Multilingual RECIST classification of radiology reports using supervised learning.

Objectives: The objective of this study is the exploration of Artificial Intelligence and Natural Language Processing techniques to support the automatic assignment of the four Response Evaluation Criteria in Solid Tumors (RECIST) scales based on radiology reports. We also aim at evaluating how languages and institutional specificities of Swiss teaching hospitals are likely to affect the quality of the classification in French and German languages. Methods: In our approach, 7 machine learning methods were evaluated to establish a strong baseline. Then, robust models were built, fine-tuned according to the language (French and German), and compared with the expert annotation. Results: The best strategies yield average F1-scores of 90% and 86% respectively for the 2-classes (Progressive/Non-progressive) and the 4-classes (Progressive Disease, Stable Disease, Partial Response, Complete Response) RECIST classification tasks. Conclusions: These results are competitive with the manual labeling as measured by Matthew's correlation coefficient and Cohen's Kappa (79% and 76%). On this basis, we confirm the capacity of specific models to generalize on new unseen data and we assess the impact of using Pre-trained Language Models (PLMs) on the accuracy of the classifiers.

Automated Detection of Arm-Level Alterations for Individual Cancer Patients in the Clinical Setting.

Copy number alterations are genetic events that promote tumor initiation and progression and are used in clinical care as diagnostic, prognostic, and predictive biomarkers. Based on the length of the alteration, they are roughly classified as focal and arm-level alterations. Although genome-wide techniques to detect arm-level alterations are gaining momentum in hospital laboratories, the high precision and novelty of these techniques pose new challenges: there is no consensus on the definition of an arm-level alteration and there is a lack of tools to compute them for individual patients. Based on 376 clinical samples analyzed with the OncoScan formalin-fixed, paraffin-embedded assay, a bimodal distribution of the percentage of bases with copy number alterations within a chromosomal arm was observed, with the second peak starting at 90% of arm length. Two approaches were tested for the definition of arm-level alterations: sum of altered segments (SoS) >90%, or the longest segment (LS) >90%. These approaches were validated against expert annotation of 25 clinical cases. The SoS method outperformed the LS method as indicated by a higher concordance (SoS, 95.2%; LS, 79.9%). Some of the discordances ultimately were attributed to human error, highlighting the advantages of automation. The increase in reliability led to the development of publicly available software and its inclusion into routine clinical practice at Geneva University Hospitals.

Ovarian cancer with high-level focal ERBB2 amplification responds to trastuzumab and pertuzumab.

Epithelial ovarian cancer (EOC) is usually diagnosed at an advanced stage and significantly contributes to cancer mortality in women. Despite multimodal treatment associating chemotherapy and surgery, most patients ultimately progress and require palliative systemic therapy. In EOC, the efficacy of anti-HER2 agents is minimal even after selecting patients for HER2 expression. ERBB2 gene amplification is observed in 3-10% of patients, depending on the specific method of detection and cutoffs. We report the case of a young woman with a FIGO stage IV high-grade serous ovarian cancer with an amplification of ERBB2. She was treated with the association of trastuzumab - pertuzumab after two lines of standard treatment and presented an excellent long-lasting partial response after 36 months of treatment. The association of trastuzumab and pertuzumab, without chemotherapy, has not been previously tested in this context and could be more efficacious than monotherapy with either agent. In addition, the significant benefit observed in this case could be attributed to the presence of a high-level focal amplification that is relatively rare and probably more specific than an increase in HER2 expression. In conclusion, prospective trials of the trastuzumab and pertuzumab combination should be considered in an appropriately selected EOC patient population.

Predicting immunotherapy outcomes under therapy in patients with advanced NSCLC using dNLR and its early dynamics.

BACKGROUND: dNLR at the baseline (B), defined by neutrophils/[leucocytes-neutrophils], correlates with immune-checkpoint inhibitor (ICI) outcomes in advanced non-small-cell lung cancer (aNSCLC). However, dNLR is dynamic under therapy and its longitudinal assessment may provide data predicting efficacy. We sought to examine the impact of dNLR dynamics on ICI efficacy and understand its biological significance. PATIENTS AND METHODS: aNSCLC patients receiving ICI at 17 EU/US centres were included [Feb/13-Jun/18]. As chemotherapy-only group was evaluated (NCT02105168). dNLR was determined at (B) and at cycle2 (C2) [dNLR≤3 = low]. B+C2 dNLR were combined in one score: good = low (B+C2), poor = high (B+C2), intermediate = other situations. In 57 patients, we prospectively explored the immunophenotype of circulating neutrophils, particularly the CD15+CD244-CD16lowcells (immature) by flow cytometry. RESULTS: About 1485 patients treatment with ICI were analysed. In ICI-treated patients, high dNLR (B) (~1/3rd) associated with worse progression-free (PFS)/overall survival (OS) (HR 1.56/HR 2.02, P < 0.0001) but not with chemotherapy alone (N = 173). High dNLR at C2 was associated with worse PFS/OS (HR 1.64/HR 2.15, P < 0.0001). When dNLR at both time points were considered together, those with persistently high dNLR (23%) had poor survival (mOS = 5 months (mo)), compared with high dNLR at one time point (22%; mOS = 9.2mo) and persistently low dNLR (55%; mOS = 18.6mo) (P < 0.0001). The dNLR impact remained significant after PD-L1 adjustment. By cytometry, high rate of immature neutrophils (B) (30/57) correlated with poor PFS/OS (P = 0.04; P = 0.0007), with a 12-week death rate of 49%. CONCLUSION: The dNLR (B) and its dynamics (C2) under ICI associate with ICI outcomes in aNSCLC. Persistently high dNLR (B+C2) correlated with early ICI failure. Immature neutrophils may be a key subpopulation on ICI resistance.

IL-15 superagonist RLI has potent immunostimulatory properties on NK cells: implications for antimetastatic treatment.

BACKGROUND: As the immune system is compromised in patients with cancer, therapeutic strategies to stimulate immunity appear promising, to avoid relapse and increase long-term overall survival. Interleukin-15 (IL-15) has similar properties to IL-2, but does not cause activation-induced cell death nor activation and proliferation of regulatory T cells (Treg), which makes it a serious candidate for anticancer immunotherapy. However, IL-15 has a short half-life and high doses are needed to achieve responses. Designed to enhance its activity, receptor-linker-IL-15 (RLI) (SO-C101) is a fusion molecule of human IL-15 covalently linked to the human IL-15Rα sushi+ domain currently assessed in a phase I/Ib clinical trial on patients with advanced/metastatic solid cancer. METHODS: We investigated the antimetastatic activity of RLI in a 4T1 mouse mammary carcinoma that spontaneously metastasizes and evaluated its immunomodulatory role in the metastatic lung microenvironment. We further characterized the proliferation, maturation and cytotoxic functions of natural killer (NK) cells in tumor-free mice treated with RLI. Finally, we explored the effect of RLI on human NK cells from healthy donors and patients with non-small cell lung cancer (NSCLC). RESULTS: RLI treatment displayed antimetastatic properties in the 4T1 mouse model. By characterizing the lung microenvironment, we observed that RLI restored the balance between NK cells and neutrophils (CD11b+ Ly6Ghigh Ly6Clow) that massively infiltrate lungs of 4T1-tumor bearing mice. In addition, the ratio between NK cells and Treg was strongly increased by RLI treatment. Further pharmacodynamic studies in tumor-free mice revealed superior proliferative and cytotoxic functions on NK cells after RLI treatment compared with IL-15 alone. Characterization of the maturation stage of NK cells demonstrated that RLI favored accumulation of CD11b+ CD27high KLRG1+ mature NK cells. Finally, RLI demonstrated potent immunostimulatory properties on human NK cells by inducing proliferation and activation of NK cells from healthy donors and enhancing cytotoxic responses to NKp30 crosslinking in NK cells from patients with NSCLC. CONCLUSIONS: Collectively, our work demonstrates superior activity of RLI compared with rhIL-15 in modulating and activating NK cells and provides additional evidences for a therapeutic strategy using RLI as antimetastatic molecule.

Durable response to palbociclib and letrozole in ovarian cancer with CDKN2A loss.

Alterations of the Retinoblastoma (Rb) pathway are frequent in ovarian cancer, typically resulting from CDKN2A down-regulation, CCNE1 amplification, CCND1/2 amplification, and RB1 loss. However, bi-allelic CDKN2A mutation or homozygous deletion is a very rare event, concerning less than 5% of patients.Initial trials with palbociclib in serous ovarian cancer have shown very modest benefit in unselected patient populations, thus underlining the need for a biomarker predicting response. We report the case of a heavily pre-treated patient with a serous ovarian tumor harboring a homozygous deletion of the CDKN2A gene that derived significant, prolonged clinical benefit from palbociclib, a CDK4/6 oral inhibitor, with letrozole. Treatment with palbociclib and letrozole started on February 2018, with an ongoing response after 12 months.In conclusion, homozygous CDKN2A deletion is rare and could be used to predict response to CDK4/6 inhibitors in association with other genomic features. We encourage further trials in this direction.

Association of the Lung Immune Prognostic Index With Immune Checkpoint Inhibitor Outcomes in Patients With Advanced Non-Small Cell Lung Cancer.

IMPORTANCE: Derived neutrophils/(leukocytes minus neutrophils) ratio (dNLR) and lactate dehydrogenase (LDH) level have been correlated with immune checkpoint inhibitor (ICI) outcomes in patients with melanoma. OBJECTIVE: To determine whether pretreatment dNLR and LDH are associated with resistance to ICIs in patients with advanced non-small cell lung cancer (NSCLC). DESIGN, SETTING, AND PARTICIPANTS: Multicenter retrospective study with a test (n = 161) and a validation set (n = 305) treated with programmed death 1/programmed death ligand 1 (PD-1/PD-L1) inhibitors in 8 European centers, and a control cohort (n = 162) treated with chemotherapy only. Complete blood cell counts, LDH, and albumin levels were measured before ICI treatment. A lung immune prognostic index (LIPI) based on dNLR greater than 3 and LDH greater than upper limit of normal (ULN) was developed, characterizing 3 groups (good, 0 factors; intermediate, 1 factor; poor, 2 factors). MAIN OUTCOMES AND MEASURES: The primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS) and disease control rate (DCR). RESULTS: In the pooled ICI cohort (N = 466), 301 patients (65%) were male, 422 (90%) were current or former smokers, and 401 (87%) had performance status of 1 or less; median age at diagnosis was 62 (range, 29-86) years; 270 (58%) had adenocarcinoma and 159 (34%) had squamous histologic subtype. Among 129 patients with PD-L1 data, 96 (74%) had PD-L1 of at least 1% by immunohistochemical analysis, and 33 (26%) had negative results. In the test cohort, median PFS and OS were 3 (95% CI, 2-4) and 10 (95% CI, 8-13) months, respectively. A dNLR greater than 3 and LDH greater than ULN were independently associated with OS (hazard ratio [HR] 2.22; 95% CI, 1.23-4.01 and HR, 2.51; 95% CI, 1.32-4.76, respectively). Median OS for poor, intermediate, and good LIPI was 3 months (95% CI, 1 month to not reached [NR]), 10 months (95% CI, 8 months to NR), and 34 months (95% CI, 17 months to NR), respectively, and median PFS was 2.0 (95% CI, 1.7-4.0), 3.7 (95% CI, 3.0-4.8), and 6.3 (95% CI, 5.0-8.0) months (both P < .001). Disease control rate was also correlated with dNLR greater than 3 and LDH greater than ULN. Results were reproducible in the ICI validation cohort for OS, PFS, and DCR, but were nonsignificant in the chemotherapy cohort. CONCLUSIONS AND RELEVANCE: Pretreatment LIPI, combining dNLR greater than 3 and LDH greater than ULN, was correlated with worse outcomes for ICI, but not for chemotherapy, suggesting that LIPI can serve as a potentially useful tool when selecting ICI treatment, raising the hypothesis that the LIPI might be useful for identifying patients unlikely to benefit from treatment with an ICI.

Prognostic value of HLA-A2 status in advanced non-small cell lung cancer patients.

INTRODUCTION: The class I human leucocyte antigen (HLA) molecules play a critical role as an escape mechanism of antitumoral immunity. HLA-A2 status has been evaluated as a prognostic factor in lung cancer, mostly in localized disease and with inconsistent findings. We evaluated the role of HLA-A2 status as a prognostic factor in a large and homogeneus cohort of advanced NSCLC patients. METHODS: Advanced NSCLC patients eligible for platinum-based chemotherapy were consecutively included in a single center between October 2009 and July 2015 in the prospective MSN study (NCT02105168). HLA-A2 status was analysed by flow cytometry. Clinical, pathological and molecular data were collected. A Cox model was used for prognostic analyses. RESULTS: Of 545 stage IIIB/IV NSCLC patients included, 344 (63%) were male, 466 (85%) were smokers, 447 (83%) had PS 0-1, 508 (93%) had stage IV, 407 (75%) had an adenocarcinoma and median age was 61 years (range, 21-84). Incidence of patients with EGFRmut, ALK-positive and KRASmut was 14% (49/361), 9% (29/333) and 31% (107/350), respectively. The overall rate of HLA-A2 positivity was 48%. No association was observed between HLA-A2 status and any patient or tumor characteristics analyzed. With a median follow-up of 27.1 months, median OS was 12.8 months [95%CI 11.0-14.6] in HLA-A2+ vs. 12.5 months [95%CI 10.4-15.3] in HLA-A2- patients (HR 1.05 [95%CI 0.86-1.29], p=0.61). Median progression-free survival was similar in the two cohorts. CONCLUSION: HLA-A2 status was not identified as prognostic for benefit in a large advanced NSCLC population treated with platinum-based chemotherapy.

Colon Immune-Related Adverse Events: Anti-CTLA-4 and Anti-PD-1 Blockade Induce Distinct Immunopathological Entities.

BACKGROUND AND AIM: Immune checkpoint inhibitors targeting CTLA-4 and PD-1 improve survival in cancer patients but may induce immune-related adverse events, including colitis. The immunological characteristics of anti-CTLA-4 [αCTLA-4]- and anti-PD-1 [αPD-1]-related colitis have been poorly described. The aim of the present study was to compare the immunological and histological characteristics of αCTLA-4-induced colitis and αPD-1-induced colitis. METHODS: Colonic biopsies from patients with αCTLA-4-induced colitis, αPD-1-induced colitis, and inflammatory bowel disease [IBD] were analysed by immunohistochemistry and flow cytometry. Tumour necrosis factor alpha [TNFα] concentration was assessed in biopsy supernatants. RESULTS: CD8+ T cells were found in the lamina propria and epithelium in αPD-1-induced colitis, whereas CD4+ T cells were found in the lamina propria in αCTLA-4-induced colitis. No or low intraepithelial lymphocytes were observed in αCTLA-4-induced colitis. No difference in numbers of mucosal regulatory T cells was observed between αCTLA-4- or αPD-1-induced colitis and IBD patients. Higher numbers of activated ICOS+ conventional CD4+ T cells were observed in αCTLA-4-induced colitis compared with patients with IBD. Among ICOS+CD4+ T cells, conventional CD4+ T cells were the main T cell population in patents with αCTLA-4-induced colitis, whereas Treg cells were predominant in IBD or αPD-1-induced colitis. High mucosal TNFα concentrations were observed in αCTLA-4-induced colitis. Low mucosal TNFα concentrations were associated with steroid sensitivity. CONCLUSIONS: These observations show that αCTLA-4- and αPD-1-induced colitis have distinct immunological characteristics. Mucosal TNFα concentration might detect patients at risk of developing corticosteroid resistance after CTLA-4 blockade.

Dendritic cell-derived exosomes as maintenance immunotherapy after first line chemotherapy in NSCLC.

Dendritic cell-derived exosomes (Dex) are small extracellular vesicles secreted by viable dendritic cells. In the two phase-I trials that we conducted using the first generation of Dex (IFN-γ-free) in end-stage cancer, we reported that Dex exerted natural killer (NK) cell effector functions in patients. A second generation of Dex (IFN-γ-Dex) was manufactured with the aim of boosting NK and T cell immune responses. We carried out a phase II clinical trial testing the clinical benefit of IFN-γ-Dex loaded with MHC class I- and class II-restricted cancer antigens as maintenance immunotherapy after induction chemotherapy in patients bearing inoperable non-small cell lung cancer (NSCLC) without tumor progression. The primary endpoint was to observe at least 50% of patients with progression-free survival (PFS) at 4 mo after chemotherapy cessation. Twenty-two patients received IFN-γ-Dex. One patient exhibited a grade three hepatotoxicity. The median time to progression was 2.2 mo and median overall survival (OS) was 15 mo. Seven patients (32%) experienced stabilization of >4 mo. The primary endpoint was not reached. An increase in NKp30-dependent NK cell functions were evidenced in a fraction of these NSCLC patients presenting with defective NKp30 expression. Importantly, MHC class II expression levels of the final IFN-γ-Dex product correlated with expression levels of the NKp30 ligand BAG6 on Dex, and with NKp30-dependent NK functions, the latter being associated with longer progression-free survival. This phase II trial confirmed the capacity of Dex to boost the NK cell arm of antitumor immunity in patients with advanced NSCLC.

Dendritic cell-derived exosomes as immunotherapies in the fight against cancer.

Exosomes are nanometric membrane vesicles of late endosomal origin released by most, if not all, cell types as a means of sophisticated intercellular communication. A multitude of studies showed how exosomes can mediate and regulate immune responses against tumors. Dendritic cell-derived exosomes (Dex) have received much attention as immunotherapeutic anticancer agents since the discovery that they harbor functional MHC-peptide complexes, in addition to various other immune-stimulating components, that together facilitate immune cell-dependent tumor rejection. The therapeutic potential of Dex has been substantiated with their development and clinical testing in the treatment of cancer. This review focuses on mechanisms by which Dex interact with and influence immune cells and describes how they can be engineered to promote their immunogenic capacity as novel and dynamic anticancer agents.

Quantitation of human herpesvirus-6A, -6B and -7 DNAs in whole blood, mononuclear and polymorphonuclear cell fractions from healthy blood donors.

BACKGROUND: Diagnosis of human herpesvirus-6A (HHV-6A), -6B (HHV-6B) or -7 (HHV-7) infections is often based on the measure of viral load in blood. OBJECTIVES: The aim of this study was to define usual values of HHV-6A, HHV-6B and HHV-7 loads in blood fractions (whole blood [WB], mononuclear cells [PBMCs], polymorphonuclear leukocytes [PMNLs]) of blood donors. STUDY DESIGN: HHV-6A, HHV-6B and -7 DNAs were quantitated using real-time PCR assays in WB, PBMCs and PMNLs separated on Ficoll or dextran gradients, respectively, for 200 blood donors. Viral loads were expressed as the number of viral genomic copies per million cells (Cop/M) for all fractions, and also per milliliter for WB. RESULTS: HHV-6B DNA was rarely detected in WB (8%), PBMCs (16.5%), and PMNLs (10.5%), HHV-6A was never detected, whereas HHV-7 DNA was often present in WB (51.5%), PBMCs (62%) and PMNLs (51.5%). Median loads were low with 81 Cop/M in WB, 62 Cop/M in PBMCs and 34.5 Cop/M in PMNLs for HHV-6B, and 129 Cop/M in WB, 225 Cop/M in PBMCs and 62 Cop/M in PMNLs for HHV-7. Viral load expression per million cells and per mL were equivalent. One subject had chromosomally integrated HHV-6 with high viral loads ranging from 2.23×10(6) to 3.21×10(6) Cop/M in all compartments and plasma. CONCLUSIONS: These results allow to propose viral load in WB as a sensitive and suitable marker, with values for healthy subjects at approximately 100 Cop/M for both viruses. The prevalence of chromosomally integrated HHV-6 was 0.5%.