A comprehensive analysis of the immune cell infiltrate collected from pleural fluid and from biopsy specimens of malignant pleural mesothelioma (MPM) may contribute to understanding the ...immune-evasion mechanisms related to tumor progression, aiding in differential diagnosis and potential prognostic stratification. Until now such approach has not routinely been verified.
We enrolled 275 patients with an initial clinical diagnosis of pleural effusion. Specimens of pleural fluids and pleural biopsy samples used for the pathologic diagnosis and the immune phenotype analyses were blindly investigated by multiparametric flow cytometry. The results were analyzed using the Kruskal-Wallis test. The Kaplan-Meier and log-rank tests were used to correlate immune phenotype data with patients’ outcome.
The cutoffs of intratumor T-regulatory (>1.1%) cells, M2-macrophages (>36%), granulocytic and monocytic myeloid-derived suppressor cells (MDSC; >5.1% and 4.2%, respectively), CD4 molecule–positive (CD4+) programmed death 1–positive (PD-1+) (>5.2%) and CD8+PD-1+ (6.4%) cells, CD4+ lymphocyte activating 3–positive (LAG-3+) (>2.8% ) and CD8+LAG-3+ (>2.8%) cells, CD4+ T cell immunoglobulin and mucin domain 3–positive (TIM-3+) (>2.5%), and CD8+TIM-3+ (>2.6%) cells discriminated MPM from pleuritis with 100% sensitivity and 89% specificity. The presence of intratumor MDSC contributed to the anergy of tumor-infiltrating lymphocytes. The immune phenotype of pleural fluid cells had no prognostic significance. By contrast, the intratumor T-regulatory and MDSC levels significantly correlated with progression-free and overall survival, the PD-1+/LAG-3+/TIM-3+ CD4+ tumor-infiltrating lymphocytes correlated with overall survival.
A clear immune signature of pleural fluids and tissues of MPM patients may contribute to better predict patients’ outcome.
Summary Several microRNAs (miRNAs) were shown to be deregulated in adrenocortical carcinoma (ACC) as compared with adenoma, but a detailed assessment of their expression in its histologic variants ...and correlation with clinicopathologic characteristics has not been performed, so far. Our aim was to assess the expression of 5 selected miRNAs ( IGF2 gene–related miR-483-3p and 5p and hypoxia-induced miR-210, miR-195, and miR-1974) in a series of 51 ACCs (35 classical, 6 myxoid, and 10 oncocytic) as compared with clinical and pathologic features and immunohistochemical expression of prognostic markers, including steroidogenic factor 1, p53, β -catenin, and glucose transporter 1. Oncocytic carcinomas had a reduced expression of miR-483-3p ( P = .0325), miR-483-5p ( P = .0175), and miR-210 ( P = .0366), as compared with other histotypes. Overexpression of miR-210 was associated with the presence of necrosis ( P = .0035), high Ki-67 index ( P = .0013), and high glucose transporter 1 expression ( P = .0043), whereas an inverse correlation with mitotic rate was observed in cases with high miR-493-3p ( P = .0191) and miR-1974 ( P = .0017) expression. High miR-1974 was also associated with low Ki-67 ( P = .0312) and European Network for the Study of Adrenal Tumors stage ( P = .0082) and negative p53 ( P = .0013). At univariate analysis myxoid/classic histotype ( P = .026), high miR-210 ( P = .0465), high steroidogenic factor 1 protein ( P = .0017), high Ki-67 ( P = .0066), and high mitotic index ( P = .0006) were significantly associated the shorter overall survival, the latter being the sole independent prognostic factor at multivariate analysis ( P = .017). In conclusion, ( a ) miR-483-3p, miR-483-5p, and miR-210 are differentially expressed in ACC variants, and ( b ) high miR-210 is associated with clinicopathologic parameters of aggressiveness and a poor prognosis.
Histopathological subtyping of nonsmall cell lung cancer (NSCLC) is currently relevant in treatment decision because of a differential activity of specific therapeutic agents. Immunohistochemistry ...highlights cell differentiation lineages and, in this study, it was applied to maximize the proportion of accurately subtyped NSCLC not otherwise specified (NOS) on fine-needle aspiration cytology (FNAC) samples.
Cell blocks from 103 FNAC samples with a morphological diagnosis of NSCLC-NOS were immunostained for cytokeratin (CK) 7, CK5, TTF1, and p63, whereas p40, napsin A (Naps-A), and desmocollin-3 (DSC-3) were only assessed in a subgroup of cases with discordant (CK7 and TTF1+ for nonsquamous, CK5 and p63+ for squamous) findings. Results were correlated with surgical specimens evaluated by morphology alone.
Thirty-seven (36%) tumors with CK7/TTF1+ and CK5/p63- corresponded to 35 cases of adenocarcinoma (ADC) and 2 cases of large cell carcinoma, whereas 9 (9%) cases with the reverse immunoprofile were squamous cell carcinoma (SQCC) at surgery (P < .001). Although the remaining 57 cases had different marker combinations, a correlation was found with ADC histology for TTF1+ samples (independent of other markers) and with SQCC for p63+/TTF1- immunophenotype (P < .001). p40 was never expressed in p63+ ADC, whereas Naps-A was restricted to ADC and DSC-3 to SQCC lineage. The percentage of unclassified NSCLC-NOS decreased from 36% to 14%. Combinations of 2 antibodies (TTF1/DSC-3 or p63/Naps-A) in the same section allowed diagnostic optimization in scant cytological samples.
corrected This 4-antibody panel approach may contribute to refine lung cancer classification in FNAC cell blocks, remarkably reducing the NSCLC-NOS diagnostic category.
The relationship between thymidylate synthase (TS) expression and outcome in patients with malignant pleural mesothelioma (MPM) treated with pemetrexed (P) was retrospectively evaluated.
Sixty ...histologically confirmed patients with MPM previously treated with P and platinum (45 of 60) or as single agent (15 of 60) were retrospectively considered. Eighty-one control patients with MPM not P-treated were also evaluated. TS and excision repair cross-complementation group 1 (ERCC1) gene expression levels were evaluated by real-time polymerase chain reaction and by immunohistochemistry using the H-score.
Median TS H-score value was 90 (range, 5 to 240). A significant correlation between low TS protein expression and longer time to progression (TTP; 17.9 v 7.9 months; hazard ratio HR, 2.05, 95% CI, 1.19 to 3.77; P = .02) or overall survival (OS; 30 v 16.7 months; HR, 2.38; 95% CI, 1.15 to 4.91; P = .019) was found when patients were divided according to median H-score. Conversely, TS mRNA levels were not significantly correlated with outcome. In platinum-treated patients (n = 45), no correlation was found with survival according to ERCC1 median H-score, but patients in the lower tertile had a significantly shorter survival (HR, 3.06; 95% CI, 1.08 to 8.69; P = .035). In control MPMs, TS had no prognostic role. At multivariate analysis, TS protein levels were the only independent prognostic factor for both TTP (HR, 2.71; 95% CI, 1.13 to 6.49; P = .02) and OS (HR, 6.91; 95% CI, 1.90 to 25.07; P = .003).
In patients with MPM treated with P-based chemotherapy, low TS protein levels are predictive of improved TTP and OS. The role of TS assessment is worth of prospective validation in future studies on MPM.
In this study, our aim was to describe quality of life (QoL) prevalence and heterogeneity in QoL reporting in colorectal cancer phase III trials.
We included all phase III trials evaluating ...anticancer drugs in colorectal cancer patients published between 2012 and 2018 by 11 major journals.
Out of the 67 publications identified, in 41 (61.2 %) QoL was not listed among endpoints. Out of 26 primary publications of trials including QoL among endpoints, QoL results were not reported in 10 (38.5 %). Overall, no QoL data were available in 51/67 (76.1 %) primary publications. In particular, in the metastatic setting, QoL data were not available in 12/18 (66.7 %) trials with primary endpoint overall survival, and in 20/29 (69.0 %) trials with other primary endpoints.
QoL was absent in a high proportion of recently published phase III trials in colorectal cancer, even in trials of second or further lines, where attention to QoL should be particularly high.
The new-generation hormonal agent enzalutamide has been approved for the treatment of metastatic castration-resistant prostate cancer (CRPC), in both post- and predocetaxel setting, due to the ...significant improvement in overall survival. More recently, enzalutamide also showed impressive results in the treatment of men with nonmetastatic CRPC. Unfortunately, not all patients with CRPC are responsive to enzalutamide, and even in responders, benefits are limited by the development of drug resistance. Adaptive resistance of metastatic prostate cancer to enzalutamide treatment can be due to the activation of both androgen receptor (AR)-dependent pathways (expression of constitutively active AR splice variants, AR point mutations, gene amplification and overexpression) and mechanisms independent of AR signaling pathway (altered steroidogenesis, upregulation of the glucocorticoid receptor, epithelial-mesenchymal transition, neuroendocrine transformation, autophagy and activation of the immune system). In this review, we focus on resistance mechanisms to enzalutamide, exploring how we could overcome them through novel therapeutic options.
Malignant pleural mesothelioma (MPM) is a global health issue, the principal cause of which is exposure to asbestos. The prevalence is anticipated to rise over the next 2 decades, particularly in ...developing countries, due to the 30-50-year latency period between exposure to asbestos and carcinogenic development. Unresectable MPM has a poor prognosis and limited treatment options and, as such, there is a broad range of therapeutic targets of interest, including angiogenesis, immune checkpoints, mesothelin, as well as chemotherapeutic agents. Recently, the results of several randomized trials in the first-line setting combining antiangiogenic agents with chemotherapy have been reported. This review examines the scientific rationale for targeting angiogenesis in the treatment of unresectable MPM and analyzes recent clinical results with antiangiogenic agents in development (bevacizumab, nintedanib, and cediranib) for the management of MPM.
Among the several agents targeting the programmed cell death 1 (PD-1) pathway, pembrolizumab is currently the only one approved for the treatment of patients with NSCLC in association with a ...companion diagnostic assay, the anti–PD-L1 immunohistochemical (IHC) 22C3 PharmDx (Agilent Technologies, Santa Clara, CA) using the Dako Autostainer (Dako, Carpinteria, CA). However, the Dako platform is not present in each pathology department, and this technical limitation is a major problem for the diffusion of the PD-L1 IHC predictive test for pembrolizumab.
The Italian Society of Anatomic Pathology and Cytopathology and the Italian Association of Medical Oncology in an independent, multicenter study compared the in vitro diagnostics PD-L1 IHC 22C3 pharmDx test (Agilent) on the Dako Autostainer and the in vitro diagnostics Ventana PD-L1 (SP263) test on the Ventana BenchMark platform (Ventana Medical Systems, Tucson, AZ). Using serial sections from tissue microarrays, 100 lung adenocarcinomas were locally stained and scored in four centers with the same antibody batches.
A high analytical correlation (more than 90% at the lower 95% confidence interval CI value) between PD-L1 expression levels obtained with the 22C3 and SP263 assays was observed. At the proposed clinically relevant cutoffs (≥50% and ≥1%), the overall concordances between 22C3 and SP263 data were 0.99 (95% CI: 0.96–1) and 0.80 (95% CI: 0.68–0.91), respectively. The lower agreement between data obtained with the 22C3 and SP263 clones at the cutoff of 1% or higher was mainly related to the lower (about 80%) interrater agreement at this cutoff with each clone.
These results indicate a high correlation between PD-L1 IHC expression data obtained with the Agilent PD-L1 IHC 22C3 pharmDx and the Ventana PD-L1 (SP263) tests in NSCLC and suggest that the two assays could be utilized interchangeably as an aid to select patients for first-line and second-line treatment with pembrolizumab and potentially with other anti–PD-1/PD-L1 checkpoint inhibitors.
Nintedanib targets VEGF receptors 1-3, PDGF receptors α and β, FGF receptors 1-3, and Src and Abl kinases, which are all implicated in malignant pleural mesothelioma pathogenesis. Here, we report the ...final results of the phase 3 part of the LUME-Meso trial, which aimed to investigate the efficacy and safety of pemetrexed plus cisplatin combined with nintedanib or placebo in unresectable malignant pleural mesothelioma.
This double-blind, randomised, placebo-controlled phase 3 trial was done at 120 academic medical centres and community clinics in 27 countries across the world. Chemotherapy-naive adults (aged ≥18 years) with unresectable epithelioid malignant pleural mesothelioma and ECOG performance status 0-1 were randomly assigned 1:1 via an independently verified random number-generating system to receive up to six 21-day cycles of pemetrexed (500 mg/m
) plus cisplatin (75 mg/m
) on day 1, then nintedanib (200 mg twice daily) or matched placebo on days 2-21. Patients without disease progression after six cycles received nintedanib or placebo maintenance on days 1-21 of each cycle. The primary endpoint was progression-free survival (investigator-assessed according to mRECIST) in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of their assigned study drug. This study is registered with ClinicalTrials.gov, number NCT01907100.
Between April 14, 2016, and Jan 5, 2018, 541 patients were screened and 458 were randomly assigned to either the nintedanib group (n=229) or the placebo group (n=229). Median treatment duration was 5·3 months (IQR 2·8-7·3) in the nintedanib group and 5·1 months (2·7-7·8) in the placebo group. After 250 events, progression-free survival was not different between the nintedanib group (median 6·8 months 95% CI 6·1-7·0) and the placebo group (7·0 months 6·7-7·2; HR 1·01 95% CI 0·79-1·30, p=0·91). The most frequently reported grade 3 or worse adverse event in both treatment groups was neutropenia (73 32% in the nintedanib group vs 54 24% in the placebo group). Serious adverse events were reported in 99 (44%) patients in the nintedanib group and 89 (39%) patients in the placebo group. The only serious adverse event occurring in at least 5% of patients in either group was pulmonary embolism (13 6% vs seven 3%).
The primary progression-free survival endpoint of the phase 3 part of LUME-Meso was not met and phase 2 findings were not confirmed. No unexpected safety findings were reported.
Boehringer Ingelheim.
PDF
