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Introduction: Patients with advanced ALK-positive non-small cell lung cancer (NSCLC) typically have poor response to immunotherapy; the benefit of consolidation durvalumab in patients with unresectable stage III ALK-positive NSCLC remains unclear. Herein, we compare the efficacy and safety of consolidation ALK tyrosine kinase inhibitor (TKI) versus durvalumab or observation after concurrent chemoradiation (cCRT)., Methods: We conducted a retrospective study using a multi-center study of 17 institutions globally. Patients with unresectable stage III ALK-positive NSCLC treated between 2015-2022 were included. Patients received ALK TKI, durvalumab, or observation after cCRT. Real-world progression-free survival (rwPFS) and overall survival (OS) were estimated using Kaplan-Meier method. Treatment-related adverse events (trAE) were classified by Common Terminology Criteria for Adverse Events v5.0. Outcomes were assessed by multivariable Cox regression analysis., Results: Sixty-seven patients were included, of whom 39 (58%) were female. Median age was 57 years (IQR: 49-67). Fifteen received consolidation ALK TKI, 30 received durvalumab, and 22 underwent observation. Baseline characteristics were similar across the 3 groups other than differences in race. After adjusting for stage, age, and nodal status, median rwPFS was significantly longer for ALK TKI (rwPFS not reached [NR], 95% CI 22.7-NR) versus durvalumab (11.3 months, 95% CI 8.9-18.5, hazard ratio [HR]=0.12, 95% CI: 0.026-0.5, p-adjusted=0.006) or observation (7.2 months, 95% CI 3.4-10.6, HR=0.04, 95% CI: 0.009-0.2, p-adjusted<0.0001). Durvalumab significantly improved median rwPFS compared to observation (HR=0.37, 95% CI: 0.19-0.71, p-adj = 0.002, p-adjusted=0.002). Median OS in the ALK TKI and durvalumab cohorts was significantly improved compared to patients on observation (ALK TKI-observation: p=0.04; durvalumab-observation: p=0.03). TrAE of any grade occurred in 8 (53%) and 11 (37%) patients treated with ALK-TKI and durvalumab, respectively. Grade ≥3 trAEs occurred in 27% (n=4) of patients treated with ALK TKI and 6.7% of patients treated with durvalumab., Conclusions: Patients with ALK-positive NSCLC experience significantly improved rwPFS when treated with consolidation ALK TKI therapy, surpassing outcomes seen with either durvalumab or observation. While both ALK TKI therapy and durvalumab offer an extension in OS compared to observation alone, it appears that ALK TKI therapy is the superior choice, underscoring its pivotal role in enhancing patient survival., (Crown Copyright © 2024. Published by Elsevier Inc. All rights reserved.)

Introduction: Durvalumab improves survival when used as consolidation therapy after chemoradiation (CRT) in patients with stage III NSCLC. The optimal consolidation therapy for patients with EGFR-mutant (EGFRmut) stage III NSCLC remains unknown., Methods: In this multi-institutional, international retrospective analysis across 24 institutions, we evaluated outcomes in patients with stage III EGFRmut NSCLC treated with concurrent CRT followed by consolidation therapy with osimertinib, durvalumab, or observation between 2015 and 2022. Kaplan-Meier method was used to estimate real-world progression-free survival (rwPFS, primary end point) and overall survival (secondary end point). Treatment-related adverse events (trAEs) during consolidation treatment were defined using Common Terminology Criteria for Adverse Events version 5.0. Multivariable Cox regression analysis was used., Results: Of 136 patients with stage III EGFRmut NSCLC treated with definitive concurrent CRT, 56 received consolidation durvalumab, 33 received consolidation osimertinib, and 47 was on observation alone. Baseline characteristics were similar across the three cohorts. With a median follow-up of 46 months for the entire cohort, the median duration of treatment was not reached (NR) for osimertinib (interquartile range: NR-NR) and was 5.5 (interquartile range: 2.4-10.8) months with durvalumab. After adjusting for nodal status, stage III A/B/C, and age, patients treated with consolidation osimertinib had significantly longer 24-month rwPFS compared to those treated with durvalumab or in the observation cohorts (osimertinib: 86%, durvalumab: 30%, observation: 27%, p < 0.001 for both comparisons). There was no difference in rwPFS between the durvalumab and the observation cohorts. No significant difference in overall survival across the three cohorts was detected, likely due to the limited follow-up. Any-grade trAE occurred in 52% (2 [6.1%] grade ≥3) and 48% (10 [18%] grade ≥3) of patients treated with osimertinib and durvalumab, respectively. Of 45 patients who progressed on consolidation durvalumab, 37 (82%) subsequently received EGFR tyrosine kinase inhibitors. Of these, 14 (38%) patients developed trAEs including five patients with pneumonitis (14%; 2 [5.4%] grade ≥3) and five patients with diarrhea (14%; 1 [2.7%] grade ≥3)., Conclusions: This study suggests that among patients with stage III unresectable NSCLC with a sensitizing EGFR mutation, consolidation osimertinib was associated with a significantly longer rwPFS compared to durvalumab or observation. No unanticipated safety signals were observed with consolidation osimertinib., Competing Interests: Disclosure Dr. Nassar receives honoraria from OncLive, TEMPUS, and Korean Society for Medical Oncology and consulting fees from Guidepoint Global. Dr. Kim is on the advisory board for Amgen. Dr. Shepherd reports having stock and other ownership interests from Eli Lilly and AstraZeneca; receiving honoraria from AstraZeneca, Merck Serono, Takeda, and Daiichi Sankyo; having consulting/advisory role at AstraZeneca and Merck Serono; and receiving research funding from Eli Lilly (inst), Pfizer (inst), Bristol-Myers Squibb (inst), AstraZeneca/MedImmune (inst), and Roche Canada (inst). Dr. Gray reports receiving grants from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, G1 Therapeutics, Ludwig Institute of Cancer Research, Merck & Co., Inc., Novartis, and Pfizer; receiving consulting fees from AbbVie, AstraZeneca, Blueprint Medicines, EMD Serono, Gilead Sciences, Inc., Janssen Scientific Affairs, LLC, Jazz Pharmaceuticals, Loxo Oncology Inc., Merck & Co., Inc., Novartis, OncoCyte Biotechnology, Spectrum ODAC, Takeda Pharmaceuticals, and Triptych Health Partners; and having leadership role as SWOG Lung Committee Chair, IASLC Board of Director member, and ASCO Education Committee Ex-Chair. Dr. Dilling reports receiving consulting fees from AstraZeneca and support for travel from NCCN. Dr. Neal reports receiving grants from Genentech/Roche, Merck, Novartis, Boehringer Ingelheim, Exelixis, Nektar Therapeutics, Takeda Pharmaceuticals, Adaptimmune, GlaxoSmithKline, Janssen, AbbVie, and Novocure; receiving consulting fees from AstraZeneca, Genentech/Roche, Exelixis, Takeda Pharmaceuticals, Eli Lilly and Company, Amgen, Iovance Biotherapeutics, Blueprint Pharmaceuticals, Regeneron Pharmaceuticals, Natera, Sanofi/Regeneron, D2G Oncology, Surface Oncology, Turning Point Therapeutics, Mirati Therapeutics, Gilead Sciences, AbbVie, Summit Therapeutics, Novartis, Novocure, Janssen Oncology, and AnHeart Therapeutics; and receiving honorarium from CME Matters, Clinical Care Options CME, Research to Practice CME, Medscape CME, Biomedical Learning Institute CME, MLI Peerview CME, Prime Oncology CME, Projects in Knowledge CME, Rockpointe CME, MJH Life Sciences CME, Medical Educator Consortium, and HMP Education. Dr. Wakelee reports receiving grants from Arrys Therapeutics Research, AstraZeneca/Medimmune, Bristol-Myers Squibb, Genentech/Roche, Merck, Helsinn, Seagen, and Xcovery; and serving on the advisory board of Mirati (compensated)—ended November 2022, IOBiotech (compensated)—October 2023, Merck (NOT compensated), and Genentech/Roche/Bristol-Myers Squibb/AstraZeneca (NOT compensated). Dr. S.H. Lin reports receiving grants from STCube Pharmaceuticals, Beyond Spring, and Nektar Therapeutics; consulting fees from XRAD Therapeutics; serving on the advisory board of AstraZeneca; having stock/stock options from Apple, Google, Amazon, Tesla, Meta, Rivian, and CreatvMicrotech; and having other support from SEEK Diagnostics (co-founder). Dr. Patil reports receiving grants from Gilead Research Scholars and LUNGevity Foundation Award; consulting fees from AstraZeneca, Boehringer Ingelheim, Bicara, Daiichi, Janssen, Jazz Pharmaceuticals, Mirati Therapeutics, Pfizer, Sanofi, Regeneron, Roche/Genentech, Takeda, Gilead Research Scholars, and LUNGevity Foundation Award; and honorarium from Janssen. Dr. Bar reports receiving grants from Merck Sharp & Dohme, AstraZeneca, Roche, Bristol-Myers Squibb, Takeda, AbbVie, Bayer, Boehringer Ingelheim, and Pfizer; receiving consulting fees from AstraZeneca, Merck Sharp & Dohme, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Takeda, AbbVie, Pfizer, Bayer, and VBL; and having leadership role from Lung Ambition Consortium, Israel Lung Cancer Group, and IASLC committee. Dr. Marron receives grants from Regeneron, Bristol-Myers Squibb, Merck, Boehringer Ingelheim, NCI, and Cancer Research Institute; and serving on the advisory board of AbbVie, Celldex, and Rockefeller University. Dr. Yu receives grants/contracts from AstraZeneca, Pfizer, Daiichi Cullinan Oncology, Janssen, Novartis, Blueprint med, Black Diamond, and Systimmune and consulting fees from AstraZeneca, Daiichi, Taiho, Takeda, Janssen, Amgen, AbbVie, Novocure, and Ipsen. Dr. Owen receives grants/contracts from Bristol-Myers Squibb, Merck, Palobiofarma, Genentech, Onc.AI, and Pfizer; and travel support from Amgen, AstraZeneca, and Genentech. Rocha receives grants/contracts from SEOM, ESMO Fellowship, and AECC; and travel support from Merck Sharp & Dohme, AstraZeneca, and Bristol-Myers Squibb. Dr. Arriola receives grants/contracts from AstraZeneca and Bristol-Myers Squibb; honorarium from Eli Lilly, AstraZeneca, Roche, Takeda, Merck Sharp & Dohme, Pfizer, Janssen, and Bristol-Myers Squibb; and travel support from AstraZeneca, Roche, and Pfizer. Dr. Cheng receives grants/contracts from AstraZeneca and Genentech; and serving on the advisory board of Janssen, G1 Therapeutics, and AstraZeneca. Dr. Parikh receives consulting fees from Jazz Pharmaceuticals, Guardant Health, and AstraZeneca; and honorarium from MJH Life Sciences. Dr. Harris receives grants/contract from NIH P30CA062203, the UC Irvine Comprehensive Cancer Center using UCI Anti-Cancer Challenge Grant, and ACS Seed Grant 129801-IRG-16-187-13-IRG; and serving on the advisory board of UC Irvine as DSMB member. Dr. Nagasaka receives consulting fees from Caris Life Sciences; honorarium/speaker fees from AstraZeneca, Daiichi, Novartis, EMD Serono self, Pfizer, Eli Lilly, Genentech, Regeneron, Takeda, Janssen, Blueprint, and Mirati; travel support from AnHeart Therapeutics; and stock/stock options from Mbrace Therapeutics. Dr. Valazquez receives grants/contracts from ASCO, American Association for Cancer Research (AACR), LUNGevity, NIA P30AG015272, NCI 5U54CA242646-03 Conquer Cancer and Niarchos Foundation, UCSF Clinical Practice Group, and AAMC; consulting fees from AstraZeneca, Merus, Novocure, and Cadence Communications & Research; and having stock/stock options from Corbus Pharmaceuticals. Dr. J.J. Lin receives grants/contracts from Hengrui Therapeutics, Turning Point Therapeutics, Neon Therapeutics, Relay Therapeutics, Bayer, Elevation Oncology, Roche, Linnaeus Therapeutics, Nuvalent, and Novartis; consulting fees from Genentech, C4 Therapeutics, Blueprint Medicines, Nuvalent, Bayer, Elevation Oncology, Novartis, Mirati Therapeutics, AnHeart Therapeutics, Takeda, CLaiM Therapeutics, Regeneron, Pfizer, Turning Point Therapeutics, Daiichi Sankyo, AstraZeneca, and Merus. Dr. Piotrowska receives grants/contracts from Novartis, Takeda, Spectrum, AstraZeneca, Tesaro/GlaxoSmithKline, Cullinan Oncology, Daiichi Sankyo, AbbVie, Janssen, and Blueprint; consulting fees from Taiho, Janssen, Takeda, AstraZeneca, Cullinan Oncology, C4 Therapeutics, Jazz Pharmaceuticals, and Blueprint; and honorarium from Daiichi Sankyo, Janssen, and Eli Lilly (honoraria for nonpromotional educational events). Dr. Reuss receives grants/contracts from Genentech/Roche, Verastem, Nuvalent, and LUNGevity Foundation; consulting fees from Genentech/Roche, Sanofi/Genzyme, Personalis, Guardant, AstraZeneca, Bristol-Myers Squibb, Arcus, AbbVie, Daiichi Sankyo, Catalym, Seagen, and Gilead; and honorarium from AstraZeneca and Merck. Dr. Baena Espinar receives consulting fees from AstraZeneca, Roche, and Merck Sharp & Dohme; honorarium from AstraZeneca, Roche, and Merck Sharp & Dohme; payment for expert testimony from Roche; and travel support from Roche and Janssen. Leal receives research funding to institution from Pfizer, Advaxis, and Bayer, outside the submitted work. Dr. Mak receives grants/contracts from ViewRay; consulting fees from AstraZeneca, Novartis, and Sio Capital Management; and other support from Founder of HealthAI. Dr. Naqash receives grants/contracts from SWOG Hope Foundation and FDA Broad Agency Contract; serving on the advisory board of JCO Precision Oncology; receiving travel support from SITC/American Association for Cancer Research (AACR)/Conquer Cancer Foundation/BinayTara Foundation and Foundation Med/Caris Life Sciences, and Jazz Pharmaceuticals; and funding to institution for trials from Loxo@Lilly, Surface Oncology, ADC Therapeutics, IGM Biosciences, EMD Serono, Aravive, Nikang Therapeutics, Inspirna, Exelexis, Revolution Medicine, Jacobio, Pionyr, Jazz Pharmaceuticals, NGM Biopharmaceuticals, Immunophotonics, and Selexine. Dr. Goldberg receives grants/contracts from AstraZeneca, Boehringer Ingelheim, and Mirati; and serving on the advisory board of AstraZeneca, Bristol-Myers Squibb, Amgen, Sanofi, Genzyme, Daiichi Sankyo, Regeneron, Takeda, Janssen, Summit, and Merck. The remaining authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: Osimertinib is recommended by major guidelines for use in the adjuvant setting in patients with EGFR mutation-positive NSCLC following the significant improvement in disease-free survival observed in the Phase III ADAURA trials. Due to limited real-world data in the adjuvant setting, little guidance exists on how to approach potential recurrences either during or after the completion of the treatment. This study aimed to reach a broad consensus on key treatment decision criteria in the events of recurrence., Methods: To reach a broad consensus, a modified Delphi panel study was conducted consisting of two rounds of surveys, followed by two consensus meetings and a final offline review of key statements. An international panel of experts in the field of NSCLC (n=12) was used to provide clinical insights regarding patient management at various stages of NSCLC disease including patient monitoring, diagnostics, and treatment approach for specific recurrence scenarios. This study tested recurrences occurring 1) within or outside the central nervous system (CNS), 2) during or after the adjuvant-osimertinib regimen in NSCLC disease which is 3) amenable or not amenable to local consolidative therapy., Results: Panellists agreed on various aspects of patient monitoring and diagnostics including the use of standard techniques (e.g., CT, MRI) and tumour biomarker assessment using tissue and liquid biopsies. Consensus was reached on 6 statements describing treatment considerations for the specific NSCLC recurrence scenarios. Panellists agreed on the value of osimertinib as a monotherapy or as part of the overall treatment strategy within the probed recurrence scenarios and acknowledged that more clinical evidence is required before precise recommendations for specific patient populations can be made., Discussion: This study provides a qualitative expert opinion framework for clinicians to consider within their treatment decision-making when faced with recurrence during or after adjuvant-osimertinib treatment., Competing Interests: NL reports research funding from Amgen, AstraZeneca Canada, Bayer, EMD Serono, Guardant Health, Lilly, MSD, MSD Oncology, Roche Canada, and Takeda; travel and accommodation support from Merck Sharp & Dohme. CN reports advisor to Medtronic, Johnson & Johnson; speaker fees from AstraZeneca, Merck Sharp & Dohme, Roche, Medtronic, Johnson & Johnson. DP reports being an advisor to AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, Novartis, Pfizer, Roche, Janssen, and Abbvie; honoraria from AstraZeneca, Bristol-Myers Squibb, Celgene, Eli Lilly, Merck, Novartis, Pfizer, Roche, Janssen, and Abbvie; travel and accommodation grants from AstraZeneca, Roche, Novartis, and Pfizer; and conducting clinical trials research as principal or co-investigator institutional financial interests for AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, Medimmun, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo, Abbvie, and Janssen. SP reports consultancy to Amgen, AstraZeneca, Bayer, BeiGene, Blueprint, BMS, Boehringer Ingelheim, Daiichi Sankyo, EQRx, GlaxoSmithKline, Guardant Health, Janssen, Lilly, Merck KGaA, MSD, Novartis, Pfizer, Roche, Sanofi, Seattle Genetics, Takeda, and Turning Point Therapeutics. JR reports being an advisor to AbbVie, Amgen, AstraZeneca, BioAtla, BMS, Daichi-Sankyo, G1 Therapeutics, Genentech, Gritstone Bio, Guardant, Janssen, Lilly, Jazz, Summit Therapeutics Takeda; speaker fees from AstraZeneca; institutional research funding from BioAtla, AbbVie, AstraZeneca, Blueprint, RedCloud, Loxo Oncology, Daiichi Sankyo, Enliven, ORIC, and Summit. ES reports being an advisor to AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Lilly, Merck KGaA, MSD Oncology, Novartis, Roche/Genentech, Seagen, and Takeda; honoraria from AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo/Astra Zeneca, and Merck KGaA; research funding from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, and Roche/Genentech. RS reports being an advisor to Amgen, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Janssen, Lily, Merck, Merck Serono, Novartis, Pfizer, Puma, Roche, Taiho, Takeda, Thermo Fisher, Yuhan and has received research grants from AstraZeneca and Boehringer Ingelheim. MT reports being an advisor to AstraZeneca Japan, Chugai Pharma, Lilly Japan, MSD, Novartis and MiREXS; honoraria from AstraZeneca Japan, Bristol-Myers Squibb Japan, Chugai Pharma, Johnson & Johnson, Lilly Japan, Medtronic, MSD K.K, Novartis, Ono Pharmaceutical, Taiho Pharmaceutical, and Teijin Pharma; research funding from AstraZeneca Japan, Boehringer Ingelheim KK, Bristol-Myers Squibb KK, Merck, Ono Pharmaceutical, BMG Incorporated, and MiREXS. FY reports speaker fees from MSD, Pfizer, Roche, AstraZeneca, and Bristol-Myers Squibb. BS reports wife’s employment with PPD and Xalud Therapeutics; leadership at Verrica Pharmaceuticals; stock and other ownership interests in Pfizer, PPD, and Xalud Therapeutics; personal honoraria from AstraZeneca, Bristol Myers Squibb, Genentech, and Pfizer; consulting or advisor role at AstraZeneca, Gala Therapeutics, Medtronic, Arcus Biosciences, and Pfizer; research funding from Bristol Myers Squibb Foundation; patents, royalties, and other intellectual property related with a therapeutic antibody targeting ART1, an extracellular mono-ADP ribosyltransferase, for the treatment of cancer patent application filed; other relationship with Lung Cancer Research Foundation and Lungevity. CG reports being an advisor to AstraZeneca, Boehringer Ingelheim, and MSD Oncology; honoraria from AstraZeneca, Boehringer Ingelheim, Lilly, MSD Oncology, Novartis, Roche, and Takeda; research funding from AstraZeneca; travel and accommodation support from Boehringer Ingelheim, Bristol-Myers Squibb, and Roche. Y-LW reports being an advisor to AstraZeneca, Boehringer Ingelheim, Roche, and Takeda; honoraria from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb/China, Hengrui Pharmaceutical, Lilly, MSD Oncology, Pfizer, and Roche; research funding from Boehringer Ingelheim, Pfizer, and Roche. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Mirza, Shrivastava, Matthews, Leighl, Ng, Planchard, Popat, Rotow, Smit, Soo, Tsuboi, Yang, Stiles, Grohe and Wu.)

Purpose: The phase III ADAURA (ClinicalTrials.gov identifier: NCT02511106) primary analysis demonstrated a clinically significant disease-free survival (DFS) benefit with adjuvant osimertinib versus placebo in EGFR-mutated stage IB-IIIA non-small-cell lung cancer (NSCLC) after complete tumor resection (DFS hazard ratio [HR], 0.20 [99.12% CI, 0.14 to 0.30]; P < .001). We report an updated exploratory analysis of final DFS data., Methods: Overall, 682 patients with stage IB-IIIA (American Joint Committee on Cancer/Union for International Cancer Control, seventh edition) EGFR-mutated (exon 19 deletion/L858R) NSCLC were randomly assigned 1:1 (stratified by stage, mutational status, and race) to receive osimertinib 80 mg once-daily or placebo for 3 years. The primary end point was DFS by investigator assessment in stage II-IIIA disease analyzed by stratified log-rank test; following early reporting of statistical significance in DFS, no further formal statistical testing was planned. Secondary end points included DFS in stage IB-IIIA, overall survival, and safety. Patterns of recurrence and CNS DFS were prespecified exploratory end points., Results: At data cutoff (April 11, 2022), in stage II-IIIA disease, median follow-up was 44.2 months (osimertinib) and 19.6 months (placebo); the DFS HR was 0.23 (95% CI, 0.18 to 0.30); 4-year DFS rate was 70% (osimertinib) and 29% (placebo). In the overall population, DFS HR was 0.27 (95% CI, 0.21 to 0.34); 4-year DFS rate was 73% (osimertinib) and 38% (placebo). Fewer patients treated with osimertinib had local/regional and distant recurrence versus placebo. CNS DFS HR in stage II-IIIA was 0.24 (95% CI, 0.14 to 0.42). The long-term safety profile of osimertinib was consistent with the primary analysis., Conclusion: These updated data demonstrate prolonged DFS benefit over placebo, reduced risk of local and distant recurrence, improved CNS DFS, and a consistent safety profile, supporting the efficacy of adjuvant osimertinib in resected EGFR-mutated NSCLC.

Purpose: In the phase III ADAURA trial, adjuvant treatment with osimertinib versus placebo, with/without prior adjuvant chemotherapy, resulted in a statistically significant and clinically meaningful disease-free survival benefit in completely resected stage IB-IIIA EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC). We report health-related quality of life (HRQoL) outcomes from ADAURA., Patients and Methods: Patients randomized 1:1 received oral osimertinib 80 mg or placebo for 3 years or until recurrence/discontinuation. HRQoL (secondary endpoint) was measured using the Short Form-36 (SF-36) health survey at baseline, 12, and 24 weeks, then every 24 weeks until recurrence or treatment completion/discontinuation. Exploratory analyses of SF-36 score changes from baseline until week 96 and time to deterioration (TTD) were performed in the overall population (stage IB-IIIA; N = 682). Clinically meaningful changes were defined using the SF-36 manual., Results: Baseline physical/mental component summary (PCS/MCS) scores were comparable between osimertinib and placebo (range, 46-47) and maintained to Week 96, with no clinically meaningful differences between arms; difference in adjusted least squares (LS) mean [95% confidence intervals (CI), -1.18 (-2.02 to -0.34) and -1.34 (-2.40 to -0.28), for PCS and MCS, respectively. There were no differences between arms for TTD of PCS and MCS; HR, 1.17 (95% CI, 0.82-1.67) and HR, 0.98 (95% CI, 0.70-1.39), respectively., Conclusions: HRQoL was maintained with adjuvant osimertinib in patients with stage IB-IIIA EGFRm NSCLC, who were disease-free after complete resection, with no clinically meaningful differences versus placebo, further supporting adjuvant osimertinib as a new treatment in this setting. See related commentary by Patil and Bunn, p. 2204., (©2022 The Authors; Published by the American Association for Cancer Research.)

Introduction: Adjuvant chemotherapy is recommended in patients with resected stages II to IIIA (and select IB) NSCLC; however, recurrence rates are high. In the phase 3 ADAURA study (NCT02511106), osimertinib was found to have a clinically meaningful improvement in disease-free survival (DFS) in patients with resected stages IB to IIIA EGFR-mutated (EGFRm) NSCLC. Here, we report prespecified and exploratory analyses of adjuvant chemotherapy use and outcomes from ADAURA., Methods: Patients with resected stages IB to IIIA EGFRm NSCLC were randomized 1:1 to receive osimertinib or placebo for 3 years. Adjuvant chemotherapy before randomization was not mandatory, per physician and patient choice. DFS in the overall population (IB-IIIA), with and without adjuvant chemotherapy, was a prespecified analysis. Exploratory analyses included the following: adjuvant chemotherapy use by patient age, disease stage, and geographic location; DFS by adjuvant chemotherapy use and disease stage., Results: Overall, 410 of 682 patients (60%) received adjuvant chemotherapy (osimertinib, n = 203; placebo, n = 207) for a median duration of 4.0 cycles. Adjuvant chemotherapy use was more frequent in patients: aged less than 70 years (338 of 509; 66%) versus more than or equal to 70 years (72 of 173; 42%); with stages II to IIIA (352 of 466; 76%) versus stage IB (57 of 216; 26%); and enrolled in Asia (268 of 414; 65%) versus outside of Asia (142 of 268; 53%). A DFS benefit favoring osimertinib versus placebo was observed in patients with (DFS hazard ratio = 0.16, 95% confidence interval: 0.10-0.26) and without adjuvant chemotherapy (hazard ratio = 0.23, 95% confidence interval: 0.13-0.40), regardless of disease stage., Conclusions: These findings support adjuvant osimertinib as an effective treatment for patients with stages IB to IIIA EGFRm NSCLC after resection, with or without previous adjuvant chemotherapy., (Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) are standard of care in the first-line (1L) setting for patients with metastatic non-small cell lung cancer (mNSCLC) with activating EGFR mutations. EGFR-activating mutations are a predictive factor for response to EGFR-TKIs. Meta-analyses have shown that patients with exon 21&#95;L858R mutations exhibit reduced sensitivity to EGFR-TKIs, resulting in inferior patient outcomes compared to those with exon 19 deletion mutations, with worse overall survival, progression-free survival, objective response, and disease control rates. Clinical activity observed with 1L therapy with first-generation (1G), second-generation (2G), and third-generation (3G) EGFR-TKIs is not permanent, and resistance inevitably develops in all cases, supporting the importance of overall treatment planning. The introduction of the 3G EGFR-TKI, osimertinib, provides an opportunity to overcome T790M-mediated resistance to 1G, and 2G EGFR-TKIs. Additionally, with the use of osimertinib, fewer T790M mutations are being detected as T790M is not a reported resistance mechanism to 3G EGFR-TKIs. However, there are currently no approved targeted therapies after 3G EGFR-TKIs. In order to further improve patient outcomes, there is a need to explore additional options for the overall treatment strategy for patients, including 1L and beyond. Combination of vascular endothelial growth factor (VEGF) inhibitors and EGFR-TKIs or chemotherapy and EGFR-TKIs may be a potential therapeutic approach in the 1L setting. This review discusses current treatment options for mNSCLC with activating EGFR mutations based on tumor, patient, and treatment characteristics and how an overall treatment plan may be developed., (Copyright © 2021 Eli Lilly and Company. Published by Elsevier Inc. All rights reserved.)

Here, we summarize the initial results from the ADAURA clinical study looking at treatment with osimertinib in patients with a specific type of non-small cell lung cancer (also called NSCLC). Osimertinib (TAGRISSO®) is a medication used to treat a type of NSCLC with a change (mutation) in the EGFR gene, known as EGFR-mutated NSCLC. EGFR stands for 'epidermal growth factor receptor'. It is a protein present on the surface of both healthy and cancer cells that can regulate how cells grow and divide. Sometimes, certain mutations in EGFR can result in the EGFR protein malfunctioning, which can lead to the formation of cancer, like EGFR-mutated NSCLC. Based on previous clinical studies, osimertinib is already approved for use in patients with EGFR-mutated NSCLC that has spread beyond the lung (metastatic disease). This medication works to stop, prevent, or slow the growth of EGFR-mutated NSCLC tumors, by specifically blocking the activity of EGFR. In the ADAURA clinical study, participants had resectable EGFR-mutated NSCLC, which means they had tumors that can be removed by surgery. Participants took either osimertinib or a placebo (a dummy drug with no active ingredient) after having their tumors removed by surgery. Post-surgery chemotherapy was allowed, but not compulsory (this was decided by the participant and their doctor). To date, the study has shown that osimertinib could be beneficial for patients with resectable EGFR-mutated NSCLC. Participants who took osimertinib have stayed cancer-free for longer than those who took the placebo, regardless of whether or not they received chemotherapy after surgery. Osimertinib treatment also reduced the risk of tumors spreading to the brain and spinal cord, otherwise known as the central nervous system (also called CNS). The side effects experienced by the participants taking osimertinib have been consistent with what we already know. Based on the results from ADAURA, osimertinib has been approved for the treatment of resectable EGFR-mutated NSCLC after tumor removal. The ADAURA study is still ongoing and more results are expected to be released in the future. ClinicalTrials.gov NCT number: NCT02511106.

Background: Pirfenidone has been shown to slow disease progression in patients with idiopathic pulmonary fibrosis (IPF). However, there are few treatment options for progressive fibrotic interstitial lung diseases (ILDs)) other than IPF. In view of the pathomechanistic and clinical similarities between IPF and other progressive fibrotic ILDs, we aimed to assess the efficacy and safety of pirfenidone in patients with four non-IPF progressive fibrotic ILDs., Methods: We did a multicentre, double-blind, randomised, placebo-controlled, parallel phase 2b trial (RELIEF) in 17 centres with expertise in ILD in Germany. Eligible participants were patients aged 18-80 years with progressive fibrotic ILD due to four diagnoses: collagen or vascular diseases (ie, connective tissue disease-associated ILDs), fibrotic non-specific interstitial pneumonia, chronic hypersensitivity pneumonitis, or asbestos-induced lung fibrosis. Other eligibility criteria included a forced vital capacity (FVC) of 40-90% predicted, a diffusing capacity of the lung for carbon monoxide of 10-90% predicted, and an annual decline of FVC of at least 5% predicted despite conventional therapy, based on at least three measurements within 6-24 months before enrolment. Patients who had received any previous antifibrotic therapy were excluded. We randomly assigned patients (1:1) to either oral pirfenidone (267 mg three times per day in week 1, 534 mg three times per day in week 2, and 801 mg three times per day thereafter) or matched placebo, added to their ongoing medication. Randomisation was done centrally using permuted block randomisation with varying block sizes stratified by the four diagnostic groups. Patients, investigators, statisticians, monitors, and the study coordinator were masked to treatment assignment until database closure. The placebo-controlled study period was 48 weeks (including up-titration). The primary endpoint was absolute change in percentage of predicted FVC (FVC % predicted) from baseline to week 48 in the intention-to-treat population, with imputation of missing data by the smallest sum of squared differences and attribution of deceased patients to the lowest rank in a rank ANCOVA model. Additionally, we did linear mixed-model repeated measures slope analyses of FVC % predicted longitudinal data over the course of the study as a prespecified sensitivity analysis and post-hoc sensitivity analyses of the primary endpoint in the intention-to-treat population using imputation methods of last observation carried forward [LOCF] and a regression-based multiple imputation procedure. Safety was assessed in all patients who received at least one dose of study medication. This trial is registered with EudraCT 2014-000861-32; DRKS00009822 and is no longer recruiting., Findings: Between April 5, 2016, and Oct 4, 2018, we randomly assigned 127 patients to treatment: 64 to pirfenidone, 63 to placebo. After 127 patients had been randomised, the study was prematurely terminated on the basis of an interim analysis for futility triggered by slow recruitment. After 48 weeks and in the overall population of 127 patients, rank ANCOVA with diagnostic group included as a factor showed a significantly lower decline in FVC % predicted in the pirfenidone group compared with placebo (p=0·043); the result was similar when the model was stratified by diagnostic group (p=0·042). A significant treatment effect was also observed when applying the LOCF and multiple imputation methods to analyses of the primary endpoint. The median difference (Hodges-Lehmann estimate) between pirfenidone and placebo groups for the primary endpoint was 1·69 FVC % predicted (95% CI -0·65 to 4·03). In the linear mixed-model repeated measures slope analysis of FVC % predicted, the estimated difference between treatment and placebo groups from baseline to week 48 was 3·53 FVC % predicted (95% CI 0·21 to 6·86) with imputation of deaths as prespecified, or 2·79 FVC % predicted (95% CI 0·03 to 5·54) without imputation. One death (non-respiratory) occurred in the pirfenidone group (2%) and five deaths (three of which were respiratory) occurred in the placebo group (8%). The most frequent serious adverse events in both groups were infections and infestations (five [8%] in the pirfenidone group, ten [16%] in the placebo group); general disorders including disease worsening (two [3%] in the pirfenidone group, seven [11%] in the placebo group); and cardiac disorders (one ([2%] in the pirfenidone group, 5 [8%] in the placebo group). Adverse events (grade 3-4) of nausea (two patients on pirfenidone, two on placebo), dyspnoea (one patient on pirfenidone, one on placebo), and diarrhoea (one patient on pirfenidone) were also observed., Interpretation: In view of the premature study termination, results should be interpreted with care. Nevertheless, our data suggest that in patients with fibrotic ILDs other than IPF who deteriorate despite conventional therapy, adding pirfenidone to existing treatment might attenuate disease progression as measured by decline in FVC., Funding: German Center for Lung Research, Roche Pharma., Competing Interests: Declaration of interests JB reports personal fees from Boehringer Ingelheim, Bristol Myers Squibb, Biogen, Galapagos, Promedior, Roche, and the German Center for Lung Research (DZL). SB reports personal fees and non-financial support from Roche, Bayer, Novartis, and Boehringer Ingelheim; personal fees from Merck Serono; and non-financial support from Teva, Gilead, Lucane Pharma, Actelion, CSL Behring, and Vertex. FB reports personal fees for consultancy, lecturing, and travel support from Boehringer Ingelheim and Roche. MC reports grants from DZL. JHF reports personal fees, grants, and non-financial support from Roche; and personal fees and non-financial support from Boehringer Ingelheim. AG reports grants from DZL, Boehringer Ingelheim, and Roche. MH reports grants from Actelion; honoraria for lectures from Actelion, Bayer Healthcare, Berlin Chemie, Boehringer Ingelheim, GlaxoSmithKline (GSK), Merck Sharp & Dohme (MSD), Novartis, OMT, Pfizer, and Roche; honoraria for advisory boards from Actelion, Bayer, Boehringer Ingelheim, GSK, MSD, and Roche; and honoraria for clinical trials from Actelion, Bayer, GSK, Pfizer, and United Therapeutics. NKn reports personal fees from Roche. DK reports personal fees from Roche; and personal fees and non-financial support from Boehringer Ingelheim. MK reports grants from DZL; and grants and personal fees from Boehringer Ingelheim and Roche. AP reports grants from DZL; grants, personal fees, and non-financial support from Boehringer Ingelheim and AstraZeneca; personal fees and non-financial support from Roche, Pliant, Chiesi Pharmaceuticals, and Nitto Denko; personal fees from Amgen; and non-financial support from Galapagos. KFR reports grants and personal fees from Boehringer Ingelheim and AstraZeneca; and personal fees from Novartis, Sanofi, Regeneron, Roche, and Chiesi Pharmaceuticals. TW reports grants from Roche; and personal fees from Boehringer Ingelheim, Roche, and Novartis. HWil reports personal fees for lectures or consultations from Actelion–Janssen, Bayer, Biotest, Boehringer Ingelheim, GSK, Pfizer, and Roche. HWir reports lecture fees from Roche. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Osimertinib is standard-of-care therapy for previously untreated epidermal growth factor receptor ( EGFR ) mutation-positive advanced non-small-cell lung cancer (NSCLC). The efficacy and safety of osimertinib as adjuvant therapy are unknown., Methods: In this double-blind, phase 3 trial, we randomly assigned patients with completely resected EGFR mutation-positive NSCLC in a 1:1 ratio to receive either osimertinib (80 mg once daily) or placebo for 3 years. The primary end point was disease-free survival among patients with stage II to IIIA disease (according to investigator assessment). The secondary end points included disease-free survival in the overall population of patients with stage IB to IIIA disease, overall survival, and safety., Results: A total of 682 patients underwent randomization (339 to the osimertinib group and 343 to the placebo group). At 24 months, 90% of the patients with stage II to IIIA disease in the osimertinib group (95% confidence interval [CI], 84 to 93) and 44% of those in the placebo group (95% CI, 37 to 51) were alive and disease-free (overall hazard ratio for disease recurrence or death, 0.17; 99.06% CI, 0.11 to 0.26; P<0.001). In the overall population, 89% of the patients in the osimertinib group (95% CI, 85 to 92) and 52% of those in the placebo group (95% CI, 46 to 58) were alive and disease-free at 24 months (overall hazard ratio for disease recurrence or death, 0.20; 99.12% CI, 0.14 to 0.30; P<0.001). At 24 months, 98% of the patients in the osimertinib group (95% CI, 95 to 99) and 85% of those in the placebo group (95% CI, 80 to 89) were alive and did not have central nervous system disease (overall hazard ratio for disease recurrence or death, 0.18; 95% CI, 0.10 to 0.33). Overall survival data were immature; 29 patients died (9 in the osimertinib group and 20 in the placebo group). No new safety concerns were noted., Conclusions: In patients with stage IB to IIIA EGFR mutation-positive NSCLC, disease-free survival was significantly longer among those who received osimertinib than among those who received placebo. (Funded by AstraZeneca; ADAURA ClinicalTrials.gov number, NCT02511106.)., (Copyright © 2020 Massachusetts Medical Society.)

Claudins are integral components of tight junctions (TJs) in epithelia and endothelia. When expressed in cell lines devoid of TJs, claudins are able to form TJ-like strands at contacts between adjacent cells. According to a current model of TJ strand formation, claudin protomers assemble in an antiparallel double row within the plasma membrane of each cell (cis-interaction) while binding to corresponding double rows from the neighboring cells (trans-interaction). Cis-interaction was proposed to involve two interfaces of the protomers' first extracellular segment (extracellular loop (ECL)1). In the current study, three naturally occurring claudin-10 isoforms and two claudin-10 chimeras were used to investigate strand formation. All constructs were able to interact in cis (Förster/fluorescence resonance energy transfer (FRET)), to integrate into TJs of MDCK-C7 cells (confocal laser scanning microscopy), and to form TJ-like strands in HEK293 cells (freeze-fracture electron microscopy). Strand formation occurred despite the fact that isoform claudin-10a&#95;i1 lacks both structural ECL1 elements reported to be crucial for cis-interaction. Furthermore, results from FRET experiments on claudin-10 chimeras indicated that identity of the first transmembrane region rather than ECL1 is decisive for claudin-10 cis-interaction. Therefore, in addition to the interaction interfaces suggested in the current model for TJ strand assembly, alternative interfaces must exist., (© 2017 New York Academy of Sciences.)

Ion channels involved in cardiac excitation-contraction coupling are linked to the cytoskeleton. Therefore changes in the cytoskeletal actin filaments may influence cardiac membrane currents and electro-mechanical coupling. Depolymerization of actin filaments by gelsolin (gsn) is involved in the organisation of the cytoskeleton by leading to a lower polymerization state. Gsn is activated by Ca(2+) and inhibited by phosphoinositol-bisphosphate (PIP2). Furthermore, gsn has been linked to pathological conditions with reduced contractility like heart failure, amyloidosis and apoptosis. Thus, we hypothesize, that gsn deficiency may change electromechanical properties of freshly isolated ventricular cardiomyocytes. We recorded L-type Ca(2+) current (ICa,L) in whole-cell patch clamp mode in freshly isolated ventricular cardiomyocytes from gsn deficient ((-/-)) and control (gsn(+/+)) mice. Sarcomere shortening was monitored in field-stimulated myocytes from 0.5 Hz to 10 Hz by video microscopy. Shortening-frequency relation, post-rest potentiation and β-adrenergic stimulation were investigated. ICa,L was increased in gsn(-/-) vs. gsn(+/+) myocytes. Sarcomere shortening amplitude and velocity were enhanced in gsn(-/-) vs. gsn(+/+) at all frequencies. Shortening-frequency relationship showed a biphasic pattern with decay in shortening amplitude between 0.5 and 2 Hz and an increase at higher frequencies in both genotypes. Post-rest characteristics revealed a frequency-dependent decay of post-rest potentiation in gsn(+/+) while it remained stable in gsn(-/-). In gsn(-/-) a reduced response to β-adrenergic stimulation was observed. Resting sarcomere length was shorter in gsn(-/-) but neither increasing frequency nor β-adrenergic stimulation induced further decay in any of the genotypes. In summary, gsn deficiency had a profound effect on excitiation-contraction properties and improved systolic function while not affecting diastolic function in unloaded isolated cardiomyocytes. Therefore, gsn mediated effects on contractility may play a role in patients with heart failure and cancer, where gsn levels are known to be elevated.

Background: Patients with squamous non-small-cell lung cancer that is refractory to multiple treatments have poor outcomes. We assessed the activity of nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, for patients with advanced, refractory, squamous non-small-cell lung cancer., Methods: We did this phase 2, single-arm trial at 27 sites (academic, hospital, and private cancer centres) in France, Germany, Italy, and USA. Patients who had received two or more previous treatments received intravenous nivolumab (3 mg/kg) every 2 weeks until progression or unacceptable toxic effects. The primary endpoint was the proportion of patients with a confirmed objective response as assessed by an independent radiology review committee. We included all treated patients in the analyses. This study is registered with ClinicalTrials.gov, number NCT01721759., Findings: Between Nov 16, 2012, and July 22, 2013, we enrolled and treated 117 patients. 17 (14·5%, 95% CI 8·7-22·2) of 117 patients had an objective response as assessed by an independent radiology review committee. Median time to response was 3·3 months (IQR 2·2-4·8), and median duration of response was not reached (95% CI 8·31-not applicable); 13 (77%) of 17 of responses were ongoing at the time of analysis. 30 (26%) of 117 patients had stable disease (median duration 6·0 months, 95% CI 4·7-10·9). 20 (17%) of 117 patients reported grade 3-4 treatment-related adverse events, including: fatigue (five [4%] of 117 patients), pneumonitis (four [3%]), and diarrhoea (three [3%]). There were two treatment-associated deaths caused by pneumonia and ischaemic stroke that occurred in patients with multiple comorbidities in the setting of progressive disease., Interpretation: Nivolumab has clinically meaningful activity and a manageable safety profile in previously treated patients with advanced, refractory, squamous non-small cell lung cancer. These data support the assessment of nivolumab in randomised, controlled, phase 3 studies of first-line and second-line treatment., Funding: Bristol-Myers Squibb., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Sarcoidosis is a systemic granulomatous disease with unknown etiology. Lungs and lymph nodes are commonly affected. Also, cases of pulmonary hypertension (PH) and pulmonary arterial hypertension (PAH) are described. However, the exact prevalence of PAH in patients with sarcoidosis is unclear. A 111 patients with proven sarcoidosis were recruited from January 2010 to October 2010. All patients were studied prospectively by transthoracic echocardiography (TTE) for the presence of PH. In assumed PH, a right heart catheterization (RHC) followed if there were no other reasons for PH. In 23 of the 111 patients (21%) PH was assumed in TTE. Three patients presented with severe mitral insufficiency III° and IV°, in eight patients PH was supposed to be caused by chronic heart failure or relevant diastolic dysfunction > II°, two patients declined undergoing RHC. Of the ten patients investigated with RHC, four showed a precapillary pulmonary arterial hypertension and in one patient a postcapillary hypertension was diagnosed. All four patients with precapillary PH had a radiologic stage III and IV. In three of the four patients a significantly reduced transfer factor for carbon monoxide (TLCO) <50% was found. All patients with precapillary PH had a chronic course of sarcoidosis lasting ≥13 years. This is the first study which prospectively investigated a large cohort of patients with sarcoidosis for the prevalence of PH and PAH. The prevalence of precapillary PH was found to be at least 3.6% (4/111) and therefore exceeds the prevalence of PAH in the normal population by far. A chronic and progressive lung involvement due to sarcoidosis seems to be the most evident risk factor for developing a sarcoidosis PH.

The etiology of inflammatory diseases of the lung like sarcoidosis and chronic obstructive pulmonary disease (COPD) is multifactorial. The main trigger for developing a COPD is tobacco smoking while exogenous factors causing sarcoidosis are unclear. In both diseases there is an underlying genetic susceptibility determining both the onset and the course of the diseases. Toll-like receptor (TLR)-9 plays an important role in innate immunity by recognizing bacterial CpG-DNA motifs. It is unclear whether single nucleotide polymorphisms (SNPs) in TLR-9 are able to alter the course of sarcoidosis or COPD, or raise the susceptibility for developing one of the disorders. We examined two SNPs in the promoter region of the TLR-9 gene (T1486C and T1237C) in 175 COPD patients (59% with a stable course of the disease, 41% with an instable course with more than 3 exacerbations over the last 3 years) and 166 sarcoidosis patients (19% with an acute and 81% with a chronic course of the disease lasting >2 years) comparing each group to 233 healthy controls. Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis was used for genotyping. The C-allele frequency of T1486C was significantly elevated in COPD patients (p = 0.008). For T1237C there were no significant associations comparing the COPD cohort with the controls. In the sarcoidosis cohort, we could observe a significantly higher prevalence of the C-allele for T1237C in the chronic sarcoidosis cohort in comparison to the control group (p = 0.026). For T1486 there no statistical association was observed. This is the first study showing an association between a SNP (T1486C) in the TLR-9 gene and the onset of COPD. Moreover, we could demonstrate that T1237C is able to alter the course of sarcoidosis as a disease-modifying gene. This study underlines that SNPs in TLR-9 might be involved in acquiring and maintaining lung diseases such as sarcoidosis and COPD.

In the 2009 European Guidelines on the diagnosis and treatment of pulmonary hypertension (PH), one section covers aspects of pathophysiology, diagnosis and treatment of chronic thromboembolic pulmonary hypertension (CTEPH). The practical implementation of the guidelines for this disease is of crucial importance, because CTEPH is a subset of PH which can potentially be cured by pulmonary endarterectomy (PEA). Nowadays, CTEPH is commonly underdiagnosed and not properly managed. Any patient with unexplained PH should be evaluated for the presence of CTEPH, and a ventilation/perfusion (V/Q) lung scan is recommended as screening method of choice. If the V/Q scan or CT angiography reveals signs of CTEPH, the patient should be referred to a specialized center with expertise in the medical and surgical management of this disease. Every case has to be reviewed by an experienced PEA surgeon for the assessment of operability. In this updated recommendation, important contents of the European guidelines were commented, and more recent information regarding diagnosis and treatment was added., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Over the last years, several new systemic cancer therapy strategies have been introduced to turn the growing insights of molecular aberrations involved in the development and progression of lung cancer into better treatment options fort the patients. This review presents some of the most important biological targets and biomarkers relevant in the treatment of non-small cell lung cancer. Especially EGFR mutations, anti-angiogenesis, multi kinase inhibition, vascular disrupting agents, vaccines, m-TOR inhibitors, TRAIL inhibition and several biomarkers are highlighted including current study results.

In the 2009 European Guidelines on pulmonary hypertension one section covers aspects of pathophysiology, diagnosis and treatment of chronic thromboembolic pulmonary hypertension (CTEPH). The practical implementation of the guidelines for this disease is of crucial importance, because CTEPH is a form of pulmonary hypertension which can be surgically cured. It is, however, frequently diagnosed late in the course of disease and often treated not correctly. In the European Guidelines CTEPH is addressed relatively briefly, although it is a common form of PH which is often overlooked. Any patient with unexplained PH should be evaluated for the presence of CTEPH. A ventilation/perfusion lung scan is recommended as the first step to exclude CTEPH. If the ventilation/perfusion lung scan or multislice CT angiography reveals perfusions defects suggesting the diagnosis of CTEPH, the patient should be referred to a centre with expertise in the medical and surgical management of these patients. After diagnosis of CTEPH the case has to be reviewed by an experienced surgeon in a PEA centre for assessment of operability. The recommendations of the European guidelines are summarized in the current manuscript with additional comments regarding diagnosis and treatment according to most recent evidence., (© Georg Thieme Verlag KG Stuttgart · New York.)

The aim of this study was to investigate whether the L-type calcium current (I(Ca.L)) may be altered in aged hearts and whether the classical calcium antagonist verapamil may exhibit altered pharmacological profile in aged hearts. We examined male New Zealand rabbits aged either 6 months or 26 months. To examine I(Ca.L) whole-cell patch-clamp technique was performed on isolated cells. Moreover, activation-recovery intervals (ARI) of isolated hearts (Langendorff method) were assessed using an epicardial 256 channel mapping system. We found that the I(Ca.L) density, normalised to the cell volume was significantly reduced (p<0.001). Maximum conductance was also significantly decreased (p=0.01) and steady state inactivation was shifted to more positive potentials in aged hearts (p<0.001). A slightly reduced effect of beta-adrenergic modulation of the I(Ca.L) in aged hearts, and a significantly reduced effect of carbachol on isoprenaline-stimulated I(Ca.L) in aged hearts was observed. L-type alpha 1c subunit, SERCA2-ATPase and the Na(+)/Ca(2+)-exchanger expression were neither significantly different in atrial and ventricular tissues nor between young and old animals. Using the mapping system, isolated hearts were exposed to verapamil (0.005, 0.01, 0.02, 0.05 microM/L). While verapamil did not affect ARI in young hearts, in aged hearts ARI was concentration-dependently reduced and the negative inotropic effect of verapamil was significantly attenuated in aged hearts (p<0.05). From these results we conclude that there are distinct alterations in the electrophysiology of I(Ca.L) (reduced maximum conductance, a shift of the steady state inactivation) in the aged heart which may influence the response to verapamil.

History and Clinical Findings: A 58-years-old non-smoking woman presented at our Thoracic Centre with increasing exertional dyspnea and on examination was found to have wheezing and decreased breath sounds over the left lung., Investigations: Chest X-ray revealed an atelectasis of the left anterobasal lung segment. Computed tomography revealed a 3.5 cm mass at the left inferior lobe. Bronchioscopy showed a total occlusion of the segmental bronchus because of an endobronchial tumor. Histology of a biopsy showed the tumor to be a carcinoid. Staging by whole-body ocreotide scintigraphy showed no evidence of metastases., Treatment and Course: The patient recovered quickly from resection of the left inferior lobe and radical lymphadenectomy. Two years later, she has remained free of symptoms and without evidence of recurrence., Conclusions: Although rare (ca. 1.0 % of all primary lung tumors), the differential diagnosis of dyspnea and uniliteral wheezing should include a bronchial carcinoid. It is a potentially curable tumor, if detected and treated early. An interdisciplinary approach is pivotal to its perioperative management.

Purpose: Outcomes in patients with brain metastases undergoing whole-brain radiotherapy (WBRT) are hardly encouraging, and an improvement in results is therefore needed. One possible approach is the addition of chemotherapeutics. However the data presented thus far are also disappointing. A promising substance in this setting could become topotecan, which is known to cross the blood-brain barrier and additionally offers radiosensitizing effects. Therefore we performed a phase I/II trial to evaluate the feasibility of a concurrent radiochemotherapy regimen., Methods and Materials: From January 1999 to July 2001, a total of 75 patients (10 in phase I and 65 in phase II) were included. The WBRT was applied with a fraction size of 2 Gy/day for a total of 40 Gy. Topotecan was administered as a 30-min infusion with 0.2 to 0.5 mg/m(2)/day for 5 days over 4 weeks within 2 h to radiation therapy., Results: Because of the higher toxic rates seen in patients receiving 0.5 mg/m(2)/day, the recommended dosage for phase II was 0.4 mg/m(2)/day. In this group Grade 3/4 hematologic and nonhematologic side effects occurred in 19% and 21% of the patients, respectively. The overall response rate was 72% with an overall survival of 17 weeks and 30 weeks among the responders., Conclusions: Based on the moderate toxicity profile presented here we recommend to perform a phase III trial to confirm the promising phase I/II data.

Female gender and estrogen-replacement therapy in postmenopausal women are associated with improved heart failure survival, and physiological replacement of 17beta-estradiol (E2) reduces infarct size and cardiomyocyte apoptosis in animal models of myocardial infarction (MI). Here, we characterize the molecular mechanisms of E2 effects on cardiomyocyte survival in vivo and in vitro. Ovariectomized female mice were treated with placebo or physiological E2 replacement, followed by coronary artery ligation (placebo-MI or E2-MI) or sham operation (sham) and hearts were harvested 6, 24, and 72 hours later. After MI, E2 replacement significantly increased activation of the prosurvival kinase, Akt, and decreased cardiomyocyte apoptosis assessed by terminal deoxynucleotidyltransferase dUTP nick-end labeling (TUNEL) staining and caspase 3 activation. In vitro, E2 at 1 or 10 nmol/L caused a rapid 2.7-fold increase in Akt phosphorylation and a decrease in apoptosis as measured by TUNEL staining, caspase 3 activation, and DNA laddering in cultured neonatal rat cardiomyocytes. The E2-mediated reduction in apoptosis was reversed by an estrogen receptor (ER) antagonist, ICI 182,780, and by phospho-inositide-3 kinase inhibitors, LY294002 and Wortmannin. Overexpression of a dominant negative-Akt construct also blocked E2-mediated reduction in cardiomyocyte apoptosis. These data show that E2 reduces cardiomyocyte apoptosis in vivo and in vitro by ER- and phospho-inositide-3 kinase-Akt-dependent pathways and support the relevance of these pathways in the observed estrogen-mediated reduction in myocardial injury.

Chronic heart failure is a major cause for mortality and morbidity in western civilizations. Previous hypothesises regarding the pathogenesis of chronic heart failure did not sufficiently explain the aetiology and the progression of the disease. However, it has been shown that a group of peptides called cytokines are expressed during chronic heart failure and that cytokines might play an important role for the pathogenesis. The expression of cytokines can be modulated from specific ACE-inhibitors as well as from different beta-blockers and angiotensin type 1 antagonists. Numerous investigations have shown that cytokines depress left ventricular function and can be responsible for different characteristics of chronic heart failure. The present article resumes experimental and clinical investigations and recent pharmacologic attempts for the treatment of chronic heart failure. The previous results demonstrate the importance to further investigate anti-inflammatory approaches to treat chronic heart failure.

Objectives: This study was designed to examine the effects of estrogen replacement on infarct size, ventricular remodeling, and mortality after myocardial infarction (MI) in mice., Background: Observational and clinical studies suggest that the cardiovascular effects of hormone replacement therapy can differ depending on the patient population studied. No prospective studies have examined the effect of estrogen on outcomes following MI. We now examine the effects of estrogen replacement on infarct size, ventricular remodeling, and mortality after MI in mice., Methods: Myocardial infarction was induced by left coronary artery ligation in ovariectomized female mice treated with 17-beta-estradiol (E2) or placebo. At either one day or six weeks after MI, hemodynamic function was assessed, animals were euthanized, and infarct size was determined., Results: 17-beta-estradiol-treated mice had smaller infarcts than placebo-treated animals both one day (18% decrease; p < 0.01), and six weeks (14% decrease; p < 0.05) following MI. E2 reduced cardiomyocyte apoptosis as assessed by the terminal deoxynucleotidyl transferase uridine nucleotide end-labeling method (50% reduction, p < 0.05) and caspase 3 activation (33% reduction, p < 0.05). Despite having smaller infarcts, however, left ventricular mass increased more in the E2-treated animals (16% greater; p < 0.01). Left ventricular weight was positively correlated with infarct size in the estrogen-treated animals (R2 = 0.79, p = 0.0001). 17-beta-estradiol treatment also significantly increased mortality in the infarcted animals (relative risk of death = 2.4; 95% confidence interval 1.2 to 5.3)., Conclusions: Estrogen replacement therapy reduces infarct size and cardiomyocyte apoptosis in mice. However, estrogen increased post-MI ventricular remodeling and mortality. Further studies will be necessary to elucidate the mechanisms underlying the complex effects of estrogen observed in the present study.

Knowledge of the developmental changes of cardiovascular parameters in the genetic background of a mouse strain is important for understanding phenotypic changes in transgenic or knockout mouse models for heart disease. We studied arterial blood pressure and myocardial contractility in mice of the common background strain C57BL/6, aged 21 days [postnatal day 21 (P21)] to 580 days. Heart rate increased during maturation from 396 beats/min at P21 to 551 beats/min at postnatal day 50 (P50), and mean arterial blood pressure increased in parallel from 86 to 110 mmHg and remained constant afterward. Echocardiographically determined left ventricular myocardial wall dimensions (R = 0.79, P < 0.0001) and left ventricular mass calculated using the area-length algorithm correlated strongly with histomorphometrical measurements (R = 0.93, P < 0.001). Sarcomere shortening records from isolated ventricular myocytes used as a measure for myocardial contractility revealed a negative shortening-frequency relation under a pacing frequency of 2 Hz and a positive relation above 2 Hz. Shortening amplitudes recorded from P21 myocytes were smaller, and the shortening-frequency relation was less steep than in adult myocytes. A stimulation pause was followed by a negative "staircase" at pacing frequency of < or =6 Hz and a positive staircase at > or =6 Hz. P21 myocytes developed positive staircases at 8 and 10 Hz, and adult myocytes also developed them at 6 Hz. Blood pressure increase during maturation until P50 may originate from increasing single cardiomyocyte contractility.

Cardiovascular diseases are the leading cause of death in the industrialised countries and display significant gender-based differences. Estrogen plays an important role in the pathogenesis of heart disease and is able to modulate the progression of cardiovascular disease. The focus on the beneficial influence of estrogen is gradually shifting from the vascular system to the myocardium. The presence of functional estrogen receptors in the myocardium has been demonstrated. Estrogen is important for cardiovascular baseline physiology and modulates the myocardial response under pathological conditions. Here we summarise the current knowledge of the regulatory network of estrogenic action in the myocardium and its effects on cardiovascular function.

Estrogen and insulin-like-growth factor 1 (IGF-1) are potent mitogenic stimuli that share important properties in the control of cellular proliferation. However, the coupling between the signaling cascades of estrogen receptors alpha and beta and the IGF-1 receptor (IGF-1R) is poorly understood. Therefore, we selectively transfected estrogen receptor alpha or beta in COS7 and HEK293 cells, which contain IGF-1R. In presence of estrogen receptor alpha but not beta, 17beta-estradiol (E2) rapidly induces phosphorylation of the IGF-1R and the extracellular signal-regulated kinases 1/2. Furthermore, upon stimulation with E2, estrogen receptor alpha but not beta bound rapidly to the IGF-1R in COS7 as well as L6 cells, which express all investigated receptors endogenously. Control experiments in the IGF-1R-deficient fibroblast cell line R(-) showed that after stimulation with E2 only estrogen receptor alpha bound to the transfected IGF-1R. Overexpression of dominant negative mitogen-activated protein kinases kinase inhibited this effect. Finally, estrogen receptor alpha but not beta is required to induce the activation of the estrogen receptor-responsive reporter ERE-LUC in IGF-1-stimulated cells. Taken together, these data demonstrate that ligand bound estrogen receptor alpha is required for rapid activation of the IGF-1R signaling cascade.

Purpose: To evaluate a T2-weighted URSE sequence for the assessment of pulmonary infiltrations in comparison to CT., Methods: 28 MRT scans of 22 patients with confirmed pneumonia were recorded on a 1.5 Tesla apparatus with an expiratory and diastolic triggered, T2-weighted ultrafast-spin-echo sequence in axial slice mode with the following parameters: TReff/TE/Turbo-factor 2000-4000/90 ms/21-23; slice thickness/separation 6/0.6 mm; FOV 360 mm; 24 slices. 24 spiral CTs (since thickness/table advance: 1-2 mm/10mm) were available for comparison. The separate evaluation of MRTs and CTs was performed by three radiologists in a consensus procedure with regard to pulmonary lesions (e.g., infiltration, round foci, net patterns) and image quality of the MRTs (4-step scale)., Results: In 71% of the cases the CTs and MRTs agreed with the diagnosis and representation of the lesions, in 25% MRT was superior. MRT was better for the detection of pulmonary abscesses. In 93% the image quality of the MRT was very good to good., Conclusions: MRT in the technique presented here is in most cases equal to CT for the detection of pneumonia. Diagnosis of pulmonary abscesses seems to be better with MRT.

A 41-year-old homosexual man complained about weight loss of 14 kg over a period of 6 months. He developed exertional dyspnea and fever up to 39.6 degrees C. The ESR was elevated and the fraction of immature neutrophils increased. Penicillin was administered with no effect, chest X-ray showed basal pulmonary infiltrates, P. carinii was found in bronchioalveolar fluid. HIV-serology was positive. Sulfamethoxazole/trimethoprim (1600/320 mg daily) and 100 mg of prednisolone/die led to reduction of fever. Prevention of P. carinii pneumonia relapse is currently underway with bi-weekly inhalation of pentamidine-isethionate aerosol.