Anti-PD1/PD-L1 directed immune checkpoint inhibitors (ICI) are widely used to treat patients with advanced non-small-cell lung cancer (NSCLC). The activity of ICI across NSCLC harboring oncogenic ...alterations is poorly characterized. The aim of our study was to address the efficacy of ICI in the context of oncogenic addiction.
We conducted a retrospective study for patients receiving ICI monotherapy for advanced NSCLC with at least one oncogenic driver alteration. Anonymized data were evaluated for clinicopathologic characteristics and outcomes for ICI therapy: best response (RECIST 1.1), progression-free survival (PFS), and overall survival (OS) from ICI initiation. The primary end point was PFS under ICI. Secondary end points were best response (RECIST 1.1) and OS from ICI initiation.
We studied 551 patients treated in 24 centers from 10 countries. The molecular alterations involved KRAS (n=271), EGFR (n=125), BRAF (n=43), MET (n=36), HER2 (n=29), ALK (n=23), RET (n=16), ROS1 (n=7), and multiple drivers (n=1). Median age was 60years, gender ratio was 1:1, never/former/current smokers were 28%/51%/21%, respectively, and the majority of tumors were adenocarcinoma. The objective response rate by driver alteration was: KRAS=26%, BRAF=24%, ROS1=17%, MET=16%, EGFR=12%, HER2=7%, RET=6%, and ALK=0%. In the entire cohort, median PFS was 2.8months, OS 13.3months, and the best response rate 19%. In a subgroup analysis, median PFS (in months) was 2.1 for EGFR, 3.2 for KRAS, 2.5 for ALK, 3.1 for BRAF, 2.5 for HER2, 2.1 for RET, and 3.4 for MET. In certain subgroups, PFS was positively associated with PD-L1 expression (KRAS, EGFR) and with smoking status (BRAF, HER2).
: ICI induced regression in some tumors with actionable driver alterations, but clinical activity was lower compared with the KRAS group and the lack of response in the ALK group was notable. Patients with actionable tumor alterations should receive targeted therapies and chemotherapy before considering immunotherapy as a single agent.
Ab initio molecular dynamics simulations were used to explore changes in the vacancy-formation energy for Ti atoms and Ti–O bond characteristics in the outermost monolayers of the (100) and (010) ...prism faces of α quartz. Within 2 or 3 polyhedral layers of the crystal surface, the Ti vacancy-formation energy is substantially smaller than the bulk-lattice value of 11.8eV. This is true of both oxygen-terminated surfaces and the geologically more realistic case in which the outermost oxygens are bonded to hydrogen. A key additional finding is that the Ti vacancy-formation energy near the H-terminated (100) surface differs by 1–2eV from that near the H-terminated (010) surface. This difference means that the energy change accompanying Ti↔Si exchange between the bulk lattice and the near surface is also different for (100) and (010). Ultimately, therefore, the equilibrium concentrations of Ti near these two prism faces will not be the same. During crystal growth, this compositional difference may be “captured” by the quartz lattice and preserved as sectoral variation in Ti content—a feature commonly observed in both synthetic and natural α quartz. In this respect, the MD simulations provide direct support for the growth entrapment model (GEM; Watson, 2004) for non-equilibrium uptake of trace elements.
To complement the vacancy-formation energy results, we used the first-principles metadynamics method to calculate diffusion pathways and free energy barriers for Ti diffusion in the bulk α quartz lattice and in the near-surface region. The computed estimate of the bulk-lattice activation energy compares favorably with the experimentally determined value of 2.8eV (Cherniak et al., 2007), lending credence to the method. Diffusion results for the near-surface reveal a steep decrease in the activation energy for Ti diffusion approaching the surface in the outermost 2–3 polyhedral layers of the crystal. This finding implies depth-dependent Ti diffusion in the near-surface (∼0.5nm), which is also a key aspect of the growth-entrapment model.
Although our results are strictly applicable only to Ti in α quartz, the demonstration that impurity atom energetics and diffusion are functions of depth in the near-surface region may be broadly applicable, given the similarity in measured length scale of the near-surface relaxed region in a wide variety of minerals. Kinetic models of impurity uptake that do not consider these factors may be incomplete.
The prediction of tumor behavior for patients with oral carcinomas remains a challenge for clinicians. The presence of lymph node metastasis is the most important prognostic factor but it is limited ...in predicting local relapse or survival. This highlights the need for identifying biomarkers that may effectively contribute to prediction of recurrence and tumor spread. In this study, we used one- and two-dimensional gel electrophoresis, mass spectrometry and immunodetection methods to analyze protein expression in oral squamous cell carcinomas. Using a refinement for classifying oral carcinomas in regard to prognosis, we analyzed small but lymph node metastasis-positive versus large, lymph node metastasis-negative tumors in order to contribute to the molecular characterization of subgroups with risk of dissemination. Specific protein patterns favoring metastasis were observed in the "more-aggressive" group defined by the present study. This group displayed upregulation of proteins involved in migration, adhesion, angiogenesis, cell cycle regulation, anti-apoptosis and epithelial to mesenchymal transition, whereas the "less-aggressive" group was engaged in keratinocyte differentiation, epidermis development, inflammation and immune response. Besides the identification of several proteins not yet described as deregulated in oral carcinomas, the present study demonstrated for the first time the role of cofilin-1 in modulating cell invasion in oral carcinomas.
The subject of this work is accelerating data uncertainty quantification. In particular, we are interested in expediting the stochastic estimation of the diagonal of the inverse covariance ...(precision) matrix that holds a wealth of information concerning the quality of data collections, especially when the matrices are symmetric positive definite and dense. Schemes built on direct methods incur a prohibitive cubic cost. Recently proposed iterative methods can remedy this but the overall cost is raised again as the convergence of stochastic estimators can be slow. The motivation behind our approach stems from the fact that the computational bottleneck in stochastic estimation is the application of the precision matrix on a set of appropriately selected vectors. The proposed method combines block conjugate gradient with a block-seed approach for multiple right-hand sides, taking advantage of the nature of the right-hand sides and the fact that the diagonal is not sought to high accuracy. Our method is applicable if the matrix is only known implicitly and also produces a matrix-free diagonal preconditioner that can be applied to further accelerate the method. Numerical experiments confirm that the approach is promising and helps contain the overall cost of diagonal estimation as the number of samples grows.
Malignant pleural mesothelioma (MPM) is an aggressive malignancy characterised by limited treatment options and a poor prognosis. At relapse after platinum-based chemotherapy, single-agent ...chemotherapy is commonly used and single-arm trials of immune-checkpoint inhibitors have demonstrated encouraging activity.
PROMISE-meso is an open-label 1:1 randomised phase III trial investigating the efficacy of pembrolizumab (200 mg/Q3W) versus institutional choice single-agent chemotherapy (gemcitabine or vinorelbine) in relapsed MPM patients with progression after/on previous platinum-based chemotherapy. Patients were performance status 0–1 and unselected for programmed cell death ligand 1 (PD-L1) status. At progression, patients randomly assigned to receive chemotherapy were allowed to crossover to pembrolizumab. The primary end point was progression-free survival (PFS), assessed by blinded independent central review (BICR). Secondary end points were overall survival (OS), investigator-assessed PFS, objective response rate (ORR), and safety. Efficacy by PD-L1 status was investigated in exploratory analyses.
Between September 2017 and August 2018, 144 patients were randomly allocated (pembrolizumab: 73; chemotherapy: 71). At data cut-off 20 February 2019, median follow-up of 11.8 months (interquartile range: 9.9–14.5), 118 BICR-PFS events were observed. No difference in BICR-PFS was detected hazard ratio = 1.06, 95% confidence interval (CI): 0.73–1.53; P = 0.76, and median BICR-PFS (95% CI) for pembrolizumab was 2.5 (2.1–4.2), compared with 3.4 (2.2–4.3) months for chemotherapy. A difference in ORR for pembrolizumab was identified (22%, 95% CI: 13% to 33%), over chemotherapy (6%, 95% CI: 2% to 14%; P = 0.004). Forty-five patients (63%) assigned to chemotherapy received pembrolizumab at progression. With follow-up to 21 August 2019 17.5 months: (14.8–19.7), no difference in OS was detected between groups (HR = 1.12, 95% CI: 0.74–1.69; P = 0.59), even after adjusting for crossover. Pembrolizumab safety was consistent with previous observations. Exploratory efficacy analyses by PD-L1 status demonstrated no improvements in ORR/PFS/OS.
This is the first randomised trial evaluating the efficacy of pembrolizumab in MPM patients progressing after/on previous platinum-based chemotherapy. In biologically unselected patients, although associated with an improved ORR, pembrolizumab improves neither PFS nor OS over single-agent chemotherapy.
•First randomised, controlled trial evaluating efficacy of an anti-PD1 agent versus chemotherapy in relapsed MPM, with immunotherapy crossover allowed.•Objective response rate was significantly improved for pembrolizumab (22% versus 6%, P = 0.004).•No improvement for independently reviewed PFS for pembrolizumab over chemotherapy (HR = 1.06, 95% CI: 0.73–1.53, P = 0.76).•No overall survival improvement for pembrolizumab over chemotherapy (HR = 1.04, 95% CI: 0.66–1.67, P = 0.85).
Background
Cigarette consumption has been identified as the main non‐etiological factor in head and neck cancer (HNC) development. One of the main compounds in cigarettes is nicotine, which binds ...directly to nicotine acetylcholine receptors (nAchRs) in the body, which are encoded by different genes of the CHRNA family. Polymorphisms in some of these genes have been studied in relation to the risk of HNC and cigarette consumption intensity. The aim of this study was to evaluate whether there were associations between the CHRNA3 (rs578776) and CHRNA5 (rs16969968) polymorphisms and HNC risk and between the polymorphisms and the intensity of cigarette consumption.
Methods
A total of 1,067 individuals from Heliopolis Hospital in São Paulo were investigated, including 619 patients with HNC and 448 patients without diagnosed tumors. All participants answered a questionnaire about sociodemographic information and cigarette consumption data. The polymorphisms were determined by TaqMan genotyping by real‐time PCR.
Results
The polymorphisms studied, rs578776 (CHRNA3) and rs16969968 (CHRNA5), did not have an association with HNC risk, but the rs16969968 homozygous genotype was associated with increased cigarette consumption intensity (OR 1.93, 95% CI 1.05–3.58).
Conclusion
The polymorphism CHRNA5 can be considered an indirect risk factor for neoplasms in these Brazilian samples when cigarette consumption increased.
The gene CHRNA5, that encoded the α5 subunit of nicotinic receptor, increased the cigarette consumption intensity in Brazilian sample. Once tobacco consumed is a risk factor to the head and neck cancer development, these polymorphism can be considered an indirect risk factor for these neoplasm.
Many testicular germ cell cancers are curable despite metastatic disease, but about 10-15% of patients fail cisplatin-based first-line treatment. Immunotherapy is considered as additional treatment ...approach for these patients. Inhibition of the interaction between Programmed Death Receptor 1 (PD-1) and Programmed Death Receptor Ligand 1 (PD-L1) enhances T-cell responses in vitro and mediates clinical antitumour activity. We analysed the expression of PD-L1 in testicular germ cell tumours to evaluate its potential as target for immunotherapeutic strategies.
Immunohistochemistry was performed in 479 formalin-fixed paraffin-embedded specimens using a rabbit monoclonal antibody (E1L3N). The tissue microarray consisted of 208 pure seminomas, 121 non-seminomas, 20 intratubular germ cell neoplasia unclassified (IGCNU) and 20 specimens of non-neoplastic testicular tissue.
Programmed Death Receptor Ligand-1 expression was found in 73% of all seminomas and in 64% of all non-seminomas. None of 20 IGCNU and none of 20 normal tissue specimens exhibited PD-L1 expression. PD-L1 positive stromal cells were only detected in seminomas, but not in non-seminomas. The anti PD-L1 antibody showed a pre-dominantly membranous staining pattern in testicular tumour cells, as well as expression in stromal cells.
This frequent expression of PD-L1 in human testicular germ cell tumours suggests that patients with testicular germ cell tumours could profit from immunotherapeutic strategies using anti-PD1 and anti-PDL1 antibodies.
Liquid biopsy is a rapidly emerging tool of precision oncology enabling minimally invasive molecular diagnostics and longitudinal monitoring of treatment response. For the clinical management of ...advanced stage lung cancer patients, detection and quantification of circulating tumor DNA (ctDNA) is now widely adopted into clinical practice. Still, interpretation of results and validation of ctDNA-based treatment decisions remain challenging. We report here our experience implementing liquid biopsies into the clinical management of lung cancer. We discuss advantages and limitations of distinct ctDNA assay techniques and highlight our approach to the analysis of recurrent molecular alterations found in lung cancer. Moreover, we report three exemplary clinical cases illustrating the complexity of interpreting liquid biopsy results in clinical practice. These cases underscore the potential and current limitations of liquid biopsy, focusing on the difficulty of interpreting discordant findings. In our view, despite all current limitations, the analysis of ctDNA in lung cancer patients is an essential and highly versatile complementary diagnostic tool for the clinical management of lung cancer patients in the era of precision oncology.
PDF
