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Background Epidermal growth factor receptor tyrosine kinase inhibitors (TKIs) administered concurrently with chemotherapy did not improve outcome in non-small-cell lung cancer (NSCLC). However, in preclinical models and early phase noncomparative studies, pharmacodynamic separation of chemotherapy and TKIs did show a synergistic effect. Patients and methods A randomized phase II study was carried out in patients with advanced NSCLC who had progressed on or following first-line chemotherapy. Erlotinib 150 mg daily (monotherapy) or erlotinib 150 mg during 15 days intercalated with four 21-day cycles docetaxel for squamous (SQ) or pemetrexed for nonsquamous (NSQ) patients was administered (combination therapy). After completion of chemotherapy, erlotinib was continued daily. Primary end point was progression-free survival (PFS). Results Two hundred and thirty-one patients were randomized, 115 in the monotherapy arm and 116 in the combination arm. The adjusted hazard ratio for PFS was 0.76 [95% confidence interval (CI) 0.58–1.02; P = 0.06], for overall survival (OS) 0.67 (95% CI 0.49–0.91; P = 0.01) favoring the combination arm. This improvement was primarily observed in NSQ subgroup. Common Toxicity Criteria grade 3+ toxic effect occurred in 20% versus 56%, rash in 7% versus 15% and febrile neutropenia in 0% versus 6% in monotherapy and combination therapy, respectively. Conclusions PFS was not significantly different between the arms. OS was significantly improved in the combination arm, an effect restricted to NSQ histology. Study Registration number NCT00835471. [ABSTRACT FROM PUBLISHER]

Background: Translating results from randomized clinical trials (RCTs) to individual patients in clinical practice is challenging, as treatment effects can vary substantially among individuals. Data from RCTs can be used for individualized treatment effect prediction, to identify patients who benefit from specific treatments. In this study, we developed and validated a prediction model for estimating absolute treatment effect of pemetrexed plus carboplatin versus single-agent pemetrexed in the second-line treatment of non-squamous non-small-cell lung cancer (NSCLC). Patients and methods: Using data of relapsed patients with advanced non-squamous NSCLC from the NVALT-7 trial, a Weibull model for prediction of gain in median progression-free survival (PFS) by pemetrexed-carboplatin was derived based on patient and tumor characteristics. The model was externally validated in the GOIRC 02-2006 trial. The applicability of the model for guiding clinical decision-making was evaluated using decision curve analysis. Results: A wide distribution of predicted gain in median PFS by pemetrexed-carboplatin over pemetrexed was found, with a median of 0.7 months (interquartile range: -0.1 to 1.5 months). Patients who benefited most included women, those with stage IV, high body mass index and/or adenocarcinoma. External validation showed satisfactory calibration and moderate discrimination (C-index: 0.61, 95% confidence interval 0.56-0.67). Decision curve analysis confirmed that the model adequately identified patients who benefit from pemetrexed-carboplatin, as prediction-based treatment led to improvement in net benefit with regard to PFS and overall survival when assuming a treatment threshold of 0-5 months gain in PFS, compared with other treatment strategies. Conclusions: The effects of pemetrexed-carboplatin can be predicted for individual patients based on routinely available patient and tumor characteristics. There is important heterogeneity in the effects on PFS of pemetrexed-carboplatin versus pemetrexed in pretreated patients with advanced non-squamous NSCLC. Individualized prediction of treatment effect could be used to guide shared decision-making by discriminating patients who benefit most, to improve clinical outcome. [ABSTRACT FROM AUTHOR]

Background: Peritoneal mesothelioma (PeM) is a rare malignancy with a poor prognosis. Currently there is a lack of effective systemic therapies. Due to the rarity of PeM, it is challenging to study new treatment options. Off-label use of targeted drugs could be an effective approach. This scoping review aims to explore the genomic landscape of PeM to identify potential therapeutic targets., Materials and Methods: A systematic literature search of Embase, Medline, Web of Science, the Cochrane Library, and Google Scholar was carried out up to 1 November 2022. Studies that reported on molecular alterations in PeM detected by high-throughput sequencing techniques were included. Genes that were altered in ≥1% of PeMs were selected for the identification of potential targeted therapies., Results: Thirteen articles were included, comprising 824 PeM patients. In total, 142 genes were altered in ≥1% of patients, of which 7 genes were altered in ≥10%. BAP1 was the most commonly altered gene (50%). Other commonly altered genes were NF2 (25%), CDKN2A (23%), CDKN2B (17%), PBRM1 (15%), TP53 (14%), and SETD2 (13%). In total, 17% of PeM patients were carriers of a germline mutation, mainly in BAP1 (7%)., Conclusions: This scoping review provides an overview of the mutational landscape of PeM. Germline mutations might be a larger contributor to the incidence of PeM than previously thought. Currently available targeted therapy options are limited, but several targeted agents [such as poly (ADP-ribose) polymerase (PARP), enhancer of zeste homolog 2 (EZH2), and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors] were identified that might provide new targeted therapy options in the future., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The data described was acquired as part of a clinical study with the aim to investigate the potential of tumor-reactive T-cell response as response to vaccination of pancreatic cancer patients with an allogenic tumor cell lysate vaccine (Lau et al., 2022). Proteomics analysis was carried out to identify tumor antigens that are shared between the allogeneic tumor cell lysate used for the vaccine and pancreatic ductal adenocarcinoma (PDAC) tissue samples. To this objective, cell lysates of the vaccine and of nine tissue samples were enzymatically digested and isotopically labeled with tandem mass tags (TMT) in a so-called six-plex manner (Thermo Fisher Scientific). Three pools were prepared by mixing the samples according to their TMT-labels. Subsequently, the three sample pools were fractionated into 24 fractions with high-pH reversed phase chromatography. These fractions were first analyzed on a nano-liquid chromatography (LC) system online coupled to a high-resolution Eclipse Orbitrap mass spectrometer (MS) equipped with a high-field asymmetric-waveform ion-mobility spectrometry (FAIMS) source using a data-dependent MS2 shotgun method. Overall, 126,618 unique peptide sequences, on basis of 768,638 peptide spectra matches and corresponding to 7,597 protein groups, were identified in the total sample set including 61 tumor antigens (Supplement Table S2 in Lau et al. 2022) that were prioritized by Cheever and co-workers as vaccine target antigens on basis of a series of objective criteria (Cheever et al., 2009). In the second phase of the experiment, this set of tumor antigens was targeted using a serial precursor selection (SPS) MS3 method. From this data, ion trap MS2 and Orbitrap MS3 fragment spectra were extracted for peptide identification (protein sequence database-dependent search) and relative quantification using the TMT labels, respectively. The dataset ultimately allowed the identification and quantification of 51 proteins and 163 related peptide precursors with the TMT labels (see Fig. 2B and Supplemental Fig. 8, Lau et al. 2022)., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Please declare any financial interests/personal relationships which may be considered as potential competing interests here: J.G.A: Stock or other Ownership: Amphera. Consulting or Advisory Role: Eli-Lilly, MSD Oncology, Bristol-Myers Squibb, Roche, AstraZeneca. Rest of the authors have no relationship to disclose in relation to the submitted work., (© 2022 Published by Elsevier Inc.)

Background: To stratify the prognosis of patients with programmed cell death-ligand 1 (PD-L1) ≥ 50% advanced non-small-cell lung cancer (aNSCLC) treated with first-line immunotherapy., Methods: Baseline clinical prognostic factors, the neutrophil-to-lymphocyte ratio (NLR), PD-L1 tumour cell expression level, lactate dehydrogenase (LDH) and their combination were investigated by a retrospective analysis of 784 patients divided between statistically powered training (n = 201) and validation (n = 583) cohorts. Cut-offs were explored by receiver operating characteristic (ROC) curves and a risk model built with validated independent factors by multivariate analysis., Results: NLR < 4 was a significant prognostic factor in both cohorts (P < 0.001). It represented 53% of patients in the validation cohort, with 1-year overall survival (OS) of 76.6% versus 44.8% with NLR > 4, in the validation series. The addition of PD-L1 ≥ 80% (21% of patients) or LDH < 252 U/l (25%) to NLR < 4 did not result in better 1-year OS (of 72.6% and 74.1%, respectively, in the validation cohort). Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2 [P < 0.001, hazard ratio (HR) 2.04], pretreatment steroids (P < 0.001, HR 1.67) and NLR < 4 (P < 0.001, HR 2.29) resulted in independent prognostic factors. A risk model with these three factors, namely, the lung immuno-oncology prognostic score (LIPS)-3, accurately stratified three OS risk-validated categories of patients: favourable (0 risk factors, 40%, 1-year OS of 78.2% in the whole series), intermediate (1 or 2 risk factors, 54%, 1-year OS 53.8%) and poor (>2 risk factors, 5%, 1-year OS 10.7%) prognosis., Conclusions: We advocate the use of LIPS-3 as an easy-to-assess and inexpensive adjuvant prognostic tool for patients with PD-L1 ≥ 50% aNSCLC., Competing Interests: Disclosure AC received speaker fees and grant consultancies from AstraZeneca, MSD, BMS, Roche, Novartis and Astellas. EB received speaker and travel fees from MSD, Astra-Zeneca, Pfizer, Helsinn, Eli-Lilly, BMS, Novartis and Roche; received grant consultancies from Roche and Pfizer. MT received speaker fees and grant consultancies from AstraZeneca, Pfizer, Eli-Lilly, BMS, Novartis, Roche, MSD, Boehringer Ingelheim, Otsuka, Takeda and Pierre Fabre. AM received speaker fees from Astra, Roche, BMS, MSD, Boehringer, Pfizer and Takeda. FM received grant consultancies from MSD and Takeda. RG received speaker fees and grant consultancies from AstraZeneca and Roche. AF received grant consultancies from Roche, Pfizer, Astellas and BMS. AA received grant consultancies from Takeda, MSD, BMJ, AstraZeneca, Roche and Pfizer. RC received speaker fees from BMS, MSD, Takeda, Pfizer, Roche and AstraZeneca. CG received speaker fees/grant consultancies from Astra Zeneca, BMS and Boehringer-Ingelheim. GLB personal fees from Janssen Cilag, Boehringer Ingelheim, AstraZeneca and Roche, outside the submitted work. All other authors have declared no conflicts of interest. Data sharing The datasets used during this study are available from the corresponding author upon reasonable request., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: An increase in detection of early-stage asymptomatic lung tumors could increase the overall survival rate of lung cancer patients. A new approach to cancer (pre-)screening focusses on detecting field cancerization instead of the tumor itself. The objective of this study was to investigate the use of optical spectroscopy to detect field cancerization in the buccal mucosa of lung cancer patients., Methods: Optical buccal mucosa measurements were performed in lung cancer patients and controls using multidiameter single-fiber reflectance spectroscopy. We analyzed whether the measured optical parameters could distinguish lung cancer patients from controls., Results: Twenty-three lung cancer patients, 24 chronic obstructive pulmonary disease (COPD) control patients, and 36 non-COPD controls were included. The majority of tumors were non-small-cell lung carcinomas (96%) and classified as stage I (48%). The tissue scattering properties μ s ' and γ at 800 nm and the tissue bilirubin concentration were all near-significantly different (P=.072, 0.058, and 0.060, respectively) between the lung cancer and COPD group. μ s ' at 800 nm had a sensitivity of 74% and a specificity of 63%. The microvascular blood oxygen saturation of the lung cancer patients was also higher than the COPD patients (78% vs. 62%, P=.002), this is probably a consequence of the systemic effect of COPD., Conclusions: We have demonstrated that μ s ' at 800 nm is increased in the buccal mucosa of patients with lung cancer compared to controls with COPD. This might be an indication of field cancerization in the oral cavity of patients with lung cancer., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

A clinicoradiological presentation of thoracic sarcoidosis requires histopathology in order to establish the diagnosis. Flexible bronchoscopy has a reasonable diagnostic yield and is the procedure of first choice for diagnosis. Endoscopic ultrasound (endoscopic ultrasound-guided fine needle aspiration/endobronchial ultrasound-guided transbronchial needle aspiration) can help in the diagnosis of sarcoidosis. An implementation strategy of endoscopic ultrasound for the diagnosis of sarcoidosis following negative flexible bronchoscopy results was examined prospectively in 15 clinics. A total of 137 patients (92 males; median age 43 yrs) were included, and sarcoidosis was found in 115 (84%). Alternative diagnoses were tuberculosis, lymphangitis carcinomatosa, pneumoconiosis and alveolitis. All patients were sent for flexible bronchoscopy, which was performed in 121 (88%), resulting in a definite diagnosis in 57 (42%). A total of 80 patients were sent for endoscopic ultrasound, which could be performed in 72 (90%), yielding a definite diagnosis in 47 (59%). Endoscopic ultrasound following negative flexible bronchoscopy avoided a surgical procedure in 47 out of 80 patients. The sensitivity of flexible bronchoscopy for sarcoidosis was 45% (95% confidence interval 35-54%), but 62% (50-72%) if biopsy specimens were taken. The sensitivity of endoscopic ultrasound following negative flexible bronchoscopy results was 71% (58-82%). With this strategy, 97 out of 115 (84% (76-90%)) of proven sarcoidosis was diagnosed using endoscopy. This large prospective implementation study (trial number NCT00888212; ClinicalTrials.gov) shows that endoscopic ultrasound is valuable for diagnosing sarcoidosis after negative flexible bronchoscopy results.

Introduction: The objectives of this trial were to evaluate the activity and safety of gemcitabine carboplatin as induction therapy in patients with locally advanced non-small cell lung cancer, Methods: Patients received two cycles of gemcitabine (1250 mg/m on day 1 and 8), plus carboplatin (area under the curve = 5 on day 1), after which response was established. Patients received a third course only in the case of an objective response (OR). Non-responding patients were directly irradiated. Toxicity was assessed according to the NCI-CTC version 2, radiation toxicity was assessed according to RTOG criteria. Response evaluation was performed according to RECIST criteria., Results: We identified 42 patients, of whom 37 were eligible. Of these, 51% (95% CI, 34%-68%) achieved an OR, all partial responses. No disease progression on therapy was established. Toxicity was mostly hematological: 35% trombocytopenia grade 3 and 4, and 40% neutropenia grade 3 and 4. No severe bleeding or hospitalization because of febrile neutropenia occurred., Conclusions: Gemcitabine and carboplatin administered according to a 3-week schedule is an active and safe induction regimen. Pending the results of a phase III study, we believe that it is a reasonable alternative among patients for whom cisplatin-based chemotherapy is contraindicated.

In patients with severe chronic obstructive pulmonary disease (COPD), lung emptying may be affected by flow limitation. We tested the hypothesis that the airway compression leading to flow limitation can be counteracted by controlling the expiratory flow. The effects of an external resistor on lung emptying were studied in six patients with COPD, who were mechanically ventilated whilst sedated and paralysed. Respiratory mechanics were obtained during ventilatory support with and without the resistor. Airway compression was assessed using the interruptor method. For the study, a turbulent resistor was applied with the highest resistance level that did not increase the end-expiratory lung volume. At this resistance level, external positive end-expiratory pressure (PEEP) was generated in all patients. As total PEEP levels remained unchanged at both settings during the controlled expiration, the levels of intrinsic PEEP were significantly decreased from 0.96+/-0.30 to 0.53+/-0.19 kPa (mean+/-SD). Comparison of the expiratory flow-volume curves at both settings revealed that, during the controlled expiration, the flows were significantly decreased during the first 40% of the expired volume and significantly increased during the last 60%. As the end-expiratory lung volumes remained unchanged during both settings, these increments in flow indicated a decrease in effective resistance. Airway compression was observed during unimpeded expirations in all patients using the interruptor method. During the application of the resistor, airway compression was no longer detectable. In patients with chronic obstructive pulmonary disease receiving ventilatory support, the application of an external resistor could decrease effective expiratory resistance by counteracting airway compression, without increments in end-expiratory lung volume.

In patients with airflow obstruction, flow limitation can be established in various ways. Using body plethysmography, flow limitation is assumed when expiratory flow decreases whilst alveolar pressure increases at the same time. During forced expiration, flow limitation can be established by means of the flow interruptor technique; flow limitation is assumed when, after release of an occlusion, a spike flow superimposed on the ongoing alveolar flow (delta peak flow) is detected. In this study, the flow interruptor technique was applied to detect flow limitation during tidal breathing. The results were compared to those obtained with the body plethysmograph. The expiratory flow pattern, post-interruption, was analysed in 33 subjects; 11 patients with airflow obstruction and flow limitation established with the body plethysmograph (AO+); 11 patients with airflow obstruction without flow limitation (AO-); and 11 healthy volunteers. Mean spike areas were 27.6 +/- 18.3, 4.6 +/- 2.3 and 3.4 +/- 2.0 mL for the AO+, AO- and control group, respectively, showing a highly significant difference between the AO+ patients and the other groups. Also, significantly higher delta peak flows were found in the AO+ patients compared to the other groups. No differences in delta peak flows or spike areas could be established between patients without flow limitation and controls. We conclude that the interruptor technique may be a useful means of assessing flow limitation during tidal breathing.

Methacholine provocation tests are aimed at determining bronchial responsiveness. Recent investigations stress the importance of considering the entire log-dose response curve, yielding not only the provocative dose producing a 20% change in forced expiratory volume in one second (FEV1) (PC20), but also the plateau value and the steepest slope of the curve (reactivity). In three control subjects and seven patients with mild to moderate asthma, we have obtained methacholine log-dose response curves in which a plateau was reached. A new model, the Cumulative Gaussian Distribution (CGD) function was fitted to the whole curve. The upper part of the curve was also analysed with the Hofstee equation, which has been used in a number of other investigations and aimed at plateau estimation. The plateau values obtained by the fits were compared with the values actually measured (average response of last 3 points with a variation coefficient < 5% of the mean value) by using the coefficient of determination (R2) (Applied Statistics. Sachs). If all data points were considered, both fits yielded a plateau which slightly overestimated the measured plateau values. R2 for the CGD fit ranged from 0.93-0.99, indicating a highly significant correlation between actual and fitted data points. If the curves were truncated, such that the last four provocative doses were omitted from the analysis, the CGD fit still yielded plateau values; the mean difference from the measured plateaux, in % of the measured plateau values, was -2.6% (SD 18.2). In only three out of the 10 cases did the Hofstee equation yield plateau values with a deviation from 'measured' < 47% of the measured value.(ABSTRACT TRUNCATED AT 250 WORDS)