative" > group4 "no specific molecular profile with high DNA damage" > group5 "TP53 mutated/Non Homologous End-Joining positive"; p = 0.0002). Actionable targets were also different among subsets. Group3 had significantly higher infiltration of PD-1+ immune cells (p = 0.003), segregating with group1. Group2 had frequent PI3K pathway mutations and ER positivity. While group5, with the worst prognosis, had high DNA damage and PARP-1 expression providing a rationale for PARP inhibition. Our findings have refined the TransPORTEC prognostic classification of high-risk endometrial cancer into five distinct subgroups by integrating DNA damage response biomarkers and identified molecular subtype-specific therapeutic strategies.