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Culturable bacteria numbers, kinetics of colony formation, community structure analyses in terms of ecological (r/K-strategists) and cytochemical approaches were used to assess the bacteria responses to soil treatment with high concentrations of Cu or Cd over time. The soil treatment resulted in high concentrations of water-soluble forms of the metals. Bacterial numbers significantly decreased in the metal-treated soil shortly after the soil contamination, their numbers however increased during incubation time. The short- or long-term contact of bacteria with the metals significantly decreased or increased the rate of cell proliferations, respectively. The populations represented by slow-growing K-strategists dominated the structures of bacterial communities with time. The results of fatty acid methyl ester analyses indicated that Gram-positive bacteria dominated shortly after soil contamination; however, changes in the community structures with stimulation of Pseudomonas in the Cd-treated soil occurred after prolonged exposure to the metal. This study shows that short- or long-term exposition to heavy metals may cause different quantitative and qualitative effects on culturable bacteria in soil.

Abstract Background Adipokines such as leptin, visfatin and chemerin play a pivotal role not only in the pathogenesis of excessive weight gain but also impact on hepatic metabolism. However, alterations in the production of these peptides in the liver of overweight individuals have not been fully elucidated yet. The aim of the study was to evaluate changes in leptin, visfatin and chemerin biosynthesis in the liver of men with different BMI. Methods Fourteen adult men without symptoms from the digestive system were recruited. Research material consisted of liver samples. Study participants were divided into two groups: lean (BMI ≤ 25 kg/m2) and overweight subjects (BMI > 25 kg/m2). Paraffin liver sections were processed by immunohistochemistry for detection of leptin, visfatin and chemerin. Hepatic expression of leptin, visfatin and chemerin genes was determined by qRT-PCR method. Results Increased immunoreactivity for leptin and chemerin, and decreased immunoreaction for visfatin were observed in the liver of overweight men in comparison to lean subjects. Overweight subjects with hepatic steatosis displayed increased immunoreactivity for leptin and weaker immunoreaction against visfatin and chemerin in the liver, compared to individuals with normal organ structure. Expression of leptin and chemerin was enhanced in the liver of overweight individuals, with the highest expression observed in subjects with hepatic steatosis. Conversely, expression of visfatin in the male liver was decreased in overweight subjects and those with and liver steatosis. Conclusions The present study proves that the expression of leptin, visfatin and chemerin in the male liver is altered in overweight individuals. Our report also indicates the potential importance of these peptides in hepatic steatosis associated with overweight.

Abstract  Changes in microbial biomass and activity were determined in a sandy-loam soil treated with successive dosages of oxytetracycline (a bactericide) or captan (a fungicide) throughout 98 days of incubation under laboratory conditions. The numbers of culturable bacteria and fungi, total bacterial and fungal biomass (as amounts of phospholipid fatty acids, PLFA), the fungal/bacterial ratio, activities of acid and alkaline phosphatases and urease as well as concentrations of N-NH4 + and N-NO3 − were assessed. Both oxytetracycline and captan significantly decreased numbers of culturable bacteria whereas total bacterial biomass (bactPLFA) was not affected. Oxytetracycline did not effect on the fungal biomass, however their numbers were reduced after the first and second time of soil amendment with the bactericide. Conversely, fungal numbers and biomass (PLFA 18:2ω6,9) significantly decreased in response to soil treatment with the fungicide. Compared to oxytetracycline, captan significantly decreased activities of acid and alkaline phosphatases. For urease activity, the decreased activity was only observed in the soil after the third dosage of captan. Both biocides significantly increased concentrations of N-NH4 + and decreased concentrations of N-NO3 − after the soil treatments. The results of this study indicate that successive soil treatment with oxytetracycline or captan dosages may negatively affect non-target soil microorganisms and their activities. [ABSTRACT FROM AUTHOR]

Purpose: Temozolomide plus PARP inhibition has shown promise in small cell lung cancer (SCLC). We previously reported outcomes from the first 50 patients (cohort 1) of a phase I/II trial of olaparib/temozolomide in recurrent SCLC. Here, we report a final analysis of this trial, including a second cohort with an alternate dosing strategy and an exploratory analysis of CNS-specific outcomes., Methods: This was an open-label phase I/II trial testing the combination of olaparib and temozolomide in relapsed SCLC. The primary endpoint was ORR. Secondary endpoints were safety, PFS, and OS. We tested escalating doses of olaparib/temozolomide across two cohorts, both of which had temozolomide dosed on D1-7 of each 21-days cycle. In previously published cohort 1, olaparib was dosed on D1-7; in cohort 2 olaparib was dosed continuously., Results: Sixty-six patients were enrolled across the two cohorts, 50 in cohort 1 and 16 in cohort 2. The confirmed ORR of cohort 1 was 41.7% (20/48 evaluable), and the confirmed ORR of cohort 2 was 7% (1/14 evaluable; closed after dose escalation to enrollment for lack of observed efficacy). Among 15/66 patients (22.7%) with untreated brain metastases at enrollment, best overall intracranial response was CR in 6/15 patients, PR in 4/15 patients, and SD in 3/15 patients for a CNS disease control rate of 87% (95% CI: 59.5-98.3%)., Conclusions: Olaparib/temozolomide may be effective in relapsed SCLC, especially for patients with CNS disease. Ongoing analyses regarding optimal dosing schedule will inform potential for future use of this combination in SCLC.

Purpose: Seizure-related homolog protein 6 (SEZ6) is a novel target expressed in small cell lung cancer (SCLC). ABBV-011, a SEZ6-targeted antibody conjugated to calicheamicin, was evaluated in a phase I study (NCT03639194) in patients with relapsed/refractory SCLC. We report initial outcomes of ABBV-011 monotherapy., Patients and Methods: ABBV-011 was administered intravenously once every 3 weeks (Q3W) during dose escalation (0.3-2 mg/kg) and expansion. Patients with SEZ6-positive tumors (≥25% of tumor cells with ≥1+ staining intensity by immunohistochemistry) were preselected for expansion. Safety, tolerability, antitumor activity, and pharmacokinetics were evaluated., Results: As of August 2022, 99 patients received ABBV-011 monotherapy (dose escalation, n=36; Japanese dose evaluation, n=3; dose expansion, n=60 [1 mg/kg, n=40]); median age was 63 years (range, 41-79). Thirty-two percent, 41%, and 26% of patients received 1, 2, and ≥3 prior therapies, respectively. The maximum tolerated dose was not reached through 2.0 mg/kg. Most common treatment-emergent adverse events (TEAEs) were fatigue (50%), nausea (42%), and thrombocytopenia (41%). Most common hepatic TEAEs were increased aspartate aminotransferase (22%), increased g-glutamyltransferase (21%), and hyperbilirubinemia (17%); 2 patients experienced veno-occlusive liver disease. Objective response rate (ORR) was 19% (19/98). In the 1-mg/kg dose-expansion cohort (n=40), ORR was 25%; median response duration was 4.2 months (95% CI, 2.6-6.7) and median progression-free survival was 3.5 months (95% CI, 1.5-4.2)., Conclusions: ABBV-011 1.0 mg/kg Q3W monotherapy was well tolerated and demonstrated encouraging antitumor activity in heavily pretreated patients with relapsed/refractory SCLC. SEZ6 is a promising novel SCLC target and warrants further investigation.

Purpose: Histologic transformation to small cell lung cancer (SCLC) is a mechanism of treatment resistance in patients with advanced oncogene-driven lung adenocarcinoma (LUAD) that currently requires histologic review for diagnosis. Herein, we sought to develop an epigenomic cell-free DNA (cfDNA)-based approach to noninvasively detect small cell transformation in patients with EGFR mutant (EGFRm) LUAD., Experimental Design: To characterize the epigenomic landscape of transformed (t)SCLC relative to LUAD and de novo SCLC, we performed chromatin immunoprecipitation sequencing (ChIP-seq) to profile the histone modifications H3K27ac, H3K4me3, and H3K27me3; methylated DNA immunoprecipitation sequencing (MeDIP-seq); assay for transposase-accessible chromatin sequencing; and RNA sequencing on 26 lung cancer patient-derived xenograft (PDX) tumors. We then generated and analyzed H3K27ac ChIP-seq, MeDIP-seq, and whole genome sequencing cfDNA data from 1 mL aliquots of plasma from patients with EGFRm LUAD with or without tSCLC., Results: Analysis of 126 epigenomic libraries from the lung cancer PDXs revealed widespread epigenomic reprogramming between LUAD and tSCLC, with a large number of differential H3K27ac (n = 24,424), DNA methylation (n = 3,298), and chromatin accessibility (n = 16,352) sites between the two histologies. Tumor-informed analysis of each of these three epigenomic features in cfDNA resulted in accurate noninvasive discrimination between patients with EGFRm LUAD versus tSCLC [area under the receiver operating characteristic curve (AUROC) = 0.82-0.87]. A multianalyte cfDNA-based classifier integrating these three epigenomic features discriminated between EGFRm LUAD versus tSCLC with an AUROC of 0.94., Conclusions: These data demonstrate the feasibility of detecting small cell transformation in patients with EGFRm LUAD through epigenomic cfDNA profiling of 1 mL of patient plasma., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: The role of adding immune checkpoint inhibitors to chemotherapy in tyrosine kinase inhibitor (TKI)-resistant, epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) remains unknown. We carried out a meta-analysis to comprehensively assess the role of chemoimmunotherapy combinations, with and without vascular endothelial growth factor (VEGF) inhibition, in TKI-resistant, EGFR-mutant NSCLC., Materials and Methods: We systemically searched PubMed/MEDLINE and the proceedings of key annual meetings between 2018 and 2024 to identify randomized studies that evaluated chemoimmunotherapy combinations and included patients with EGFR-mutant NSCLC. Six randomized, phase III trials (CheckMate-722, KEYNOTE-789, ORIENT-31, IMpower150, IMpower151, and ATTLAS) were included in the meta-analysis. To compare progression-free survival (PFS) and overall survival (OS) outcomes, we extracted hazard ratio (HR) and 95% confidence interval (CI) for PFS and OS for EGFR-mutant subgroups from each study. We used the fixed effects model with inverse variance weighting to estimate the overall effect sizes for PFS and OS for chemoimmunotherapy combinations (with and without VEGF inhibitors) versus control arms., Results: A total of 1772 patients with EGFR-mutant NSCLC were included. Adding programmed death-ligand 1 [PD-(L)1] inhibitors to chemotherapy significantly improved PFS (HR 0.77, 95% CI 0.67-0.88, P = 0.0002). This effect was greater when both PD-(L)1 and VEGF inhibition were utilized (PFS: HR 0.62, 95% CI 0.52-0.73, P < 0.0001). The pooled OS HR was 0.86 (95% CI 0.75-1.00, P = 0.0429) with the chemotherapy + PD-(L)1 combinations and 0.98 (95% CI 0.79-1.22, P = 0.8463) with dual PD-(L)1/VEGF inhibition., Conclusions: Despite modest improvements in PFS, most pronounced when both PD-(L)1 and VEGF inhibitors are added to chemotherapy, neither strategy led to clinically meaningful improvements in OS. Our results do not support the broad use of chemoimmunotherapy combinations in TKI-resistant, EGFR-mutant lung cancer. Novel immunotherapy approaches are urgently needed for oncogene-driven NSCLC., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The role of tyrosine kinase inhibitors (TKIs) in early-stage and metastatic oncogene-driven non-small cell lung cancer (NSCLC) is established, but it remains unknown how best to integrate TKIs with concurrent chemoradiotherapy (cCRT) in locally advanced disease. The phase 2 ASCENT trial assessed the efficacy and safety of afatinib and cCRT with or without surgery in locally advanced epidermal growth factor receptor (EGFR)-mutant NSCLC., Patients and Methods: Adults ≥18 years with histologically confirmed stage III (AJCC 7th edition) NSCLC with activating EGFR mutations were enrolled at Mass General and Dana-Farber/Brigham Cancer Centers, Boston, Massachusetts. Patients received induction afatinib 40 mg daily for 2 months, then cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 IV every 3 weeks during RT (definitive or neoadjuvant dosing). Patients with resectable disease underwent surgery. All patients were offered consolidation afatinib for 2 years. The primary endpoint was the objective response rate (ORR) to induction TKI. Secondary endpoints were safety, conversion to operability, progression-free survival (PFS), and overall survival (OS). Analyses were performed on the intention-to-treat population., Results: Nineteen patients (median age 56 years; 74% female) were enrolled. ORR to induction afatinib was 63%. Seventeen patients received cCRT; 2/9 previously unresectable became resectable. Ten underwent surgery; 6 had a major or complete pathological response. Thirteen received consolidation afatinib. With a median follow-up of 5.0 years, median PFS and OS were 2.6 (95% CI, 1.4-3.1) and 5.8 years (2.9-NR), respectively. Sixteen recurred or died; 6 recurrences were isolated to CNS. The median time to progression after stopping consolidation TKI was 2.9 months (95% CI, 1.1-7.2). Four developed grade 2 pneumonitis. There were no treatment-related deaths., Conclusion: We explored the efficacy of combining TKI with cCRT in oncogene-driven NSCLC. Induction TKI did not compromise subsequent receipt of multimodality therapy. PFS was promising, but the prevalence of CNS-only recurrences and rapid progression after TKI discontinuation speak to unmet needs in measuring and eradicating micrometastatic disease., (© The Author(s) 2024. Published by Oxford University Press.)

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.)

Purpose: Although several agents targeting epidermal growth factor receptor ( EGFR ) exon 20 insertions (ex20ins) have recently been approved by the US Food and Drug Administration, toxicities related to the inhibition of wild-type (WT) EGFR are common with these agents and affect overall tolerability. Zipalertinib (CLN-081, TAS6417) is an oral EGFR tyrosine kinase inhibitor (TKI) with a novel pyrrolopyrimidine scaffold leading to enhanced selectivity for EGFR ex20ins-mutant versus WT EGFR with potent inhibition of cell growth in EGFR ex20ins-positive cell lines., Methods: This phase 1/2a study of zipalertinib enrolled patients with recurrent or metastatic EGFR ex20ins-mutant non-small-cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy., Results: Seventy-three patients were treated with zipalertinib at dose levels including 30, 45, 65, 100, and 150 mg orally twice a day. Patients were predominantly female (56%), had a median age of 64 years, and were heavily pretreated (median previous systemic therapies 2, range 1-9). Thirty six percent of patients had received previous non-ex20ins EGFR TKIs and 3/73 (4.1%) patients received previous EGFR ex20ins TKIs. The most frequently reported treatment-related adverse events of any grade included rash (80%), paronychia (32%), diarrhea (30%), and fatigue (21%). No cases of grade 3 or higher drug-related rash or diarrhea were observed at 100 mg twice a day or below. Objective responses occurred across all zipalertinib dose levels tested, with confirmed partial response (PR) observed in 28/73 (38.4%) response-evaluable patients. Confirmed PRs were seen in 16/39 (41%) response-evaluable patients at the dose of 100 mg twice a day., Conclusion: Zipalertinib has encouraging preliminary antitumor activity in heavily pretreated patients with EGFR ex20ins-mutant NSCLC, with an acceptable safety profile, including low frequency of high-grade diarrhea and rash.

Introduction: Thoracic radiotherapy (TRT) is increasingly used in patients receiving osimertinib for advanced NSCLC, and the risk of pneumonitis is not established. We investigated the risk of pneumonitis and potential risk factors in this population., Methods: We performed a multi-institutional retrospective analysis of patients under active treatment with osimertinib who received TRT between April 2016 and July 2022 at two institutions. Clinical characteristics, including whether osimertinib was held during TRT and pneumonitis incidence and grade (Common Terminology Criteria for Adverse Events version 5.0) were documented. Logistic regression analysis was performed to identify risk factors associated with grade 2 or higher (2+) pneumonitis., Results: The median follow-up was 10.2 months (range: 1.9-53.2). Of 102 patients, 14 (13.7%) developed grade 2+ pneumonitis, with a median time to pneumonitis of 3.2 months (range: 1.5-6.3). Pneumonitis risk was not significantly increased in patients who continued osimertinib during TRT compared with patients who held osimertinib during TRT (9.1% versus 15.0%, p  = 0.729). Three patients (2.9%) had grade 3 pneumonitis, none had grade 4, and two patients had grade 5 events (2.0%, diagnosed 3.2 mo and 4.4 mo post-TRT). Mean lung dose was associated with the development of grade 2+ pneumonitis in multivariate analysis (OR = 1.19, p  = 0.021)., Conclusions: Although the overall rate of pneumonitis in patients receiving TRT and osimertinib was relatively low, there was a small risk of severe toxicity. The mean lung dose was associated with an increased risk of developing pneumonitis. These findings inform decision-making for patients and providers., (© 2023 The Authors.)

Acquired drug resistance to anticancer targeted therapies remains an unsolved clinical problem. Although many drivers of acquired drug resistance have been identified 1-4 , the underlying molecular mechanisms shaping tumour evolution during treatment are incompletely understood. Genomic profiling of patient tumours has implicated apolipoprotein B messenger RNA editing catalytic polypeptide-like (APOBEC) cytidine deaminases in tumour evolution; however, their role during therapy and the development of acquired drug resistance is undefined. Here we report that lung cancer targeted therapies commonly used in the clinic can induce cytidine deaminase APOBEC3A (A3A), leading to sustained mutagenesis in drug-tolerant cancer cells persisting during therapy. Therapy-induced A3A promotes the formation of double-strand DNA breaks, increasing genomic instability in drug-tolerant persisters. Deletion of A3A reduces APOBEC mutations and structural variations in persister cells and delays the development of drug resistance. APOBEC mutational signatures are enriched in tumours from patients with lung cancer who progressed after extended responses to targeted therapies. This study shows that induction of A3A in response to targeted therapies drives evolution of drug-tolerant persister cells, suggesting that suppression of A3A expression or activity may represent a potential therapeutic strategy in the prevention or delay of acquired resistance to lung cancer targeted therapy., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

The concept of the study resulted from numerous concerns around bisphenol A (BPA) and bisphenol S (BPS) in aquatic environments. In this study, river water and sediment microcosms highly polluted with bisphenols and bioaugmented with two BPs-removing bacterial strains were constructed. The study aimed to determine the rate of high-concentrated BPA and BPS (BPs) removal from river water and sediment microniches, and the effect of water bioaugmentation with bacterial consortium on the removal rates of these pollutants. Moreover, the impact of introduced strains and exposure to BPs on the structural and functional composition of the autochthonous bacterial communities was elucidated. Our findings indicate that the removal activity of autochthonous bacteria was sufficient for effectively BPA elimination and reducing BPS content in the microcosms. The number of introduced bacterial cells decreased continuously until day 40, and on consecutive sampling days, no bioaugmented cells were detected. Sequencing analysis of the total 16S rRNA genes revealed that the community composition in bioaugmented microcosms amended with BPs differed significantly from those treated either with bacteria or BPs. A metagenomic analysis found an increase in the abundance of proteins responsible for xenobiotics removal in BPs-amended microcosms. This study provides new insights into the effects of bioaugmentation with a bacterial consortium on bacterial diversity and BPs removal in aquatic environments., (© 2023. The Author(s).)

Purpose: The uncommon EGFR exon 19 deletion (ex19del), L747&#95;A750>P, demonstrates reduced sensitivity to osimertinib compared with the common ex19del, E746&#95;A750del in preclinical models. The clinical efficacy of osimertinib in patients with non-small cell lung cancer harboring L747&#95;A750>P and other uncommon ex19dels is not known., Experimental Design: The AACR GENIE database was interrogated to characterize the frequency of individual ex19dels relative to other variants, and a multicenter retrospective cohort was used to compare clinical outcomes for patients with tumors harboring E746&#95;A750del, L747&#95;A750>P, and other uncommon ex19dels who received osimertinib in the first line (1L) or in second or later lines of therapy and were T790M+ (≥2L)., Results: ex19dels comprised 45% of EGFR mutations, with 72 distinct variants ranging in frequency from 28.1% (E746&#95;A750del) to 0.03%, with L747&#95;A750>P representing 1.8% of the EGFR mutant cohort. In our multi-institutional cohort (N = 200), E746&#95;A750del was associated with significantly prolonged progression-free survival (PFS) with 1L osimertinib versus L747&#95;A750>P [median 21.3 months (95% confidence interval, 17.0-31.7) vs. 11.7 months (10.8-29.4); adjusted HR 0.52 (0.28-0.98); P = 0.043]. Osimertinib efficacy in patients with other uncommon ex19dels varied on the basis of the specific mutation present., Conclusions: The ex19del L747&#95;A750>P is associated with inferior PFS compared with the common E746&#95;A750del mutation in patients treated with 1L osimertinib. Understanding differences in osimertinib efficacy among EGFR ex19del subtypes could alter management of these patients in the future., (©2023 American Association for Cancer Research.)

Background and Objective: Lineage transformation is a known mechanism of acquired resistance to targeted therapies in non-small cell lung cancer (NSCLC). Transformation to small cell and squamous carcinoma and epithelial-to-mesenchymal transition (EMT) have all been identified as recurrent but rare events in ALK-positive NSCLC. However, centralized data informing our understanding of the biology and clinical implications of lineage transformation in ALK-positive NSCLC are lacking., Methods: We performed a narrative review by searching the PubMed and clinicaltrials.gov databases for articles published in English from August, 2007 until October, 2022 and reviewing the bibliographies of key references to identify important literature related to lineage transformation in ALK-positive NSCLC., Key Content and Findings: In this review, we aimed to synthesize the published literature describing the incidence, mechanism(s), and clinical outcomes of lineage transformation in ALK-positive NSCLC. Lineage transformation as a mechanism of resistance to ALK TKIs in ALK-positive NSCLC is reported at a frequency of <5%. Available data across molecular subtypes of NSCLC suggest that the process of lineage transformation is likely to be driven by transcriptional reprogramming rather than acquired genomic mutations. Retrospective cohorts including tissue-based translational studies together with clinical outcomes make up the highest level of evidence that exists to inform treatment approach for patients with transfomed ALK-positive NSCLC., Conclusions: The clinicopathologic features of transformed ALK-positive NSCLC as well as the biologic mechanisms underling lineage transformation remain incompletely understood. Prospective data are needed to develop improved diagnostic and treatment algorithms for patients with ALK-positive NSCLC that undergo lineage transformation., Competing Interests: Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-867/coif). The series "ALK Positive NSCLC” was commissioned by the editorial office without any funding or sponsorship. ZP reports consulting fees/honoraria for advisory board participation from Sanofi, Taiho, Janssen, Takeda, AstraZeneca, Cullinan Oncology, C4 Therapuetics, Jazz Pharmaceuticals and Blueprint, honoraria for educational events from Daiichi Sankyo, Janssen and Eli Lilly and research support (to institution) from Novartis, Takeda, Spectrum, AstraZeneca, Tesaro/GSK, Cullinan Oncology, Daiichi Sankyo, AbbVie, Janssen and Blueprint. The authors have no other conflicts of interest to declare., (2023 Translational Lung Cancer Research. All rights reserved.)

The O-specific polysaccharide (OPS) was isolated from the lipopolysaccharide of Pseudomonas sp. Strain L1, the endophytic bacteria of Lolium perenne (ryegrass) plants growing in soil in an industrial area in the Silesia region (Zabrze, Southern Poland). The high-molecular-weight O-PS fraction liberated from Pseudomonas sp. L1 lipopolysaccharide by mild acid hydrolysis was studied using chemical methods, MALDI-TOF mass spectrometry, and 1D and 2D NMR spectroscopy techniques. It was found that the O-specific polysaccharide was built of tetrasaccharide repeating units composed of d-FucpN, d-Fucp4N, and two d-QuipN residues. The following structure of the O-PS of Pseudomonas sp. Strain L1 was established: [Formula: see text]., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Introduction: EGFR mutations drive a subset of NSCLC. Patients harboring the common EGFR mutations, deletion of exon 19 and L858R, respond well to osimertinib, a third-generation tyrosine kinase inhibitor. Nevertheless, the effect of osimertinib on NSCLC with atypical EGFR mutations is not well described. This multicenter retrospective study evaluates the efficacy of osimertinib among patients with NSCLC harboring atypical EGFR mutations., Methods: Patients with metastatic NSCLC treated with osimertinib, harboring at least one atypical EGFR mutation, excluding concurrent deletion of exon 19, L858R, or T790M mutations, from six U.S. academic cancer centers were included. Baseline clinical characteristics were collected. The primary end point was the time to treatment discontinuation (TTD) of osimertinib. Objective response rate by the Response Evaluation Criteria in Solid Tumors version 1.1 was also assessed., Results: A total of 50 patients with NSCLC with uncommon EGFR mutations were identified. The most frequent EGFR mutations were L861Q (40%, n = 18), G719X (28%, n = 14), and exon 20 insertion (14%, n = 7). The median TTD of osimertinib was 9.7 months (95% confidence interval [CI]: 6.5-12.9 mo) overall and 10.7 months (95% CI: 3.2-18.1 mo) in the first-line setting (n = 20). The objective response rate was 31.7% (95% CI: 18.1%-48.1%) overall and 41.2% (95% CI: 18.4%-67.1%) in the first-line setting. The median TTD varied among patients with L861Q (17.2 mo), G719X (7.8 mo), and exon 20 insertion (1.5 mo) mutations., Conclusions: Osimertinib has activity in patients with NSCLC harboring atypical EGFR mutations. Osimertinib activity differs by the type of atypical EGFR -activating mutation., (© 2023 The Authors.)

Background: Mobocertinib has demonstrated durable clinical benefit in platinum-pretreated patients (PPP) with epidermal growth factor receptor exon 20 insertion-positive non-small cell lung cancer (NSCLC)., Research Design and Methods: Pooled safety analysis of two studies included patients with NSCLC (N = 257) treated with the recommended phase 2 dose (RP2D) of mobocertinib (160 mg once daily). We report overall safety (treatment-emergent adverse events [TEAEs]) in the RP2D population; characterization of GI and skin-related events in 114 PPP from a phase 1/2 study (NCT02716116); and clinical activity in PPP with and without dose reductions due to TEAEs., Results: In the RP2D population (N = 257), the most common TEAEs were diarrhea (93%), nausea (47%), rash (38%), and vomiting (37%). In PPP (N = 114), median times to diarrhea onset and resolution were 5 and 2 days, respectively. Median times to onset and resolution of skin-related events were 9 and 78 days, respectively. Among PPP with (n = 29) or without (n = 85) dose reductions due to TEAEs, overall response rates were 21% and 31% and median durations of response were 5.7 and 17.5 months, respectively., Conclusions: GI and skin-related events are common with mobocertinib; minimizing dose reductions with proactive management may improve clinical outcomes., Trial Registration: NCT02716116; NCT03807778.

The discovery of activating mutations in epidermal growth factor receptor (EGFR) in non-small-cell lung cancer transformed the care and prognosis of patients and heralded the era of 'personalized medicine' in thoracic oncology. Osimertinib, a third-generation EGFR inhibitor, has been established as the preferred EGFR inhibitor for newly diagnosed patients which urged the need to develop treatment options for patients progressing on first-line osimertinib. However, acquired resistance invariably emerges and numerous efforts have been attempted to delay or overcome acquired resistance. In this article, we thoroughly reviewed the current understanding of osimertinib resistance mechanisms and explored the established and emerging treatment options. Newer treatment strategies targeting EGFR-dependent or -independent resistance mechanisms, novel approaches using bispecific antibodies and antibody-drug conjugates will be discussed. Moreover, what to do with brain only progression, and how to incorporate immunotherapy in EGFR-mutant lung cancer will be discussed. Lastly, future perspectives on the ongoing clinical trials and combination of front-line therapy will be introduced., Competing Interests: Dr Soo is a part of advisory board of Amgen, Astra-Zeneca, Bayer, BMS, Boehringer Ingelheim, Janssen, J Ints Bio, Lily, Merck, Merck Serono, Novartis, Pfizer, Puma, Roche, Taiho, Takeda, Thermo Fisher, and Yuhan. Dr. Soo reports research grants from Astra-Zeneca and Boehringer Ingelheim. Dr. Piotrowska has received consulting fees/honoraria from AstraZeneca, Janssen, Eli Lilly, Daiichi Sankyo, Takeda, Cullinan Oncology, C4 Therapeutics, and receives research support (to institution) from Novartis, Takeda, Spectrum, AstraZeneca, Tesaro/GSK, Cullinan Oncology, Daiichi Sankyo, AbbVie, Janssen, and Blueprint Medicines. Dr. Lim reports grants from Yuhan, Beigene, Boehringer Ingelheim, BridgeBio Therapeutics, Roche, GSK, Jiangsu Hengrui, AstraZeneca, Lilly, Takeda, Daiichi Sankyo, and J Ints Bio. The remaining authors declare that there is no conflict of interest., (© The Author(s), 2022.)

Changes in soil microbial communities in response to hydrocarbon pollution are critical indicators of disturbed ecosystem conditions. A core component of these communities that is functionally adjusted to the life-history traits of the host and environmental factors consists of arbuscular mycorrhizal fungi (AMF). AMF communities associated with Poa trivialis and Phragmites australis growing at a phenol and polynuclear aromatic hydrocarbon (PAH)-contaminated site and at an uncontaminated site were compared based on LSU rDNA sequencing. Dissimilarities in species composition and community structures indicated soil pollution as the main factor negatively affecting the AMF diversity. The AMF communities at the contaminated site were dominated by fungal generalists ( Rhizophagus , Funneliformis , Claroideoglomus , Paraglomus ) with wide ecological tolerance. At the control site, the AMF communities were characterized by higher taxonomic and functional diversity than those exposed to the contamination. The host plant identity was the main driver distinguishing the two AMF metacommunities. The AMF communities at the uncontaminated site were represented by Polonospora , Paraglomus , Oehlia , Nanoglomus , Rhizoglomus , Dominikia , and Microdominikia . Polonosporaceae and Paraglomeraceae were particularly dominant in the Ph. australis mycorrhizosphere. The high abundance of early diverging AMF could be due to the use of primers able to detect lineages such as Paraglomeracae that have not been recognized by previously used 18S rDNA primers.

Dark septate endophytes (DSEs) comprise a diverse and ubiquitous group of fungal generalists with broad habitat niches that robustly colonize the roots of plants in stressful environments. DSEs possess adaptation strategies that determine their high tolerance to heavy metal (HM) contamination, drought, and salinity. Most DSEs developed efficient melanin-dependent and melanin-independent mechanisms of HM detoxification and osmoprotection, including intracellular immobilization and extracellular efflux of HMs and excess ions, and the scavenging of reactive oxygen species. DSEs form mutualistic relationship with plants according to the hypothesis of "habitat-adapted associations", supporting the survival of their hosts under stressful conditions. As saprophytes, DSEs mineralize a complex soil substrate improving plants' nutrition and physiological parameters. They can protect the host plant from HMs by limiting HM accumulation in plant tissues and causing their sequestration in root cell walls as insoluble compounds, preventing further HM translocation to shoots. The presence of DSE in drought-affected plants can substantially ameliorate the physiology and architecture of root systems, improving their hydraulic properties. Plant growth-promoting features, supported by the versatility and easy culturing of DSEs, determine their high potential to enhance phytoremediation and revegetation projects for HM-contaminated, saline, and desertic lands reclamation., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Co-occurring mutations in KRAS -mutant NSCLC are associated with discrete biological properties and modulate therapeutic susceptibilities. As G12D-specific inhibitors are expected to enter the clinic, we sought to investigate the characteristics and outcomes of patients with KRAS G12D-mutant NSCLC., Methods: This was a retrospective single-institution study. Patients with NSCLC and KRAS G12D mutations detected by the Massachusetts General Hospital SNaPshot next-generation sequencing assay were identified. Clinical and pathologic characteristics were collected by chart review., Results: A total of 107 patients with KRAS G12D-mutant NSCLC were identified. Most patients were former smokers (80, 74.8%) and had tumors with adenocarcinoma pathologic subtype (93, 86.9%). Among 56 patients evaluated for programmed death-ligand 1 expression, tumor proportion score was less than 50% in 43 (76.8%). Concomitant mutations were identified in STK11 (17 of 107, 15.9%), KEAP1 (10 of 58, 17.2%), TP53 (36 of 107, 33.6%), and SMARCA4 (11 of 107, 10.3%). Among 57 patients treated with first-line therapy, patients with STK11 co-mutations had shorter progression-free survival (1.2 mo, 95% confidence interval [CI]: 0.6-2.9 versus 4.1 mo, 95% CI: 2.5-6.0, p  = 0.0235) and overall survival (4.3 mo, 95% CI: 1.2-10.6 versus 17.9 mo, 95% CI: 8.6-31.1, p  = 0.0018) compared with wild type. Patients with KEAP1 co-mutations had shorter overall survival (4.6 mo, 95% CI: 1.2-10.6 versus 17.9 mo, 95% CI: 7.1-30.1, p  = 0.0125) than those without. TP53 co-mutations exerted no influence on survival., Conclusions: Co-occurring mutations were common in patients with KRAS G12D-mutant NSCLC. STK11 and KEAP1 co-mutations were associated with worse clinical outcomes, whereas co-occurring TP53 did not affect survival., (© 2022 The Authors.)

Introduction: The central nervous system (CNS) is a common site of progression among patients with ROS1 -rearranged lung cancer receiving crizotinib. We conducted a phase 2 study to evaluate the intracranial efficacy of lorlatinib in patients with ROS1 -rearranged lung cancer who developed CNS-only progression on crizotinib., Methods: Patients with metastatic ROS1 -rearranged lung cancer with CNS-only progression on crizotinib received lorlatinib 100 mg daily. The primary end point was intracranial disease control rate at 12 weeks per modified Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included intracranial and extracranial progression-free survival, intracranial objective response rate, and safety/tolerability., Results: A total of 16 patients were enrolled between November 2016 and January 2019. Nine patients (56%) had received prior CNS radiation, with a median of 10.9 months between radiation and lorlatinib. At 12 weeks, the intracranial disease control rate was 100% and intracranial objective response rate was 87%. While on study, the complee intracranial response rate was 60%. With median follow-up of 22 months, seven patients experienced disease progression, including five patients with CNS relapse. The median intracranial and extracranial progression-free survivals were 38.8 months (95% confidence interval: 16.9-not reported) and 41.1 months (95% confidence interval: 17.6-not reported), respectively. Molecular analysis of plasma or tissue from patients with extracranial progression on lorlatinib revealed ROS1 G2032R (n = 1), ROS1 L2086F (n = 1), and CCDC6-RET fusion plus ROS1 G2032R (n = 1). The safety profile of lorlatinib was consistent with prior studies. There were 11 patients (69%) who required dose reduction, including one patient who discontinued treatment for grade 3 edema. No grade greater than or equal to 4 adverse events were observed., Conclusions: Lorlatinib induced durable intracranial responses in patients with ROS1 -rearranged NSCLC and prior isolated CNS progression on crizotinib., (© 2022 The Authors.)

This study aims to provide numerous environmental research approaches to understand the formation of mineral and organic mercury compounds in self-heating coal waste dumps of the Upper Silesian Coal Basin (USCB). The results are combined with environmental and health risk assessments. The mineralogy comprised accessory minerals in the fine fraction of thermally affected waste, i.e., Hg sulfides, most likely cinnabar or metacinnabar. Moreover, other metals, e.g., Pb, Zn and Cu, were found as sulfide forms. Apart from Hg, the ICP-ES/MS data confirmed the high content of Mn, Zn, Pb, Hg, Cr and Ba in these wastes. The high concentration of available Hg resulted in elevated MeHg concentrations in the dumps. There were no correlations or trends between MeHg concentrations and elemental Hg, TS, TOC, and pH. Furthermore, we did not detect microbial genes responsible for Hg methylation. The organic compounds identified in waste and emitted gases, such as organic acids, or free methyl radicals, common in such burn environments, could be responsible for the formation of MeHg. The concentration levels of gases, e.g., benzene, formaldehyde, NH 3 , emitted by the vents, reached or surpassed acceptable levels numerous times. The potential ecological and human health risks of these dumps were moderate to very high due to the significant influence of the high Hg concentrations., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Plants have co-evolved with diverse microorganisms that have developed different mechanisms of direct and indirect interactions with their host. Recently, greater attention has been paid to a direct "message" delivery pathway from bacteria to plants, mediated by the outer membrane vesicles (OMVs). OMVs produced by Gram-negative bacteria play significant roles in multiple interactions with other bacteria within the same community, the environment, and colonized hosts. The combined forces of innovative technologies and experience in the area of plant-bacterial interactions have put pressure on a detailed examination of the OMVs composition, the routes of their delivery to plant cells, and their significance in pathogenesis, protection, and plant growth promotion. This review synthesizes the available knowledge on OMVs in the context of possible mechanisms of interactions between OMVs, bacteria, and plant cells. OMVs are considered to be potential stimulators of the plant immune system, holding potential for application in plant bioprotection., Competing Interests: The 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 © 2022 Rudnicka, Noszczyńska, Malicka, Kasperkiewicz, Pawlik and Piotrowska-Seget.)

Introduction: Patients with EGFR-mutant lung cancer who have had disease progression on osimertinib commonly receive platinum doublet chemotherapy, but whether adding immunotherapy or bevacizumab provides additional benefit is unknown., Materials and Methods: This was a retrospective analysis at 2 university-affiliated institutions. Patients with EGFR-mutant lung cancer who had progression on osimertinib and received next-line therapy with platinum doublet chemotherapy (chemo), platinum doublet chemotherapy plus immunotherapy (chemo-IO), or platinum doublet chemotherapy plus bevacizumab (chemo-bev), were identified; patients who continued osimertinib with these regimens were included. Efficacy outcomes including duration on treatment (DOT) and overall survival (OS) from the start of chemotherapy were assessed. Associations of treatment regimen with outcomes were evaluated using adjusted Cox regression models, using pairwise comparisons between groups., Results: 104 patients were included: 57 received chemo, 12 received chemo-IO, and 35 received chemo-bev. In adjusted models, patients who received chemo-IO had worse OS than did those who received chemo (hazard ratio (HR) 2.66, 95% CI 1.25-5.65; P= .011) or those who received chemo-bev (HR 2.37, 95% CI 1.09-5.65; P= .030). A statistically significant difference in OS could not be detected in patients who received chemo-bev versus those who received chemo (HR 1.50, 95% CI 0.84-2.69; P= .17)., Conclusion: In this retrospective study, giving immunotherapy with platinum doublet chemotherapy after progression on osimertinib was associated with a worse OS compared with platinum doublet chemotherapy alone. Platinum doublet chemotherapy without immunotherapy (with consideration of continuation of osimertinib, in selected cases) is a reasonable choice in this setting, while we await results of clinical trials examining optimal next-line chemotherapy-based regimens in EGFR-mutant lung cancer., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: This multicenter review evaluated the efficacy and safety of osimertinib dose escalation for central nervous system (CNS) progression developing on osimertinib 80 mg in EGFR -mutant NSCLC., Methods: Retrospective review identified 105 patients from eight institutions with advanced EGFR -mutant NSCLC treated with osimertinib 160 mg daily between October 2013 and January 2020. Radiographic responses were clinically assessed, and Kaplan-Meier analyses were used. We defined CNS disease control as the interval from osimertinib 160 mg initiation to CNS progression or discontinuation of osimertinib 160 mg., Results: Among 105 patients treated with osimertinib 160 mg, 69 were escalated for CNS progression, including 24 treated with dose escalation alone (cohort A), 34 who received dose-escalated osimertinib plus concurrent chemotherapy and/or radiation (cohort B), and 11 who received osimertinib 160 mg without any prior 80 mg exposure. The median duration of CNS control was 3.8 months (95% confidence interval [CI], 1.7-5.8) in cohort A, 5.1 months (95% CI, 3.1-6.5) in cohort B, and 4.2 months (95% CI 1.6-not reached) in cohort C. Across all cohorts, the median duration of CNS control was 6.0 months (95% CI, 5.1-9.0) in isolated leptomeningeal progression (n = 27) and 3.3 months (95% CI, 1.0-3.1) among those with parenchymal-only metastases (n = 23). Patients on osimertinib 160 mg experienced no severe or unexpected side effects., Conclusion: Among patients with EGFR -mutant NSCLC experiencing CNS progression on osimertinib 80 mg daily, dose escalation to 160 mg provided modest benefit with CNS control lasting approximately 3 to 6 months and seemed more effective in patients with isolated leptomeningeal CNS progression., (© 2022 The Authors.)

Cancer-associated fibroblasts (CAFs) are highly heterogeneous. With the lack of a comprehensive understanding of CAFs' functional distinctions, it remains unclear how cancer treatments could be personalized based on CAFs in a patient's tumor. We have established a living biobank of CAFs derived from biopsies of patients' non-small lung cancer (NSCLC) that encompasses a broad molecular spectrum of CAFs in clinical NSCLC. By functionally interrogating CAF heterogeneity using the same therapeutics received by patients, we identify three functional subtypes: (1) robustly protective of cancers and highly expressing HGF and FGF7; (2) moderately protective of cancers and highly expressing FGF7; and (3) those providing minimal protection. These functional differences among CAFs are governed by their intrinsic TGF-β signaling, which suppresses HGF and FGF7 expression. This CAF functional classification correlates with patients' clinical response to targeted therapies and also associates with the tumor immune microenvironment, therefore providing an avenue to guide personalized treatment., Competing Interests: Declaration of interests Z.P. receives commercial research support from Novartis, Tesaro, Spectrum, AstraZeneca, and Takeda; and serves as a consultant/advisory board member for AstraZeneca, Takeda, Novartis, ImmunoGen, Guardant Health, and Spectrum. L.V.S. serves as a compensated consultant or received honoraria from AstraZeneca, Janssen, Merrimack, and Genentech; and receives institutional research funding from AstraZeneca, Boehringer Ingelheim, Novartis, Genentech, Merrimack, Blueprint Medicines, and LOXO. C.H.B.’s laboratory received support for research from Novartis, Amgen, and Araxes. A.T.S. is an employee of Novartis and a paid consultant for Pfizer, Genentech/Roche, Ariad/Takeda, Syros, Blueprint Medicine, KSQ Therapeutics, TP Therapeutics, Chugai, Daiichi-Sankyo, LOXO/Bayer, Achilles, Archer, Foundation Medicine, and Guardant. M.M.-K. serves as a consultant for Merrimack Pharmaceuticals and H3 Biomedicine. A.N.H. receives commercial research grants from Amgen, Novartis, Relay Therapeutics, Pfizer, and Roche/Genentech. R.S.H. receives consulting honoraria from Boehringer Ingelheim, Tarveda, and Apollomics; and receives institutional research funding from Daichii Sankyo, Agios, Novartis, Corvus, Mirati, Genentech Roche, Incyte, Abbvie, Celgene, and Exelixis. L.P. has financial interests in Edilytics. L.P.’s interests were reviewed and are managed by Massachusetts General Hospital and Partners Health Care in accordance with their conflict-of-interest policies. J.J.W., Y.-Q.M., and R.-P.H. are employees of RayBiotech Inc. M.J.N. is a Novartis employee and equity holder. D.P.K., C.H.B., and J.A.E. are Novartis employees (contribution at Massachusetts General Hospital). The other authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Osimertinib, a third-generation, irreversible, epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), selectively inhibits both EGFR-TKI sensitizing (EGFRm) and EGFR T790M resistance mutations and has demonstrated efficacy in non-small cell lung cancer (NSCLC) CNS metastases. Most patients with EGFRm NSCLC treated with osimertinib will eventually develop resistance. ORCHARD (NCT03944772) is a phase II study aiming to characterize first-line osimertinib resistance and identify post-progression treatments., Methods: Adults aged ≥ 18 years (Japan ≥ 20 years), with EGFRm locally advanced/metastatic NSCLC will be allocated to one of three groups after first-line osimertinib progression, based on molecular profiling from a post-progression tumor biopsy. Group A will evaluate patients with protocol-determined biomarkers of resistance treated with novel osimertinib combination therapies, Group B will evaluate patients without a detectable protocol-determined biomarker treated with non-biomarker selected therapies that are chemotherapy- or EGFR-TKI-based, and Group C (observational) includes patients with histologically transformed disease, and/or a biomarker with an available therapy not investigated in ORCHARD. Group C patients will be treated as per local practice and followed to assess overall survival. The study's platform design allows for adaptability to include emerging treatments related to novel resistance mechanisms. The primary endpoint is confirmed objective response rate (investigator assessed). Other endpoints are progression-free survival, duration of response, overall survival, pharmacokinetics and safety., Conclusions: ORCHARD aims to characterize mechanisms of resistance to first-line osimertinib and explore treatments to overcome acquired resistance. The modular design allows for additional biomarker-directed cohorts and treatment options as understanding of osimertinib resistance mechanisms evolves., Competing Interests: Disclosure H Yu has received research funding to her institution from AstraZeneca, Pfizer, Cullinan, Daiichi, Novartis, Lilly and advisory board fees from AstraZeneca, Blueprint Medicine and Janssen. S Goldberg has received research funding from AstraZeneca and Boehringer Ingelheim, received advisory board/personal fees from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Genentech and Spectrum. Z Piotrowska has received research funding to her institution from Novartis, Takeda, Spectrum, AstraZeneca, Tesaro, Cullinan, Daiichi and AbbVie and has received advisory board fees from AstraZeneca, Blueprint Medicines, Janssen, Takeda, Jazz Pharmaceuticals and C4 Therapeutics. X Le receives consulting/advisory fees from EMD Serono (Merck KGaA), AstraZeneca, Spectrum Pharmaceutics, Eli Lilly, Boehringer Ingelheim, and Research Funding from Eli Lilly and Boehringer Ingelheim. JW Riess has received research funding from AstraZeneca, Merck, Spectrum, Revolution Medicines and Novartis, received advisory board/personal fees from Novartis, Medtronic, Blueprint Medicines, Boehringer Ingelheim and Spectrum. G Patel is an employee of AstraZeneca. H Ambrose, J Chmielecki, G Doughton, S Kraljevic, X Li-Sucholeiki, J Maidment and P Szekeres are employees of AstraZeneca and hold stock/stock options., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Approximately 10% of EGFR -activating mutations occur as in-frame insertion mutations in exon 20 of the EGFR kinase domain ( EGFR ins20). EGFR ins20 mutations have not demonstrated the same sensitivity to early generations of EGFR tyrosine kinase inhibitors (TKI) as canonical activating EGFR mutations such as del19 and L858R. Development of effective therapies for this subset of patients has been challenging, but recent years have seen more rapid progress in these efforts. In this review, we describe the molecular and clinicopathologic features of EGFR ins20 mutations and summarize recent data on emerging therapies for patients with this subtype of EGFR -mutant non-small cell lung cancer (NSCLC). SIGNIFICANCE: When activating mutations in EGFR were first discovered in lung cancer, the lack of sensitivity of tumors harboring EGFR ins20 mutations to early-generation EGFR TKIs resulted in this subset of EGFR -mutant tumors being initially classified as an untargetable or intrinsically resistant subpopulation. In addition, the diversity of mutations within EGFR exon 20 and resultant challenges identifying them on routine clinical genotyping tests led to underestimation of their frequency. However, recent scientific progress in targeting EGFR ins20 mutations as well as more effective identification of this clinical cohort has enhanced our ability to develop effective therapies for patients with this subtype of EGFR -mutant NSCLC., (©2021 American Association for Cancer Research.)