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Background: A novel approach for managing malignant pleural mesothelioma, surgery for mesothelioma after radiotherapy (SMART), consisting of a short accelerated course of high-dose, hemithoracic, intensity modulated radiotherapy (IMRT) followed by extrapleural pneumonectomy was developed. The aim of this study was to evaluate the clinical feasibility of the SMART protocol.Methods: In this single-centre, phase 2 trial, patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-2, with histologically proven, resectable, cT1-3N0M0 disease who had previously untreated malignant pleural mesothelioma were eligible for inclusion. Patients received 25 Gy in five daily fractions over 1 week to the entire ipsilateral hemithorax with a concomitant 5 Gy boost to high risk areas followed by extrapleural pneumonectomy within 1 week. Adjuvant chemotherapy was offered to patients with ypN+ disease on final pathology. The primary endpoint was feasibility, which was defined as the number of patients with 30-day perioperative treatment-related death (grade 5 events) or morbidity (grade 3 or 4 events). A key secondary endpoint was cumulative incidence of distant recurrence. The final analysis was done on an intention-to-treat basis (including all eligible patients). This trial is registered with ClinicalTrials.gov, NCT00797719.Findings: Between Nov 1, 2008, and Oct 31, 2019, 102 patients were enrolled onto the trial and 96 eligible patients were treated with SMART on protocol and included in the analysis. Extrapleural pneumonectomy was done at a median of 5 days (range 2-12) after completing IMRT. 47 (49%) patients had 30-day perioperative grade 3-4 events and one (1%) patient died within 30 days perioperatively (grade 5 event; pneumonia). After a median follow-up of 46·8 months (IQR 13·4-61·2), the 5-year cumulative incidence of distant recurrence was 62 (63·3% [95% CI 52·3-74·4]). The most common first sites of recurrence were the contralateral chest (33 [46%] of 72 patients) and the peritoneal cavity (32 [44%]).Interpretation: Results from this study suggest that extrapleural pneumonectomy after radiotherapy can be done with good early and long-term results. However, minimising grade 4 events on the protocol is technically demanding and might affect survival beyond the post-operative period.Funding: Princess Margaret Hospital Foundation Mesothelioma Research Fund. [ABSTRACT FROM AUTHOR]

Abstract: The purpose of this study was to evaluate the volumetric change of the upper airway space in 36 Class III patients who had undergone bimaxillary surgery or isolated mandibular setback, and, further, to analyse the relation between post-surgical stability and airway change using cone-beam computed tomography (CBCT). A three-dimensional (3D) CBCT examination was performed at three stages: T0 (before surgery), T1 (an average of 4.6 months after surgery), and T2 (an average of 1.4 years after surgery). The results showed that the volumes of the oropharyngeal and hypopharyngeal airways decreased significantly 4.6 months post-surgery in the mandibular setback group (p <0.05), and these diminished airways had not recovered 1.4 years post-surgery. In the bimaxillary surgery group, the volume of the oropharyngeal airway also decreased. A Spearman correlation analysis showed that the anteroposterior length of the hypopharyngeal area had a correlation with post-surgical stability in the isolated mandibular surgery group, and that the cross-sectional area of the nasopharynx was correlated with maxillary relapse only in the bimaxillary surgery group (p <0.05). [Copyright &y& Elsevier]

Abstract: The inflammatory response accompanies and exacerbates the developing injury after cerebral ischemia. Ibuprofen, a non-steroidal anti-inflammatory drug, has been shown to attenuate injuries in animal models of various neurological diseases. In the present study, we investigated ibuprofen’s neuroprotective effects in rats exposed to transient forebrain ischemia and in cultures exposed to oxygen glucose deprivation (OGD). Rats treated with ibuprofen after transient forebrain ischemia displayed long-lasting protection of CA1 hippocampal neurons. There were selective increases in interleukin-1 receptor antagonist gene and protein expression in ibuprofen-treated OGD microglia. Furthermore, treatment with ibuprofen in neuron/microglia co-cultures increased the number of surviving HC2S2 neurons against OGD whereas IL-1ra neutralizing antibody reversed the ibuprofen-induced neuroprotection. The data indicate that ibuprofen-induced IL-1ra secretion is involved in neuroprotection against ischemic conditions. [Copyright &y& Elsevier]

Background: Dietary fats alter LDL and HDL cholesterol while serving as precursors of postprandial triacylglycerol-rich lipoproteins (TRLs). Objective: We hypothesized that the saturated fatty acid (SFA)- mediated increase and the polyunsaturated fatty acid (PUFA)-mediated decrease in endogenous lipoprotein cholesterol are promoted by postprandial TRLs. Design: We performed a 16-d crossover diet study to examine the effect of PUFA-rich [ratio of PUFAs to SFAs (P:S) = 2.0] and SFA-rich (P:S=0.25) diets on fasting and postprandial plasma lipid and lipoprotein-cholesterol concentrations in 16 normolipidemic subjects. Results: Fasting plasma cholesterol decreased significantly after a PUFA-rich diet because of a decrease in LDL (-12.3%; P < 0.05) and HDL (-3.8%; NS), but did not change after an SFA-rich diet. The appearance of postprandial TRLs in plasma at 4 h was linked to a significant lowering of both LDL(-7.4%) and HDL(-4.8%) after a PUFA-rich diet; no such effect was observed after the SFA-rich diet. At 7 h, LDL and HDL cholesterol returned to near fasting concentrations without postprandial TRL accumulation after a PUFA-rich diet but with a significant postprandial TRL accumulation after an SFA-rich diet. Thus, the in vivo postprandial clearance of cholesterol in LDL+HDLwas greater after a PUFA-rich diet than after an SFA-rich diet. The appearance of postprandial TRLs in plasma increased the cholesteryl ester transfer protein-mediated transfer of cholesteryl ester from LDL+HDL to TRLs in vitro without a significant influence from dietary fat. Conclusion: Dietary fat-mediated alterations in the rate of hepatic removal of postprandial TRLs, which carry cholesterol accepted from LDL+HDL via cholesteryl ester transfer protein in vivo, may contribute to the dietary fat-mediated change in endogenous lipoprotein cholesterol. [ABSTRACT FROM AUTHOR]

Background: Moderate alcohol consumption increases plasma HDL and lowers cardiovascular disease risk while transiently enhancing postprandial lipemia. Objective:We hypothesized that the alcohol-mediated increase in postprandial triacylglycerol-rich lipoproteins (TRLs) and their clearance elevate HDL cholesterol and reverse cholesterol transport. Design: We determined the effect in normolipidemic humans (n = 14) of postprandial lipemia produced 4 h after a test meal (M) or a test meal + 0.5 g alcohol/kg body wt (M+A) on postprandial changes in plasma lipids and on the balance of cholesterol between TRL and the cholesterol-rich LDL and HDL fractions (CRL) or red blood cells (RBCs) in fresh and incubated plasma or blood. Results: Postprandial lipemia after the M and M+A test meals caused a 56% and 89% increase in plasma triacylglycerol, a 30% and 74% increase in TRL cholesterol, and a 3.8% and 6.6% decrease in CRL cholesterol, respectively. In vitro reaction of endogenous lecithin:cholesterol acyltransferase (EC 2.3.1.43) and cholesteryl ester transfer proteins via incubation of fasting plasma samples and postprandial M and M+A plasma samples for 16 h increased TRL cholesterol by 22.8% (0.08 mmol/L), 32.6% (0.16 mmol/L), and 45.8% (0.28 mmol/L) in plasma and by 71.1% (0.27 mmol/L), 89.4% (0.45 mmol/L), and 112.5% (0.70 mmol/L) in RBC-enriched blood, respectively. After the in vitro lipolysis of TRL, the elevation of HDL cholesterol in postprandial M+A plasma, but not in postprandialMplasma, was significantly greater than in fasting plasma. Conclusion: The alcohol-mediated increase in postprandial TRL flux and the hepatic removal of postprandial TRL after the acceptance of cholesterol from CRL and cell membranes contribute to increased HDL cholesterol and enhancement of reverse cholesterol transport in humans. [ABSTRACT FROM AUTHOR]

Hanbang, the Korean medical practice with origins in classical Chinese texts, is a prominent part of the Korean health care system. Hanbang physicians, called hanuisas, are looked down on by biomedical doctors, but their practice has enjoyed increasing popularity for several decades. As the market for herbal preparations has become more lucrative, biomedical pharmacists have begun to participate in it. The Pharmaceutical Act in 1993 explicitly allowed pharmacists to prescribe and dispense herbal drugs. This provoked a bitter public conflict between hanuisas and pharmacists, involving street demonstrations and strikes. The hanuisas asserted that the pharmacists were unqualified to assume their traditional practice. They also agitated for recognition in the state-sponsored system of health care and for the state's support for developing Hanbang medicine. This paper attributes the conflicts concerning Hanbang to the expanding market for herbal preparations, Korean nationalism, and to the oversupply of biomedical pharmacists. [ABSTRACT FROM AUTHOR]

Cytotoxic CD8+ tumor infiltrating lymphocytes (TILs) can contribute to the benefit of hypofractionated radiation, but programmed cell death pathways (programmed cell death 1 and programmed cell death ligand 1 [PD-1/PD-L1]) may provide a mechanism of tumor immune escape. We therefore reviewed the influence of PD-1/PD-L1 and CD8+ TILs on survival after accelerated hypofractionated hemithoracic radiation followed by extrapleural pneumonectomy for malignant pleural mesothelioma (MPM). Sixty-nine consecutive patients undergoing the protocol of Surgery for Mesothelioma after Radiation Therapy (SMART) between November 2008 and February 2016 were analyzed for the presence of PD-L1 on tumor cells, PD-1 on inflammatory cells, and CD8+ TILs. Comparison was made with a cohort of patients undergoing extrapleural pneumonectomy after induction chemotherapy (n = 14) and no induction (n = 2) between March 2005 and October 2008. PD-L1 expression on tumor cells ≥1% was considered positive. CD8+ TILs and PD-1 expression were scored as a percentage of positive cells. PD-L1 was negative in 75% of MPM after completion of SMART. CD8+ TILs ranged between 0.24% and 8.47% (median 2%). CD8+ TILs ≥2% was associated with significantly better survival in epithelioid MPM (median survival 3.7 years vs 2.3 years in CD8+ TILs <2%; P =.02). PD-L1 positivity was associated with worse survival in biphasic MPM (median survival, 0.4 years vs 1.5 years in biphasic PD-L1 negative tumors; P =.07) after SMART. Multivariate analysis demonstrated that epithelioid MPM, nodal disease, and CD8+ TILs were independent predictors of survival after SMART. The influence of tumor microenvironment on survival differs between epithelioid and nonepithelioid MPM. CD8+ TILs is an independent factor associated with better survival in epithelioid MPM treated with SMART. An accelerated course of hypofractionated radiation is applied to the tumor, leading to immunogenic cell death with release of double stranded DNA, tumor-associated antigens and type I interferon (α and β) that leads to an activation of dendritic cells in the draining lymph nodes and, consequently, the priming of CD8+ T cells against the tumor. Tumor cells then upregulate programmed cell death ligand 1 as a mechanism of protection against antitumoral CD8+ T cells. [ABSTRACT FROM AUTHOR]

Background Osimertinib is a 3rd-generation, irreversible, oral EGFR-TKI that potently and selectively inhibits both EGFR-mutated (EGFRm) and EGFR T790M resistance mutations, and has demonstrated efficacy in NSCLC CNS metastases. In the Phase III FLAURA study (NCT02296125), osimertinib resulted in significant progression-free survival (PFS) benefit (primary endpoint; datacut off [DCO] 12 June 2017) over comparator EGFR-TKI (HR 0.46, p < 0.001). Overall survival (OS) data were immature (25% maturity) at that time. Here, we report the final OS analysis (58% maturity). Methods Eligible patients (pts): ≥18 years (Japan: ≥20), treatment-naïve with Ex19del/L858R EGFRm advanced NSCLC; WHO performance status 0–1. Pts with stable CNS metastases not requiring steroids for ≥2 weeks were allowed. Pts were randomised 1:1 to osimertinib 80 mg once daily (qd) orally (po) or comparator EGFR-TKI (gefitinib 250 mg qd/erlotinib 150 mg qd po), stratified by mutation status (Ex19del/L858R) and race (Asian/non-Asian). Crossover was allowed for pts in the comparator EGFR-TKI arm upon central confirmation of progression and T790M positivity. Primary endpoint: PFS by RECIST v1.1, per investigator. OS was a secondary endpoint. DCO 25 June 2019. Results Globally, 556 pts were randomised to osimertinib (n = 279) or comparator EGFR-TKI (n = 277). Per study protocol, 70 (25%) pts crossed over from comparator EGFR-TKI to osimertinib. Osimertinib significantly improved OS vs comparator EGFR-TKI. All causality AEs, per investigator: osimertinib, 98% (grade ≥3, 42%); comparator EGFR-TKI, 98% (grade ≥3, 47%). AEs leading to discontinuation: osimertinib, 15%; comparator EGFR-TKI, 18%. The safety profile appears consistent with previously reported data. Table: LBA16 Efficacy output  Osimertinib n = 279  Comparator EGFR-TKI n = 277  OS hazard ratio  0.799 (0.641, 0.997); p = 0.0462  (95.05% confidence interval)  Median OS, months  38.6 (34.5, 41.8)  31.8 (26.6, 36.0)  (95% confidence interval)      Deaths, total pts (%)  155 (56)  166 (60)  Median follow-up for OS in all pts, months  35.8  27.0  Median follow-up for OS in censored * pts, months  43.1  43.1  12-month survival rate, % (95% confidence interval)  89 (85, 92)  83 (77, 87)  24-month survival rate, % (95% confidence interval)  74 (69, 79)  59 (53, 65)      36-month survival rate, % (95% confidence interval)  54 (48, 60)  44 (38, 50)      Efficacy output  Osimertinib n = 279  Comparator EGFR-TKI n = 277  OS hazard ratio  0.799 (0.641, 0.997); p = 0.0462  (95.05% confidence interval)  Median OS, months  38.6 (34.5, 41.8)  31.8 (26.6, 36.0)  (95% confidence interval)      Deaths, total pts (%)  155 (56)  166 (60)  Median follow-up for OS in all pts, months  35.8  27.0  Median follow-up for OS in censored * pts, months  43.1  43.1  12-month survival rate, % (95% confidence interval)  89 (85, 92)  83 (77, 87)  24-month survival rate, % (95% confidence interval)  74 (69, 79)  59 (53, 65)      36-month survival rate, % (95% confidence interval)  54 (48, 60)  44 (38, 50)      OS for patients in the full analysis set was analysed using a log rank test (stratified by race and mutation type) for generation of the p-value and using the Breslow approach for handling ties. The median OS with 95% confidence intervals were calculated by Kaplan Meier technique. For statistical significance, a 2-sided p-value of less than 0.0495, as determined by the O'Brien-Fleming approach was required due the previous interim analysis. * Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. Table: LBA16 Efficacy output  Osimertinib n = 279  Comparator EGFR-TKI n = 277  OS hazard ratio  0.799 (0.641, 0.997); p = 0.0462  (95.05% confidence interval)  Median OS, months  38.6 (34.5, 41.8)  31.8 (26.6, 36.0)  (95% confidence interval)      Deaths, total pts (%)  155 (56)  166 (60)  Median follow-up for OS in all pts, months  35.8  27.0  Median follow-up for OS in censored * pts, months  43.1  43.1  12-month survival rate, % (95% confidence interval)  89 (85, 92)  83 (77, 87)  24-month survival rate, % (95% confidence interval)  74 (69, 79)  59 (53, 65)      36-month survival rate, % (95% confidence interval)  54 (48, 60)  44 (38, 50)      Efficacy output  Osimertinib n = 279  Comparator EGFR-TKI n = 277  OS hazard ratio  0.799 (0.641, 0.997); p = 0.0462  (95.05% confidence interval)  Median OS, months  38.6 (34.5, 41.8)  31.8 (26.6, 36.0)  (95% confidence interval)      Deaths, total pts (%)  155 (56)  166 (60)  Median follow-up for OS in all pts, months  35.8  27.0  Median follow-up for OS in censored * pts, months  43.1  43.1  12-month survival rate, % (95% confidence interval)  89 (85, 92)  83 (77, 87)  24-month survival rate, % (95% confidence interval)  74 (69, 79)  59 (53, 65)      36-month survival rate, % (95% confidence interval)  54 (48, 60)  44 (38, 50)      OS for patients in the full analysis set was analysed using a log rank test (stratified by race and mutation type) for generation of the p-value and using the Breslow approach for handling ties. The median OS with 95% confidence intervals were calculated by Kaplan Meier technique. For statistical significance, a 2-sided p-value of less than 0.0495, as determined by the O'Brien-Fleming approach was required due the previous interim analysis. * Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. Conclusions Osimertinib provided a statistically significant and clinically meaningful improvement in OS vs comparator EGFR-TKI in first-line pts with EGFRm advanced NSCLC. Clinical trial identification NCT02296125. Editorial acknowledgement Natalie Griffiths, PhD, from iMed Comms, an Ashfield Company, funded by AstraZeneca. Legal entity responsible for the study AstraZeneca. Funding AstraZeneca. Disclosure B.C. Cho: Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Janssen, Yuhan, Ono Pharmaceutical, Dizal Pharma, MSD; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution), Licensing / Royalties: Champions Oncology; Honoraria (institution), Advisory / Consultancy: Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Pfizer, Eli Lilly, Takeda; Shareholder / Stockholder / Stock options: TheraCanVac Inc. Y. Ohe: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca, Chugai, Dainippon Lilly, Ono, BMS Japan, Daiichi Sankyo, BI, Bayer, Ignyta, Pfizer, MSD, Taiho, Novartis, Kyorin, Kyowa Hakko Kirin, Takeda, Celltrion, Kissei, Amgen, Janssen, Roxo. C. Zhou: Honoraria (self): Roche, Eli Lilly, BI, Merck, Hengrui, Qiru. B. Chewaskulyong: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca. D. Planchard: Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, MedImmune, Novartis, Pfizer, prIME Oncology, Peer CME, Roche; Honoraria (self): AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche; Research grant / Funding (institution): AstraZeneca, Bristol-Myers Squibb, AbbVie, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, MedImmune, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo; Travel / Accommodation / Expenses: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim , Roche, Merck, Novartis, prIME Oncology, Pfizer. J.F. Vansteenkiste: Research grant / Funding (institution): MSD; Advisory / Consultancy: – Apotex, AstraZeneca, Boehringer Ingelheim, MSD, Novartis, Roche; Speaker Bureau / Expert testimony: – AstraZeneca, BMS, MSD, Roche. J.E. Gray: Honoraria (self): AstraZeneca, Bristol-Myers Squibb, Takeda; Advisory / Consultancy: Bristol-Myers Squibb, Celgene, Takeda; Research grant / Funding (institution): Array, Merck, AstraZeneca, Genentech, Boehringer Ingelheim, Bristol-Myers Squibb. R. Shah: Honoraria (self), Travel / Accommodation / Expenses: Boehringer Ingelheim, Roche, AstraZeneca. P.K. Cheema: Honoraria (self), Advisory / Consultancy: AstraZeneca, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Merck, Takeda, Novartis, Genomic Health, Pfizer. M. Tiseo: Advisory / Consultancy: AstraZeneca, Bristol-Myers Squibb, MSD, Boehringer Ingelheim, Takeda; Research grant / Funding (institution): AstraZeneca, Boehringer Ingelheim. T. John: Advisory / Consultancy: Roche, Bristol-Myers Squibb, Merck, Ignyta, AstraZeneca, Takeda, Boehringer Ingelheim, Pfizer. R. Hodge: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. Y. Rukazenkov: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. J. Soria: Advisory / Consultancy: AstraZeneca, Astex, Clovis, GSK, GamaMabs, Lilly, MSD, Mission Therapeutics, Merus, Pfizer, PharmaMar, Pierre Fabre, Roche/Genentech, Sanofi, Servier, Symphogen, Takeda; Shareholder / Stockholder / Stock options: AstraZeneca, Gritstone; Full / Part-time employment: AstraZeneca. F. Imamura: Honoraria (self), Research grant / Funding (institution): AstraZeneca. S.S. Ramalingam: Honoraria (self), Advisory / Consultancy: AstraZeneca, Amgen, Bristol-Myers Squibb, Merck, Roche/Genentech, Loxo, Nektar, Tesaro; Research grant / Funding (institution): AstraZeneca, Amgen, Bristol-Myers Squibb, Merck, Tesaro, Advaxis, Takeda. [ABSTRACT FROM AUTHOR]

Background In MYSTIC, an open-label, phase 3 trial of first-line D (anti-PD-L1) ± T (anti-CTLA-4) vs CT, while not statistically significant, a clinically meaningful improvement in overall survival (OS) was seen with D vs CT in patients with tumour cell PD-L1 expression ≥25% (TC ≥ 25% [primary analysis population]; D vs CT, HR 0.76 [97.54% CI 0.56–1.02]; D+T vs CT, HR 0.85 [98.77% CI 0.61–1.17]). Here we report results in a subpopulation of Asian patients. Methods Immunotherapy/CT-naïve patients with metastatic NSCLC were randomized (1:1:1) to D (20 mg/kg q4w); D (20 mg/kg q4w) + T (1 mg/kg q4w ≤4 doses); or CT. In this analysis in a subpopulation of Asian patients, efficacy outcomes were evaluated in patients with PD-L1 TC ≥25%; safety was evaluated in all treated patients (regardless of PD-L1 expression). Results Of the 488 patients in the primary analysis population (PD-L1 TC ≥25%), 156 (32%) were Asian (D, 59; D+T, 50; CT, 47). Baseline characteristics in the Asian population were balanced between treatment arms. OS was improved in Asian patients (PD-L1 TC ≥25%) with D vs CT (HR 0.69 [95% CI 0.43–1.09]) and D+T vs CT (HR 0.64 [95% CI 0.40-1.03]); more patients receiving D or D+T remained in response at 6 months vs CT (Table). Grade ≥3 treatment-related adverse events (TRAEs) and any grade TRAEs leading to discontinuation occurred in 19.7% and 9.0% (D); 23.9% and 14.5% (D+T); 23.4% and 7.2% (CT) patients in the Asian subpopulation, respectively. Table: 474O   Durvalumab   Durvalumab + tremelimumab   Chemotherapy     Overall (n = 163)  Asian (n = 59)  Overall (n = 163)  Asian (n = 50)  Overall (n = 162)  Asian (n = 47)  Median OS, mo  16.3 (12.2–20.8)  18.8 (9.2–28.4)  11.9 (9.0–17.7)  17.7 (11.6–27.3)  12.9 (10.5–15.0)  10.6 (7.0–14.6)  24-mo OS rate, %  38.3  43.8  35.4  42.0  22.7  22.3  OS HR vs CT (95% CI)  0.76 (0.56–1.02) *   0.69 (0.43–1.09)  0.85 (0.61–1.17)†  0.64 (0.40–1.03)  –  –  ORR, n (%)  58 (35.6)  19 (32.2)  56 (34.4)  18 (36)  61 (37.7)  17 (36.2)  Patients remaining in response (%) at              6 mo  66.9  68.4  67.6  52.7  32.4  34.3  12 mo  61.3  62.2  54.9  26.3  18.0  NR    Durvalumab   Durvalumab + tremelimumab   Chemotherapy     Overall (n = 163)  Asian (n = 59)  Overall (n = 163)  Asian (n = 50)  Overall (n = 162)  Asian (n = 47)  Median OS, mo  16.3 (12.2–20.8)  18.8 (9.2–28.4)  11.9 (9.0–17.7)  17.7 (11.6–27.3)  12.9 (10.5–15.0)  10.6 (7.0–14.6)  24-mo OS rate, %  38.3  43.8  35.4  42.0  22.7  22.3  OS HR vs CT (95% CI)  0.76 (0.56–1.02) *   0.69 (0.43–1.09)  0.85 (0.61–1.17)†  0.64 (0.40–1.03)  –  –  ORR, n (%)  58 (35.6)  19 (32.2)  56 (34.4)  18 (36)  61 (37.7)  17 (36.2)  Patients remaining in response (%) at              6 mo  66.9  68.4  67.6  52.7  32.4  34.3  12 mo  61.3  62.2  54.9  26.3  18.0  NR  Overall and Asian populations include patients with PD-L1 TC ≥25%;. * 97.54% CI; †98.77% CI; ORR occurred on June 1, 2017; DoR, duration of response; NR, not reached; ORR, objective response rate; OS, overall survival. Table: 474O   Durvalumab   Durvalumab + tremelimumab   Chemotherapy     Overall (n = 163)  Asian (n = 59)  Overall (n = 163)  Asian (n = 50)  Overall (n = 162)  Asian (n = 47)  Median OS, mo  16.3 (12.2–20.8)  18.8 (9.2–28.4)  11.9 (9.0–17.7)  17.7 (11.6–27.3)  12.9 (10.5–15.0)  10.6 (7.0–14.6)  24-mo OS rate, %  38.3  43.8  35.4  42.0  22.7  22.3  OS HR vs CT (95% CI)  0.76 (0.56–1.02) *   0.69 (0.43–1.09)  0.85 (0.61–1.17)†  0.64 (0.40–1.03)  –  –  ORR, n (%)  58 (35.6)  19 (32.2)  56 (34.4)  18 (36)  61 (37.7)  17 (36.2)  Patients remaining in response (%) at              6 mo  66.9  68.4  67.6  52.7  32.4  34.3  12 mo  61.3  62.2  54.9  26.3  18.0  NR    Durvalumab   Durvalumab + tremelimumab   Chemotherapy     Overall (n = 163)  Asian (n = 59)  Overall (n = 163)  Asian (n = 50)  Overall (n = 162)  Asian (n = 47)  Median OS, mo  16.3 (12.2–20.8)  18.8 (9.2–28.4)  11.9 (9.0–17.7)  17.7 (11.6–27.3)  12.9 (10.5–15.0)  10.6 (7.0–14.6)  24-mo OS rate, %  38.3  43.8  35.4  42.0  22.7  22.3  OS HR vs CT (95% CI)  0.76 (0.56–1.02) *   0.69 (0.43–1.09)  0.85 (0.61–1.17)†  0.64 (0.40–1.03)  –  –  ORR, n (%)  58 (35.6)  19 (32.2)  56 (34.4)  18 (36)  61 (37.7)  17 (36.2)  Patients remaining in response (%) at              6 mo  66.9  68.4  67.6  52.7  32.4  34.3  12 mo  61.3  62.2  54.9  26.3  18.0  NR  Overall and Asian populations include patients with PD-L1 TC ≥25%;. * 97.54% CI; †98.77% CI; ORR occurred on June 1, 2017; DoR, duration of response; NR, not reached; ORR, objective response rate; OS, overall survival. Conclusions Durvalumab resulted in a favourable HR for OS compared to CT in patients with PD-L1 TC≥25% in the Asian subpopulation, which was consistent with the primary analysis population. OS HR for D+T vs CT appeared to be more favourable in the Asian subpopulation compared to the primary analysis population, although results should be interpreted with caution due to small sample sizes. The safety profile of D±T in the subpopulation of Asian patients was manageable and consistent with the primary analysis population. Clinical trial identification NCT02453282. Editorial acknowledgement Medical writing support, which was in accordance with Good Publication Practice (GPP3) guidelines, was provided by Beena John, PhD of Cirrus Communications (Macclesfield, UK), an Ashfield company, and was funded by AstraZeneca. Legal entity responsible for the study AstraZeneca. Funding AstraZeneca. Disclosure B.C. Cho: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): MOGAM Institute; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Roche; Advisory / Consultancy: BMS; Advisory / Consultancy, Research grant / Funding (institution): Ono; Advisory / Consultancy, Research grant / Funding (institution): Yuhan; Advisory / Consultancy, Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Champions Oncology; Research grant / Funding (institution): Dong-A ST; Research grant / Funding (institution): Dizal Pharma; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Takeda; Shareholder / Stockholder / Stock options: TheraCanVac Inc. K.H. Lee: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: BMS. S. Lucien Geater: Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Samsung. T.V. Ngoc: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): GSK; Research grant / Funding (institution): Novartis. S. Clarke: Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca. S. Kuyama: Speaker Bureau / Expert testimony, Lecture fees: AstraZeneca; Speaker Bureau / Expert testimony, Lecture fees: Pfizer; Speaker Bureau / Expert testimony, Lecture fees: Eli Lilly; Speaker Bureau / Expert testimony, Lecture fees: Boehringer Ingelheim; Speaker Bureau / Expert testimony, Lecture fees: MSD; Speaker Bureau / Expert testimony, Lecture fees: Taiho; Speaker Bureau / Expert testimony, Lecture fees: Chughai. K. Nakagawa: Honoraria (institution), Research grant / Funding (institution): MSD / Takeda / SymBio Pharmaceuticals / Daiichi Sankyo; Honoraria (self), Research grant / Funding (institution): Eli Lilly Japan; Honoraria (self), Research grant / Funding (institution): BMS; Honoraria (self), Research grant / Funding (institution): Taiho /Ono / Chughai; Honoraria (self), Research grant / Funding (institution): AstraZeneca / Astellas Pharma / Novartis / Nippon Boehringer Ingelheim / Pfizer Japan; Research grant / Funding (institution): Merck Serono / ICON Japan /PAREXEL / IQVIA Services Japan / A2 Healthcare / AbbVie; Research grant / Funding (institution): EP-CRSU / Linical / Otsuka Pharmaceuticals / EPS International / Quintiles / CMIC Shift Zero / Eisai / Kissei Pharmaceutical ; Research grant / Funding (institution): Kyowa Hakko Kirin / EPS Corporation / Bayer Yakuhin / inVentiv Health Japan / Gritstone Oncology / GSK / Yakult Honsha / Covance ; Honoraria (self): Kyorin Pharmaceutical / CareNet / Nichi-Iko Pharmaceutical / Hisamitsu Pharmaceutical / Yodosha / Clinical Trial / Reno Medical / Nanzando / Medical Review; Honoraria (self): Medicus Shuppan / Ayumi Pharmaceutical / Thermo Fisher Scientific / Yomiuri Telecasting Corporation / Nikkei Business Publications. F. Liu: Full / Part-time employment, Full-time employee: AstraZeneca. D. Clemett: Full / Part-time employment, Full-time employee: AstraZeneca. U. Scheuring: Full / Part-time employment, Full-time employee: AstraZeneca. S. Peters: Honoraria (self), Advisory / Consultancy: AbbVie; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Amgen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca / Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bayer / Seattle Genetics and Takeda; Honoraria (self), Advisory / Consultancy: Biocartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): BMS; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Clovis; Honoraria (self), Advisory / Consultancy: Daiichi Sankyo / Regeneron / Sanofi; Honoraria (self), Advisory / Consultancy: Debiopharm; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): F Hoffmann-La Roche; Honoraria (self), Advisory / Consultancy: Foundation Medicine; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Illumina; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Merck Sharp & Dohme; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck Serono; Honoraria (self), Advisory / Consultancy: Merrimack; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy: Pharma Mar. N. Rizvi: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy: Novartis; Advisory / Consultancy: Merck Sharp & Dohme; Advisory / Consultancy: BMS; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Lilly; Advisory / Consultancy: AbbVie; Advisory / Consultancy: Regeneron; Advisory / Consultancy: Janssen; Leadership role, Shareholder / Stockholder / Stock options: ARMO BioSciences; Shareholder / Stockholder / Stock options: Gritstone Oncology. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background Overexpression of interleukin (IL)-1β has been described in solid tumors, including lung. IL-1β can promote angiogenesis, tumor invasiveness, and induces tumor-associated immunosuppression through myeloid-derived suppressor cell (MDSC) accumulation in tumors. Pre-clinical data has shown that IL-1β inhibition reduced tumor growth, by limiting pro-tumorigenic inflammation and polarization of MDSCs into M1 phenotype. Canakinumab is a human monoclonal antibody with high affinity and specificity for IL-1β. Recently, it was found that canakinumab was associated with a significant and dose-dependent reduction in incidence and mortality from lung cancer based on CANTOS study. Trial design CANOPY-A (NCT03447769) is a phase III, randomized, double-blind, placebo-controlled study designed to evaluate efficacy and safety of adjuvant canakinumab vs placebo in pts with surgically resected NSCLC. This trial will enroll adult pts, with completely resected (R0) AJCC/UICC v.8 stages II-IIIA and IIIB (T > 5 cm and N2) NSCLC, who have completed standard-of-care adjuvant treatments, including cisplatin-based chemotherapy and mediastinal radiation therapy (if applicable). Prior treatment with neoadjuvant chemotherapy or neoadjuvant radiotherapy is not permitted. Approximately 1500 pts will be randomized 1:1 to receive canakinumab (200 mg Q3W, s.c) or placebo (Q3W, s.c.) for 18 cycles or until disease recurrence, unacceptable toxicity, treatment discontinuation at the discretion of the investigator or pt, death, or loss to follow-up. Randomization will be stratified by AJCC/UICC v.8 stage, tumor histology, and region. In the amended protocol, a sub-study was included to determine the biomarker levels in the blood at pre- and post-surgery, and to establish their association with canakinumab efficacy. The primary objective is disease-free survival (per investigator assessment). Secondary objectives include overall survival (key secondary objective), lung cancer-specific survival, safety, pharmacokinetics and immunogenicity of canakinumab, and pt-reported outcomes. Enrollment is ongoing. Clinical trial identification CACZ885T2301. Legal entity responsible for the study Novartis. Funding Novartis. Disclosure B.C. Cho: Honoraria (self): Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD; Advisory / Consultancy: Novartis, AstraZeneca, Boehringer Ingelheim, Roche, BMS, Ono, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda, MSD; Research grant / Funding (self): Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD; Shareholder / Stockholder / Stock options: TheraCanVac Inc; Licensing / Royalties: Champions Oncology. G-C. Chang: Honoraria (self): F. Hoffmann–La Roche, Ltd, Eli Lilly and Company Oncology, AstraZeneca, Pfizer, Boehringer Ingelheim, Bristol-Myers Squibb, and Merck Sharp & Dohme. Y-C. Kim: Honoraria (self): AstraZeneca, Roche, Boehringer Ingelheim; Research grant / Funding (self): AstraZeneca, Roche, Boehringer Ingelheim. S. Geater: Honoraria (self): AstraZeneca, Boehringer Ingelheim, Roche; Advisory / Consultancy: Boehringer Ingelheim; Research grant / Funding (institution): AstraZeneca, Boehringer Ingelheim, Roche, MSD; Travel / Accommodation / Expenses: AstraZeneca, Boehringer Ingelheim, Roche. S. Saeteng: Honoraria (self): AstraZeneca, Novartis : Speaker. Y. Goto: Speaker Bureau / Expert testimony: AstraZeneca, Eli Lilly, Chugai, Taiho Pharmaceutical, Boehringer Ingelheim, Ono Pharmaceutical, Bristol-Myers Squibb, Pfizer, MSD, Shionogi Pharma, Novartis; Advisory / Consultancy: Eli Lilly, Chugai, Taiho Pharmaceutical, Boehringer Ingelheim, Pfizer, Novartis, AstraZeneca, Glaxo Smith Kline; Research grant / Funding (self): AbbVie, Eli Lilly, Taiho Pharmaceutical, Bristol-Myers Squibb, Ono Pharmaceutical, Daiichi Sankyo, Pfizer, Novartis, Kyorin. S. Lu: Research grant / Funding (self): AstraZeneca, Hutchison, Roche; Advisory / Consultancy: AstraZeneca, Boehringer Ingelheim, Hutchison MediPharma, Simcere, Roche; Honoraria (self): AstraZeneca, Roche. A. Ardizzoni: Advisory / Consultancy: MDS, Roche; Honoraria (self): MSD, BMS, Pfizer, Lilly; Research grant / Funding (self): BMS, Celgene, Roche; Leadership role: Member Educational Committee. F. Barlesi: Honoraria (self): AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly Oncology,. P. De Marchi: Advisory / Consultancy: Roche, Bayer, Msd, BMS, Pfizer, AstraZeneca; Speaker Bureau / Expert Testimony: Roche, Bayer, MSD, BMS, Pfizer, AstraZeneca; Travel / Accommodation / Expenses: Roche, MSD, BMS, AstraZeneca. L. Paz-Ares: Advisory / Consultancy: Roche, Lilly, Novartis, Pfizer, BMS, MSD, Takeda, AstraZeneca, Boehringer Ingelheim, Bayer, Janssen, Celgene; Honoraria (self): Roche, Lilly, Novartis, Pfizer, BMS, MSD, Amgen, Merck, Sanofi, Takeda, AstraZeneca, Boehringer Ingelheim, Bayer, Janssen, PharmaMar, Celgene. D.R. Spigel: Advisory / Consultancy: AbbVie (Inst); Amgen (Inst); AstraZeneca (Inst); Boehringer Ingelheim (Inst); Bristol-Myers Squibb (Inst); Celgene (Inst); Evelo Therapeutics (Inst); Foundation Medicine (Inst); Genentech/Roche (Inst); GlaxoSmithKline (Inst); Illumina (Inst); Lilly (Inst); Research grant / Funding (institution): AbbVie (Inst); Acerta Pharma (Inst); Aeglea Biotherapeutics (Inst); Amgen (Inst); ARMO BioSciences (Inst); Astellas Pharma (Inst); AstraZeneca (Inst); Boehringer Ingelheim (Inst); Bristol-Myers Squibb (Inst); Celgene (Inst); Celldex (Inst); Clovis Oncolog; Travel / Accommodation / Expenses: AstraZeneca; Boehringer Ingelheim; Bristol-Myers Squibb; Celgene; EMD Serono; Genentech; Genzyme; Intuitive Surgical; Lilly; Merck; Pfizer; Purdue Pharma; Spectrum Pharmaceuticals; Sysmex. M. Thomas: Advisory / Consultancy: Novartis, Lilly, Pfizer, Bristol-Myers Squibb, Roche, AstraZeneca, Boehringer Ingelheim, MSD; Honoraria (self): Roche, Bristol-Myers Squibb, Lilly, AstraZeneca, Novartis, Pfizer, Boehringer Ingelheim, MSD; Research grant / Funding (self): Roche, BMS, MSD, AstraZeneca, Takeda. E.B. Garon: Advisory / Consultancy: Dracen, EMD Serono; Research grant / Funding (self): AstraZeneca, BMS, Eli Lilly, Genentech, Merck, Novartis, Neon, Iovance, Dynavax, Mirati. M. Leung: Shareholder / Stockholder / Stock options: Novartis; Full / Part-time employment: Novartis. J. Baum: Shareholder / Stockholder / Stock options: Novartis stock; Full / Part-time employment: Novartis. Spouse (Lauren Baum) – Abbot Laboratories. Z. Zewen: Full / Part-time employment: Novartis; Shareholder / Stockholder / Stock options: Novartis. B. Mookerjee: Full / Part-time employment: Novartis; Shareholder / Stockholder / Stock options: Novartis, GlaxoSmithKline, Incyte, AstraZeneca. J.C-H. Yang: Advisory / Consultancy: Boehringer Ingelheim, Eli Lilly, Bayer, Roche/Genentech, Chugai Pharmaceutical, MSD, Merck Serono, Pfizer, Novartis, Celgene, Merrimack, Yuhan Pharmaceuticals, BMS, Ono Pharmaceuticals, Daiichi-Sankyo, Hansoh Pharmaceuticals, Takeda Pharmaceuticals, Bluep; Honoraria (self): Boehringer Ingelheim, Eli Lilly, Bayer, Roche/Genentech, Chugai Pharmaceutical, MSD, Merck Serono, Pfizer, Novartis, Celgene, Merrimack, Yuhan Pharmaceuticals, BMS, Ono Pharmaceuticals, Daiichi-Sankyo, Hansoh Pharmaceuticals, Takeda Pharmaceuticals, Bluep; Leadership role: IASLC CME activity: Author/Board of Directors/Presenter/Reviewer. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a chronic, relapsing, and highly pruritic inflammatory skin disease affecting up to 20% of children and 1% of adults worldwide. Current evidence suggests that both impairment of epidermal barrier function and T helper 2 cell-mediated inflammatory pathway contribute to the pathogenesis of AD. Exosomes are nano-sized membrane-bound vesicles (30 – 200 nm) constantly released by almost all cells. The ability of exosomes to travel between cells and deliver genetic materials, such as microRNAs and proteins, makes them an appealing cell-free therapy option to treat multiple diseases by overcoming many drawbacks of cell-based therapy. In particular, exosomes derived from mesenchymal stem cells (MSCs) have been shown to facilitate tissue repair and regeneration, and reduce inflammation. Here, we for the first time investigated whether human adipose tissue-derived mesenchymal stem cell-derived exosomes (ASC-exosomes) can ameliorate AD. Human ASC-exosomes were isolated from the serum-free conditioned media by sequential filtration method and characterized as recommended by the International Society for Extracellular Vesicles (ISEV). AD-like skin lesions were induced in mice by treatment with a house dust mite antigen or a chemical irritant. When injected either intravenously (IV) or subcutaneously (SC) into murine model of AD, ASC-exosomes were found to significantly attenuate AD-like symptoms, such as skin lesion severity, serum IgE levels, and infiltrated mast cells. It was also found that ASC-exosomes significantly decreased mRNA levels of various inflammatory cytokines, such as interleukin (IL)-4, IL-23, IL31, and tumor necrosis factor-α (TNF-α) in AD skin lesions. Furthermore, ASC-exosomes led to the improvement of skin barrier function as evidenced by enhanced skin hydration and reduced trans-epidermal water loss (TEWL) in skin lesions. Taken together, our data suggests that ASC-exosomes could be a novel promising cell-free therapeutic modality for AD treatment. [ABSTRACT FROM AUTHOR]

Abstract Purpose Stereotactic body radiation therapy is a promising treatment modality for locally advanced pancreatic cancer. To determine the optimal radiation treatment, we compared the plan characteristics of volumetric-modulated arc therapy and intensity-modulated radiation therapy when administered with stereotactic body radiation therapy to treat pancreatic cancer. Patients and methods Fifteen patients with locally advanced pancreatic cancer were treated by stereotactic body radiation therapy at a dose of 24–32 Gy in four fractions with marker-guided gated volumetric-modulated arc therapy. Four dimensional-computed tomography scans were used to assess the target and surrounding normal organs. The same images, contours, and dose constraints were used for dual-arc volumetric-modulated arc therapy and 9-field intensity-modulated radiation therapy planning. Plans were compared using dosimetric parameters and treatment performance. Results Volumetric-modulated arc therapy required significantly lower monitor units (1726 vs. 4188; P < 0.001) and shorter treatment delivery time in comparison with intensity-modulated radiation therapy (22.5 min vs. 52.4 min; P < 0.001). Regarding target volume coverage, both modalities demonstrated comparable results (V 95% , 99.3% vs. 99.4%; P = 0.796). Both modalities satisfied the dosimetric determinants for duodenal toxicity and the maximum and mean doses administered to normal organ were also statistically similar. Conclusion In comparison with 9-field intensity-modulated radiation therapy, volumetric-modulated arc therapy significantly reduces the number of monitoring units and treatment delivery times while administering similar dosimetric quality. Based on these results, volumetric-modulated arc therapy might be an appropriate treatment for locally advanced pancreatic cancer when combined with stereotactic body radiation therapy. [ABSTRACT FROM AUTHOR]

Patients with non-small-cell lung cancer (NSCLC) whose tumours harbour activating mutations within the epidermal growth factor receptor (EGFR) frequently derive significant clinical and radiographic benefits from treatment with EGFR tyrosine kinase inhibitors (TKIs). As such, prospective identification of EGFR mutations is now the standard of care worldwide. However, acquired therapeutic resistance to these agents invariably develops. Over the past 10 years, great strides have been made in defining the molecular mechanisms of EGFR TKI resistance in an effort to design rational strategies to overcome this acquired drug resistance. Approximately 60% of patients with acquired resistance to the EGFR TKIs (erlotinib, gefitinib, and afatinib) develop a new mutation within the drug target. This mutation—T790M—has been shown to alter drug binding and enzymatic activity of the mutant EGF receptor. Less common mechanisms of acquired resistance include MET amplification, ERBB2 amplification, transformation to small-cell lung cancer, and others. Here, we present a condensed overview of the literature on EGFR -mutant NSCLC, paying particular attention to mechanisms of drug resistance, recent clinical trial results, and novel strategies for identifying and confronting drug resistance, while also striving to identify gaps in current knowledge. These advances are rapidly altering the treatment landscape for EGFR -mutant NSCLC, expanding the armamentarium of available therapies to maximize patient benefit. [ABSTRACT FROM AUTHOR]