CEA, CYFRA21-1 and NSE are tumor markers used for monitoring the response to chemotherapy in advanced adenocarcinoma, squamous cell carcinoma and small-cell lung cancer, respectively. Their role in ...cancer immunotherapy needs to be elucidated.
Patients with advanced non-small cell lung cancer (NSCLC) were treated with nivolumab 3 mg/kg every 2 weeks within the Italian Nivolumab Expanded Access Program. Blood samples were collected at baseline, at each cycle up to cycle 5 and then every two cycles until patient's withdrawn from the study. All patients underwent a CT-scan after every 4 cycles of treatment and responses were classified according to RECIST 1.1. The biomarkers serum levels were measured with a chemiluminescent microparticle immunoassay for CEA and with an immuno radiometric assay for CYFRA21-1 and NSE. The markers values at baseline and after 4 cycles were used to analyze the relationship between their variation over baseline and the tumor response, evaluated as disease control rate (DCR: CR + PR + SD), and survival (PFS and OS).
A total of 70 patients were evaluable for the analysis. Overall, a disease control was obtained in 24 patients (35.8%, 4 PR + 20 SD). After 4 cycles of nivolumab a CEA or CYFRA21-1 reduction ≥ 20% over the baseline was significantly associated with DCR (CEA, p = 0.021; CYFRA21-1, p < 0.001), PFS (CEA, p = 0.028; CYFRA21-1, p < 0.001) and OS (CEA, p = 0.026; CYFRA21-1, p = 0.019). Multivariate analysis confirmed the ability of CYFRA21-1 reduction ≥ 20% to predict DCR (p = 0.002) and PFS (p < 0.001).
The reduction in serum level of CYFRA21-1 or CEA might be a reliable biomarker to predict immunotherapy efficacy in NSCLC patients. NSE was not significant for monitoring the efficacy of nivolumab.
Purpose
Immune checkpoint inhibitors (ICPIs) disrupting PD-1/PD-L1 axis have revolutionized the management of advanced non-small cell lung cancer (NSCLC). Some studies identified the development of ...endocrine toxicity as predictor of better survival in cancer patients treated with ICPIs. The aim of study was to evaluate survival and new onset of immune-related endocrine adverse events (irAEs) in patients treated with nivolumab for advanced NSCLC.
Methods
In a prospective study, 73 patients with previously treated advanced NSCLC received nivolumab in monotherapy. Blood samples were collected at each cycle to monitor thyroid autoimmunity, thyroid, adrenal and somatotroph axes, while thyroid morphology was evaluated by ultrasonography.
Results
An impaired thyroid function was recorded in 23.4% of patients (
n
= 15). Eight patients developed asymptomatic transient thyrotoxicosis (ATT) evolving to hypothyroidism in 50% of cases. In addition, seven patients developed overt hypothyroidism without ATT and with negative autoantibodies. Patients who developed hypothyroidism proved to have better overall survival (OS) as compared with non-developers at both univariate (
p
= 0.021) and multivariate analyses (
p
= 0.023). The survival curve of patients with reduced IGF-I at baseline, or displaying its reduction during the follow-up, showed significantly reduced median survival compared to patients with normal/high IGF-I levels (
p
= 0.031).
Conclusions
Thyroid function abnormalities are the major irAEs in patients treated with nivolumab, and hypothyroidism onset is associated with prolonged survival. Our findings indicate that the development of hypothyroidism is a positive predictive biomarker of nivolumab antitumor efficacy in patients with NSCLC. Low IGF-I levels could represent a negative prognostic factor during nivolumab therapy.
Malignant mesothelioma (MM) is an aggressive tumor, mainly derived from the pleura, which is predominantly associated with exposure to asbestos fibers. The prognosis of MM patients is particularly ...severe, with a median survival of approximately 9–12 months and latency between exposure and diagnosis ranging from 20–50 years (median 30 years). Emerging evidence has demonstrated that tumor aggressiveness is associated with genome and gene expression abnormalities; therefore, several studies have recently focused on the role of microRNAs (miRNAs) in MM tumorigenesis. miRNAs are small non-protein coding single-stranded RNAs (17–22 nucleotides) involved in numerous cellular processes that negatively regulate gene expression by modulating the expression of downstream target genes. miRNAs are often deregulated in cancer; in particular, the differential miRNA expression profiles of MM cells compared to unaffected mesothelial cells have suggested potential roles of miRNAs as either oncogenes or tumor suppressor genes in MM oncogenesis. In this review, the mechanism of MM carcinogenesis was evaluated through the analysis of the published miRNA expression data. The roles of miRNAs as diagnostic biomarkers and prognostic factors for potential therapeutic strategies will be presented and discussed.
Preclinical studies have suggested that combining cytotoxic agents with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs) to treat EGFR‐mutated tumors may increase their ...inhibitory effect depending on the order of drug administration. The antitumor efficacy of different treatment sequences using vinorelbine (VNB) and gefitinib (GEF) was investigated both in vitro and in vivo in non‐small cell lung cancer (NSCLC) cell lines with the rationale of potentially translating these findings into the clinical setting. The EGFR‐wild‐type A549 and the EGFR‐mutated (exon 21 L858R/exon 20 T790M) H1975 cell lines were treated as follows: GEF followed by VNB, VNB followed by GEF and the two drugs applied individually or concurrently. Results in vitro demonstrated that the sequence of VNB followed by GEF was significantly more active than single‐agent treatments. The expression of activated EGFR and its downstream pathway genes indicated that the increased cytotoxic effect of the VNB and GEF treatment sequence was accompanied by inhibition of EGFR, AKT and ERK1/2. Moreover, the increased inhibition of tumor growth after treatment with VNB followed by GEF was also confirmed in CD1‐nude mice that were xenotransplanted with H1975 cells (p < 0.0001). This effect was paralleled by a corresponding decrease in cancer glucose consumption, as assessed by micro‐positron emission tomography scans (p < 0.05). These preclinical findings in NSCLC cell lines, which are poorly responsive to EGFR‐TKIs, demonstrated that the sequential treatment of VNB followed by GEF induced a significant antitumor effect, which supports the translation of this treatment schedule into a clinical setting.
What's new?
Chemotherapy and EGFR‐TKIs may produce enhanced effect when combined together, but this is influenced by the choice of the drug and the sequence of administration. This study reports that NSCLC cell line carrying the EGFR‐L858R/T790M mutations showed increased sensitivity to the sequential schedule of vinorelbine followed by gefitinib in vitro and in vivo. These preclinical findings support the application of this treatment scheme in lung tumors poorly responsive to reversible EGFR‐TKIs.
VeriStrat is a blood-based proteomic test with predictive and prognostic significance in second-line treatments for non-small cell lung cancer (NSCLC). This trial was designed to investigate the role ...of VeriStrat in first-line treatment of advanced NSCLC with standard chemotherapy. Here we present the results for 76 non-squamous patients treated with a combination of carboplatin or cisplatin with pemetrexed.
The test-assigned classifications of VeriStrat Good or VeriStrat Poor to samples collected at baseline. The primary end point was progression-free survival (PFS); secondary end points included overall survival (OS) and objective response. Exploratory analyses of end points separately in carboplatin/pemetrexed and cisplatin/pemetrexed subgroups were also conducted.
Patients classified as VeriStrat Good had longer PFS and OS than VeriStrat Poor: 6.5 vs 1.6 months and 10.8 vs 3.4 months, respectively; the corresponding hazard ratios (HRs) were 0.36 (P<0.0001) and 0.26 (P<0.0001); they were also more likely to achieve objective response. Prognostic significance of VeriStrat was confirmed in multivariate analysis. Significant differences in OS and PFS between Veristrat classifications were also found when treatment subgroups were analysed separately.
The trial demonstrated clinical utility of VeriStrat as a prognostic test for standard first-line chemotherapy of non-squamous advanced NSCLC.
Vinflunine belongs to the class of vinca alkaloids and acts by disrupting the microtubule dynamics during cell cycle; this agent is currently available for previously treated advanced transitional ...cell carcinoma in Europe. The aim of this invited review is to evaluate the potential role of vinflunine for the treatment of non-small cell lung cancer (NSCLC). Areas covered: The potential role of vinflunine in NSCLC is discussed on the basis of the available data, including full papers and meeting abstracts. Relevant preclinical studies describing the pharmacological properties of vinflunine are also included. The review also summarizes clinical studies, including phase I trials involving NSCLC among other tumors as well as phase II/III trials specifically addressing this malignancy. Additionally, the safety profile and the current regulatory status of vinflunine is discussed. Expert opinion: Vinflunine is active as single agent and as part of platinum-based combinations in NSCLC. It results non-inferior to docetaxel in a randomized phase III trial including previously treated NSCLC patients; additionally, its safety profile is generally considered manageable. Ultimately, further studies are needed to confirm the role of vinflunine in NSCLC, in consideration of the evolving evidence regarding targeted therapies and immune check-point inhibitors.
Background
Treatment of moderate‐to‐severe atopic dermatitis (AD) in the elderly may be challenging, due to side‐effects of traditional anti‐inflammatory drugs and to comorbidities often found in ...this age group. Furthermore, efficacy and safety of innovative drugs such as dupilumab are not yet well known.
Objectives
A multicentre retrospective, observational, real‐life study on the efficacy and safety of dupilumab was conducted in a group of patients aged ≥65 years and affected by severe AD. Their main clinical features were also examined.
Methods
Data of elderly patients with severe (EASI ≥24) AD treated with dupilumab at label dosage for 16 weeks were retrospectively collected. Treatment outcome was assessed by comparing objective (EASI) and subjective (P‐NRS, S‐NRS and DLQI) scores at baseline and after 16 weeks of treatment.
Results
Two hundred and seventy‐six patients were enrolled in the study. They represented 11.37% of all patients with severe AD. Flexural eczema was the most frequent clinical phenotype, followed by prurigo nodularis. The coexistence of more than one phenotype was found in 63/276 (22.82%) subjects. Data on the 16‐week treatment with dupilumab were available for 253 (91.67%) patients. Efficacy of dupilumab was demonstrated by a significant reduction of all the scores. No statistically significant difference regarding efficacy was found in elderly patients when compared to the group of our AD patients aged 18–64 years, treated with dupilumab over the same period. Furthermore, only 18 (6.52%) patients discontinued the drug due to inefficacy. Sixty‐one (22.51%) patients reported adverse events, conjunctivitis and flushing being the most frequent. One (0.36%) patient only discontinued dupilumab due to an adverse event.
Conclusions
Therapy with dupilumab led to a significant improvement of AD over a 16‐week treatment period, with a good safety profile. Therefore, dupilumab could be considered as an efficacious and safe treatment for AD also in the elderly.
We studied the effect of the entomopathogenic fungus Beauveria bassiana strain GHA on a) colony development of the beetles Tribolium castaneum (Herbst) and Ulomoides dermestoides (Fairmaire) ...(Coleoptera: Tenebrionidae) under laboratory conditions; and 2) the volatile blend released by both beetles, containing defensive pheromones, by using the solid phase microextraction technique. Colony development of both species was strongly altered 3 mo after treatment with B. bassiana, showing a significant reduction in progeny of 37.5% for T. castaneum and 50.0% for U. dermestoides. We also showed that the volatiles released by T. castaneum diminished close to 20% compared with those of healthy beetles, whereas in U. dermestoides secretions dramatically dropped to 5%, 7 d after immersion in 1 × 10⁹ conidia per ml. These results suggest that after infection events take place, fungus-induced diminished secretion of the defensive pheromones may be a physiologic clue for behavioral changes in infected beetles.
The composition of volatile organic compounds (VOC) released by the entomopathogenic fungus
Beauveria bassiana (Hyphomycete: Deuteromycotina) utilizing two different carbon sources was investigated. ...Analyses were performed by solid-phase microextraction (SPME) coupled to capillary gas chromatography (CGC) and CGC-mass spectrometry (MS). Major components in glucose-grown cultures were diisopropyl naphthalenes, ethanol, and sesquiterpenes. Alkane-grown fungal VOC switched to a fingerprint with prevalence of
n-decane. This is the first report on the volatiles released by entomopathogenic fungi.
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