Multiomic analysis of malignant pleural mesothelioma identifies molecular axes and specialized tumor profiles driving intertumor heterogeneity.

Malignant pleural mesothelioma (MPM) is an aggressive cancer with rising incidence and challenging clinical management. Through a large series of whole-genome sequencing data, integrated with transcriptomic and epigenomic data using multiomics factor analysis, we demonstrate that the current World Health Organization classification only accounts for up to 10% of interpatient molecular differences. Instead, the MESOMICS project paves the way for a morphomolecular classification of MPM based on four dimensions: ploidy, tumor cell morphology, adaptive immune response and CpG island methylator profile. We show that these four dimensions are complementary, capture major interpatient molecular differences and are delimited by extreme phenotypes that-in the case of the interdependent tumor cell morphology and adapted immune response-reflect tumor specialization. These findings unearth the interplay between MPM functional biology and its genomic history, and provide insights into the variations observed in the clinical behavior of patients with MPM.

Characteristics and outcomes of patients with ophthalmologic involvement in giant-cell arteritis: A case-control study.

PURPOSE: To describe the characteristics and outcome of patients with giant-cell arteritis (GCA)-related ophthalmologic involvement at diagnosis. METHODS: In a retrospective single-center cohort of 409 consecutive patients with GCA, we retrieved 104 patients with visual symptoms at GCA diagnosis and we compared them to 104 age- and sex-matched controls without ophthalmologic involvement. Each visual symptom was associated to an ophthalmologic diagnosis that was centrally re-assessed by an ophthalmologist. RESULTS: Compared to controls, patients with visual symptoms showed less fever (p = 0.0006), less polymyalgia rheumatica (p = 0.02) and lower acute phase reactants (p = 0.004). Blurred vision (in 60% of patients), amaurosis fugax (in 18%), diplopia (in 13%) and permanent visual loss (in 9%) were the four visual symptoms described by patients before GCA diagnosis. Anterior ischemic optic neuropathy (AION) was found in 47 (45%) patients, followed by central retinal artery occlusion (CRAO) in 15 (15%). Two patients had both involvements. The delay of glucocorticoids initiation was not different between patients with and without visual symptoms (p = 0.06). Among the 60 patients with initial AION and/or CRAO, 39 (65%) kept definite blindness or important visual damage, although 45 (75%) had received intravenous (IV) pulses of methylprednisolone. A new ischemic event (AION in all cases) occurred in 4% of patients with visual symptoms despite the initiation of treatment. CONCLUSION: Ophthalmologic involvement was observed in one-quarter of our GCA patients. AION is still associated with the worst visual prognosis, and IV methylprednisolone pulses did not reduce the risk of blindness in our study.

Comprehensive Molecular and Pathologic Evaluation of Transitional Mesothelioma Assisted by Deep Learning Approach: A Multi-Institutional Study of the International Mesothelioma Panel from the MESOPATH Reference Center.

INTRODUCTION: Histologic subtypes of malignant pleural mesothelioma are a major prognostic indicator and decision denominator for all therapeutic strategies. In an ambiguous case, a rare transitional mesothelioma (TM) pattern may be diagnosed by pathologists either as epithelioid mesothelioma (EM), biphasic mesothelioma (BM), or sarcomatoid mesothelioma (SM). This study aimed to better characterize the TM subtype from a histological, immunohistochemical, and molecular standpoint. Deep learning of pathologic slides was applied to this cohort. METHODS: A random selection of 49 representative digitalized sections from surgical biopsies of TM was reviewed by 16 panelists. We evaluated BAP1 expression and CDKN2A (p16) homozygous deletion. We conducted a comprehensive, integrated, transcriptomic analysis. An unsupervised deep learning algorithm was trained to classify tumors. RESULTS: The 16 panelists recorded 784 diagnoses on the 49 cases. Even though a Kappa value of 0.42 is moderate, the presence of a TM component was diagnosed in 51%. In 49% of the histological evaluation, the reviewers classified the lesion as EM in 53%, SM in 33%, or BM in 14%. Median survival was 6.7 months. Loss of BAP1 observed in 44% was less frequent in TM than in EM and BM. p16 homozygous deletion was higher in TM (73%), followed by BM (63%) and SM (46%). RNA sequencing unsupervised clustering analysis revealed that TM grouped together and were closer to SM than to EM. Deep learning analysis achieved 94% accuracy for TM identification. CONCLUSION: These results revealed that the TM pattern should be classified as non-EM or at minimum as a subgroup of the SM type.

Vascular Presentation and Outcomes of Patients With Giant Cell Arteritis and Isolated Symptomatic Limb Involvement.

OBJECTIVE: The aims of this study were to describe and assess the vascular outcomes of patients with giant cell arteritis (GCA) presenting with only symptomatic isolated limb involvement (LI-GCA). METHODS: We recruited patients from 5 tertiary centers who were diagnosed with GCA based on histology or vasculitis demonstration on imaging and who presented with isolated symptomatic limb involvement at diagnosis. For each included patient, we randomly selected 3 control patients who satisfied the 5 criteria from the American College of Rheumatology at diagnosis. RESULTS: We included 27 LI-GCA patients and 81 control patients. Compared with the controls, the patients with LI-GCA were younger (p = 0.005), exhibited a more delayed diagnosis (p = 0.006), and had lower C-reactive protein levels (p = 0.001), but they did not show more cardiovascular risk factors. Glucocorticoid use (starting and tapering doses) and relapse rates did not differ in the 2 groups, but the patients with LI-GCA received longer treatment (p = 0.02). Cardiovascular complications occurred in 67% of the patients with LI-GCA versus 21% of the control patients (p < 0.0001), especially ischemic events (p < 0.0001) including stroke (p = 0.03) and myocardial infarction (p = 0.01). Vascular surgery was required in 44% of the patients with LI-GCA versus 2% of the controls (p < 0.0001). Excluding vascular surgery, the cumulative incidence of cardiovascular complications was higher in the patients with LI-GCA (log-rank test: p < 0.0001) than in the controls (hazard ratio, 5.73; 95% confidence interval, 2.94-11.28; p < 0.0001). CONCLUSIONS: Compared with the typical cranial form of GCA, LI-GCA has a worse cardiovascular-related prognosis. Further studies are required to determine the best management of these patients.

Factors Associated with Relapse and Dependence on Glucocorticoids in Giant Cell Arteritis.

OBJECTIVE: To identify characteristics and factors associated with relapse and glucocorticoid (GC) dependence in patients with giant cell arteritis (GCA). METHODS: We retrospectively analyzed 326 consecutive patients with GCA followed for at least 12 months. Factors associated with relapse and GC dependence were identified in multivariable analyses. RESULTS: The 326 patients (73% women) were followed up for 62 (12-262) months. During followup, 171 (52%) patients relapsed, including 113 (35%) who developed GC dependence. Relapsing patients had less history of stroke (p = 0.01) and presented large-vessel vasculitis (LVV) more frequently on imaging (p = 0.01) than patients without relapse. During the first months, therapeutic strategy did not differ among relapsing and nonrelapsing patients. GC-dependent patients were less likely to have a history of stroke (p = 0.004) and presented LVV on imaging more frequently (p = 0.005) than patients without GC-dependent disease. In multivariable analyses, LVV was an independent predictive factor of relapse (HR 1.49, 95% CI 1.002-2.12; p = 0.04) and GC dependence (OR 2.19, 95% CI 1.19-4.05; p = 0.01). Conversely, stroke was a protective factor against relapse (HR 0.21, 95% CI 0.03-0.68; p = 0.005) and GC-dependent disease (OR 0.10, 95% CI 0.001-0.31; p = 0.0005). Patients with a GC-dependent disease who received a GC-sparing agent had a shorter GC treatment duration than those without (p = 0.008). CONCLUSION: In this study, LVV was an independent predictor of relapse and GC dependence. Further prospective studies are needed to confirm these findings and to determine whether patients with LVV require a different treatment approach.

Redefining malignant pleural mesothelioma types as a continuum uncovers immune-vascular interactions.

BACKGROUND: Malignant Pleural Mesothelioma (MPM) is an aggressive disease related to asbestos exposure, with no effective therapeutic options. METHODS: We undertook unsupervised analyses of RNA-sequencing data of 284 MPMs, with no assumption of discreteness. Using immunohistochemistry, we performed an orthogonal validation on a subset of 103 samples and a biological replication in an independent series of 77 samples. FINDINGS: A continuum of molecular profiles explained the prognosis of the disease better than any discrete model. The immune and vascular pathways were the major sources of molecular variation, with strong differences in the expression of immune checkpoints and pro-angiogenic genes; the extrema of this continuum had specific molecular profiles: a "hot" bad-prognosis profile, with high lymphocyte infiltration and high expression of immune checkpoints and pro-angiogenic genes; a "cold" bad-prognosis profile, with low lymphocyte infiltration and high expression of pro-angiogenic genes; and a "VEGFR2+/VISTA+" better-prognosis profile, with high expression of immune checkpoint VISTA and pro-angiogenic gene VEGFR2. We validated the gene expression levels at the protein level for a subset of five selected genes belonging to the immune and vascular pathways (CD8A, PDL1, VEGFR3, VEGFR2, and VISTA), in the validation series, and replicated the molecular profiles as well as their prognostic value in the replication series. INTERPRETATION: The prognosis of MPM is best explained by a continuous model, which extremes show specific expression patterns of genes involved in angiogenesis and immune response.

Promoter Hypermethylation of Genes Encoding for RASSF/Hippo Pathway Members Reveals Specific Alteration Pattern in Diffuse Gliomas.

Ras association domain family (RASSF)/Hippo pathway alterations are poorly characterized in diffuse gliomas. We assayed promoter methylation of LATS1/2, MST1(STK4)/MST2(STK3), RASSF1, RASSF2, Nore1A/RASSF5, RASSF6, and RASSF10 genes in 133 diffuse gliomas. The RASSF/Hippo pathway was highly silenced in gliomas, particularly RASSF1A (79.4%) and LATS2 (35.9%). The most frequent combination of promoter hypermethylation of one RASSF gene and one Hippo pathway member's gene was RASSF1/LATS2-coupled hypermethylation [n = 44 (33.08%)]. Hypermethylated profiles were related to IDH mutation, yet not randomly in IDH-mutated gliomas, because LATS2 promoter hypermethylation was more frequent in oligodendroglioma than in astrocytoma. RASSF1 and LATS2 promoter hypermethylation predicted a longer overall survival (OS). Considering hypermethylation of these two promoters, Cox proportional hazard regression analysis categorized the patients into three prognostic groups: i) high risk of death (n = 24; both RASSF1 and LATS2 unmethylated promoters; median OS, 13 months); ii) intermediate risk of death (n = 65; RASSF1 or LATS2 hypermethylated promoter; median OS, 50.5 months; HR = 3.3; 95% CI, 1.6-6.4; P = 0.001); and iii) low risk of death (n = 44; both RASSF1 and LATS2 hypermethylated promoters; median OS, 119 months; HR = 75.1; 95% CI, 3.3-15.1; P = 0.001). We have thus highlighted a simple two-gene (RASSF1/LATS2) methylation signature as a tool to stratify different prognostic groups of patients with diffuse glioma, adding further prognostic information within the IDH-mutated group.

Intra-Alveolar Haemorrhage Complicating IgA Vasculitis: A Case Report, Literature Review and Discussion of Treatment.

INTRODUCTION: Immunoglobulin A vasculitis (IgAV) is a small-vessel vasculitis with IgA-dominant immune deposits. IgAV frequently involves the skin, gastrointestinal tract, joints and kidneys. In contrast to other types of small-vessel vasculitis, IgAV is rarely complicated by intra-alveolar haemorrhage (IAH). METHODS/RESULTS: We describe a patient with relapsing bladder cancer who presented with IAH during the course of IgAV successfully treated with corticosteroids alone. CONCLUSION: This case report reminds us that IgAV can manifest with IAH. There are no robust data to support the systematic use of cyclophosphamide or plasma exchange as first-line therapy for IgAV with IAH. LEARNING POINTS: Intra-alveolar haemorrhage in IgA vasculitis is an uncommon but important condition.The treatment strategies for IgA vasculitis and intra-alveolar haemorrhage and their rare association are discussed with reference to the literature.

Off-Label Use of Crizotinib as a Neoadjuvant Treatment for a Young Patient When Conventional Chemotherapy Gave No Benefits in Stage IIIA Non-Small Cell Lung Cancer.

BACKGROUND The treatment of locally advanced non-small cell lung cancer involves a combination of chemotherapy, surgery, and radiotherapy. Each case is discussed and the best strategy is chosen individually, following international guidelines. CASE REPORT A 37-year-old man was diagnosed with locally advanced broncho-pulmonary adenocarcinoma (stage IIIA). The disease was stable after 2 cycles of cisplatin plus Navelbine used as neoadjuvant therapy. FISH analysis revealed an ALK rearrangement. The patient then received unlicensed crizotinib as second-line neoadjuvant treatment, which led to an almost complete radiological and metabolic response. A left upper lobectomy was performed, followed by post-operative chemotherapy and radiotherapy. At 18 months post-surgery, the patient is still disease-free according to the last CT scan. CONCLUSIONS Targeted therapy was an alternative solution when chemotherapy was not helping. Randomized studies are needed to define its precise role in the neoadjuvant scheme.

Assessment of SPAG9 Transcript in Fine Needle Aspirates of Thyroid Nodules.

OBJECTIVES: Sperm-associated antigen 9 (SPAG9) has been suggested as a possible biomarker in several malignancies including thyroid cancer. We investigated the expression of SPAG9 mRNA in fine needle aspiration (FNA) material from papillary thyroid carcinoma (PTC) and benign thyroid nodules. STUDY DESIGN: SPAG9 expression was assessed in 36 FNA samples corresponding to 16 PTC and 20 benign nodules using the original method detecting the SPAG9 transcript containing intron 21 (NCBI X91879). The presence of the BRAF V600E point mutation was also analyzed by pyrosequencing. RESULTS: Six of 16 (38%) PTC samples were positive for X91879 SPAG9 transcript compared to 8 of 20 (40%) benign samples (p = 0.88). Out of 12 BRAF-positive PTC, 3 (25%) also expressed the SPAG9 transcript compared to 3 out of 4 BRAF-negative PTC (75%; p = 0.12). CONCLUSIONS: The X91879 SPAG9 transcript originally described does not appear to be overexpressed in FNA material from PTC or to be clinically relevant in the diagnosis of thyroid nodules.