Filters applied: from 2022/10/1 - 2022/10/31. 

1. Science. 2022 Oct 14;378(6616):eabq0132. doi: 10.1126/science.abq0132. Epub 2022 Oct 14.

A bacterial phospholipid phosphatase inhibits host pyroptosis by hijacking

ubiquitin.

Chai Q(#)(1), Yu S(#)(2), Zhong Y(#)(1)(3), Lu Z(1)(3), Qiu C(1)(3), Yu Y(1)(3),

Zhang X(1)(3), Zhang Y(1), Lei Z(1)(3), Qiang L(1)(3), Li BX(1), Pang Y(2), Qiu

XB(4)(5), Wang J(1), Liu CH(1)(3).

Author information:

(1)CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of

Microbiology, Chinese Academy of Sciences, Beijing 100101, China.

(2)Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest

Hospital, Capital Medical University, Beijing 101149, China.

(3)Savaid Medical School, University of Chinese Academy of Sciences, Beijing

101408, China.

(4)State Key Laboratory of Natural Medicines, China Pharmaceutical University,

Nanjing, Jiangsu 211198, China.

(5)Ministry of Education Key Laboratory of Cell Proliferation and Regulation

Biology, College of Life Sciences, Beijing Normal University, Beijing 100875,

China.

(#)Contributed equally

The inflammasome-mediated cleavage of gasdermin D (GSDMD) causes pyroptosis and

inflammatory cytokine release to control pathogen infection, but how pathogens

evade this immune response remains largely unexplored. Here we identify the

known protein phosphatase PtpB from Mycobacterium tuberculosis as a phospholipid

phosphatase inhibiting the host inflammasome-pyroptosis pathway.

Mechanistically, PtpB dephosphorylated phosphatidylinositol-4-monophosphate and

phosphatidylinositol-(4,5)-bisphosphate in host cell membrane, thus disrupting

the membrane localization of the cleaved GSDMD to inhibit cytokine release and

pyroptosis of macrophages. Notably, this phosphatase activity requires PtpB

binding to ubiquitin. Disrupting phospholipid phosphatase activity or the

ubiquitin-interacting motif of PtpB enhanced host GSDMD-dependent immune

responses and reduced intracellular pathogen survival. Thus, pathogens inhibit

pyroptosis and counteract host immunity by altering host membrane composition.

DOI: 10.1126/science.abq0132

PMID: 36227980 [Indexed for MEDLINE]

2. Cancer Cell. 2022 Oct 14:S1535-6108(22)00480-9. doi:

10.1016/j.ccell.2022.09.018. Online ahead of print.

Squamous cell lung cancer: Current landscape and future therapeutic options.

Lau SCM(1), Pan Y(1), Velcheti V(1), Wong KK(2).

Author information:

(1)Department of Medical Oncology, Laura & Issac Perlmutter Cancer Center, NYU

Grossman School of Medicine, NYU Langone Health, Smilow Building 10th Floor,

Suite 1001, New York, NY 10016, USA.

(2)Department of Medical Oncology, Laura & Issac Perlmutter Cancer Center, NYU

Grossman School of Medicine, NYU Langone Health, Smilow Building 10th Floor,

Suite 1001, New York, NY 10016, USA. Electronic address:

kwok-kin.wong@nyulangone.org.

Squamous cell lung cancers (lung squamous cell carcinomas [LUSCs]) are

associated with high mortality and a lack of therapies specific to this disease.

Although recurrent molecular aberrations are present in LUSCs, efforts to

develop targeted therapies against receptor tyrosine kinases, signaling

transduction, and cell cycle checkpoints in LUSCs were met with significant

challenges. The present therapeutic landscape focuses on epigenetic therapies to

modulate the expression of lineage-dependent survival pathways and undruggable

oncogenes. Another important therapeutic approach is to exploit metabolic

vulnerabilities unique to LUSCs. These novel therapies may synergize with immune

checkpoint inhibitors in the right therapeutic context. For example, the

recognition that alterations in KEAP1-NFE2L2 in LUSCs affected antitumor immune

responses created unique opportunities for targeted, metabolic, and immune

combinations. This article provides a perspective on how lessons learned from

the past influence the current therapeutic landscape and opportunities for

future drug development for LUSCs.

Copyright © 2022 Elsevier Inc. All rights reserved.

DOI: 10.1016/j.ccell.2022.09.018

PMID: 36270277

3. Lancet Oncol. 2022 Nov;23(11):1465-1474. doi: 10.1016/S1470-2045(22)00600-3.

Epub 2022 Oct 18.

Association of the interaction between mosaic chromosomal alterations and

polygenic risk score with the risk of lung cancer: an array-based case-control

association and prospective cohort study.

Qin N(1), Wang C(2), Chen C(3), Yang L(3), Liu S(3), Xiang J(3), Xie Y(4), Liang

S(3), Zhou J(3), Xu X(3), Zhao X(3), Zhu M(5), Jin G(6), Ma H(7), Dai J(8), Hu

Z(9), Shen H(10).

Author information:

(1)State Key Laboratory of Reproductive Medicine, School of Public Health,

Nanjing Medical University, Nanjing, China; Department of Epidemiology, Centre

for Global Health, School of Public Health, Nanjing Medical University, Nanjing,

China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment,

Collaborative Innovation Centre for Cancer Medicine, Nanjing Medical University,

Nanjing, China.

(2)Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative

Innovation Centre for Cancer Medicine, Nanjing Medical University, Nanjing,

China; Department of Bioinformatics, School of Biomedical Engineering and

Informatics, Nanjing Medical University, Nanjing, China.

(3)Department of Epidemiology, Centre for Global Health, School of Public

Health, Nanjing Medical University, Nanjing, China.

…

BACKGROUND: Mosaic chromosomal alterations (mCAs) detected from blood-derived

DNA are large structural alterations of clonal haematopoietic origin and are

associated with various diseases, such as haematological malignancies,

infections, and solid cancers. We aimed to investigate whether mCAs contribute

to the risk of lung cancer and modify the effect of polygenic risk score (PRS)

on lung cancer risk prediction.

METHODS: The blood-derived DNA of patients with lung cancer and cancer-free

controls with Chinese ancestry from the Nanjing Lung Cancer Cohort (NJLCC) study

were genotyped with a Global Screening Array, and mCAs were detected with the

Mosaic Chromosomal Alterations (MoChA) pipeline. mCA call sets of individuals

with European ancestry were obtained from the prospective cohort UK Biobank

(UKB) study, including documented incident lung cancer. All patients with lung

cancer from the NJLCC study (aged 15 years or older at diagnosis) were

histopathologically confirmed as new lung cancer cases by at least two

pathologists and were free of chemotherapy or radiotherapy before diagnosis.

Participants with incident lung cancer (aged 37-73 years at assessment)

diagnosed after recruitment to the UKB were identified through linkage to

national cancer registries. Logistic regression and Cox proportional hazard

models were applied to evaluate associations between mCAs and risk of lung

cancer in the NJLCC (logistic regression) and UKB (Cox proportional hazard

model) studies.

FINDINGS: The NJLCC study included 10 248 individuals (6445 [62·89%] men and

3803 [37·11%] women; median age 60·0 years [IQR 53·0-66·0]) with lung cancer and 9298 individuals (5871 [63·14%] men and 3427 [36·86%] women; median age 60·0 years [52·0-65·0]) without lung cancer recruited from three sub-regions (north, central, and south) across China between April 15, 2003, and Aug 18, 2017. The UKB included 450 821 individuals recruited from 22 centres across the UK between March 13, 2006, and Nov 1, 2010, including 2088 individuals with lung cancer (1075 [51·48%] men and 1013 [48·52%] women; median age 63·0 years [IQR

59·0-66·0]), and 448 733 participants were free of lung cancer (204 713 [45·62%]

men and 244 020 [54·38%] women; median age 58·0 years [IQR 50·0-63·0]). Compared with non-carriers of mosaic losses, carriers had a significantly increased risk of lung cancer in the NJLCC (odds ratio [OR] 1·81, 95% CI 1·43-2·28; p=6·69 × 10-7) and UKB (hazard ratio [HR] 1·40, 95% CI 1·00-1·95; p=0·048) studies. This increased risk was even higher in patients with expanded cell fractions of mCAs (ie, cell fractions ≥10% vs cell fractions<10%) in the NJLCC (OR 1·61 [95% CI 1·26-2·08] vs 1·03 [0·83-1·26]; p for heterogeneity

test=6·41 × 10-3). A significant multiplicative interaction was observed between PRS and mosaic losses on the risk of lung cancer in both the NJLCC (interaction p value=0·030) and UKB (p=0·043). Compared with non-carriers of mosaic loss abnormalities with low genetic risk, participants with expanded mosaic losses (cell fractions ≥10%) and high genetic risk had around a six-times increased risk of lung cancer in the NJLCC study (OR 6·40 [95% CI 3·22-12·69]), and an almost four-times increased risk of lung cancer (HR 3·75 [95% CI 1·86-7·55]) in the UKB study. The additive interaction also contributed a 3·67 (95% CI 0·49-6·85) relative excess risk of developing lung cancer in the NJLCC study,

and a 2·15 (0·12-4·19) relative excess risk in the UKB study.

INTERPRETATION: mCAs act as a new endogenous indicator for the risk of lung

cancer and might be jointly used with PRS to optimise personalised risk

stratification for lung cancer.

FUNDING: National Natural Science Foundation of China, Outstanding Youth

Foundation of Jiangsu Province, Natural Science Foundation of Jiangsu Province,

and Postdoctoral Science Foundation of China.

TRANSLATION: For the Chinese translation of the abstract see Supplementary

Materials section.

Copyright © 2022 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1470-2045(22)00600-3

PMID: 36265503 [Indexed for MEDLINE]

4. Cancer Cell. 2022 Oct 10;40(10):1128-1144.e8. doi: 10.1016/j.ccell.2022.08.015.

Epub 2022 Sep 22.

MPS1 inhibition primes immunogenicity of KRAS-LKB1 mutant lung cancer.

Kitajima S(1), Tani T(2), Springer BF(3), Campisi M(2), Osaki T(4), Haratani

K(2), Chen M(5), Knelson EH(2), Mahadevan NR(6), Ritter J(7), Yoshida R(2),

Köhler J(2), Ogino A(2), Nozawa RS(8), Sundararaman SK(9), Thai TC(2), Homme

M(10), Piel B(2), Kivlehan S(11), Obua BN(11), Purcell C(12), Yajima M(13),

Barbie TU(14), Lizotte PH(11), Jänne PA(2), Paweletz CP(11), Gokhale PC(3),

Barbie DA(15).

Author information:

(1)Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline

Avenue, Boston, MA LC4115, USA; Department of Cell Biology, Cancer Institute,

Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto, Tokyo, Japan.

Electronic address: shunsuke.kitajima@jfcr.or.jp.

(2)Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline

Avenue, Boston, MA LC4115, USA.

(3)Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline

Avenue, Boston, MA LC4115, USA; Experimental Therapeutics Core, Dana-Farber

Cancer Institute, Boston, MA, USA; Belfer Center for Applied Cancer Science,

Dana-Farber Cancer Institute, Boston, MA, USA.

…

Comment in

    Cancer Cell. 2022 Oct 10;40(10):1073-1076.

KRAS-LKB1 (KL) mutant lung cancers silence STING owing to intrinsic

mitochondrial dysfunction, resulting in T cell exclusion and resistance to

programmed cell death (ligand) 1 (PD-[L]1) blockade. Here we discover that KL

cells also minimize intracellular accumulation of 2'3'-cyclic GMP-AMP

(2'3'-cGAMP) to further avoid downstream STING and STAT1 activation. An unbiased

screen to co-opt this vulnerability reveals that transient MPS1 inhibition

(MPS1i) potently re-engages this pathway in KL cells via micronuclei generation.

This effect is markedly amplified by epigenetic de-repression of STING and only

requires pulse MPS1i treatment, creating a therapeutic window compared with

non-dividing cells. A single course of decitabine treatment followed by pulse

MPS1i therapy restores T cell infiltration in vivo, enhances anti-PD-1 efficacy,

and results in a durable response without evidence of significant toxicity.

Copyright © 2022 Elsevier Inc. All rights reserved.

DOI: 10.1016/j.ccell.2022.08.015

PMCID: PMC9561026

PMID: 36150391 [Indexed for MEDLINE]

5. Cancer Cell. 2022 Oct 10;40(10):1223-1239.e6. doi: 10.1016/j.ccell.2022.08.013.

Epub 2022 Sep 15.

Analyses of rare predisposing variants of lung cancer in 6,004 whole genomes in

Chinese.

Wang C(1), Dai J(2), Qin N(2), Fan J(2), Ma H(3), Chen C(2), An M(2), Zhang

J(2), Yan C(2), Gu Y(4), Xie Y(5), He Y(4), Jiang Y(6), Zhu M(2), Song C(2),

Jiang T(7), Liu J(8), Zhou J(2), Wang N(2), Hua T(2), Liang S(2), Wang L(8), Xu

J(9), Yin R(10), Chen L(9), Xu L(10), Jin G(6), Lin D(11), Hu Z(12), Shen H(13).

Author information:

(1)Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative

Innovation Center for Cancer Personalized Medicine, Nanjing Medical University,

Nanjing 211166, Jiangsu, China; State Key Laboratory of Reproductive Medicine,

Nanjing Medical University, Nanjing 211166, Jiangsu, China; Department of

Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical

University, Nanjing 211166, Jiangsu, China; Department of Bioinformatics, School

of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing

211166, Jiangsu, China.

(2)Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative

Innovation Center for Cancer Personalized Medicine, Nanjing Medical University,

Nanjing 211166, Jiangsu, China; Department of Epidemiology, Center for Global

Health, School of Public Health, Nanjing Medical University, Nanjing 211166,

Jiangsu, China.

(3)Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative

Innovation Center for Cancer Personalized Medicine, Nanjing Medical University,

Nanjing 211166, Jiangsu, China; State Key Laboratory of Reproductive Medicine,

Nanjing Medical University, Nanjing 211166, Jiangsu, China; Department of

Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical

University, Nanjing 211166, Jiangsu, China; State Key Laboratory of Reproductive

Medicine (Suzhou Centre), Gusu School, Nanjing Medical University, Suzhou

215002, Jiangsu, China; Research Units of Cohort Study on Cardiovascular

Diseases and Cancers, Chinese Academy of Medical Sciences, Beijing 100730,

China.

…

Comment in

    Cancer Cell. 2022 Oct 10;40(10):1081-1083.

We present the largest whole-genome sequencing (WGS) study of non-small cell

lung cancer (NSCLC) to date among 6,004 individuals of Chinese ancestry, coupled

with 23,049 individuals genotyped by SNP array. We construct a high-quality

haplotype reference panel for imputation and identify 20 common and

low-frequency loci (minor allele frequency [MAF] ≥ 0.5%), including five loci

that have never been reported before. For rare loss-of-function (LoF) variants

(MAF < 0.5%), we identify BRCA2 and 18 other cancer predisposition genes that

affect 5.29% of individuals with NSCLC, and 98.91% (181 of 183) of LoF variants

have not been linked previously to NSCLC risk. Promoter variants of BRCA2 also

have a substantial effect on NSCLC risk, and their prevalence is comparable with

BRCA2 LoF variants. The associations are validated in an independent

case-control study including 4,410 individuals and a prospective cohort study

including 23,826 individuals. Our findings not only provide a high-quality

reference panel for future array-based association studies but depict the whole

picture of rare pathogenic variants for NSCLC.

Copyright © 2022 Elsevier Inc. All rights reserved.

DOI: 10.1016/j.ccell.2022.08.013

PMID: 36113475 [Indexed for MEDLINE]

6. Lancet Oncol. 2022 Oct;23(10):1274-1286. doi: 10.1016/S1470-2045(22)00518-6.

Epub 2022 Sep 12.

Pembrolizumab versus placebo as adjuvant therapy for completely resected stage

IB-IIIA non-small-cell lung cancer (PEARLS/KEYNOTE-091): an interim analysis of

a randomised, triple-blind, phase 3 trial.

O'Brien M(1), Paz-Ares L(2), Marreaud S(3), Dafni U(4), Oselin K(5), Havel L(6),

Esteban E(7), Isla D(8), Martinez-Marti A(9), Faehling M(10), Tsuboi M(11), Lee

JS(12), Nakagawa K(13), Yang J(14), Samkari A(14), Keller SM(14), Mauer M(3),

Jha N(3), Stahel R(15), Besse B(16), Peters S(17); EORTC-1416-LCG/ETOP 8-15 –

PEARLS/KEYNOTE-091 Investigators.

Author information:

(1)Lung Unit, Royal Marsden Hospital, London, UK. Electronic address:

mary.obrien@rmh.nhs.uk.

(2)Hospital Universitario 12 de Octubre, CNIO, Ciberonc & Universidad

Complutense, Madrid, Spain.

(3)European Organisation for Research and Treatment of Cancer, Brussels,

Belgium.

…

BACKGROUND: Pembrolizumab is a standard-of-care for advanced non-small-cell lung

cancer (NSCLC). We assessed pembrolizumab as adjuvant therapy for completely

resected stage IB-IIIA NSCLC.

METHODS: In this randomised, triple-blind, phase 3 trial (PEARLS/KEYNOTE-091),

patients were recruited from 196 medical centres in 29 countries. Eligible

patients were aged 18 years or older, with completely resected, pathologically

confirmed stage IB (tumours of ≥4 cm in diameter), II, or IIIA NSCLC per the

American Joint Committee on Cancer staging system (7th edition) of any histology

or PD-L1 expression level, and an Eastern Cooperative Oncology Group performance

status of 0 or 1; adjuvant chemotherapy was to be considered for stage IB

disease and was strongly recommended for stage II and IIIA disease, according to

national and local guidelines. Using a central interactive voice-response

system, eligible participants were randomly assigned (1:1), using a minimisation

technique and stratified by disease stage, previous adjuvant chemotherapy, PD-L1

expression, and geographical region, to pembrolizumab 200 mg or placebo, both

administered intravenously every 3 weeks for up to 18 cycles. Participants,

investigators, and analysts were masked to treatment assignment. Dual primary

endpoints were disease-free survival in the overall population and in the

population with PD-L1 tumour proportion score (TPS) of 50% or greater. Efficacy

was assessed in the intention-to-treat (ITT) population (ie, all participants

randomly assigned to a treatment group). Safety was assessed in all participants

randomly assigned to treatment who received at least one dose of study

treatment. Here we report results of the second interim analysis, prespecified

to occur when approximately 118 disease-free survival events had occurred in the

PD-L1 TPS of 50% or greater population. This study is registered with

ClinicalTrials.gov, NCT02504372, and is active but not recruiting.

FINDINGS: Between Jan 20, 2016, and May 6, 2020, 1177 (60%) of 1955 screened

participants were randomly assigned to pembrolizumab (n=590, including n=168

with PD-L1 TPS of ≥50%) or placebo (n=587; including n=165 with PD-L1 TPS of

≥50%) and included in the ITT population. Median follow-up as of data cutoff

(Sept 20, 2021) for this interim analysis was 35·6 months (IQR 27·1-45·5). In

the overall population, median disease-free survival was 53·6 months (95% CI

39·2 to not reached) in the pembrolizumab group versus 42·0 months (31·3 to not reached) in the placebo group (HR 0·76 [95% CI 0·63-0·91], p=0·0014). In the PD-L1 TPS of 50% or greater population, median disease-free survival was not

reached in either the pembrolizumab group (95% CI 44·3 to not reached) or the

placebo group (95% CI 35·8 to not reached; HR 0·82 [95% CI 0·57-1·18]; p=0·14).

Grade 3 or worse adverse events occurred in 198 (34%) of 580 participants who

received pembrolizumab and 150 (26%) of 581 participants who received placebo.

Grade 3 or worse events that occurred in at least ten participants in either

treatment group were hypertension (35 [6%]) and pneumonia (12 [2%]) with

pembrolizumab and hypertension (32 [6%]) with placebo. Serious adverse events

occurred in 142 (24%) participants in the pembrolizumab group and 90 (15%) in

the placebo group; serious adverse events that occurred in more than 1% of

participants were pneumonia (13 [2%]), pneumonitis (12 [2%]), and diarrhoea

(seven [1%]) with pembrolizumab and pneumonia (nine [2%]) with placebo.

Treatment-related adverse events led to death in four (1%) participants treated

with pembrolizumab (one due to both cardiogenic shock and myocarditis, one due

to both septic shock and myocarditis, one due to pneumonia, and one due to

sudden death) and in no participants treated with placebo.

INTERPRETATION: Pembrolizumab significantly improved disease-free survival

compared with placebo and was not associated with new safety signals in

completely resected, PD-L1-unselected, stage IB-IIIA NSCLC. Pembrolizumab is

potentially a new treatment option for stage IB-IIIA NSCLC after complete

resection and, when recommended, adjuvant chemotherapy, regardless of PD-L1

expression.

FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.

Copyright © 2022 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1470-2045(22)00518-6

PMID: 36108662 [Indexed for MEDLINE]

7. Nat Med. 2022 Oct;28(10):2155-2161. doi: 10.1038/s41591-022-01962-5. Epub 2022

Sep 12.

Neoadjuvant atezolizumab for resectable non-small cell lung cancer: an

open-label, single-arm phase II trial.

Chaft JE(#)(1)(2), Oezkan F(#)(3)(4)(5)(6), Kris MG(1)(2), Bunn PA(7), Wistuba

II(8), Kwiatkowski DJ(9)(10), Owen DH(3)(11), Tang Y(10), Johnson BE(9)(10), Lee

JM(12), Lozanski G(11), Pietrzak M(11), Seweryn M(11)(13)(14), Byun WY(11),

Schulze K(15), Nicholas A(15), Johnson A(15), Grindheim J(15), Hilz S(15),

Shames DS(15), Rivard C(7), Toloza E(16), Haura EB(16), McNamee CJ(9)(10),

Patterson GA(17), Waqar SN(17), Rusch VW(1), Carbone DP(18)(19); LCMC study

investigators.

Collaborators: Waqar SN, Shum E, Nagasaka M, Koczywas M, Garon EB, Finley DJ,

Camidge DR, Carlisle JW, Blasberg JD.

Author information:

(1)Memorial Sloan Kettering Cancer Center, New York, NY, USA.

(2)Weill Cornell Medical College, New York, NY, USA.

(3)The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.

…

In an ongoing, open-label, single-arm phase II study ( NCT02927301 ), 181

patients with untreated, resectable, stage IB-IIIB non-small cell lung cancer

received two doses of neoadjuvant atezolizumab monotherapy. The primary end

point was major pathological response (MPR; ≤10% viable malignant cells) in

resected tumors without EGFR or ALK alterations. Of the 143 patients in the

primary end point analysis, the MPR was 20% (95% confidence interval, 14-28%).

With a minimum duration of follow-up of 3 years, the 3-year survival rate of 80%

was encouraging. The most common adverse events during the neoadjuvant phase

were fatigue (39%, 71 of 181) and procedural pain (29%, 53 of 181), along with

expected immune-related toxicities; there were no unexpected safety signals. In

exploratory analyses, MPR was predicted using the pre-treatment peripheral blood

immunophenotype based on 14 immune cell subsets. Immune cell subsets predictive

of MPR in the peripheral blood were also identified in the tumor

microenvironment and were associated with MPR. This study of neoadjuvant

atezolizumab in a large cohort of patients with resectable non-small cell lung

cancer was safe and met its primary end point of MPR ≥ 15%. Data from this

single-arm, non-randomized trial suggest that profiles of innate immune cells in

pre-treatment peripheral blood may predict pathological response after

neoadjuvant atezolizumab, but additional studies are needed to determine whether

these profiles can inform patient selection and new therapeutic approaches.

© 2022. The Author(s).

DOI: 10.1038/s41591-022-01962-5

PMCID: PMC9556329

PMID: 36097216 [Indexed for MEDLINE]

8. J Clin Oncol. 2022 Oct 28:JCO2102885. doi: 10.1200/JCO.21.02885. Online ahead of print.

Five-Year Outcomes With Pembrolizumab Versus Chemotherapy as First-Line Therapy

in Patients With Non-Small-Cell Lung Cancer and Programmed Death Ligand-1 Tumor

Proportion Score ≥ 1% in the KEYNOTE-042 Study.

de Castro G Jr(1), Kudaba I(2), Wu YL(3), Lopes G(4), Kowalski DM(5), Turna

HZ(6), Caglevic C(7), Zhang L(8), Karaszewska B(9), Laktionov KK(10),

Srimuninnimit V(11), Bondarenko I(12), Kubota K(13), Mukherjee R(14), Lin J(14),

Souza F(14), Mok TSK(15), Cho BC(16).

Author information:

(1)Instituto do Câncer do Estado de São Paulo, São Paulo, Brazil.

(2)Latvian Oncology Center, Riga East Clinical University, Riga, Latvia.

(3)Guangdong Lung Cancer Institute, Guangdong Provinicial People's Hospital and

Guangdong Academy of Medical Sciences, Guandong, 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.We report 5-year results from the

phase III KEYNOTE-042 study (ClinicalTrials.gov identifier: NCT02220894).

Eligible patients with locally advanced/metastatic non-small-cell lung cancer

(NSCLC) without EGFR/ALK alterations and with programmed death ligand-1 (PD-L1)

tumor proportion score (TPS) ≥ 1% received pembrolizumab 200 mg once every 3

weeks for 35 cycles or chemotherapy (carboplatin + paclitaxel or pemetrexed) for

4-6 cycles with optional maintenance pemetrexed. Primary end points were overall

survival (OS) in PD-L1 TPS ≥ 50%, ≥ 20%, and ≥ 1% groups. Patients who completed

35 cycles of pembrolizumab with ≥ stable disease could begin second-course

pembrolizumab upon progression. One thousand two hundred seventy-four patients

were randomly assigned (pembrolizumab, n = 637; chemotherapy, n = 637). Median

follow-up time was 61.1 (range, 50.0-76.3) months. OS outcomes favored

pembrolizumab (v chemotherapy) regardless of PD-L1 TPS (hazard ratio [95% CI]

for TPS ≥ 50%, 0.68 [0.57 to 0.81]; TPS ≥ 20%, 0.75 [0.64 to 0.87]; TPS ≥ 1%,

0.79 [0.70 to 0.89]), with estimated 5-year OS rates with pembrolizumab of

21.9%, 19.4%, and 16.6%, respectively. No new toxicities were identified.

Objective response rate was 84.3% among 102 patients who completed 35 cycles of

pembrolizumab and 15.2% among 33 patients who received second-course

pembrolizumab. First-line pembrolizumab monotherapy continued to show durable

clinical benefit versus chemotherapy after 5 years of follow-up in

PD-L1-positive, locally advanced/metastatic NSCLC without EGFR/ALK alterations

and remains a standard of care.

DOI: 10.1200/JCO.21.02885

PMID: 36306479

9. J Clin Oncol. 2022 Oct 26:JCO2200739. doi: 10.1200/JCO.22.00739. Online ahead of print.

Phase Ib Study of Telisotuzumab Vedotin in Combination With Erlotinib in

Patients With c-Met Protein-Expressing Non-Small-Cell Lung Cancer.

Camidge DR(1), Barlesi F(2)(3), Goldman JW(4), Morgensztern D(5), Heist R(6),

Vokes E(7), Spira A(8), Angevin E(9), Su WC(10), Hong DS(11), Strickler JH(12),

Motwani M(13), Dunbar M(13), Parikh A(14), Noon E(13), Blot V(13), Wu J(13),

Kelly K(15).

Author information:

(1)University of Colorado Cancer Center, Aurora, CO.

(2)Multidisciplinary Oncology and Therapeutic Innovations Department, Aix

Marseille University, Assistance Publique Hôpitaux de Marseille, Inserm U911

CRO2, Marseille, France.

(3)Medical Oncology Department, Gustave Roussy, Villejuif, France.

…

PURPOSE: Overexpression of c-Met protein and epidermal growth factor receptor

(EGFR) mutations can co-occur in non-small-cell lung cancer (NSCLC), providing

strong rationale for dual targeting. Telisotuzumab vedotin (Teliso-V), a

first-in-class antibody-drug conjugate targeting c-Met, has shown a tolerable

safety profile and antitumor activity as monotherapy. Herein, we report the

results of a phase Ib study (NCT02099058) evaluating Teliso-V plus erlotinib, an

EGFR tyrosine kinase inhibitor (TKI), in patients with c-Met-positive (+) NSCLC.

PATIENTS AND METHODS: This study evaluated Teliso-V (2.7 mg/kg once every 21

days) plus erlotinib (150 mg once daily) in adult patients (age ≥ 18 years) with

c-Met+ NSCLC. Later enrollment required presence of an EGFR-activating mutation

(EGFR-M+) and progression on a prior EGFR TKI. End points included safety,

pharmacokinetics, objective response rate (ORR), and progression-free survival

(PFS). The efficacy-evaluable population consisted of c-Met+ patients (confirmed

histology [H]-score ≥ 150) who had at least one postbaseline scan; c-Met+

patients with H-scores ≥ 225 were classified as c-Met high.

RESULTS: As of January 2020, 42 patients were enrolled (N = 36

efficacy-evaluable). Neuropathies were the most common any-grade adverse events

reported, with 24 of 42 patients (57%) experiencing at least one event. The

pharmacokinetic profile of Teliso-V plus erlotinib was similar to Teliso-V

monotherapy. Median PFS for all efficacy-evaluable patients was 5.9 months (95%

CI, 2.8 to not reached). ORR for EGFR-M+ patients (n = 28) was 32.1%. Of EGFR-M+

patients, those who were c-Met high (n = 15) had an ORR of 52.6%. Median PFS was

6.8 months for non-T790M+ and for those whose T790M status was unknown, versus

3.7 months for T790M+.

CONCLUSION: Teliso-V plus erlotinib showed encouraging antitumor activity and

acceptable toxicity in EGFR TKI-pretreated patients with EGFR-M+, c-Met+ NSCLC.

DOI: 10.1200/JCO.22.00739

PMID: 36288547

10. Cancer Discov. 2022 Oct 20:CD-22-0586. doi: 10.1158/2159-8290.CD-22-0586. Online ahead of print.

Osimertinib+Savolitinib to Overcome Acquired MET-Mediated Resistance in

Epidermal Growth Factor Receptor Mutated MET-Amplified Non-Small Cell Lung

Cancer: TATTON.

Hartmaier RJ(1), Markovets AA(1), Ahn MJ(2), Sequist LV(3), Han JY(4), Cho

BC(5), Yu HA(6), Kim SW(7), Yang JC(8), Lee JS(9), Su WC(10), Kowalski DM(11),

Orlov S(12), Ren S(13), Frewer P(14), Ou X(15), Cross DA(16), Kurian N(17),

Cantarini M(15), Janne PA(18).

Author information:

(1)AstraZeneca (United States), Boston, MA, United States.

(2)Sungkyunkwan University School of Medicine, Seoul, Korea (South), Republic

of.

(3)Massachusetts General Hospital, Boston, MA, United States.

…

MET-inhibitor and epidermal growth factor receptor (EGFR)-tyrosine kinase

inhibitor (TKI) combination therapy could overcome acquired MET-mediated

osimertinib resistance. We present the final PhIb TATTON (NCT02143466) analysis

(Part B, n=138/Part D, n=42) assessing oral savolitinib 600 mg/300 mg once daily

(QD) + osimertinib 80 mg QD in patients with MET amplified EGFR mutated (EGFRm)

advanced non-small cell lung cancer (NSCLC) and progression on prior EGFR-TKI.

An acceptable safety profile was observed. In Parts B and D, respectively,

objective response rates were 33-67% and 62%, and median progression-free

survival (PFS) was 5.5-11.1 and 9.0 months. Increased antitumor activity may

occur with MET copy-number ≥10. EGFRm circulating tumor DNA clearance on

treatment predicted longer PFS in patients with detectable baseline ctDNA, while

acquired resistance mechanisms to osimertinib+savolitinib were mediated by MET,

EGFR, or KRAS alterations.

DOI: 10.1158/2159-8290.CD-22-0586

PMID: 36264123

11. Nat Commun. 2022 Oct 19;13(1):6203. doi: 10.1038/s41467-022-33968-5.

Remodelling of tumour microenvironment by microwave ablation potentiates

immunotherapy of AXL-specific CAR T cells against non-small cell lung cancer.

Cao B(#)(1)(2), Liu M(#)(1)(2), Wang L(2), Zhu K(1), Cai M(1), Chen X(2), Feng

Y(2), Yang S(3)(4), Fu S(3), Zhi C(5), Ye X(2), Zhang J(2), Zhang Z(2), Yang

X(6), Zhao M(7), Wu Q(8), Xu L(9), Yang L(10), Lian H(1), Zhao Q(11), Zhang

Z(12)(13).

Author information:

(1)Department of Minimally Invasive Interventional Radiology, the Second

Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, China.

(2)Central Laboratory, the Second Affiliated Hospital of Guangzhou Medical

University, Guangzhou, 510260, China.

(3)Institute of Translational Medicine, Cancer Centre, Faculty of Health

Sciences, University of Macau, Macau SAR, 999078, China.

…

The complex immunosuppressive tumour microenvironment (TME) and lack of

tumour-specific targets hinder the application of chimeric antigen receptor

(CAR) T cells in the treatment of solid tumours. Combining local treatment with

CAR T cell immunotherapy may regulate the TME and enhance the killing potency of

CAR T cells in solid tumours. Here, we show that AXL, which is highly expressed

in non-small cell lung cancer (NSCLC) but not in normal tissues, might be a

target for CAR T cell therapy. AXL-CAR T cells alone cause moderate tumour

regression in subcutaneous and pulmonary metastatic lung cancer cell-derived

xenograft models. Combination of microwave ablation (MWA) and AXL-CAR T cells

have superior antitumour efficacy. MWA enhances the activation, infiltration,

persistence and tumour suppressive properties of AXL-CAR T cells in AXL-positive

NSCLC patient-derived xenograft tumours via TME remodelling. The combination

therapy increases the mitochondrial oxidative metabolism of tumour-infiltrating

CAR T cells. Combination treatment induces significant tumour suppression

without observed toxicities in humanized immunocompetent mice. The synergistic

therapeutic effect of MWA and AXL-CAR T cells may be valuable for NSCLC

treatment.

© 2022. The Author(s).

DOI: 10.1038/s41467-022-33968-5

PMCID: PMC9581911

PMID: 36261437 [Indexed for MEDLINE]

12. Nat Commun. 2022 Oct 15;13(1):6095. doi: 10.1038/s41467-022-33719-6.

Phase I trial of the TNF-α inhibitor certolizumab plus chemotherapy in stage IV

lung adenocarcinomas.

Paik PK(1)(2), Luo J(3), Ai N(4), Kim R(3), Ahn L(3), Biswas A(5), Coker C(5),

Ma W(5), Wong P(6), Buonocore DJ(7), Lai WV(3)(8), Chaft JE(3)(8), Acharyya

S(5)(9)(10), Massagué J(11), Kris MG(3)(8).

Author information:

(1)Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of

Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

paikp@mskcc.org.

(2)Department of Medicine, Weill Cornell Medical College, New York, NY, USA.

paikp@mskcc.org.

(3)Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of

Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

…

We previously identified a chemotherapy-induced paracrine inflammatory loop that

paradoxically mitigates the anti-tumor effect of chemotherapy and triggers

metastatic propagation in breast and lung cancer models. Therefore, we sought to

further validate and translate these findings into patient care by coupling the

anti-TNF-α drug certolizumab pegol with standard cisplatin doublet chemotherapy.

Here we first validate the anti-metastatic effect of certolizumab in a

liver-metastatic Lewis Lung Carcinoma model. We then evaluate the safety,

efficacy, and pharmacodynamic effects of certolizumab with cisplatin and

pemetrexed in an open label Phase 1 clinical trial (NCT02120807) of eighteen

adult patients with stage IV lung adenocarcinomas. The primary outcome is

maximum tolerated dose. Secondary outcomes are response rate and

progression-free survival (PFS); pharmacodynamic changes in blood and tumor are

evaluated as a correlative outcome. There were nine partial responses among 16

patients evaluable (56%, 95% CI 30 to 80%). The median duration of response was

9.0 months (range 5.9 to 42.6 months) and median PFS was 7.1 months (95% CI 6.3

to NR). The standard 400 mg dose of certolizumab, added to cisplatin and

pemetrexed, is well-tolerated and, as a correlative endpoint, demonstrates

potent pharmacodynamic inhibition of peripheral cytokines associated with the

paracrine inflammatory loop.

© 2022. The Author(s).

DOI: 10.1038/s41467-022-33719-6

PMCID: PMC9568581

PMID: 36241629 [Indexed for MEDLINE]

13. Nat Commun. 2022 Oct 11;13(1):5992. doi: 10.1038/s41467-022-33736-5.

Lysyl-tRNA synthetase, a target for urgently needed M. tuberculosis drugs.

Green SR(1), Davis SH(1), Damerow S(1), Engelhart CA(2), Mathieson M(1),

Baragaña B(1), Robinson DA(1), Tamjar J(1), Dawson A(1), Tamaki FK(1), Buchanan

KI(1), Post J(1), Dowers K(1), Shepherd SM(1), Jansen C(1), Zuccotto F(1),

Gilbert IH(1), Epemolu O(1), Riley J(1), Stojanovski L(1), Osuna-Cabello M(1),

Pérez-Herrán E(3), Rebollo MJ(3), Guijarro López L(3), Casado Castro P(3),

Camino I(3), Kim HC(2), Bean JM(4), Nahiyaan N(2), Rhee KY(2), Wang Q(5), Tan

VY(5), Boshoff HIM(5), Converse PJ(6), Li SY(6), Chang YS(6), Fotouhi N(7),

Upton AM(7), Nuermberger EL(6), Schnappinger D(2), Read KD(1), Encinas L(3),

Bates RH(3), Wyatt PG(1), Cleghorn LAT(8).

Author information:

(1)Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division

of Biological Chemistry and Drug Discovery, College of Life Sciences, University

of Dundee, Dundee, DD1 5EH, UK.

(2)Dept. of Microbiology and Immunology, Weill Cornell Medical College, New

York, NY, USA.

(3)Global Health Medicines R&D, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos,

28760, Madrid, Spain.

…

Tuberculosis is a major global cause of both mortality and financial burden

mainly in low and middle-income countries. Given the significant and ongoing

rise of drug-resistant strains of Mycobacterium tuberculosis within the clinical

setting, there is an urgent need for the development of new, safe and effective

treatments. Here the development of a drug-like series based on a fused

dihydropyrrolidino-pyrimidine scaffold is described. The series has been

developed against M. tuberculosis lysyl-tRNA synthetase (LysRS) and cellular

studies support this mechanism of action. DDD02049209, the lead compound, is

efficacious in mouse models of acute and chronic tuberculosis and has suitable

physicochemical, pharmacokinetic properties and an in vitro safety profile that

supports further development. Importantly, preliminary analysis using clinical

resistant strains shows no pre-existing clinical resistance towards this

scaffold.

© 2022. The Author(s).

DOI: 10.1038/s41467-022-33736-5

PMCID: PMC9552147

PMID: 36220877 [Indexed for MEDLINE]

14. Clin Microbiol Rev. 2022 Oct 6:e0018019. doi: 10.1128/cmr.00180-19. Online ahead of print.

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

PMID: 36200885

15. Sci Transl Med. 2022 Oct 5;14(665):eabo1050. doi: 10.1126/ scitranslmed. abo1050. Epub 2022 Oct 5.

A germline SNP in BRMS1 predisposes patients with lung adenocarcinoma to

metastasis and can be ameliorated by targeting c-fos.

Liu Y(1)(2), Chudgar N(1), Mastrogiacomo B(1)(3), He D(1), Lankadasari MB(1),

Bapat S(1), Jones GD(1), Sanchez-Vega F(3), Tan KS(4), Schultz N(3), Mukherjee

S(5), Offit K(5), Bao Y(6), Bott MJ(1)(3), Rekhtman N(2)(7), Adusumilli

PS(1)(2), Li BT(2)(5), Mayo MW(8), Jones DR(1)(2).

Author information:

(1)Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer

Center, New York, NY 10065, USA.

(2)Druckenmiller Center for Lung Cancer Research, Memorial Sloan Kettering

Cancer Center, New York, NY 10065, USA.

(3)Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New

York, NY 10065, USA.

…

About 50% of patients with early-stage, surgically resected lung cancer will

develop distant metastasis. There remains an unmet need to identify patients

likely to develop recurrence and to design innovative therapies to decrease this

risk. Two primary isoforms of BRMS1, v1 and v2, are present in humans. Using

next-generation sequencing of BRMS1 on matched human noncancerous lung tissue

and non-small cell lung cancer (NSCLC) specimens, we identified

single-nucleotide polymorphism (SNP) rs1052566 that results in an A273V mutation

of BRMS1v2. This SNP is homozygous (BRMS1v2A273V/A273V) in 8% of the population

and correlates with aggressive biology in lung adenocarcinoma (LUAD).

Mechanistically, we show that BRMS1v2 A273V abolishes the metastasis suppressor

function of BRMS1v2 and promotes robust cell invasion and metastases by

activation of c-fos-mediated gene-specific transcriptional regulation. BRMS1v2

A273V increases cell invasion in vitro and increases metastases in both

tail-vein injection xenografts and LUAD patient-derived organoid (PDO)

intracardiac injection metastasis in vivo models. Moreover, we show that BRMS1v2

A273V fails to interact with nuclear Src, thereby activating intratumoral c-fos

in vitro. Higher c-fos results in up-regulation of CEACAM6, which drives

metastases in vitro and in vivo. Using both xenograft and PDO metastasis models,

we repurposed T5224 for treatment, a c-fos pharmacologic inhibitor investigated

in clinical trials for arthritis, and observed suppression of metastases in

BRMS1v2A273V/A273V LUAD in mice. Collectively, we elucidate the mechanism of

BRMS1v2A273V/A273V-induced metastases and offer a putative therapeutic strategy

for patients with LUAD who have this germline alteration.

DOI: 10.1126/scitranslmed.abo1050

PMID: 36197962 [Indexed for MEDLINE]

16. J Natl Cancer Inst. 2022 Oct 6;114(10):1410-1419. doi: 10.1093/jnci/djac127.

A Randomized Trial of Telephone-Based Smoking Cessation Treatment in the Lung

Cancer Screening Setting.

Taylor KL(1), Williams RM(1), Li T(2), Luta G(2), Smith L(1), Davis KM(1),

Stanton CA(3), Niaura R(4), Abrams D(4), Lobo T(1), Mandelblatt J(1), Jayasekera

J(1), Meza R(5), Jeon J(5), Cao P(5), Anderson ED(6); Georgetown Lung Screening,

Tobacco, and Health Trial.

Author information:

(1)Cancer Prevention and Control Program, Lombardi Comprehensive Cancer Center,

Georgetown University Medical Center, Washington, DC, USA.

(2)Department of Biostatistics, Bioinformatics, and Biomathematics, Georgetown

University Medical Center, Washington, DC, USA.

(3)Behavioral Health, Westat, Rockville, MD, USA.

(4)School of Global Public Health, New York University, New York, NY, USA.

(5)Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA.

(6)Department of Pulmonary and Sleep Medicine, Georgetown University Medical

Center, Washington, DC, USA.

BACKGROUND: Lung cancer mortality is reduced via low-dose computed tomography

screening and treatment of early-stage disease. Evidence-based smoking cessation

treatment in the lung screening setting can further reduce mortality. We report

the results of a cessation trial from the National Cancer Institute's Smoking

Cessation at Lung Examination collaboration.

METHODS: Eligible patients (n = 818) aged 50-80 years were randomly assigned

(May 2017-January 2021) to the intensive vs minimal arms (8 vs 3 phone sessions

plus 8 vs 2 weeks of nicotine patches, respectively). Bio-verified (primary) and

self-reported 7-day abstinence rates were assessed at 3, 6, and 12 months post

random assignment. Logistic regression analyses evaluated the effects of study

arm. All statistical tests were 2-sided.

RESULTS: Participants reported 48.0 (SD = 17.2) pack-years, and 51.6% were not

ready to quit in less than 30 days. Self-reported 3-month quit rates were

statistically significantly higher in the intensive vs minimal arm (14.3% vs

7.9%; odds ratio [OR] = 2.00, 95% confidence interval [CI] = 1.26 to 3.18).

Bio-verified abstinence was lower but with similar relative differences between

arms (9.1% vs 3.9%; OR = 2.70, 95% CI = 1.44 to 5.08). Compared with the minimal

arm, the intensive arm was more effective among those with greater nicotine

dependence (OR = 3.47, 95% CI = 1.55 to 7.76), normal screening results

(OR = 2.58, 95% CI = 1.32 to 5.03), high engagement in counseling (OR = 3.03,

95% CI = 1.50 to 6.14), and patch use (OR = 2.81, 95% CI = 1.39 to 5.68).

Abstinence rates did not differ statistically significantly between arms at 6

months (OR = 1.2, 95% CI = 0.68 to 2.11) or 12 months (OR = 1.4, 95% CI = 0.82

to 2.42).

CONCLUSIONS: Delivering intensive telephone counseling and nicotine replacement

with lung screening is an effective strategy to increase short-term smoking

cessation. Methods to maintain short-term effects are needed. Even with modest

quit rates, integrating cessation treatment into lung screening programs may

have a large impact on tobacco-related mortality.

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

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

DOI: 10.1093/jnci/djac127

PMCID: PMC9552302

PMID: 35818122 [Indexed for MEDLINE]

17. Am J Respir Crit Care Med. 2022 Oct 1;206(7):892-900. doi:

10.1164/rccm.202202-0259OC.

The Contribution of Chest Radiography to the Clinical Management of Children

Exposed to Tuberculosis.

Huang CC(1)(2), Tan Q(2)(3), Becerra MC(1)(2), Calderon R(4), Chiang SS(5)(6),

Contreras C(4), Lecca L(2)(4), Jimenez J(4), Perez-Velez CM(7)(8), Roya-Pabon

CL(7), Yataco R(4), Xu H(9), Zhang Z(1), Murray M(1)(2)(10).

Author information:

(1)Division of Global Health Equity, Brigham and Women's Hospital, Boston,

Massachusetts.

(2)Department of Global Health and Social Medicine, Harvard Medical School,

Boston, Massachusetts.

(3)Department of Respiratory and Critical Care Medicine and.

…

Comment in

    Am J Respir Crit Care Med. 2022 Oct 1;206(7):814-816.

Rationale: Although World Health Organization guidelines emphasize contact

investigation for tuberculosis (TB)-exposed children, data that support chest

radiography as a useful tool are lacking. Objectives: We evaluated the

diagnostic and prognostic information of chest radiography in children exposed

to TB and measured the efficacy of isoniazid preventive therapy (IPT) in those

with relevant radiographic abnormalities. Methods: Between September 2009 and

August 2012, we enrolled 4,468 TB-exposed children who were screened by

tuberculin skin testing, symptom assessment, and chest radiography. Those

negative for TB disease were followed for 1 year for the occurrence of new TB

diagnoses. We assessed the protective efficacy of IPT in children with and

without abnormal chest radiographs. Measurements and Main Results: Compared with

asymptomatic children with normal chest films, asymptomatic children with

abnormal radiographs were 25.1-fold more likely to have coprevalent TB (95%

confidence interval [CI], 1.02-613.76) and 26.7-fold more likely to be diagnosed

with incident TB disease during follow-up (95% CI, 10.44-68.30). Among the 29

symptom-negative and CXR-abnormal child contacts, 20% (3/15) of the isoniazid

recipients developed incident TB, compared with 57% (8/14) of those who did not

receive IPT (82% IPT efficacy). Conclusions: Our results strongly support the

use of chest radiography as a routine screening tool for the evaluation of child

TB contacts, which is readily available. Radiographic abnormalities not usually

considered suggestive of TB may indicate incipient or subclinical disease,

although TB preventive treatment is adequate in most cases.

DOI: 10.1164/rccm.202202-0259OC

PMID: 35608549 [Indexed for MEDLINE]