Filters applied: from 2022/12/1 - 2022/12/25.

1. Lancet. 2022 Dec 20:S0140-6736(22)01694-4. doi: 10.1016/S0140-6736(22)01694-4. Online ahead of print.

Lung cancer screening.

Adams SJ(1), Stone E(2), Baldwin DR(3), Vliegenthart R(4), Lee P(5), Fintelmann

FJ(6).

Author information:

(1)Department of Radiology, Massachusetts General Hospital, Boston, MA, USA;

Harvard Medical School, Boston, MA, USA. Electronic address:

scott.adams@usask.ca.

(2)Faculty of Medicine, University of New South Wales and Department of Lung

Transplantation and Thoracic Medicine, St Vincent's Hospital, Sydney, NSW,

Australia.

(3)Respiratory Medicine Unit, David Evans Research Centre, Nottingham University

Hospitals NHS Trust, Nottingham, UK.

(4)Department of Radiology, University Medical Center Groningen, Groningen,

Netherlands.

(5)Division of Respiratory and Critical Care Medicine, National University

Hospital and National University of Singapore, Singapore.

(6)Department of Radiology, Massachusetts General Hospital, Boston, MA, USA;

Harvard Medical School, Boston, MA, USA.

Randomised controlled trials, including the National Lung Screening Trial (NLST)

and the NELSON trial, have shown reduced mortality with lung cancer screening

with low-dose CT compared with chest radiography or no screening. Although

research has provided clarity on key issues of lung cancer screening,

uncertainty remains about aspects that might be critical to optimise clinical

effectiveness and cost-effectiveness. This Review brings together current

evidence on lung cancer screening, including an overview of clinical trials,

considerations regarding the identification of individuals who benefit from lung

cancer screening, management of screen-detected findings, smoking cessation

interventions, cost-effectiveness, the role of artificial intelligence and

biomarkers, and current challenges, solutions, and opportunities surrounding the

implementation of lung cancer screening programmes from an international

perspective. Further research into risk models for patient selection,

personalised screening intervals, novel biomarkers, integrated cardiovascular

disease and chronic obstructive pulmonary disease assessments, smoking cessation

interventions, and artificial intelligence for lung nodule detection and risk

stratification are key opportunities to increase the efficiency of lung cancer

screening and ensure equity of access.

Copyright © 2022 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S0140-6736(22)01694-4

PMID: 36563698

2. N Engl J Med. 2022 Dec 22;387(25):2331-2343. doi: 10.1056/NEJMoa2117166.

A 24-Week, All-Oral Regimen for Rifampin-Resistant Tuberculosis.

Nyang'wa BT(1), Berry C(1), Kazounis E(1), Motta I(1), Parpieva N(1), Tigay

Z(1), Solodovnikova V(1), Liverko I(1), Moodliar R(1), Dodd M(1), Ngubane N(1),

Rassool M(1), McHugh TD(1), Spigelman M(1), Moore DAJ(1), Ritmeijer K(1), du

Cros P(1), Fielding K(1); TB-PRACTECAL Study Collaborators.

Author information:

(1)From the Public Health Department, Operational Center Amsterdam (OCA),

Médecins sans Frontières, Amsterdam (B.-T.N., K.R.); the Public Health

Department, OCA, Médecins sans Frontières (C.B., E.K., I.M.), the London School

of Hygiene and Tropical Medicine (B.-T.N., M.D., D.A.J.M., K.F.), and University

College London (T.D.M.) - all in London; the Republican Specialized Scientific

and Practical Medical Center of Phthisiology and Pulmonology, Tashkent (N.P.,

I.L.), and the Republican Phthisiological Hospital No. 2, Nukus (Z.T.) - both in

Uzbekistan; the Republican Scientific and Practical Center for Pulmonology and

Tuberculosis, Minsk, Belarus (V.S.); THINK TB and HIV Investigative Network,

Durban (R.M.), and Wits Health Consortium, Johannesburg (N.N., M.R.) - both in

South Africa; the Global Alliance for TB Drug Development, New York (M.S.); and

the Burnet Institute, Melbourne, VIC, Australia (P.C.).

BACKGROUND: In patients with rifampin-resistant tuberculosis, all-oral treatment

regimens that are more effective, shorter, and have a more acceptable

side-effect profile than current regimens are needed.

METHODS: We conducted an open-label, phase 2-3, multicenter, randomized,

controlled, noninferiority trial to evaluate the efficacy and safety of three

24-week, all-oral regimens for the treatment of rifampin-resistant tuberculosis.

Patients in Belarus, South Africa, and Uzbekistan who were 15 years of age or

older and had rifampin-resistant pulmonary tuberculosis were enrolled. In stage

2 of the trial, a 24-week regimen of bedaquiline, pretomanid, linezolid, and

moxifloxacin (BPaLM) was compared with a 9-to-20-month standard-care regimen.

The primary outcome was an unfavorable status (a composite of death, treatment

failure, treatment discontinuation, loss to follow-up, or recurrence of

tuberculosis) at 72 weeks after randomization. The noninferiority margin was 12

percentage points.

RESULTS: Recruitment was terminated early. Of 301 patients in stage 2 of the

trial, 145, 128, and 90 patients were evaluable in the intention-to-treat,

modified intention-to-treat, and per-protocol populations, respectively. In the

modified intention-to-treat analysis, 11% of the patients in the BPaLM group and

48% of those in the standard-care group had a primary-outcome event (risk

difference, -37 percentage points; 96.6% confidence interval [CI], -53 to -22).

In the per-protocol analysis, 4% of the patients in the BPaLM group and 12% of

those in the standard-care group had a primary-outcome event (risk difference,

-9 percentage points; 96.6% CI, -22 to 4). In the as-treated population, the

incidence of adverse events of grade 3 or higher or serious adverse events was

lower in the BPaLM group than in the standard-care group (19% vs. 59%).

CONCLUSIONS: In patients with rifampin-resistant pulmonary tuberculosis, a

24-week, all-oral regimen was noninferior to the accepted standard-care

treatment, and it had a better safety profile. (Funded by Médecins sans

Frontières; TB-PRACTECAL ClinicalTrials.gov number, NCT02589782.).

Copyright © 2022 Massachusetts Medical Society.

DOI: 10.1056/NEJMoa2117166

PMID: 36546625 [Indexed for MEDLINE]

3. Cell. 2022 Dec 8;185(25):4682-4702. doi: 10.1016/j.cell.2022.10.025.

Immune cell interactions in tuberculosis.

Flynn JL(1), Chan J(2).

Author information:

(1)Department of Microbiology and Molecular Genetics and the Center for Vaccine

Research, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Electronic address: joanne@pitt.edu.

(2)Department of Medicine, Center for Emerging Pathogens, Public Health Research

Institute, New Jersey Medical School, Rutgers University, Newark, NJ, USA.

Electronic address: jc2864@njms.rutgers.edu.

Despite having been identified as the organism that causes tuberculosis in 1882,

Mycobacterium tuberculosis has managed to still evade our understanding of the

protective immune response against it, defying the development of an effective

vaccine. Technology and novel experimental models have revealed much new

knowledge, particularly with respect to the heterogeneity of the bacillus and

the host response. This review focuses on certain immunological elements that

have recently yielded exciting data and highlights the importance of taking a

holistic approach to understanding the interaction of M. tuberculosis with the

many host cells that contribute to the development of protective immunity.

Copyright © 2022 Elsevier Inc. All rights reserved.

DOI: 10.1016/j.cell.2022.10.025

PMID: 36493751 [Indexed for MEDLINE]

4. Science. 2022 Dec 9;378(6624):1111-1118. doi: 10.1126/science.abq2787. Epub 2022 Dec 8.

Tuberculosis treatment failure associated with evolution of antibiotic

resilience.

Liu Q(#)(1), Zhu J(#)(1), Dulberger CL(1)(2)(3), Stanley S(1), Wilson S(2),

Chung ES(4)(5), Wang X(1), Culviner P(1), Liu YJ(1), Hicks ND(1), Babunovic

GH(1), Giffen SR(1), Aldridge BB(4)(5), Garner EC(2), Rubin EJ(1), Chao MC(1),

Fortune SM(1)(6).

Author information:

(1)Department of Immunology and Infectious Diseases, Harvard T. H. Chan School

of Public Health, Boston, MA 02115, USA.

(2)Department of Molecular and Cellular Biology, Harvard University, Boston, MA,

USA.

(3)Present address: BioNTech US, Cambridge, MA, USA.

(4)Department of Molecular Biology and Microbiology, Tufts University School of

Medicine, Boston, MA 02111, USA.

(5)Department of Biomedical Engineering, Tufts University School of Engineering,

Medford, MA 02115, USA.

(6)Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

(#)Contributed equally

The widespread use of antibiotics has placed bacterial pathogens under intense

pressure to evolve new survival mechanisms. Genomic analysis of 51,229

Mycobacterium tuberculosis (Mtb)clinical isolates has identified an essential

transcriptional regulator, Rv1830, herein called resR for resilience regulator,

as a frequent target of positive (adaptive) selection. resR mutants do not show

canonical drug resistance or drug tolerance but instead shorten the

post-antibiotic effect, meaning that they enable Mtb to resume growth after drug

exposure substantially faster than wild-type strains. We refer to this phenotype

as antibiotic resilience. ResR acts in a regulatory cascade with other

transcription factors controlling cell growth and division, which are also under

positive selection in clinical isolates of Mtb. Mutations of these genes are

associated with treatment failure and the acquisition of canonical drug

resistance.

DOI: 10.1126/science.abq2787

PMID: 36480634 [Indexed for MEDLINE]

5. Cancer Cell. 2022 Dec 7:S1535-6108(22)00562-1. doi: 10.1016/j.ccell.2022.11.015. Online ahead of print.

KMT2D deficiency drives lung squamous cell carcinoma and hypersensitivity to

RTK-RAS inhibition.

Pan Y(1), Han H(1), Hu H(1), Wang H(2), Song Y(3), Hao Y(4), Tong X(2), Patel

AS(1), Misirlioglu S(1), Tang S(1), Huang HY(1), Geng K(1), Chen T(1), Karatza

A(1), Sherman F(1), Labbe KE(1), Yang F(1), Chafitz A(1), Peng C(1), Guo C(2),

Moreira AL(5), Velcheti V(1), Lau SCM(1), Sui P(2), Chen H(6), Diehl JA(7),

Rustgi AK(8), Bass AJ(8), Poirier JT(1), Zhang X(3), Ji H(9), Zhang H(10), Wong

KK(11).

Author information:

(1)Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY,

USA.

(2)State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and

Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy

of Sciences, Shanghai, China.

(3)State Key Laboratory of Genetic Engineering, School of Life Sciences,

Zhongshan Hospital, Fudan University, Shanghai, China.

…

Lung squamous cell carcinoma (LUSC) represents a major subtype of lung cancer

with limited treatment options. KMT2D is one of the most frequently mutated

genes in LUSC (>20%), and yet its role in LUSC oncogenesis remains unknown.

Here, we identify KMT2D as a key regulator of LUSC tumorigenesis wherein Kmt2d

deletion transforms lung basal cell organoids to LUSC. Kmt2d loss increases

activation of receptor tyrosine kinases (RTKs), EGFR and ERBB2, partly through

reprogramming the chromatin landscape to repress the expression of protein

tyrosine phosphatases. These events provoke a robust elevation in the oncogenic

RTK-RAS signaling. Combining SHP2 inhibitor SHP099 and pan-ERBB inhibitor

afatinib inhibits lung tumor growth in Kmt2d-deficient LUSC murine models and in

patient-derived xenografts (PDXs) harboring KMT2D mutations. Our study

identifies KMT2D as a pivotal epigenetic modulator for LUSC oncogenesis and

suggests that KMT2D loss renders LUSC therapeutically vulnerable to RTK-RAS

inhibition.

Copyright © 2022 Elsevier Inc. All rights reserved.

DOI: 10.1016/j.ccell.2022.11.015

PMID: 36525973

6. Cancer Cell. 2022 Dec 12;40(12):1503-1520.e8. doi: 10.1016/j.ccell.2022.10.008.

Epub 2022 Nov 10.

High-resolution single-cell atlas reveals diversity and plasticity of

tissue-resident neutrophils in non-small cell lung cancer.

Salcher S(1), Sturm G(2), Horvath L(1), Untergasser G(1), Kuempers C(3), Fotakis

G(2), Panizzolo E(2), Martowicz A(4), Trebo M(1), Pall G(1), Gamerith G(1),

Sykora M(1), Augustin F(5), Schmitz K(6), Finotello F(7), Rieder D(2), Perner

S(8), Sopper S(1), Wolf D(1), Pircher A(9), Trajanoski Z(10).

Author information:

(1)Department of Internal Medicine V, Haematology & Oncology, Comprehensive

Cancer Center Innsbruck (CCCI) and Tyrolean Cancer Research Institute (TKFI),

Medical University of Innsbruck, Innsbruck, Austria.

(2)Biocenter, Institute of Bioinformatics, Medical University of Innsbruck,

Innsbruck, Austria.

(3)Institute of Pathology, University of Luebeck and University Hospital

Schleswig-Holstein, Campus Luebeck, Luebeck, Germany.

…

Non-small cell lung cancer (NSCLC) is characterized by molecular heterogeneity

with diverse immune cell infiltration patterns, which has been linked to therapy

sensitivity and resistance. However, full understanding of how immune cell

phenotypes vary across different patient subgroups is lacking. Here, we dissect

the NSCLC tumor microenvironment at high resolution by integrating 1,283,972

single cells from 556 samples and 318 patients across 29 datasets, including our

dataset capturing cells with low mRNA content. We stratify patients into

immune-deserted, B cell, T cell, and myeloid cell subtypes. Using bulk samples

with genomic and clinical information, we identify cellular components

associated with tumor histology and genotypes. We then focus on the analysis of

tissue-resident neutrophils (TRNs) and uncover distinct subpopulations that

acquire new functional properties in the tissue microenvironment, providing

evidence for the plasticity of TRNs. Finally, we show that a TRN-derived gene

signature is associated with anti-programmed cell death ligand 1 (PD-L1)

treatment failure.

Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

DOI: 10.1016/j.ccell.2022.10.008

PMCID: PMC9767679

PMID: 36368318 [Indexed for MEDLINE]

7. Nat Rev Microbiol. 2022 Dec;20(12):750-766. doi: 10.1038/s41579-022-00763-4.

Epub 2022 Jul 25.

Immune evasion and provocation by Mycobacterium tuberculosis.

Chandra P(#)(1)(2), Grigsby SJ(#)(1)(2), Philips JA(3)(4).

Author information:

(1)Division of Infectious Diseases, Department of Medicine, Washington

University School of Medicine, St Louis, MO, USA.

(2)Department of Molecular Microbiology, Washington University School of

Medicine, St Louis, MO, USA.

(3)Division of Infectious Diseases, Department of Medicine, Washington

University School of Medicine, St Louis, MO, USA. philips.j.a@wustl.edu.

(4)Department of Molecular Microbiology, Washington University School of

Medicine, St Louis, MO, USA. philips.j.a@wustl.edu.

(#)Contributed equally

Mycobacterium tuberculosis, the causative agent of tuberculosis, has infected

humans for millennia. M. tuberculosis is well adapted to establish infection,

persist in the face of the host immune response and be transmitted to uninfected

individuals. Its ability to complete this infection cycle depends on it both

evading and taking advantage of host immune responses. The outcome of M.

tuberculosis infection is often a state of equilibrium characterized by

immunological control and bacterial persistence. Recent data have highlighted

the diverse cell populations that respond to M. tuberculosis infection and the

dynamic changes in the cellular and intracellular niches of M. tuberculosis

during the course of infection. M. tuberculosis possesses an arsenal of protein

and lipid effectors that influence macrophage functions and inflammatory

responses; however, our understanding of the role that specific bacterial

virulence factors play in the context of diverse cellular reservoirs and

distinct infection stages is limited. In this Review, we discuss immune evasion

and provocation by M. tuberculosis during its infection cycle and describe how a

more detailed molecular understanding is crucial to enable the development of

novel host-directed therapies, disease biomarkers and effective vaccines.

© 2022. Springer Nature Limited.

DOI: 10.1038/s41579-022-00763-4

PMCID: PMC9310001

PMID: 35879556 [Indexed for MEDLINE]

8. J Clin Invest. 2022 Dec 22:e162434. doi: 10.1172/JCI162434. Online ahead of

print.

The UBE2C/CDH1/DEPTOR axis is an oncogene-tumor suppressor cascade in lung

cancer cells.

Zhang S(1), You X(2), Zheng Y(3), Shen Y(2), Xiong X(2), Sun Y(4).

Author information:

(1)Department of Breast Surgery and Oncology, Zhejiang University School of

Medicine, Hangzhou, China.

(2)Cancer Institute, Zhejiang University School of Medicine, Hangzhou, China.

(3)Institute of Translational Medicine, Zhejiang University School of Medicine,

Hangzhou, China.

(4)Zhejiang University School of Medicine, Hangzhou, China.

Ubiquitin-conjugating enzyme E2C (UBE2C) mediates the ubiquitylation chain

formation via the K11 linkage. While previous in vitro studies showed that UBE2C

plays a growth-promoting role in cancer cell lines, the underlying mechanism

remains elusive. Still unknown is whether and how UBE2C plays a promoting role

in vivo. Here we reported that UBE2C is indeed essential for growth and survival

of lung cancer cells harboring Kras mutations, and UBE2C is required for

KrasG12D-induced lung tumorigenesis, since Ube2c deletion significantly inhibits

tumor formation and extends the life-span of mice. Mechanistically, KrasG12D

induces expression of UBE2C, which couples with APC/CCDH1 E3 ligase to promote

ubiquitylation and degradation of DEPTOR, leading to activation of the mTORC

signals. Importantly, DEPTOR levels are fluctuated during cell cycle progression

in a manner dependent of UBE2C and CDH1, indicating their physiological

connection. Finally, Deptor deletion fully rescues the tumor inhibitory effect

of Ube2c deletion in the KrasG12D lung tumor model, indicating a causal role of

Deptor. Taken together, our study shows that the UBE2C/CDH1/DEPTOR axis forms an

oncogene-tumor suppressor cascade that regulates cell cycle progression and

autophagy and validates that UBE2C is an attractive target for lung cancer

associated with Kras mutations.

DOI: 10.1172/JCI162434

PMID: 36548081

9. J Clin Oncol. 2022 Dec 19:JCO2202124. doi: 10.1200/JCO.22.02124. Online ahead of print.

Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations: ASCO

Living Guideline, Version 2022.2.

Owen DH(1), Singh N(2), Ismaila N(3), Blanchard E(4), Celano P(5), Florez N(6),

Jain D(7), Leighl NB(8), Mamdani H(9), Masters G(10), Moffitt PR(11), Naidoo

J(12), Phillips T(13), Riely GJ(14), Robinson AG(15), Schenk E(16), Schneider

BJ(17), Sequist L(18), Spigel DR(19), Jaiyesimi IA(20).

Author information:

(1)Ohio State University, Columbus, OH.

(2)Postgraduate Institute of Medical Education and Research, Chandigarh, India.

(3)American Society of Clinical Oncology, Alexandria, VA.

…

Update of

    J Clin Oncol. 2022 Oct 1;40(28):3310-3322.

Living guidelines are developed for selected topic areas with rapidly evolving

evidence that drives frequent change in recommended clinical practice. Living

guidelines are updated on a regular schedule by a standing expert panel that

systematically reviews the health literature on a continuous basis, as described

in the ASCO Guidelines Methodology Manual. ASCO Living Guidelines follow the

ASCO Conflict of Interest Policy Implementation for Clinical Practice

Guidelines. Living Guidelines and updates are not intended to substitute for

independent professional judgment of the treating provider and do not account

for individual variation among patients. See Appendix 1 (online only) for

disclaimers and other important information. Updates are published regularly and

can be found at https://ascopubs.org/nsclc-da-living-guideline.

DOI: 10.1200/JCO.22.02124

PMID: 36534938

10. J Clin Oncol. 2022 Dec 19:JCO2202121. doi: 10.1200/JCO.22.02121. Online ahead of print.

Therapy for Stage IV Non-Small-Cell Lung Cancer Without Driver Alterations: ASCO

Living Guideline, Version 2022.2.

Owen DH(1), Singh N(2), Ismaila N(3), Blanchard E(4), Celano P(5), Florez N(6),

Jain D(7), Leighl NB(8), Mamdani H(9), Masters G(10), Moffitt PR(11), Naidoo

J(12), Phillips T(13), Riely GJ(14), Robinson AG(15), Schenk E(16), Schneider

BJ(17), Sequist L(18), Spigel DR(19), Jaiyesimi IA(20).

Author information:

(1)Ohio State University, Columbus, OH.

(2)Postgraduate Institute of Medical Education and Research, Chandigarh, India.

(3)American Society of Clinical Oncology, Alexandria, VA.

…

Update of

    J Clin Oncol. 2022 Oct 1;40(28):3323-3343.

Living guidelines are developed for selected topic areas with rapidly evolving

evidence that drives frequent change in recommended clinical practice. Living

guidelines are updated on a regular schedule by a standing expert panel that

systematically reviews the health literature on a continuous basis, as described

in the ASCO Guidelines Methodology Manual. ASCO Living Guidelines follow the

ASCO Conflict of Interest Policy Implementation for Clinical Practice

Guidelines. Living Guidelines and updates are not intended to substitute for

independent professional judgment of the treating provider and do not account

for individual variation among patients. See Appendix 1 (online only) for

disclaimers and other important information. Updates are published regularly and

can be found at https://ascopubs.org/nsclc-non-da-living-guideline.

DOI: 10.1200/JCO.22.02121

PMID: 36534935

11. Nat Commun. 2022 Dec 14;13(1):7751. doi: 10.1038/s41467-022-35453-5.

A Mycobacterium tuberculosis fingerprint in human breath allows tuberculosis

detection.

Mosquera-Restrepo SF(#)(1), Zuberogoïtia S(#)(2), Gouxette L(#)(2), Layre E(2),

Gilleron M(2), Stella A(2), Rengel D(2), Burlet-Schiltz O(2), Caro AC(3), Garcia

LF(1), Segura C(4), Peláez Jaramillo CA(3), Rojas M(5)(6), Nigou J(7).

Author information:

(1)Cellular Immunology and Immunogenetics Group (GICIG), Institute of Medical

Research, Faculty of Medicine, University Research Headquarters (SIU),

University of Antioquia (UdeA), Medellin, Colombia.

(2)Institute of Pharmacology and Structural Biology (IPBS), University of

Toulouse, CNRS, University of Toulouse III-Paul Sabatier, Toulouse, France.

(3)Interdisciplinary Group for Molecular Studies (GIEM), Institute of Chemistry,

Faculty of Exact and Natural Sciences. University of Antioquia (UdeA), Medellin,

Colombia.

…

An estimated one-third of tuberculosis (TB) cases go undiagnosed or unreported.

Sputum samples, widely used for TB diagnosis, are inefficient at detecting

infection in children and paucibacillary patients. Indeed, developing

point-of-care biomarker-based diagnostics that are not sputum-based is a major

priority for the WHO. Here, in a proof-of-concept study, we tested whether

pulmonary TB can be detected by analyzing patient exhaled breath condensate

(EBC) samples. We find that the presence of Mycobacterium tuberculosis

(Mtb)-specific lipids, lipoarabinomannan lipoglycan, and proteins in EBCs can

efficiently differentiate baseline TB patients from controls. We used EBCs to

track the longitudinal effects of antibiotic treatment in pediatric TB patients.

In addition, Mtb lipoarabinomannan and lipids were structurally distinct in EBCs

compared to ex vivo cultured bacteria, revealing specific metabolic and

biochemical states of Mtb in the human lung. This provides essential information

for the rational development or improvement of diagnostic antibodies, vaccines

and therapeutic drugs. Our data collectively indicate that EBC analysis can

potentially facilitate clinical diagnosis of TB across patient populations and

monitor treatment efficacy. This affordable, rapid and non-invasive approach

seems superior to sputum assays and has the potential to be implemented at

point-of-care.

© 2022. The Author(s).

DOI: 10.1038/s41467-022-35453-5

PMCID: PMC9751131

PMID: 36517492 [Indexed for MEDLINE]

12. Sci Transl Med. 2022 Dec 14;14(675):eabq0021. doi: 10.1126/scitranslmed.abq0021. Epub 2022 Dec 14.

Combination bezafibrate and nivolumab treatment of patients with advanced

non-small cell lung cancer.

Tanaka K(1), Chamoto K(2), Saeki S(3), Hatae R(2)(4), Ikematsu Y(5), Sakai K(6),

Ando N(1), Sonomura K(7)(8), Kojima S(9), Taketsuna M(9), Kim YH(10), Yoshida

H(10), Ozasa H(10), Sakamori Y(11), Hirano T(2), Matsuda F(7), Hirai T(10),

Nishio K(6), Sakagami T(3), Fukushima M(12), Nakanishi Y(1)(13), Honjo T(2),

Okamoto I(1).

Author information:

(1)Department of Respiratory Medicine, Graduate School of Medical Sciences,

Kyushu University, Fukuoka 812-8582, Japan.

(2)Department of Immunology and Genomic Medicine, Center for Cancer

Immunotherapy and Immunobiology, Graduate School of Medicine, Kyoto University,

Kyoto 606-8501, Japan.

(3)Department of Respiratory Medicine, Kumamoto University Hospital, Kumamoto

860-8556, Japan.

…

Despite the success of cancer immunotherapies such as programmed cell death-1

(PD-1) and PD-1 ligand 1 (PD-L1) inhibitors, patients often develop resistance.

New combination therapies with PD-1/PD-L1 inhibitors are needed to overcome this

issue. Bezafibrate, a ligand of peroxisome proliferator-activated receptor-γ

coactivator 1α/peroxisome proliferator-activated receptor complexes, has shown a synergistic antitumor effect with PD-1 blockade in mice that is mediated by

activation of mitochondria in T cells. We have therefore now performed a phase 1

trial (UMIN000017854) of bezafibrate with nivolumab in previously treated

patients with advanced non-small cell lung cancer. The primary end point was the

percentage of patients who experience dose-limiting toxicity, and this

combination regimen was found to be well tolerated. Preplanned comprehensive

analysis of plasma metabolites and gene expression in peripheral cytotoxic T

cells indicated that bezafibrate promoted T cell function through up-regulation

of mitochondrial metabolism including fatty acid oxidation and may thereby have

prolonged the duration of response. This combination strategy targeting T cell

metabolism thus has the potential to maintain antitumor activity of immune

checkpoint inhibitors and warrants further validation.

DOI: 10.1126/scitranslmed.abq0021

PMID: 36516270 [Indexed for MEDLINE]

13. Nat Commun. 2022 Dec 12;13(1):7690. doi: 10.1038/s41467-022-34889-z.

Brain metastatic outgrowth and osimertinib resistance are potentiated by RhoA in

EGFR-mutant lung cancer.

Adua SJ(1), Arnal-Estapé A(1)(2), Zhao M(1), Qi B(1), Liu ZZ(1), Kravitz C(1),

Hulme H(3), Strittmatter N(3), López-Giráldez F(4), Chande S(1), Albert AE(5),

Melnick MA(2), Hu B(1), Politi K(1)(2)(6), Chiang V(2)(7), Colclough N(8),

Goodwin RJA(3), Cross D(9), Smith P(10), Nguyen DX(11)(12)(13).

Author information:

(1)Department of Pathology, Yale University School of Medicine, New Haven, CT,

USA.

(2)Yale Cancer Center, Yale University School of Medicine, New Haven, CT, USA.

(3)Imaging and Data Analytics, Clinical Pharmacology and Safety Sciences,

AstraZeneca, Cambridge, UK.

…

The brain is a major sanctuary site for metastatic cancer cells that evade

systemic therapies. Through pre-clinical pharmacological, biological, and

molecular studies, we characterize the functional link between drug resistance

and central nervous system (CNS) relapse in Epidermal Growth Factor

Receptor- (EGFR-) mutant non-small cell lung cancer, which can progress in the

brain when treated with the CNS-penetrant EGFR inhibitor osimertinib. Despite

widespread osimertinib distribution in vivo, the brain microvascular tumor

microenvironment (TME) is associated with the persistence of malignant cell

sub-populations, which are poised to proliferate in the brain as

osimertinib-resistant lesions over time. Cellular and molecular features of this

poised state are regulated through a Ras homolog family member A (RhoA) and

Serum Responsive Factor (SRF) gene expression program. RhoA potentiates the

outgrowth of disseminated tumor cells on osimertinib treatment, preferentially

in response to extracellular laminin and in the brain. Thus, we identify

pre-existing and adaptive features of metastatic and drug-resistant cancer

cells, which are enhanced by RhoA/SRF signaling and the brain TME during the

evolution of osimertinib-resistant disease.

© 2022. The Author(s).

DOI: 10.1038/s41467-022-34889-z

PMCID: PMC9744876

PMID: 36509758 [Indexed for MEDLINE]

14. Adv Drug Deliv Rev. 2022 Dec 9;192:114641. doi: 10.1016/j.addr.2022.114641.

Online ahead of print.

Imaging drug delivery to the lungs: Methods and applications in oncology.

Man F(1), Tang J(2), Swedrowska M(1), Forbes B(1), T M de Rosales R(3).

Author information:

(1)School of Cancer & Pharmaceutical Sciences, King's College London, London,

SE1 9NH, United Kingdom.

(2)School of Biomedical Engineering & Imaging Sciences, King's College London,

London SE1 7EH, United Kingdom.

(3)School of Biomedical Engineering & Imaging Sciences, King's College London,

London SE1 7EH, United Kingdom. Electronic address: rafael.torres@kcl.ac.uk.

Direct delivery to the lung via inhalation is arguably one of the most logical

approaches to treat lung cancer using drugs. However, despite significant

efforts and investment in this area, this strategy has not progressed in

clinical trials. Imaging drug delivery is a powerful tool to understand and

develop novel drug delivery strategies. In this review we focus on imaging

studies of drug delivery by the inhalation route, to provide a broad overview of

the field to date and attempt to better understand the complexities of this

route of administration and the significant barriers that it faces, as well as

its advantages. We start with a discussion of the specific challenges for drug

delivery to the lung via inhalation. We focus on the barriers that have

prevented progress of this approach in oncology, as well as the most recent

developments in this area. This is followed by a comprehensive overview of the

different imaging modalities that are relevant to lung drug delivery, including

nuclear imaging, X-ray imaging, magnetic resonance imaging, optical imaging and

mass spectrometry imaging. For each of these modalities, examples from the

literature where these techniques have been explored are provided. Finally the

different applications of these technologies in oncology are discussed, focusing

separately on small molecules and nanomedicines. We hope that this comprehensive

review will be informative to the field and will guide the future preclinical

and clinical development of this promising drug delivery strategy to maximise

its therapeutic potential.

Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.

DOI: 10.1016/j.addr.2022.114641

PMID: 36509173

15. J Clin Oncol. 2022 Dec 8:JCO2200857. doi: 10.1200/JCO.22.00857. Online ahead of print.

Clonal Hematopoiesis and Risk of Incident Lung Cancer.

Tian R(1)(2), Wiley B(3), Liu J(3), Zong X(1), Truong B(4)(5)(6), Zhao S(7),

Uddin MM(4)(6), Niroula A(6)(8)(9), Miller CA(3)(10), Mukherjee S(11)(12),

Heiden BT(13), Luo J(1)(10), Puri V(13), Kozower BD(13), Walter MJ(3)(10), Ding

L(3)(10)(14), Link DC(3)(10), Amos CI(15)(16)(17), Ebert BL(9)(18)(19), Govindan

R(3)(10), Natarajan P(4)(6)(20), Bolton KL(3), Cao Y(1)(10).

Author information:

(1)Division of Public Health Sciences, Department of Surgery, Washington

University School of Medicine, St Louis, MO.

(2)Brown School, Washington University in St Louis, St Louis, MO.

(3)Division of Oncology, Department of Medicine, Washington University School of

Medicine, St Louis, MO.

…

PURPOSE: To prospectively examine the association between clonal hematopoiesis

(CH) and subsequent risk of lung cancer.

METHODS: Among 200,629 UK Biobank (UKBB) participants with whole-exome

sequencing, CH was identified in a nested case-control study of 832 incident

lung cancer cases and 3,951 controls (2006-2019) matched on age and year at

blood draw, sex, race, and smoking status. A similar nested case-control study

(141 cases/652 controls) was conducted among 27,975 participants with

whole-exome sequencing in the Mass General Brigham Biobank (MGBB, 2010-2021). In

parallel, we compared CH frequency in published data from 5,003 patients with

solid tumor (2,279 lung cancer) who had pretreatment blood sequencing performed

through Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable

Cancer Targets.

RESULTS: In UKBB, the presence of CH was associated with increased risk of lung

cancer (cases: 12.5% v controls: 8.7%; multivariable-adjusted odds ratio [OR],

1.36; 95% CI, 1.06 to 1.74). The association remained robust after excluding

participants with chronic obstructive pulmonary disease. No significant

interactions with known risk factors, including polygenic risk score and

C-reactive protein, were identified. In MGBB, we observed similar enrichment of

CH in lung cancer (cases: 15.6% v controls: 12.7%). The meta-analyzed OR (95%

CI) of UKBB and MGBB was 1.35 (1.08 to 1.68) for CH overall and 1.61 (1.19 to

2.18) for variant allele frequencies ≥ 10%. In Memorial Sloan

Kettering-Integrated Mutation Profiling of Actionable Cancer Targets, CH with a

variant allele frequency ≥ 10% was enriched in pretreatment lung cancer compared

with other tumors after adjusting for age, sex, and smoking (OR for lung v

breast cancer: 1.61; 95% CI, 1.03 to 2.53).

CONCLUSION: Independent of known risk factors, CH is associated with increased

risk of lung cancer.

DOI: 10.1200/JCO.22.00857

PMID: 36480766

16. Am J Respir Crit Care Med. 2022 Dec 1. doi: 10.1164/rccm.202208-1475OC. Online ahead of print.

Assessing Pretomanid for Tuberculosis (APT), a Randomized Phase 2 Trial of

Pretomanid-containing Regimens for Drug-sensitive TB: 12-Week Results.

Dooley KE(1), Hendricks B(2), Gupte N(3), Barnes G(4), Narunsky K(5), Whitelaw

C(2), Smit T(2), Ignatius EH(6), Friedman A(2), Dorman SE(7), Dawson R(2);

Assessing Pretomanid for Tuberculosis (APT) Study Team.

Author information:

(1)Vanderbilt University School of Medicine, 12327, Medicine, Nashville,

Tennessee, United States; kelly.e.dooley@vumc.org.

(2)University of Cape Town Lung Institute, 108145, Rondebosch, Western Cape,

South Africa.

(3)Johns Hopkins School of Medicine, Baltimore, Maryland, United States.

(4)Johns Hopkins University, Medicine, Baltimore, Maryland, United States.

(5)University of Cape Town, Department of Respiratory Medicine, Cape Town, South

Africa.

(6)Johns Hopkins University, Baltimore, Maryland, United States.

(7)Medical University of South Carolina, 2345, Charleston, South Carolina,

United States.

RATIONALE: Pretomanid is a new nitroimidazole with proven treatment-shortening

efficacy in drug-resistant tuberculosis. Pretomanid-rifamycin-pyrazinamide

combinations are potent in mice but have not been tested clinically. Rifampicin,

but not rifabutin, reduces pretomanid exposures.

OBJECTIVE: Evaluate the safety and efficacy of pretomanid-rifamycin-pyrazinamide

containing regimens among participants with drug-sensitive pulmonary

tuberculosis.

METHODS: Phase 2 twelve-week open-label randomized trial of isoniazid,

pyrazinamide, plus (a) pretomanid and rifampicin (Arm 1); (b) pretomanid and

rifabutin (Arm 2) or (c) rifampicin and ethambutol (standard of care, Arm 3).

Safety labs and sputum cultures were collected at Weeks 1, 2, 3, 4, 6, 8, 10,

12. Time to culture conversion on liquid media was the primary outcome.

RESULTS: Among 157 participants, 125 (80%) had cavitary disease. Median time to

liquid culture negativity in the modified intention to treat (mITT) population

(n=150) was 41 (Arm 1), 28 (Arm 2), and 55 (Arm 3) days (p=0.01)(adjusted hazard

ratios of 1.41 (0.93-2.12, p=0.10), Arm 1 vs. Arm 3) and 1.89 (1.24-2.87,

p=0.003, Arm 2 vs. Arm 3)). Eight-week liquid culture conversion was 79%, 89%,

and 69%, respectively. Grade >3 adverse events occurred in 3/56 (5%), 5/53 (9%),

and 2/56 (4%) of participants. Six participants were withdrawn owing to elevated

transaminases (5 in Arm 2, 1 in Arm 1).There were 3 serious adverse events (Arm

2) and no deaths.

CONCLUSIONS: Pretomanid enhanced the microbiologic activity of

rifamycin-pyrazinamide containing regimens. Efficacy and hepatic adverse events

appeared highest with the pretomanid and rifabutin-containing regimen. Whether

this is due to higher pretomanid concentrations merits exploration. Clinical

trial registration available at www.

CLINICALTRIALS: gov, ID: NCT02256696.

DOI: 10.1164/rccm.202208-1475OC

PMID: 36455068

17. J Exp Med. 2022 Dec 5;219(12):e20221449. doi: 10.1084/jem.20221449. Epub 2022

Oct 10.

Eating away T cell responses in lung cancer.

Ferrara R(1), Roz L(2).

Author information:

(1)Thoracic Oncology Unit, Department of Medical Oncology and Molecular

Immunology Unit, Department of Research; Fondazione IRCCS Istituto Nazionale dei

Tumori, Milan, Italy.

(2)Tumor Genomics Unit, Department of Research, Fondazione IRCCS Istituto

Nazionale dei Tumori, Milan, Italy.

Comment on

    J Exp Med. 2022 Dec 5;219(12):

Despite evidence for clinical benefit in patients suffering from lung cancer

following treatment with immune checkpoint inhibitors (ICI), it is still

uncertain how to predict which patients are likely to experience a significant

response. In their work, Valencia et al. (2022. J. Exp.

Med.https://doi.org/10.1084/jem.20220726) identify the DSTYK kinase as a cancer

cell-intrinsic modulator of response to immunotherapy. Through regulation of the

mTOR pathway and stimulation of protective autophagy, DSTYK blunts CD8+ T

cell-mediated killing of cancer cells. Accordingly, lung cancers with increased

expression of DSTYK are less responsive to ICI treatment. These observations

could be useful in the clinic towards the development of predictive biomarkers

and novel therapeutic strategies.

© 2022 Ferrara and Roz.

DOI: 10.1084/jem.20221449

PMCID: PMC9555064

PMID: 36214813 [Indexed for MEDLINE]

18. Clin Microbiol Rev. 2022 Dec 21;35(4):e0018019. doi: 10.1128/cmr.00180-19. Epub 2022 Oct 6.

The Changing Paradigm of Drug-Resistant Tuberculosis Treatment: Successes,

Pitfalls, and Future Perspectives.

Dookie N(#)(1), Ngema SL(#)(1), Perumal R(1)(2), Naicker N(1)(2), Padayatchi

N(1)(2), Naidoo K(1)(2).

Author information:

(1)Centre for the AIDS Programme of Research in South Africagrid.428428.0,

University of KwaZulu-Natal, Durban, South Africa.

(2)South African Medical Research Council-CAPRISA HIV-TB Pathogenesis and

Treatment Research Unit, Durban, South Africa.

(#)Contributed equally

Drug-resistant tuberculosis (DR-TB) remains a global crisis due to the

increasing incidence of drug-resistant forms of the disease, gaps in detection

and prevention, models of care, and limited treatment options. The DR-TB

treatment landscape has evolved over the last 10 years. Recent developments

include the remarkable activity demonstrated by the newly approved anti-TB drugs

bedaquiline and pretomanid against Mycobacterium tuberculosis. Hence, treatment

of DR-TB has drastically evolved with the introduction of the short-course

regimen for multidrug-resistant TB (MDR-TB), transitioning to injection-free

regimens and the approval of the 6-month short regimens for rifampin-resistant

TB and MDR-TB. Moreover, numerous clinical trials are under way with the aim to

reduce pill burden and shorten the DR-TB treatment duration. While there have

been apparent successes in the field, some challenges remain. These include the

ongoing inclusion of high-dose isoniazid in DR-TB regimens despite a lack of

evidence for its efficacy and the inclusion of ethambutol and pyrazinamide in

the standard short regimen despite known high levels of background resistance to

both drugs. Furthermore, antimicrobial heteroresistance, extensive cavitary

disease and intracavitary gradients, the emergence of bedaquiline resistance,

and the lack of biomarkers to monitor DR-TB treatment response remain serious

challenges to the sustained successes. In this review, we outline the impact of

the new drugs and regimens on patient treatment outcomes, explore evidence

underpinning current practices on regimen selection and duration, reflect on the

disappointments and pitfalls in the field, and highlight key areas that require

continued efforts toward improving treatment approaches and rapid biomarkers for

monitoring treatment response.

DOI: 10.1128/cmr.00180-19

PMCID: PMC9769521

PMID: 36200885 [Indexed for MEDLINE]

19. J Exp Med. 2022 Dec 5;219(12):e20220726. doi: 10.1084/jem.20220726. Epub 2022

Sep 28.

DSTYK inhibition increases the sensitivity of lung cancer cells to T

cell-mediated cytotoxicity.

Valencia K(1)(2)(3)(4), Echepare M(1)(5)(3), Teijeira Á(2)(3)(6), Pasquier

A(1)(3), Bértolo C(1), Sainz C(1)(3), Tamayo I(3)(7), Picabea B(1), Bosco G(8),

Thomas R(8)(9)(10), Agorreta J(1)(11), López-Picazo JM(12), Frigola J(13), Amat

R(13), Calvo A(1)(5)(2)(3), Felip E(13)(14), Melero I(2)(3)(12), Montuenga

LM(1)(5)(2)(3).

Author information:

(1)Program in Solid Tumors, Center for Applied Medical Research

(CIMA)-University of Navarra, Pamplona, Spain.

(2)Consorcio de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid,

Spain.

(3)Navarra Health Research Institute (IDISNA), Pamplona, Spain.

…

Comment in

    J Exp Med. 2022 Dec 5;219(12):

Lung cancer remains the leading cause of cancer-related death worldwide. We

identify DSTYK, a dual serine/threonine and tyrosine non-receptor protein

kinase, as a novel actionable target altered in non-small cell lung cancer

(NSCLC). We also show DSTYK's association with a lower overall survival (OS) and

poorer progression-free survival (PFS) in multiple patient cohorts. Abrogation

of DSTYK in lung cancer experimental systems prevents mTOR-dependent

cytoprotective autophagy, impairs lysosomal biogenesis and maturation, and

induces accumulation of autophagosomes. Moreover, DSTYK inhibition severely

affects mitochondrial fitness. We demonstrate in vivo that inhibition of DSTYK

sensitizes lung cancer cells to TNF-α-mediated CD8+-killing and immune-resistant

lung tumors to anti-PD-1 treatment. Finally, in a series of lung cancer

patients, DSTYK copy number gain predicts lack of response to the immunotherapy.

In summary, we have uncovered DSTYK as new therapeutic target in lung cancer.

Prioritization of this novel target for drug development and clinical testing

may expand the percentage of NSCLC patients benefiting from immune-based

treatments.

© 2022 Valencia et al.

DOI: 10.1084/jem.20220726

PMCID: PMC9524203

PMID: 36169652 [Indexed for MEDLINE]

20. J Natl Cancer Inst. 2022 Dec 8;114(12):1665-1673. doi: 10.1093/jnci/djac176.

Lung Cancer Absolute Risk Models for Mortality in an Asian Population using the

China Kadoorie Biobank.

Warkentin MT(1)(2), Tammemägi MC(3), Espin-Garcia O(2)(4), Budhathoki S(1), Liu

G(2)(5), Hung RJ(1)(2).

Author information:

(1)Prosserman Center for Population Health Research, Lunenfeld-Tanenbaum

Research Institute, Sinai Health, Toronto, ON, Canada.

(2)Department of Public Health Sciences, Dalla Lana School of Public Health,

University of Toronto, Toronto, ON, Canada.

(3)Department of Health Sciences, Brock University, St. Catharines, ON, Canada.

(4)Department of Biostatistics, Princess Margaret Cancer Centre, University

Health Network, Toronto, ON, Canada.

(5)Department of Medical Oncology and Hematology, Princess Margaret Cancer

Centre, Toronto, ON, Canada.

BACKGROUND: Lung cancer is the leading cause of cancer mortality globally. Early

detection through risk-based screening can markedly improve prognosis. However,

most risk models were developed in North American cohorts of smokers, whereas

less is known about risk profiles for never-smokers, which represent a growing

proportion of lung cancers, particularly in Asian populations.

METHODS: Based on the China Kadoorie Biobank, a population-based prospective

cohort of 512 639 adults with up to 12 years of follow-up, we built Asian Lung

Cancer Absolute Risk Models (ALARM) for lung cancer mortality using flexible

parametric survival models, separately for never and ever-smokers, accounting

for competing risks of mortality. Model performance was evaluated in a 25%

hold-out test set using the time-dependent area under the curve and by comparing

model-predicted and observed risks for calibration.

RESULTS: Predictors assessed in the never-smoker lung cancer mortality model

were demographics, body mass index, lung function, history of emphysema or

bronchitis, personal or family history of cancer, passive smoking, and indoor

air pollution. The ever-smoker model additionally assessed smoking history. The

5-year areas under the curve in the test set were 0.77 (95% confidence interval

= 0.73 to 0.80) and 0.81 (95% confidence interval = 0.79 to 0.84) for

ALARM-never-smokers and ALARM-ever smokers, respectively. The maximum 5-year

risk for never and ever-smokers was 2.6% and 12.7%, respectively.

CONCLUSIONS: This study is among the first to develop risk models specifically

for Asian populations separately for never and ever-smokers. Our models

accurately identify Asians at high risk of lung cancer death and may identify

those with risks exceeding common eligibility thresholds who may benefit from

screening.

© The Author(s) 2022. Published by Oxford University Press. All rights reserved.

For permissions, please email: journals.permissions@oup.com.

DOI: 10.1093/jnci/djac176

PMID: 36083018 [Indexed for MEDLINE]

21. J Clin Oncol. 2022 Dec 1;40(34):3912-3917. doi: 10.1200/JCO.22.00428. Epub 2022 Aug 26.

Updated Overall Survival and Exploratory Analysis From Randomized, Phase II EVAN

Study of Erlotinib Versus Vinorelbine Plus Cisplatin Adjuvant Therapy in Stage

IIIA Epidermal Growth Factor Receptor+ Non-Small-Cell Lung Cancer.

Yue D(1), Xu S(2), Wang Q(3), Li X(4), Shen Y(5), Zhao H(6), Chen C(7), Mao

W(8), Liu W(9), Liu J(10), Zhang L(11), Ma H(12), Li Q(13), Yang Y(14), Liu

Y(15), Chen H(16), Zhang Z(1), Zhang B(1), Wang C(1).

Author information:

(1)Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.

(2)Harbin Medical University Cancer Hospital, Harbin, China.

(3)Zhongshan Hospital, Fudan University, Shanghai, China.

…

Clinical trials frequently include multiple end points that mature at different

times. The initial report, typically based on the primary end point, may be

published when key planned co-primary or secondary analyses are not yet

available. Clinical Trial Updates provide an opportunity to disseminate

additional results from studies, published in JCO or elsewhere, for which the

primary end point has already been reported.The randomized, open-label, phase II

EVAN study investigated the efficacy (disease-free survival [DFS] and 5-year

overall survival [OS]) and safety of erlotinib versus vinorelbine/cisplatin as

adjuvant chemotherapy after complete resection (R0) for stage III epidermal

growth factor receptor (EGFR) mutation+ non-small-cell lung cancer. We describe

the updated results at the 43-month follow-up. In EVAN, patients were randomly

assigned (1:1) to erlotinib (n = 51) or vinorelbine/cisplatin (n = 51). The

median follow-up was 54.8 and 63.9 months in the erlotinib and chemotherapy

arms, respectively. With erlotinib, the respective 5-year DFS by Kaplan-Meier

analysis was 48.2% (95% CI, 29.4 to 64.7) and 46.2% (95% CI, 27.6 to 62.9) in

the intention-to-treat and per-protocol populations. The median OS was 84.2

months with erlotinib versus 61.1 months with chemotherapy (hazard ratio, 0.318;

95% CI, 0.151 to 0.670). The 5-year survival rates were 84.8% and 51.1% with

erlotinib and chemotherapy, respectively. In whole-exome sequencing analysis,

frequent genes with variants co-occurring at baseline were TP53, MUC16, FAM104B,

KMT5A, and DNAH9. With erlotinib, a single-nucleotide polymorphism mutation in

UBXN11 was associated with significantly worse DFS (P = .01). To our knowledge,

this study is the first to demonstrate clinically meaningful OS improvement with

adjuvant erlotinib compared with chemotherapy in R0 stage III EGFR+

non-small-cell lung cancer.

DOI: 10.1200/JCO.22.00428

PMID: 36027483 [Indexed for MEDLINE]

22. Am J Respir Crit Care Med. 2022 Dec 15;206(12):1480-1494. doi:

10.1164/rccm.202110-2358OC.

Transcriptional Circuitry of NKX2-1 and SOX1 Defines an Unrecognized Lineage

Subtype of Small-Cell Lung Cancer.

Kong R(1)(2)(3), Patel AS(2)(3)(4), Sato T(2)(3)(5)(6), Jiang F(2)(3), Yoo

S(7)(8), Bao L(9), Sinha A(2)(3), Tian Y(2)(3), Fridrikh M(2)(3), Liu S(10),

Feng J(11), He X(12)(13), Jiang J(1), Ma Y(1), Grullon K(2)(3), Yang

D(2)(3)(14), Powell CA(2)(3), Beasley MB(15), Zhu J(3)(7)(8), Snyder

EL(16)(17)(18), Li S(1), Watanabe H(2)(3)(7).

Author information:

(1)Department of Thoracic Surgery and.

(2)Division of Pulmonary, Critical Care and Sleep Medicine.

(3)Tisch Cancer Institute.

…

Comment in

    Am J Respir Crit Care Med. 2022 Dec 15;206(12):1441-1443.

Rationale: The current molecular classification of small-cell lung cancer (SCLC)

on the basis of the expression of four lineage transcription factors still

leaves its major subtype SCLC-A as a heterogeneous group, necessitating more

precise characterization of lineage subclasses. Objectives: To refine the

current SCLC classification with epigenomic profiles and to identify features of

the redefined SCLC subtypes. Methods: We performed unsupervised clustering of

epigenomic profiles on 25 SCLC cell lines. Functional significance of NKX2-1

(NK2 homeobox 1) was evaluated by cell growth, apoptosis, and xenograft using

clustered regularly interspaced short palindromic repeats-Cas9

(CRISPR-associated protein 9)-mediated deletion. NKX2-1-specific cistromic

profiles were determined using chromatin immunoprecipitation followed by

sequencing, and its functional transcriptional partners were determined using

coimmunoprecipitation followed by mass spectrometry. Rb1flox/flox;

Trp53flox/flox and Rb1flox/flox; Trp53flox/flox; Nkx2-1flox/flox mouse models

were engineered to explore the function of Nkx2-1 in SCLC tumorigenesis.

Epigenomic landscapes of six human SCLC specimens and 20 tumors from two mouse

models were characterized. Measurements and Main Results: We identified two

epigenomic subclusters of the major SCLC-A subtype: SCLC-Aα and SCLC-Aσ. SCLC-Aα was characterized by the presence of a super-enhancer at the NKX2-1 locus, which was observed in human SCLC specimens and a murine SCLC model. We found that

NKX2-1, a dual lung and neural lineage factor, is uniquely relevant in SCLC-Aα.

In addition, we found that maintenance of this neural identity in SCLC-Aα is

mediated by collaborative transcriptional activity with another neuronal

transcriptional factor, SOX1 (SRY-box transcription factor 1). Conclusions: We

comprehensively describe additional epigenomic heterogeneity of the major SCLC-A

subtype and define the SCLC-Aα subtype by the core regulatory circuitry of

NKX2-1 and SOX1 super-enhancers and their functional collaborations to maintain

neuronal linage state.

DOI: 10.1164/rccm.202110-2358OC

PMCID: PMC9757094

PMID: 35848993 [Indexed for MEDLINE]

23. Lancet Infect Dis. 2022 Dec;22(12):e359-e369. doi:

10.1016/S1473-3099(22)00227-4. Epub 2022 May 27.

Mycobacterial infections in adults with haematological malignancies and

haematopoietic stem cell transplants: guidelines from the 8th European

Conference on Infections in Leukaemia.

Bergeron A(1), Mikulska M(2), De Greef J(3), Bondeelle L(4), Franquet T(5),

Herrmann JL(6), Lange C(7), Spriet I(8), Akova M(9), Donnelly JP(10), Maertens

J(11), Maschmeyer G(12), Rovira M(13), Goletti D(14), de la Camara R(15);

European Conference on Infections in Leukaemia group.

Author information:

(1)Division of Pulmonology, Geneva University Hospitals, Geneva, Switzerland;

University of Paris, ECSTRRA Team, Inserm, Paris, France. Electronic address:

anne.bergeron@hcuge.ch.

(2)Division of Infectious Diseases, Department of Health Sciences, University of

Genoa, Genoa, Italy; San Martino Polyclinic Hospital, Genoa, Italy.

(3)Division of Internal Medicine and Infectious Diseases, Saint-Luc University

Clinics, Catholic University of Louvain, Brussels, Belgium.

…

Mycobacterial infections, both tuberculosis and nontuberculous, are more common

in patients with haematological malignancies and haematopoietic stem cell

transplant recipients than in the general population-although these infections

remain rare. Mycobacterial infections pose both diagnostic and therapeutic

challenges. The management of mycobacterial infections is particularly

complicated for patients in haematology because of the many drug-drug

interactions between antimycobacterial drugs and haematological and

immunosuppressive treatments. The management of mycobacterial infections must

also consider the effect of delaying haematological management. We surveyed the

management practices for latent tuberculosis infection (LTBI) in haematology

centres in Europe. We then conducted a meticulous review of the literature on

the epidemiology, diagnosis, and management of LTBI, tuberculosis, and

nontuberculous mycobacterial infections among patients in haematology, and we

formulated clinical guidelines according to standardised European Conference on

Infections in Leukaemia (ECIL) methods. In this Review, we summarise the

available literature and the recommendations of ECIL 8 for managing

mycobacterial infections in patients with haematological malignancies.

Copyright © 2022 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1473-3099(22)00227-4

PMID: 35636446 [Indexed for MEDLINE]

24. Autophagy. 2022 Dec;18(12):2926-2945. doi: 10.1080/15548627.2022.2054240. Epub 2022 Apr 5.

Chemical modulation of SQSTM1/p62-mediated xenophagy that targets a broad range

of pathogenic bacteria.

Lee YJ(1), Kim JK(2)(3)(4), Jung CH(1), Kim YJ(2)(3)(4), Jung EJ(1), Lee SH(1),

Choi HR(1), Son YS(5), Shim SM(1), Jeon SM(2)(3)(4), Choe JH(2)(3)(4), Lee

SH(6), Whang J(7), Sohn KC(3)(8), Hur GM(3)(8), Kim HT(9), Yeom J(1)(10), Jo

EK(2)(3)(4), Kwon YT(1)(9)(11)(12).

Author information:

(1)Cellular Degradation Biology Center and Department of Biomedical Sciences,

College of Medicine, Seoul National University, Seoul, Republic of Korea.

(2)Department of Microbiology, Chungnam National University School of Medicine,

Daejeon, Korea.

(3)Department of Medical Science, Chungnam National University School of

Medicine, Daejeon, Korea.

…

The N-degron pathway is a proteolytic system in which the N-terminal degrons

(N-degrons) of proteins, such as arginine (Nt-Arg), induce the degradation of

proteins and subcellular organelles via the ubiquitin-proteasome system (UPS) or

macroautophagy/autophagy-lysosome system (hereafter autophagy). Here, we

developed the chemical mimics of the N-degron Nt-Arg as a pharmaceutical means

to induce targeted degradation of intracellular bacteria via autophagy, such as

Salmonella enterica serovar Typhimurium (S. Typhimurium), Escherichia coli, and

Streptococcus pyogenes as well as Mycobacterium tuberculosis (Mtb). Upon binding

the ZZ domain of the autophagic cargo receptor SQSTM1/p62 (sequestosome 1),

these chemicals induced the biogenesis and recruitment of autophagic membranes

to intracellular bacteria via SQSTM1, leading to lysosomal degradation. The

antimicrobial efficacy was independent of rapamycin-modulated core autophagic

pathways and synergistic with the reduced production of inflammatory cytokines.

In mice, these drugs exhibited antimicrobial efficacy for S. Typhimurium,

Bacillus Calmette-Guérin (BCG), and Mtb as well as multidrug-resistant Mtb and

inhibited the production of inflammatory cytokines. This dual mode of action in

xenophagy and inflammation significantly protected mice from inflammatory

lesions in the lungs and other tissues caused by all the tested bacterial

strains. Our results suggest that the N-degron pathway provides a therapeutic

target in host-directed therapeutics for a broad range of drug-resistant

intracellular pathogens.Abbreviations: ATG: autophagy-related gene; BCG:

Bacillus Calmette-Guérin; BMDMs: bone marrow-derived macrophages;

CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CFUs: colony-forming

units; CXCL: C-X-C motif chemokine ligand; EGFP: enhanced green fluorescent

protein; IL1B/IL-1β: interleukin 1 beta; IL6: interleukin 6; LIR:

MAP1LC3/LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1

light chain 3; Mtb: Mycobacterium tuberculosis; MTOR: mechanistic target of

rapamycin kinase; NBR1: NBR1 autophagy cargo receptor; OPTN: optineurin; PB1:

Phox and Bem1; SQSTM1/p62: sequestosome 1; S. Typhimurium: Salmonella enterica

serovar Typhimurium; TAX1BP1: Tax1 binding protein 1; TNF: tumor necrosis

factor; UBA: ubiquitin-associated.

DOI: 10.1080/15548627.2022.2054240

PMCID: PMC9673928

PMID: 35316156 [Indexed for MEDLINE]

25. Autophagy. 2022 Dec;18(12):3033-3034. doi: 10.1080/15548627.2022.2069439. Epub 2022 May 9.

Mitophagy: a new actor in the efficacy of chemo-immunotherapy.

Limagne E(1)(2)(3)(4), Ghiringhelli F(1)(2)(3)(4)(5).

Author information:

(1)Cancer Biology Transfer Platform, Centre Georges-François Leclerc, Equipe

Labellisée Ligue Contre le Cancer, Dijon, France.

(2)Centre de Recherche, INSERM LNC-UMR1231, Dijon, France.

(3)Cancer Biology Transfer Platform, Univ. Bourgogne Franche-Comté, Dijon,

France.

(4)Cancer Biology Transfer Platform, Genetic and Immunology Medical Institute,

Dijon, France.

(5)Department of Medical Oncology, Centre Georges-François Leclerc, Dijon,

France.

Resistance to chemo-immunotherapy is a major issue for the treatment of

non-small cell lung cancer. In a recent paper we unravel the role of MAPK in the

capacity of restraining the therapeutic efficacy of chemo-immunotherapy.

Inhibition of the MAPK pathway using a MAP2K/MEK inhibitor in combination with

chemotherapy could promote OPTN (optineurin)-dependent mitophagy of cancer

cells. Mitochondria then degrade via autophagosomes and amphisomes and release

mitochondrial DNA, which interacts with TLR9 located in these compartments. TLR9

activation promotes the production of the chemokine CXCL10 by cancer cells,

which could further improve T cell recruitment and improve the efficacy of

immunotherapy.

DOI: 10.1080/15548627.2022.2069439

PMCID: PMC9673945

PMID: 35532360 [Indexed for MEDLINE]