derived neutrophil to lymphocyte ratio dnlr change between baseline and cycle 2 is correlated with benefit during immune checkpoint inhibitors ici in advanced non small cell lung cancer nsclc patients

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Impact of intercurrent introduction of steroids on clinical outcomes in advanced non-small-cell lung cancer (Nsclc) patients under immune-checkpoint inhibitors (ici)

Background: Baseline steroids before ICI have been associated with poor outcomes, particularly when introduced due to cancer symptoms. Methods: Retrospective analysis of advanced NSCLC patients treated with ICI. We collected the use of intercurrent steroids (≥10 mg of prednisone-equivalent) within the first eight weeks of ICI. We correlated steroid use with patient outcomes according to the indications. Results: 413 patients received ICI, 299 were steroids-naïve at baseline. A total of 49 patients received intercurrent steroids (16%), of whom 38 for cancer-related symptoms and 11 for other indications, such as immune-related events. Overall, median (m) progression-free survival (PFS) was 1.9 months (mo.) [95% CI, 1.8-2.4] and overall survival (OS) 10 mo. [95% CI, 8.1–12.9]. Intercurrent steroids under ICI correlated with a shorter PFS/OS (1.3 and 2.3 mo. respectively, both p < 0.0001). Intercurrent steroids for cancer-related symptoms correlated with poorest mPFS [1.1 mo.; 95% CI, 0.9–1.5] and mOS [1.9 mo.; 95%CI, 1.5–2.4; p < 0.0001)]. No mOS and mPFS differences were found between cancer-unrelated-steroid group and no-steroid group. Steroid use for cancer-related symptoms was an independent prognostic factor for poor PFS [HR 2.64; 95% CI, 1.2–5.6] and OS [HR 4.53; 95% CI, 1.8–11.1], both p < 0.0001. Conclusion: Intercurrent steroids during ICI had no detrimental prognostic impact if the indication was unrelated to cancer symptoms

STELLAR: Final updated results of a phase II trial of TTFields with chemotherapy for unresectable malignant pleural mesothelioma

Background: Tumor Treating Fields (TTFields), an anti-mitotic, regional treatment approved for glioblastoma utilizes low intensity, alternating electric fields delivered non-invasively to the tumor using a portable medical device. In-vitro, human mesothelioma cells were highly susceptible to TTFields. Methods: The trial accrued 80 patients with unresectable, previously untreated mesothelioma. Patients were treated with continuous 150 kHz TTFields (>18h/day) in combination with pemetrexed and cisplatin or carboplatin. Inclusion criteria included ECOG PS of 0-1 and pathologically proven mesothelioma. The primary endpoint was overall survival (OS). A visual analog scale was used to assess EOCG performance status and cancer-related pain assessed until disease progression. The sample size provided 80% power with two-sided alpha of 0.05 to detect an increase in median OS of 5.5 months compared to historical controls (Vogelzang, JCO 2003). Results: All 80 patients had a minimum follow up of 12 months. Median age was 67 (range 27-78), 84% were male and 44% (35 patients) had an ECOG PS of 1. 66% (53 patients) had epithelioid histology, similar to the Vogelzang study. Median OS was 18.2 months (95% CI 12.1-25.8) versus 12.1 months in the historical control. Median OS for epithelioid patients was 21.2 months (95% CI 13.2-25.8). ECOG score was stable during the first year of follow up. Median time to deterioration in performance status was 13.1 months. Average score of pain was lower compared to baseline during the first 7 months of the treatment and was higher later on the study, with a median time to a clinical significant 33% increase in pain of 8.4 months. No device-related serious adverse events (AEs) were reported. Expected TTFields-related dermatitis was reported in 46% (37 patients). Four patients (5%) had grade 3 dermatitis. Conclusions: The study met primary endpoint of significant extension of overall survival in previously untreated mesothelioma patients. TTFields was not associated with a decrease in performance status or an increase in pain for the duration of TTFields use. TTFields in combinati

Nintedanib Plus Pemetrexed/Cisplatin in Patients With Malignant Pleural Mesothelioma: Phase II Results From the Randomized, Placebo-Controlled LUME-Meso Trial

Purpose LUME-Meso is a phase II/III randomized, double-blind trial designed to assess efficacy and safety of nintedanib plus chemotherapy as first-line treatment of malignant pleural mesothelioma (MPM). Phase II results are reported here. Patients and Methods Chemotherapy-na¨ıve patients with unresectable, nonsarcomatoid MPM (Eastern Cooperative Oncology Group performance status 0 to 1), stratified by histology (epithelioid or biphasic), were randomly assigned in a 1:1 ratio to up to six cycles of pemetrexed and cisplatin plus nintedanib (200 mg twice daily) or placebo followed by nintedanib plus placebo monotherapy until progression. The primary end point was progression-free survival (PFS). Results Eighty-seven patients were randomly assigned. The median number of pemetrexed and cisplatin cycles was six; the median treatment duration for nintedanib was 7.8 months and 5.3 months for placebo. Primary PFS favored nintedanib (hazard ratio [HR], 0.56; 95% CI, 0.34 to 0.91; P = .017), which was confirmed in updated PFS analyses (HR, 0.54; 95% CI, 0.33 to 0.87; P = .010). A trend toward improved overall survival also favored nintedanib (HR, 0.77; 95% CI, 0.46 to 1.29; P = .319). Benefit was evident in epithelioid histology, with a median overall survival gain of 5.4 months (HR, 0.70; 95% CI, 0.40 to 1.21; P = .197; median [nintedanib v placebo], 20.6 months v 15.2 months) and median PFS gain of 4.0 months (HR, 0.49; 95% CI, 0.30 to 0.82; P = .006; median [nintedanib v placebo], 9.7 v 5.7 months). Neutropenia was the most frequent grade $ 3 adverse event (AE; nintedanib 43.2% v placebo 12.2%); rates of febrile neutropenia were low (4.5% in nintedanib group v 0% in placebo group). AEs leading to discontinuation were reported in 6.8% of those receiving nintedanib versus 17.1% of those in the placebo group. Conclusion Addition of nintedanib to pemetrexed plus cisplatin resulted in PFS improvement. AEs were manageable. The clinical benefit was evident in patients with epithelioid histology. The confirmatory phase III part of the study is ongoing

The N-Terminal residues 43 to 60 form the interface for dopamine mediated α-synuclein dimerisation

α-synuclein (α-syn) is a major component of the intracellular inclusions called Lewy bodies, which are a key pathological feature in the brains of Parkinson's disease patients. The neurotransmitter dopamine (DA) inhibits the fibrillisation of α-syn into amyloid, and promotes α-syn aggregation into SDS-stable soluble oligomers. While this inhibition of amyloid formation requires the oxidation of both DA and the methionines in α-syn, the molecular basis for these processes is still unclear. This study sought to define the protein sequences required for the generation of oligomers. We tested N- (α-syn residues 43-140) and C-terminally (1-95) truncated α-syn, and found that similar to full-length protein both truncated species formed soluble DA: α-syn oligomers, albeit 1-95 had a different profile. Using nuclear magnetic resonance (NMR), and the N-terminally truncated α-syn 43-140 protein, we analysed the structural characteristics of the DA:α-syn 43-140 dimer and α-syn 43-140 monomer and found the dimerisation interface encompassed residues 43 to 60. Narrowing the interface to this small region will help define the mechanism by which DA mediates the formation of SDS-stable soluble DA:α-syn oligomers

Ring-like N-fold Models of Aβ42 fibrils

When assembling as fibrils Aβ40 peptides can only assume U-shaped conformations while Aβ42 can also arrange as S-shaped three-stranded chains. We show that this allows Aβ42 peptides to assemble pore-like structures that may explain their higher toxicity. For this purpose, we develop a scalable model of ring-like assemblies of S-shaped Aβ1–42 chains and study the stability and structural properties of these assemblies through atomistic molecular dynamics simulations. We find that the proposed arrangements are in size and symmetry compatible with experimentally observed Aβ assemblies. We further show that the interior pore in our models allows for water leakage as a possible mechanism of cell toxicity of Aβ42 amyloids.Simulations were done on the SCHOONER cluster of the University of Oklahoma and the Extreme Science and Engineering Discovery Environment (XSEDE) which is supported by NSF under grant ACI-1053575. We acknowledge financial support from NSF CHE-1266256. Open access fees fees for this article provided whole or in part by OU Libraries Open Access Fund.Ye

Is the RASSF1A/Hippo pathway at the beginning of glioma?

International audienc

BRAF in non-small cell lung cancer (NSCLC): Pickaxing another brick in the wall

Molecular characterization of non-small cell lung cancer (NSCLC) marked an historical turning point for the treatment of lung tumors harboring kinase alterations suitable for specific targeted drugs inhibition, translating into major clinical improvements. Besides EGFR, ALK and ROS1, BRAF represents a novel therapeutic target for the treatment of advanced NSCLC. BRAF mutations, found in 1.5–3.5% of NSCLC, are responsible of the constitutive activation of mitogen activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway. Clinical trials evaluating the efficacy of the BRAF inhibitor dabrafenib in combination with the downstream MEK inhibitor trametinib in metastatic BRAF V600E -mutated NSCLC guaranteed FDA and EMA rapid approval of the combination regimen in this clinical setting. In line with the striking results observed in metastatic melanoma harboring the same molecular alteration, BRAF and MEK inhibition should be considered a new standard of care in this molecular subtype of NSCLC. In the present review, we propose an overview of the available evidence about BRAF in NSCLC mutations (V600E and non-V600E), from biological significance to emerging clinical implications of BRAF mutations detection. Focusing on the current strategies to act against the mutated kinase, we moreover approach additional strategies to overcome treatment resistance