Evaluation of the Effect of Lorlatinib on CYP2B6, CYP2C9, UGT, and P-Glycoprotein Substrates in Patients with Advanced Non-Small Cell Lung Cancer

Lorlatinib; Glycoprotein; Advanced non-small cell lung cancerLorlatinib; Glicoproteïna; Càncer de pulmó de cèl·lules no petitesLorlatinib; Glicoproteína; Cáncer de pulmón de células no pequeñasBackground and Objective Lorlatinib is a tyrosine kinase inhibitor approved for the treatment of advanced anaplastic lymphoma kinase–positive non-small cell lung cancer. This study assessed the effect of steady-state lorlatinib on the metabolic enzymes cytochrome P450 (CYP) 2B6, CYP2C9, and uridine 5′-diphospho-glucuronosyltransferase (UGT) and the P-glycoprotein (P-gp) transporter. Methods Thirty-two patients received a single oral dose of a probe drug on Day − 2 to determine the pharmacokinetics of the probe drug alone. Starting on Day 1, patients received 100 mg oral lorlatinib daily. On Day 15, a single oral dose of the probe drug was administered concurrently with lorlatinib. Pharmacokinetic parameters for these probe substrates were assessed. Results Plasma exposures of all probe substrates were reduced by lorlatinib compared with the probe alone. The greatest reduction in area under the plasma concentration–time curve from time zero to infinity (AUC∞) and maximum (peak) plasma drug concentration (Cmax) (67% and 63% decrease, respectively) was observed with the P-gp probe substrate fexofenadine. Lorlatinib coadministration also decreased the AUC∞ and Cmax of bupropion (CYP2B6 probe substrate) by 25% and 27%, tolbutamide (CYP2C9 probe substrate) by 43% and 15%, and acetaminophen (UGT probe substrate) by 45% and 28%, respectively. Conclusions Lorlatinib is a net moderate inducer of P-gp and a weak inducer of CYP2B6, CYP2C9, and UGT after steady state is achieved with daily dosing. Medications that are P-gp substrates with a narrow therapeutic window should be avoided in patients taking lorlatinib; no dose modifications are needed with substrates of CYP2B6, CYP2C9, or UGT. ClinicalTrials.gov: NCT01970865.This study was sponsored by Pfizer

Source Apportionment of PM2.5 in Florence (Italy) by PMF Analysis of Aerosol Composition Records

An extensive field campaign was carried out in Florence (Tuscany) to investigate the PM2.5 composition and to identify its sources. The scientific objective of this study is providing a reliable source apportionment, which is mandatory for the application of effective mitigation actions. Particulate matter (PM) was collected for one year, simultaneously in a traffic site, in an urban background, and in a regional background site. While the use of two filter types (quartz and Teflon) allowed obtaining a comprehensive chemical characterization (elemental and organic carbon, ions, elements) by the application of different analytical techniques, the location of the three sampling sites allowed getting a better separation among local, urban, regional and transboundary sources. During shorter periods, the aerosol was also collected by means of a streaker sampler and PIXE (Particle Induced X-ray Emission) analysis of these samples allowed the assessment of hourly resolution elemental time trends. Positive matrix factorisation (PMF) identified seven main sources: traffic, biomass burning, secondary sulphate, secondary nitrates, urban dust, Saharan dust and marine aerosol. Traffic mass concentration contributions were found to be strong only at the traffic site (~8 μg·m−3, 33% of PM2.5). Biomass burning turned out to be an important PM2.5 source in Florence (~4 μg·m−3), with very similar weights in both city sites while at the regional background site its weight was negligible. Secondary sulphate is an important PM2.5 source on a regional scale, with comparable values in all three sites (~3.5 μg·m−3). On average, the contribution of the "natural" components (e.g., mineral dust and marine aerosols) to PM2.5 is moderate (~1 μg·m−3) except during Saharan dust intrusions where this contribution is higher (detected simultaneously in all three sites). High-time resolution data confirmed and reinforced these results

Saharan dust impact in central Italy: An overview on three years elemental data records

In southern European countries, Saharan dust may episodically produce significant increases of PM10, which may also cause the exceedance of the PM10 daily limit value established by the European Directive (2008/50/EC). The detection with very high sensitivity of all the elements that constitute mineral dust makes PIXE technique a very effective tool to assess the actual impact of these episodes. In this work, a review of long-term series of elemental concentrations obtained by PIXE has been accomplished with the aim of identifying the occurrence of Saharan dust transport episodes over long periods in Tuscany and characterising them in terms of composition and impact on PM concentration, tracing back their contribution to the exceedances of the PM10 limit value. The impact of the different Saharan intrusions on PM10 showed a very high variability. During the most intense episodes (which occurred with a frequency of few times per year) the calculated soil dust concentration reached values as high as 25\u201330 \u3bcg m 123, to be compared with background values of the order of 5 \u3bcg m 123. The Saharan dust contribution was decisive to cause the exceedance of the PM10 daily limit value in the 1\u20132% of the days considered in the present work

Kynurenine/Tryptophan Ratio as a Potential Blood-Based Biomarker in Non-Small Cell Lung Cancer

The enzyme indoleamine 2,3-dioxygenase 1 (IDO1) degrade tryptophan (Trp) into kynurenine (Kyn) at the initial step of an enzymatic pathway affecting T cell proliferation. IDO1 is highly expressed in various cancer types and associated with poor prognosis. Nevertheless, the serum Kyn/Trp concentration ratio has been suggested as a marker of cancer-associated immune suppression. We measured Kyn and Trp in blood samples of a wide cohort of non-small-cell lung cancer (NSCLC) patients, before they underwent surgery, and analyzed possible correlations of the Kyn/Trp ratio with either IDO1 expression or clinical-pathological parameters. Low Kyn/Trp significantly correlated with low IDO1 expression and never-smoker patients; while high Kyn/Trp was significantly associated with older (>= 68 years) patients, advanced tumor stage, and squamous cell carcinoma (Sqcc), rather than the adenocarcinoma (Adc) histotype. Moreover, high Kyn/Trp was associated, among the Adc group, with higher tumor stages (II and III), and, among the Sqcc group, with a high density of tumor-infiltrating lymphocytes. A trend correlating the high Kyn/Trp ratio with the probability of recurrences from NSCLC was also found. In conclusion, high serum Kyn/Trp ratio, associated with clinical and histopathological parameters, may serve as a serum biomarker to optimize risk stratification and therapy of NSCLC patients

Gene identification for risk of relapse in stage I lung adenocarcinoma patients. A combined methodology of gene expression profiling and computational gene network analysis

Risk assessment and treatment choice remains a challenge in early non-smallcell lung cancer (NSCLC). The aim of this study was to identify novel genes involved in the risk of early relapse (ER) compared to no relapse (NR) in resected lung adenocarcinoma (AD) patients using a combination of high throughput technology and computational analysis. We identified 18 patients (n.13 NR and n.5 ER) with stage I AD. Frozen samples of patients in ER, NR and corresponding normal lung (NL) were subjected to Microarray technology and quantitative-PCR (Q-PCR). A gene network computational analysis was performed to select predictive genes. An independent set of 79 ADs stage I samples was used to validate selected genes by Q-PCR. From microarray analysis we selected 50 genes, using the fold change ratio of ER versus NR. They were validated both in pool and individually in patient samples (ER and NR) by Q-PCR. Fourteen increased and 25 decreased genes showed a concordance between two methods. They were used to perform a computational gene network analysis that identified 4 increased (HOXA10, CLCA2, AKR1B10, FABP3) and 6 decreased (SCGB1A1, PGC, TFF1, PSCA, SPRR1B and PRSS1) genes. Moreover, in an independent dataset of ADs samples, we showed that both high FABP3 expression and low SCGB1A1 expression was associated with a worse disease-free survival (DFS). Our results indicate that it is possible to define, through gene expression and computational analysis, a characteristic gene profiling of patients with an increased risk of relapse that may become a tool for patient selection for adjuvant therapy

Antiretroviral therapy in HIV/HCV co-infection Italian consensus workshop

About 50% of people living with the HIV infection in Italy are co-infected with HCV. In this group of patients, the primary cause of mortality is liver disease, which accounts for up to 14% of deaths. HIV/HCV co-infection also exposes patients to a higher risk of progression to AIDS, a faster evolution towards cirrhosis, more frequent drug toxicity, and lower tolerance for antiretroviral therapy. Moreover, HCV infection can play a part in increasing immune system depression; neurological, cognitive and renal damage; and bone fragility. Hence an optimal antiretroviral regimen needs to be chosen for co-administration with anti-HCV therapy and timed appropriately to improve the prognosis of co-infected HIV/HCV patients. Unfortunately, however, data on the safety and efficacy of antiretroviral drugs in these patients is scarce, as are studies of pharmacokinetics in patients with advanced liver impairment. Furthermore, restoring adequate immune constitution seems not to slow the progression of liver disease, and the metabolic and hepatic toxicity of some antiretroviral drugs can even contribute to inflammatory and fibrogenic processes. It is therefore essential that HIV/HCV co-infected patients receive only medications capable of ensuring the best immune recovery but possessing the lowest potential to trigger immune reconstitution syndrome or hepatic and metabolic damage

Bone metastases and immunotherapy in patients with advanced non-small-cell lung cancer

Background Bone metastases (BoM) are a negative prognostic factor in non-small-cell lung cancer (NSCLC). Beyond its supportive role, bone is a hematopoietic organ actively regulating immune system. We hypothesized that BoM may influence sensitivity to immunotherapy. Methods Pretreated non-squamous (cohort A) and squamous (cohort B) NSCLCs included in the Italian Expanded Access Program were evaluated for nivolumab efficacy according to BoM. Results Cohort A accounted for 1588 patients with non-squamous NSCLC, including 626 (39%) with (BoM+) and 962 (61%) without BoM (BoM-). Cohort B accounted for 371 patients with squamous histology including 120 BoM+ (32%) and 251 (68%) BoM- cases. BoM+ had lower overall response rate (ORR; Cohort A: 12% versus 23%, p < 0.0001; Cohort B: 13% versus 22%, p = 0.04), shorter progression free survival (PFS; Cohort A: 3.0 versus 4.0 months, p < 0.0001; Cohort B: 2.7 versus 5.2 months, p < 0.0001) and overall survival (OS; Cohort A: 7.4 versus 15.3 months, p < 0.0001; Cohort B: 5.0 versus 10.9 months, p < 0.0001). Moreover, BoM negatively affected outcome irrespective of performance status (PS; OS in both cohorts: p < 0.0001) and liver metastases (OS cohort A: p < 0.0001; OS Cohort B: p = 0.48). At multivariate analysis, BoM independently associated with higher risk of death (cohort A: HR 1.50; cohort B: HR 1.78). Conclusions BoM impairs immunotherapy efficacy. Accurate bone staging should be included in clinical trials with immunotherapy

Early Prediction of Response to Tyrosine Kinase Inhibitors by Quantification of EGFR Mutations in Plasma of NSCLC Patients.

IntroductionThe potential to accurately quantify epidermal growth factor receptor (EGFR) mutations in plasma from non–small-cell lung cancer patients would enable more rapid and more frequent analyses to assess disease status; however, the utility of such analyses for clinical purposes has only recently started to explore.MethodsPlasma samples were obtained from 69 patients with EGFR-mutated tumors and 21 negative control cases. EGFR mutations in plasma were analyzed by a standardized allele-specific polymerase chain reaction (PCR) test and ultra-deep next-generation sequencing (NGS). A semiquantitative index (SQI) was derived from dilutions of known EGFR mutation copy numbers. Clinical responses were evaluated by Response Evaluation Criteria in Solid Tumors 1.1 criteria and expressed as percent tumor shrinkage.ResultsThe sensitivity and specificity of the PCR test and NGS assay in plasma versus tissue were 72% versus 100% and 74% versus 100%, respectively. Quantitative indices by the PCR test and NGS were significantly correlated (p < 0.001). EGFR testing at baseline and serially at 4 to 60 days during tyrosine kinase inhibitor therapy revealed a progressive decrease in SQI, starting from day 4, in 95% of cases. The rate of SQI decrease correlated with percent tumor shrinkage at 2 months (p < 0.0001); at 14 days, it was more than 50% in 70% of patients (rapid responders). In two patients with slow response, an early increase in the circulating levels of the T790M mutation was observed. No early T790M mutations were seen in plasma samples of rapid responders.ConclusionsQuantification of EGFR mutations from plasma with a standardized PCR test is feasible. To our knowledge, this is the first study showing a strong correlation between the EGFR SQI in the first days of treatment and clinical response with relevant implications for patient management

Characterization of PM10 sources in the central Mediterranean

The Mediterranean Basin atmosphere is influenced by both strong natural and anthropogenic aerosol emissions and is also subject to important climatic forcings. Several programs have addressed the study of the Mediterranean basin; nevertheless important pieces of information are still missing. In this framework, PM10 samples were collected on a daily basis on the island of Lampedusa (35.5° N, 12.6° E; 45 m a.s.l.), which is far from continental pollution sources (the nearest coast, in Tunisia, is more than 100 km away). After mass gravimetric measurements, different portions of the samples were analyzed to determine the ionic content by ion chromatography (IC), the soluble metals by inductively coupled plasma atomic emission spectrometry (ICP-AES), and the total (soluble + insoluble) elemental composition by particle-induced x-ray emission (PIXE). Data from 2007 and 2008 are used in this study. The Positive Matrix Factorization (PMF) model was applied to the 2-year long data set of PM10 mass concentration and chemical composition to assess the aerosol sources affecting the central Mediterranean basin. Seven sources were resolved: sea salt, mineral dust, biogenic emissions, primary particulate ship emissions, secondary sulfate, secondary nitrate, and combustion emissions. Source contributions to the total PM10 mass were estimated to be about 40 % for sea salt, around 25 % for mineral dust, 10 % each for secondary nitrate and secondary sulfate, and 5 % each for primary particulate ship emissions, biogenic emissions, and combustion emissions. Large variations in absolute and relative contributions are found and appear to depend on the season and on transport episodes. In addition, the secondary sulfate due to ship emissions was estimated and found to contribute by about one-third to the total sulfate mass. Results for the sea-salt and mineral dust sources were compared with estimates of the same contributions obtained from independent approaches, leading to an estimate of the water content bound to the sea salt in the marine source

Resumption of Immune Checkpoint Inhibitor Therapy After Immune-Mediated Colitis

PURPOSE: Immune checkpoint inhibitor (ICI) therapy often is suspended because of immune-mediated diarrhea and colitis (IMDC). We examined the rate of and risk factors for IMDC recurrence after ICI resumption. METHODS: This retrospective multicenter study examined patients who resumed ICI therapy after improvement of IMDC between January 2010 and November 2018. Univariable and multivariable logistic regression analyses assessed the association of clinical covariates and IMDC recurrence. RESULTS: Of the 167 patients in our analysis, 32 resumed an anti–cytotoxic T-cell lymphocyte-4 (CTLA-4) agent, and 135 an anti–programmed cell death 1 or ligand 1 (PD-1/L1) agent. The median age was 60 years (interquartile range [IQR], 50-69 years). The median duration from IMDC to restart of ICI treatment was 49 days (IQR, 23-136 days). IMDC recurred in 57 patients (34%) overall (44% of those receiving an anti–CTLA-4 and 32% of those receiving an anti–PD-1/L1); 47 of these patients (82%) required immunosuppressive therapy for recurrent IMDC, and all required permanent discontinuation of ICI therapy. The median duration from ICI resumption to IMDC recurrence was 53 days (IQR, 22-138 days). On multivariable logistic regression, patients who received anti–PD-1/L1 therapy at initial IMDC had a higher risk of IMDC recurrence (odds ratio [OR], 3.45; 95% CI, 1.59 to 7.69; P = .002). Risk of IMDC recurrence was higher for patients who required immunosuppression for initial IMDC (OR, 3.22; 95% CI, 1.08 to 9.62; P = .019) or had a longer duration of IMDC symptoms in the initial episode (OR, 1.01; 95% CI, 1.00 to 1.03; P = .031). Risk of IMDC recurrence was lower after resumption of anti–PD-1/L1 therapy than after resumption of anti–CTLA-4 therapy (OR, 0.30; 95% CI, 0.11 to 0.81; P = .019). CONCLUSION: One third of patients who resumed ICI treatment after IMDC experienced recurrent IMDC. Recurrence of IMDC was less frequent after resumption of anti–PD-1/L1 than after resumption of anti–CTLA-