Overall Survival with Osimertinib in Resected EGFR-Mutated NSCLC.

BACKGROUND: Among patients with resected, epidermal growth factor receptor (EGFR)-mutated, stage IB to IIIA non-small-cell lung cancer (NSCLC), adjuvant osimertinib therapy, with or without previous adjuvant chemotherapy, resulted in significantly longer disease-free survival than placebo in the ADAURA trial. We report the results of the planned final analysis of overall survival. METHODS: In this phase 3, double-blind trial, we randomly assigned eligible patients in a 1:1 ratio to receive osimertinib (80 mg once daily) or placebo until disease recurrence was observed, the trial regimen was completed (3 years), or a discontinuation criterion was met. The primary end point was investigator-assessed disease-free survival among patients with stage II to IIIA disease. Secondary end points included disease-free survival among patients with stage IB to IIIA disease, overall survival, and safety. RESULTS: Of 682 patients who underwent randomization, 339 received osimertinib and 343 received placebo. Among patients with stage II to IIIA disease, the 5-year overall survival was 85% in the osimertinib group and 73% in the placebo group (overall hazard ratio for death, 0.49; 95.03% confidence interval [CI], 0.33 to 0.73; P<0.001). In the overall population (patients with stage IB to IIIA disease), the 5-year overall survival was 88% in the osimertinib group and 78% in the placebo group (overall hazard ratio for death, 0.49; 95.03% CI, 0.34 to 0.70; P<0.001). One new serious adverse event, pneumonia related to coronavirus disease 2019, was reported after the previously published data-cutoff date (the event was not considered by the investigator to be related to the trial regimen, and the patient fully recovered). Adjuvant osimertinib had a safety profile consistent with that in the primary analysis. CONCLUSIONS: Adjuvant osimertinib provided a significant overall survival benefit among patients with completely resected, EGFR-mutated, stage IB to IIIA NSCLC. (Funded by AstraZeneca; ADAURA ClinicalTrials.gov number, NCT02511106.).

First-line atezolizumab monotherapy versus single-agent chemotherapy in patients with non-small-cell lung cancer ineligible for treatment with a platinum-containing regimen (IPSOS): a phase 3, global, multicentre, open-label, randomised controlled study.

BACKGROUND: Despite immunotherapy advancements for patients with advanced or metastatic non-small-cell lung cancer (NSCLC), pivotal first-line trials were limited to patients with an Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 and a median age of 65 years or younger. We aimed to compare the efficacy and safety of first-line atezolizumab monotherapy with single-agent chemotherapy in patients ineligible for platinum-based chemotherapy. METHODS: This trial was a phase 3, open-label, randomised controlled study conducted at 91 sites in 23 countries across Asia, Europe, North America, and South America. Eligible patients had stage IIIB or IV NSCLC in whom platinum-doublet chemotherapy was deemed unsuitable by the investigator due to an ECOG PS 2 or 3, or alternatively, being 70 years or older with an ECOG PS 0-1 with substantial comorbidities or contraindications for platinum-doublet chemotherapy. Patients were randomised 2:1 by permuted-block randomisation (block size of six) to receive 1200 mg of atezolizumab given intravenously every 3 weeks or single-agent chemotherapy (vinorelbine [oral or intravenous] or gemcitabine [intravenous]; dosing per local label) at 3-weekly or 4-weekly cycles. The primary endpoint was overall survival assessed in the intention-to-treat population. Safety analyses were conducted in the safety-evaluable population, which included all randomised patients who received any amount of atezolizumab or chemotherapy. This trial is registered with ClinicalTrials.gov, NCT03191786. FINDINGS: Between Sept 11, 2017, and Sept 23, 2019, 453 patients were enrolled and randomised to receive atezolizumab (n=302) or chemotherapy (n=151). Atezolizumab improved overall survival compared with chemotherapy (median overall survival 10·3 months [95% CI 9·4-11·9] vs 9·2 months [5·9-11·2]; stratified hazard ratio 0·78 [0·63-0·97], p=0·028), with a 2-year survival rate of 24% (95% CI 19·3-29·4) with atezolizumab compared with 12% (6·7-18·0) with chemotherapy. Compared with chemotherapy, atezolizumab was associated with stabilisation or improvement of patient-reported health-related quality-of-life functioning scales and symptoms and fewer grade 3-4 treatment-related adverse events (49 [16%] of 300 vs 49 [33%] of 147) and treatment-related deaths (three [1%] vs four [3%]). INTERPRETATION: First-line treatment with atezolizumab monotherapy was associated with improved overall survival, a doubling of the 2-year survival rate, maintenance of quality of life, and a favourable safety profile compared with single-agent chemotherapy. These data support atezolizumab monotherapy as a potential first-line treatment option for patients with advanced NSCLC who are ineligible for platinum-based chemotherapy. FUNDING: F Hoffmann-La Roche and Genentech Inc, a member of the Roche group.

Treatment outcomes of patients with primary tracheal tumors - analysis of a large retrospective series.

OBJECTIVE: Primary tracheal tumors are very rare and their management is not definitely established. Due to its rarity, providing patient care in terms of optimal management poses a considerable challenge. The purpose of this study was to investigate treatment outcomes in patients with these rare tumors. METHODS: We carried out a retrospective analysis of 89 patients with primary tracheal tumors treated at the Maria Sklodowska-Curie National Research Institute of Oncology in Warsaw, Poland, over sixteen years. The study assessed patient demographics, tumor characteristics and treatment. Different treatment options were compared in terms of overall survival, disease-free survival, and progression-free survival. RESULTS: A total of 89 patients were included in the study. In the group presented, 45 patients underwent primary radical treatment and 44 were qualified for palliative treatment. Surgical resection was performed in 13 patients out of radically treated patients. The 5 year OS rates in the group of patients who underwent radical treatment and in the group of patients who underwent palliative treatment were 45.9% and 2.3%, respectively. In the group of patients who underwent radical surgical treatment, the 5 year OS was 76.9% compared to 35.8% in the group of patients who underwent nonsurgical treatment. CONCLUSION: A multidisciplinary team should decide treatment options, including in-depth consideration of surgical treatment options.

Tepotinib in Non-Small-Cell Lung Cancer with MET Exon 14 Skipping Mutations.

BACKGROUND: A splice-site mutation that results in a loss of transcription of exon 14 in the oncogenic driver MET occurs in 3 to 4% of patients with non-small-cell lung cancer (NSCLC). We evaluated the efficacy and safety of tepotinib, a highly selective MET inhibitor, in this patient population. METHODS: In this open-label, phase 2 study, we administered tepotinib (at a dose of 500 mg) once daily in patients with advanced or metastatic NSCLC with a confirmed MET exon 14 skipping mutation. The primary end point was the objective response by independent review among patients who had undergone at least 9 months of follow-up. The response was also analyzed according to whether the presence of a MET exon 14 skipping mutation was detected on liquid biopsy or tissue biopsy. RESULTS: As of January 1, 2020, a total of 152 patients had received tepotinib, and 99 patients had been followed for at least 9 months. The response rate by independent review was 46% (95% confidence interval [CI], 36 to 57), with a median duration of response of 11.1 months (95% CI, 7.2 to could not be estimated) in the combined-biopsy group. The response rate was 48% (95% CI, 36 to 61) among 66 patients in the liquid-biopsy group and 50% (95% CI, 37 to 63) among 60 patients in the tissue-biopsy group; 27 patients had positive results according to both methods. The investigator-assessed response rate was 56% (95% CI, 45 to 66) and was similar regardless of the previous therapy received for advanced or metastatic disease. Adverse events of grade 3 or higher that were considered by investigators to be related to tepotinib therapy were reported in 28% of the patients, including peripheral edema in 7%. Adverse events led to permanent discontinuation of tepotinib in 11% of the patients. A molecular response, as measured in circulating free DNA, was observed in 67% of the patients with matched liquid-biopsy samples at baseline and during treatment. CONCLUSIONS: Among patients with advanced NSCLC with a confirmed MET exon 14 skipping mutation, the use of tepotinib was associated with a partial response in approximately half the patients. Peripheral edema was the main toxic effect of grade 3 or higher. (Funded by Merck [Darmstadt, Germany]; VISION ClinicalTrials.gov number, NCT02864992.).

First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): a multicentre, randomised, open-label, phase 3 trial.

BACKGROUND: Approved systemic treatments for malignant pleural mesothelioma (MPM) have been limited to chemotherapy regimens that have moderate survival benefit with poor outcomes. Nivolumab plus ipilimumab has shown clinical benefit in other tumour types, including first-line non-small-cell lung cancer. We hypothesised that this regimen would improve overall survival in MPM. METHODS: This open-label, randomised, phase 3 study (CheckMate 743) was run at 103 hospitals across 21 countries. Eligible individuals were aged 18 years and older, with previously untreated, histologically confirmed unresectable MPM, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible participants were randomly assigned (1:1) to nivolumab (3 mg/kg intravenously once every 2 weeks) plus ipilimumab (1 mg/kg intravenously once every 6 weeks) for up to 2 years, or platinum plus pemetrexed chemotherapy (pemetrexed [500 mg/m2 intravenously] plus cisplatin [75 mg/m2 intravenously] or carboplatin [area under the concentration-time curve 5 mg/mL per min intravenously]) once every 3 weeks for up to six cycles. The primary endpoint was overall survival among all participants randomly assigned to treatment, and safety was assessed in all participants who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT02899299, and is closed to accrual. FINDINGS: Between Nov 29, 2016, and April 28, 2018, 713 patients were enrolled, of whom 605 were randomly assigned to either nivolumab plus ipilimumab (n=303) or chemotherapy (n=302). 467 (77%) of 605 participants were male and median age was 69 years (IQR 64-75). At the prespecified interim analysis (database lock April 3, 2020; median follow-up of 29·7 months [IQR 26·7-32·9]), nivolumab plus ipilimumab significantly extended overall survival versus chemotherapy (median overall survival 18·1 months [95% CI 16·8-21·4] vs 14·1 months [12·4-16·2]; hazard ratio 0·74 [96·6% CI 0·60-0·91]; p=0·0020). 2-year overall survival rates were 41% (95% CI 35·1-46·5) in the nivolumab plus ipilimumab group and 27% (21·9-32·4) in the chemotherapy group. Grade 3-4 treatment-related adverse events were reported in 91 (30%) of 300 patients treated with nivolumab plus ipilimumab and 91 (32%) of 284 treated with chemotherapy. Three (1%) treatment-related deaths occurred in the nivolumab plus ipilimumab group (pneumonitis, encephalitis, and heart failure) and one (<1%) in the chemotherapy group (myelosuppression). INTERPRETATION: Nivolumab plus ipilimumab provided significant and clinically meaningful improvements in overall survival versus standard-of-care chemotherapy, supporting the use of this first-in-class regimen that has been approved in the USA as of October, 2020, for previously untreated unresectable MPM. FUNDING: Bristol Myers Squibb.

The structure of the genetic code as an optimal graph clustering problem.

The standard genetic code (SGC) is the set of rules by which genetic information is translated into proteins, from codons, i.e. triplets of nucleotides, to amino acids. The questions about the origin and the main factor responsible for the present structure of the code are still under a hot debate. Various methodologies have been used to study the features of the code and assess the level of its potential optimality. Here, we introduced a new general approach to evaluate the quality of the genetic code structure. This methodology comes from graph theory and allows us to describe new properties of the genetic code in terms of conductance. This parameter measures the robustness of codon groups against the potential changes in translation of the protein-coding sequences generated by single nucleotide substitutions. We described the genetic code as a partition of an undirected and unweighted graph, which makes the model general and universal. Using this approach, we showed that the structure of the genetic code is a solution to the graph clustering problem. We presented and discussed the structure of the codes that are optimal according to the conductance. Despite the fact that the standard genetic code is far from being optimal according to the conductance, its structure is characterised by many codon groups reaching the minimum conductance for their size. The SGC represents most likely a local minimum in terms of errors occurring in protein-coding sequences and their translation.

Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer.

BACKGROUND: Standard first-line therapy for metastatic, squamous non-small-cell lung cancer (NSCLC) is platinum-based chemotherapy or pembrolizumab (for patients with programmed death ligand 1 [PD-L1] expression on ≥50% of tumor cells). More recently, pembrolizumab plus chemotherapy was shown to significantly prolong overall survival among patients with nonsquamous NSCLC. METHODS: In this double-blind, phase 3 trial, we randomly assigned, in a 1:1 ratio, 559 patients with untreated metastatic, squamous NSCLC to receive 200 mg of pembrolizumab or saline placebo for up to 35 cycles; all the patients also received carboplatin and either paclitaxel or nanoparticle albumin-bound [nab]-paclitaxel for the first 4 cycles. Primary end points were overall survival and progression-free survival. RESULTS: After a median follow-up of 7.8 months, the median overall survival was 15.9 months (95% confidence interval [CI], 13.2 to not reached) in the pembrolizumab-combination group and 11.3 months (95% CI, 9.5 to 14.8) in the placebo-combination group (hazard ratio for death, 0.64; 95% CI, 0.49 to 0.85; P<0.001). The overall survival benefit was consistent regardless of the level of PD-L1 expression. The median progression-free survival was 6.4 months (95% CI, 6.2 to 8.3) in the pembrolizumab-combination group and 4.8 months (95% CI, 4.3 to 5.7) in the placebo-combination group (hazard ratio for disease progression or death, 0.56; 95% CI, 0.45 to 0.70; P<0.001). Adverse events of grade 3 or higher occurred in 69.8% of the patients in the pembrolizumab-combination group and in 68.2% of the patients in the placebo-combination group. Discontinuation of treatment because of adverse events was more frequent in the pembrolizumab-combination group than in the placebo-combination group (13.3% vs. 6.4%). CONCLUSIONS: In patients with previously untreated metastatic, squamous NSCLC, the addition of pembrolizumab to chemotherapy with carboplatin plus paclitaxel or nab-paclitaxel resulted in significantly longer overall survival and progression-free survival than chemotherapy alone. (Funded by Merck Sharp & Dohme; KEYNOTE-407 ClinicalTrials.gov number, NCT02775435 .).

Influence of pipe material on biofilm microbial communities found in drinking water supply system.

The biofilms and water samples from a model installation built of PVC-U, PE-HD and cast iron pipes were investigated using standard heterotrophic plate count and 16S rRNA Next Generation Sequencing. The results of the high throughput identification imply that the construction material strongly influences the microbiome composition. PVC-U and PE-HD pipes were dominated with Proteobacteria (54-60%) while the cast pipe was overgrown by Nitrospirae (64%). It was deduced that the plastic pipes create a more convenient environment for the potentially pathogenic taxa than the cast iron. The 7-year old biofilms were described as complex habitats with sharp oxidation-reduction gradients, where co-existence of methanogenic and methanotrophic microbiota takes place. Furthermore, it was found that the drinking water distribution systems (DWDS) are a useful tool for studying the ecology of rare bacterial phyla. New ecophysiological aspects were described for Aquihabitans, Thermogutta and Vampirovibrio. The discrepancy between identity of HPC-derived bacteria and NGS-revealed composition of biofilm and water microbiomes point to the need of introducing new diagnostical protocols to enable proper assessment of the drinking water safety, especially in DWDSs operating without disinfection.

Osimertinib plus savolitinib in patients with EGFR mutation-positive, MET-amplified, non-small-cell lung cancer after progression on EGFR tyrosine kinase inhibitors: interim results from a multicentre, open-label, phase 1b study.

BACKGROUND: Preclinical data suggest that EGFR tyrosine kinase inhibitors (TKIs) plus MET TKIs are a possible treatment for EGFR mutation-positive lung cancers with MET-driven acquired resistance. Phase 1 safety data of savolitinib (also known as AZD6094, HMPL-504, volitinib), a potent, selective MET TKI, plus osimertinib, a third-generation EGFR TKI, have provided recommended doses for study. Here, we report the assessment of osimertinib plus savolitinib in two global expansion cohorts of the TATTON study. METHODS: In this multi-arm, multicentre, open-label, phase 1b study, we enrolled adult patients (aged ≥18 years) with locally advanced or metastatic, MET-amplified, EGFR mutation-positive non-small-cell lung cancer, who had progressed on EGFR TKIs. We considered two expansion cohorts: parts B and D. Part B consisted of three cohorts of patients: those who had been previously treated with a third-generation EGFR TKI (B1) and those who had not been previously treated with a third-generation EGFR TKI who were either Thr790Met negative (B2) or Thr790Met positive (B3). In part B, patients received oral osimertinib 80 mg and savolitinib 600 mg daily; after a protocol amendment (March 12, 2018), patients who weighed no more than 55 kg received a 300 mg dose of savolitinib. Part D enrolled patients who had not previously received a third-generation EGFR TKI and were Thr790Met negative; these patients received osimertinib 80 mg plus savolitinib 300 mg. Primary endpoints were safety and tolerability, which were assessed in all dosed patients. Secondary endpoints included the proportion of patients who had an objective response per RECIST 1.1 and was assessed in all dosed patients and all patients with centrally confirmed MET amplification. Here, we present an interim analysis with data cutoff on March 29, 2019. This study is registered with ClinicalTrials.gov, NCT02143466. FINDINGS: Between May 26, 2015, and Feb 14, 2019, we enrolled 144 patients into part B and 42 patients into part D. In part B, 138 patients received osimertinib plus savolitinib 600 mg (n=130) or 300 mg (n=8). In part D, 42 patients received osimertinib plus savolitinib 300 mg. 79 (57%) of 138 patients in part B and 16 (38%) of 42 patients in part D had adverse events of grade 3 or worse. 115 (83%) patients in part B and 25 (60%) patients in part D had adverse events possibly related to savolitinib and serious adverse events were reported in 62 (45%) patients in part B and 11 (26%) patients in part D; two adverse events leading to death (acute renal failure and death, cause unknown) were possibly related to treatment in part B. Objective partial responses were observed in 66 (48%; 95% CI 39-56) patients in part B and 23 (64%; 46-79) in part D. INTERPRETATION: The combination of osimertinib and savolitinib has acceptable risk-benefit profile and encouraging antitumour activity in patients with MET-amplified, EGFR mutation-positive, advanced NSCLC, who had disease progression on a previous EGFR TKI. This combination might be a potential treatment option for patients with MET-driven resistance to EGFR TKIs. FUNDING: AstraZeneca.

Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial.

BACKGROUND: First-line pembrolizumab monotherapy improves overall and progression-free survival in patients with untreated metastatic non-small-cell lung cancer with a programmed death ligand 1 (PD-L1) tumour proportion score (TPS) of 50% or greater. We investigated overall survival after treatment with pembrolizumab monotherapy in patients with a PD-L1 TPS of 1% or greater. METHODS: This randomised, open-label, phase 3 study was done in 213 medical centres in 32 countries. Eligible patients were adults (≥18 years) with previously untreated locally advanced or metastatic non-small-cell lung cancer without a sensitising EGFR mutation or ALK translocation and with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, life expectancy 3 months or longer, and a PD-L1 TPS of 1% or greater. Randomisation was computer generated, accessed via an interactive voice-response and integrated web-response system, and stratified by region of enrolment (east Asia vs rest of world), ECOG performance status score (0 vs 1), histology (squamous vs non-squamous), and PD-L1 TPS (≥50% vs 1-49%). Enrolled patients were randomly assigned 1:1 in blocks of four per stratum to receive pembrolizumab 200 mg every 3 weeks for up to 35 cycles or the investigator's choice of platinum-based chemotherapy for four to six cycles. Primary endpoints were overall survival in patients with a TPS of 50% or greater, 20% or greater, and 1% or greater (one-sided significance thresholds, p=0·0122, p=0·0120, and p=0·0124, respectively) in the intention-to-treat population, assessed sequentially if the previous findings were significant. This study is registered at ClinicalTrials.gov, number NCT02220894. FINDINGS: From Dec 19, 2014, to March 6, 2017, 1274 patients (902 men, 372 women, median age 63 years [IQR 57-69]) with a PD-L1 TPS of 1% or greater were allocated to pembrolizumab (n=637) or chemotherapy (n=637) and included in the intention-to-treat population. 599 (47%) had a TPS of 50% or greater and 818 patients (64%) had a TPS of 20% or greater. As of Feb 26, 2018, median follow-up was 12·8 months. Overall survival was significantly longer in the pembrolizumab group than in the chemotherapy group in all three TPS populations (≥50% hazard ratio 0·69, 95% CI 0·56-0·85, p=0·0003; ≥20% 0·77, 0·64-0·92, p=0·0020, and ≥1% 0·81, 0·71-0·93, p=0·0018). The median surival values by TPS population were 20·0 months (95% CI 15·4-24·9) for pembrolizumab versus 12·2 months (10·4-14·2) for chemotherapy, 17·7 months (15·3-22·1) versus 13·0 months (11·6-15·3), and 16·7 months (13·9-19·7) versus 12·1 months (11·3-13·3), respectively. Treatment-related adverse events of grade 3 or worse occurred in 113 (18%) of 636 treated patients in the pembrolizumab group and in 252 (41%) of 615 in the chemotherapy group and led to death in 13 (2%) and 14 (2%) patients, respectively. INTERPRETATION: The benefit-to-risk profile suggests that pembrolizumab monotherapy can be extended as first-line therapy to patients with locally advanced or metastatic non-small-cell lung cancer without sensitising EGFR or ALK alterations and with low PD-L1 TPS. FUNDING: Merck Sharp & Dohme.

Population morbidity in elderly lung cancer patients from Poland with specific trends in elderly women.

INTRODUCTION: Lung cancer remains a leading cause of morbidity and mortality in Poland and globally. The objective of the study was to assess lung cancer incidence among elderly patients in Poland, including data for urban and rural populations, with trend analysis between 2008 and 2012. MATERIAL AND METHODS: Differences between lung cancer prevalence in the Polish population aged 65 years or older were assessed with respect to province, gender, and rural vs. urban areas during the 2008-2012 period. Data were extracted from the Polish National Health Authority and Statistical Bureau databases. RESULTS: Lung cancer morbidity among the elderly increased by 14.05% in urban areas but only by 4.01% in rural areas. A 22.41% overall increase was noted in the elderly female population, compared to a 7.29% increase among men aged 65 years and over. Regional differences in morbidity were observed. CONCLUSIONS: The rationale behind the differences is likely to be multi-factorial. A change in risk factor exposure in the past is probably now being reflected in lung cancer morbidity. The difference between sexes can potentially be regarded as an unfortunate side-effect of increasing female empowerment. Urban vs. rural, as well as regional, variances are probably due to a multitude of factors, including differences in socio-economic status.

Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial.

BACKGROUND: Atezolizumab is a humanised antiprogrammed death-ligand 1 (PD-L1) monoclonal antibody that inhibits PD-L1 and programmed death-1 (PD-1) and PD-L1 and B7-1 interactions, reinvigorating anticancer immunity. We assessed its efficacy and safety versus docetaxel in previously treated patients with non-small-cell lung cancer. METHODS: We did a randomised, open-label, phase 3 trial (OAK) in 194 academic or community oncology centres in 31 countries. We enrolled patients who had squamous or non-squamous non-small-cell lung cancer, were 18 years or older, had measurable disease per Response Evaluation Criteria in Solid Tumors, and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients had received one to two previous cytotoxic chemotherapy regimens (one or more platinum based combination therapies) for stage IIIB or IV non-small-cell lung cancer. Patients with a history of autoimmune disease and those who had received previous treatments with docetaxel, CD137 agonists, anti-CTLA4, or therapies targeting the PD-L1 and PD-1 pathway were excluded. Patients were randomly assigned (1:1) to intravenously receive either atezolizumab 1200 mg or docetaxel 75 mg/m2 every 3 weeks by permuted block randomisation (block size of eight) via an interactive voice or web response system. Coprimary endpoints were overall survival in the intention-to-treat (ITT) and PD-L1-expression population TC1/2/3 or IC1/2/3 (≥1% PD-L1 on tumour cells or tumour-infiltrating immune cells). The primary efficacy analysis was done in the first 850 of 1225 enrolled patients. This study is registered with ClinicalTrials.gov, number NCT02008227. FINDINGS: Between March 11, 2014, and April 29, 2015, 1225 patients were recruited. In the primary population, 425 patients were randomly assigned to receive atezolizumab and 425 patients were assigned to receive docetaxel. Overall survival was significantly longer with atezolizumab in the ITT and PD-L1-expression populations. In the ITT population, overall survival was improved with atezolizumab compared with docetaxel (median overall survival was 13·8 months [95% CI 11·8-15·7] vs 9·6 months [8·6-11·2]; hazard ratio [HR] 0·73 [95% CI 0·62-0·87], p=0·0003). Overall survival in the TC1/2/3 or IC1/2/3 population was improved with atezolizumab (n=241) compared with docetaxel (n=222; median overall survival was 15·7 months [95% CI 12·6-18·0] with atezolizumab vs 10·3 months [8·8-12·0] with docetaxel; HR 0·74 [95% CI 0·58-0·93]; p=0·0102). Patients in the PD-L1 low or undetectable subgroup (TC0 and IC0) also had improved survival with atezolizumab (median overall survival 12·6 months vs 8·9 months; HR 0·75 [95% CI 0·59-0·96]). Overall survival improvement was similar in patients with squamous (HR 0·73 [95% CI 0·54-0·98]; n=112 in the atezolizumab group and n=110 in the docetaxel group) or non-squamous (0·73 [0·60-0·89]; n=313 and n=315) histology. Fewer patients had treatment-related grade 3 or 4 adverse events with atezolizumab (90 [15%] of 609 patients) versus docetaxel (247 [43%] of 578 patients). One treatment-related death from a respiratory tract infection was reported in the docetaxel group. INTERPRETATION: To our knowledge, OAK is the first randomised phase 3 study to report results of a PD-L1-targeted therapy, with atezolizumab treatment resulting in a clinically relevant improvement of overall survival versus docetaxel in previously treated non-small-cell lung cancer, regardless of PD-L1 expression or histology, with a favourable safety profile. FUNDING: F. Hoffmann-La Roche Ltd, Genentech, Inc.

Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): a multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial.

BACKGROUND: New therapeutic strategies for malignant mesothelioma are urgently needed. In the DETERMINE study, we investigated the effects of the cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibody tremelimumab in patients with previously treated advanced malignant mesothelioma. METHODS: DETERMINE was a double-blind, placebo-controlled, phase 2b trial done at 105 study centres across 19 countries in patients with unresectable pleural or peritoneal malignant mesothelioma who had progressed after one or two previous systemic treatments for advanced disease. Eligible patients were aged 18 years or older with Eastern Cooperative Oncology Group performance status of 0 or 1 and measurable disease as defined in the modified Response Evaluation Criteria In Solid Tumors (RECIST) version 1.0 for pleural mesothelioma or RECIST version 1.1 for peritoneal mesothelioma. Patients were randomly assigned (2:1) in blocks of three, stratified by European Organisation for Research and Treatment of Cancer status (low risk vs high risk), line of therapy (second line vs third line), and anatomic site (pleural vs peritoneal), by use of an interactive voice or web system, to receive intravenous tremelimumab (10 mg/kg) or placebo every 4 weeks for 7 doses and every 12 weeks thereafter until a treatment discontinuation criterion was met. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug. The trial is ongoing but no longer recruiting participants, and is registered with ClinicalTrials.gov, number NCT01843374. FINDINGS: Between May 17, 2013, and Dec 4, 2014, 571 patients were randomly assigned to receive tremelimumab (n=382) or placebo (n=189), of whom 569 patients received treatment (two patients in the tremelimumab group were excluded from the safety population because they did not receive treatment). At the data cutoff date (Jan 24, 2016), 307 (80%) of 382 patients had died in the tremelimumab group and 154 (81%) of 189 patients had died in the placebo group. Median overall survival in the intention-to-treat population did not differ between the treatment groups: 7·7 months (95% CI 6·8-8·9) in the tremelimumab group and 7·3 months (5·9-8·7) in the placebo group (hazard ratio 0·92 [95% CI 0·76-1·12], p=0·41). Treatment-emergent adverse events of grade 3 or worse occurred in 246 (65%) of 380 patients in the tremelimumab group and 91 (48%) of 189 patients in the placebo group; the most common were dyspnoea (34 [9%] patients in the tremelimumab group vs 27 [14%] patients in the placebo group), diarrhoea (58 [15%] vs one [<1%]), and colitis (26 [7%] vs none). The most common serious adverse events were diarrhoea (69 [18%] patients in the tremelimumab group vs one [<1%] patient in the placebo group), dyspnoea (29 [8%] vs 24 [13%]), and colitis (24 [6%] vs none). Treatment-emergent events leading to death occurred in 36 (9%) of 380 patients in the tremelimumab group and 12 (6%) of 189 in the placebo group; those leading to the death of more than one patient were mesothelioma (three [1%] patients in the tremelimumab group vs two [1%] in the placebo group), dyspnoea (three [1%] vs two [1%]); respiratory failure (one [<1%] vs three [2%]), myocardial infarction (three [1%] vs none), lung infection (three [1%] patients vs none), cardiac failure (one [<1%] vs one [<1%]), and colitis (two [<1%] vs none). Treatment-related adverse events leading to death occurred in five (1%) patients in the tremelimumab group and none in the placebo group. The causes of death were lung infection in one patient, intestinal perforation and small intestinal obstruction in one patient; colitis in two patients, and neuritis and skin ulcer in one patient. INTERPRETATION: Tremelimumab did not significantly prolong overall survival compared with placebo in patients with previously treated malignant mesothelioma. The safety profile of tremelimumab was consistent with the known safety profile of CTLA-4 inhibitors. Investigations into whether immunotherapy combination regimens can provide greater efficacy than monotherapies in malignant mesothelioma are ongoing. FUNDING: AstraZeneca.

Evaluation of miR-506 and miR-4316 expression in early and non-invasive diagnosis of colorectal cancer.

PURPOSE: Examination of the entire colon by colonoscopy remains the golden standard for screening of colorectal cancer (CRC). However, patients are reluctant to perform invasive colonoscopies because of interference with their intimacy. Therefore, the potential use of non-invasive analysis of microRNAs expression in liquid biopsy as a novel biomarker for early CRC has investigated in several studies. In this study, we analyzed the expression of two novel microRNAs: miR-506 and miR-4316, which have never been examined in CRC. METHODS: Plasma samples were collected from 56 patients (median age of 68 years) with operable colorectal cancer and from 70 healthy individuals (median age of 59 years). Expression of plasma microRNAs was evaluated by quantitative reverse transcription polymerase chain reaction using Eco real-time PCR device (Illumina, USA). RESULTS: We found a significant elevated expression of both examined microRNAs in early CRC patients when compared to those in healthy individuals (p = 0.0054 for miR-506 and p = 0.0025 for miR-4316). The expression of miR-506 and miR-4316 did not depend on gender, age, disease stage, and tumor localization of CRC patients. ROC curve analysis showed that both examined microRNAs could differentiate early stage colorectal cancer from healthy individuals with 76.8% specificity and 60.7% sensitivity for miR-506 analysis and 76.8% specificity and 75% specificity for miR-4316 analysis. CONCLUSION: Our study revealed that elevated expression of miR-506 and miR-4316 in peripheral blood were potential molecular markers for early colorectal cancer.

Two neoplasms rich in small lymphocytes, B1B2 thymoma and small lymphocytic lymphoma, intermingled in one tumor mass. A case report.

We present a case of a 52-year-old man with myasthenia gravis and a mediastinal tumor who was admitted to our hospital for surgical treatment. The pathologic examination of the resected tumor revealed a very rare case of a collision tumor: a B1B2 thymoma and a small lymphocytic lymphoma. Flow cytometry of the peripheral blood revealed the presence of a small number of leukemic cells. After postoperative irradiation of the mediastinum and chemotherapy a complete response in both diseases was achieved. The case confirms that a pathologist should always be aware that two different neoplasms can coexist in rare cases.

Application of plasma circulating microRNA-448, 506, 4316, and 4478 analysis for non-invasive diagnosis of lung cancer.

Aberrant expression of microRNAs (miRNAs) in cancer patients compared to healthy people as well as possibility of detection of these molecules in blood samples make them potential biomarkers of various cancers. In the present study, we investigated the potential role of four miRNAs as lung cancer (LC) biomarkers: miRNA-448, 506, 4316, and 4478. Using quantitative reverse transcription polymerase chain reaction (qRT-PCR) technique, we assessed expression of studied miRNAs in plasma samples of 90 lung cancer patients and 85 healthy individuals. Receiver operating curves (ROC) with area under the curve (AUC) were used to assess accuracy of studied miRNAs for distinguishing LC patients from healthy individuals. The miRNA-448 and 4478 were significantly overexpressed in lung cancer patients compared to healthy people and these two molecules were qualified for further analysis. Combination ROC analysis of both biomarkers reached 90 % of sensitivity and 76.3 % of specificity (AUC = 0.896) for distinguishing operable (stage IA-IIB) non-small cell lung cancer (NSCLC) patients from healthy subjects. Our results suggest that the examination of miRNAs could be considered as potential lung cancer, non-invasive biomarkers.

Structure and microbial diversity of biofilms on different pipe materials of a model drinking water distribution systems.

The experiment was conducted in three model drinking water distribution systems (DWDSs) made of unplasticized polyvinyl chloride (PVC), silane cross-linked polyethylene (PEX) and high density polyethylene (HDPE) pipes to which tap water was introduced. After 2 years of system operation, microbial communities in the DWDSs were characterized with scanning electron microscopy, heterotrophic plate count, and denaturing gradient gel electrophoresis. The most extensive biofilms were found in HDPE pipes where bacteria were either attached to mineral deposits or immersed in exopolymers. On PEX surfaces, bacteria did not form large aggregates; however, they were present in the highest number (1.24 × 10(7) cells cm(-2)). PVC biofilm did not contain mineral deposits but was made of single cells with a high abundance of Pseudomonas aeruginosa, which can be harmful to human health. The members of Proteobacteria and Bacteroidetes were found in all biofilms and the water phase. Sphingomonadales and Methylophilaceae bacteria were found only in PEX samples, whereas Geothrix fermentans, which can reduce Fe(III), were identified only in PEX biofilm. The DNA sequences closely related to the members of Alphaproteobacteria were the most characteristic and intense amplicons detected in the HDPE biofilm.

Analysis of treatment results in primary germ cell tumours with mediastinal location: own experience.

INTRODUCTION: Primary germ cell tumours with mediastinal location comprise 1-6% of mediastinal tumours and 2-5% of all germ cell tumours occurring in adults. They are identified mostly in the 3rd decade of life, in 90% of cases in men. The most common symptoms are dyspnea, chest pain, cough, fever and weight loss. The aim of the present study was the analysis of our own results of treatment of primary germ cell tumours with mediastinal location, and a review of the literature concerning this subject. MATERIAL AND METHODS: Five patients (4 males, 1 female) median age 27.8 years (range 23-30 years) treated in the period from 1999 to 2009 in Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Department of Lung Cancer and Chest Tumours in Warsaw, due to germinal tumours with primary mediastinal location, entered the study. RESULTS: All patients received chemotherapy according to the BEP regimen. All patients achieved an objective response to treatment. Two patients died due to disease progression in spite of II- and III-line treatment. Three patients are still in follow-up. The median survival time was 55.8 months (range 8.0-120.0 months). CONCLUSIONS: Primary mediastinal germ cell tumours have worse prognosis than do those with gonadal location. Based on our observations and review of the literature, it can be concluded that the results of treatment of non-seminoma type germ cell tumours with primary mediastinal location remain poor. Patients who develop early recurrence or progression during first-line chemotherapy are particularly at risk of unfavourable outcome. Identification of new standards of treatment in tumours resistant to cisplatin require further studies evaluating the effectiveness of new generation cytostatic drugs.

[The role of systemic therapies of non-small cell lung cancer and malignant pleural mesothelioma: updated expert recommendations]. / Rola systemowych metod leczenia u chorych na niedrobnokomórkowego raka pluca i zlosliwego miedzybloniaka oplucnej: uaktualnione zalecenia ekspertów.

Lung cancer is the leading cause of cancer related death in Poland. About 85% of all lung cancer constitutes non-small cancer (NSCLC), in which the role of cytotoxic and molecularly targeted drugs is increasing. This article presents the current evidence- based recommendations for the use of these methods in clinical practice in NSCLC and malignant pleural mesothelioma.

Genetic and immune factors underlying the efficacy of cetuximab and panitumumab in the treatment of patients with metastatic colorectal cancer.

Efficacy of monoclonal anti-EGFR antibodies (cetuximab, panitumumab) used in combination with chemotherapy or alone has been demonstrated in clinical trials of patients with mCRC. Both drugs block signaling EGFR pathway in malignant cells (blocking ligand binding and EGFR dimerization). Obtaining treatment responses with anti-EGFR agents is possible only in a selected subgroup of patients with mCRC. Successful treatment with cetuximab and panitumab is possible almost exclusively in patients without RAS mutations. Research on predictive value of EGFR gene copy number, PI3KCA gene mutations, P53 and PTEN, and EGFR their ligands concentrations is ongoing. Cetuximab, as IgG1 class antibody, can cause antibody dependent cellular cytotoxicity against neoplasm cells, while panitumumab, as IgG2 class antibody, does not induce such effect. Therefore a potential predictor cetuximab therapy may be the presence of different polymorphic forms of the genes for receptor immunoglobulin Fc fragments: FcγRIIa and FcγRIII subclasses.