Filters applied: from 2022/11/1 - 2022/11/30.

1. Cell. 2022 Nov 23;185(24):4467-4469. doi: 10.1016/j.cell.2022.10.029.

Need for speed: Key driver of host cell migration varies among mycobacteria.

Youngblom MA(1), Pepperell CS(2).

Author information:

(1)Microbiology Doctoral Training Program, University of Wisconsin-Madison,

Madison, WI, USA; Department of Medical Microbiology and Immunology, School of

Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.

(2)Department of Medical Microbiology and Immunology, School of Medicine and

Public Health, University of Wisconsin-Madison, Madison, WI, USA; Department of

Medicine (Infectious Diseases), School of Medicine and Public Health, University

of Wisconsin-Madison, Madison, WI, USA. Electronic address:

cspepper@medicine.wisc.edu.

In this issue of Cell, Saelens et al. describe a new function for mycobacterial

Type VII secretion systems: manipulation of host cell migration. They find that

a substantial proportion of global TB cases arise from bacteria lacking this

function, raising questions about its role in pathoadaptation of Mycobacterium

tuberculosis.

Copyright © 2022 Elsevier Inc. All rights reserved.

DOI: 10.1016/j.cell.2022.10.029

PMID: 36423577 [Indexed for MEDLINE]

2. Lancet. 2022 Nov 26;400(10366):1858-1868. doi: 10.1016/S0140-6736(22)02078-5.

Epub 2022 Nov 8.

Evaluation of two short standardised regimens for the treatment of

rifampicin-resistant tuberculosis (STREAM stage 2): an open-label, multicentre,

randomised, non-inferiority trial.

Goodall RL(1), Meredith SK(2), Nunn AJ(2), Bayissa A(3), Bhatnagar AK(4),

Bronson G(5), Chiang CY(6), Conradie F(7), Gurumurthy M(8), Kirenga B(9), Kiria

N(10), Meressa D(11), Moodliar R(12), Narendran G(13), Ngubane N(14), Rassool

M(15), Sanders K(2), Solanki R(16), Squire SB(17), Torrea G(18), Tsogt B(19),

Tudor E(20), Van Deun A(18), Rusen ID(5); STREAM study collaborators.

Author information:

(1)Medical Research Council Clinical Trials Unit at UCL, University College

London, London, UK. Electronic address: r.goodall@ucl.ac.uk.

(2)Medical Research Council Clinical Trials Unit at UCL, University College

London, London, UK.

(3)Armauer Hansen Research Institute, Addis Ababa, Ethiopia.

…

Erratum in

    Lancet. 2022 Nov 19;400(10365):1766.

Comment in

    Lancet. 2022 Nov 26;400(10366):1823-1825.

BACKGROUND: The STREAM stage 1 trial showed that a 9-month regimen for the

treatment of rifampicin-resistant tuberculosis was non-inferior to the 20-month

2011 WHO-recommended regimen. In STREAM stage 2, we aimed to compare two

bedaquiline-containing regimens with the 9-month STREAM stage 1 regimen.

METHODS: We did a randomised, phase 3, non-inferiority trial in 13 hospital

clinics in seven countries, in individuals aged 15 years or older with

rifampicin-resistant tuberculosis without fluoroquinolone or aminoglycoside

resistance. Participants were randomly assigned 1:2:2:2 to the 2011 WHO regimen

(terminated early), a 9-month control regimen, a 9-month oral regimen with

bedaquiline (primary comparison), or a 6-month regimen with bedaquiline and 8

weeks of second-line injectable. Randomisations were stratified by site, HIV

status, and CD4 count. Participants and clinicians were aware of treatment-group

assignments, but laboratory staff were masked. The primary outcome was

favourable status (negative cultures for Mycobacterium tuberculosis without a

preceding unfavourable outcome) at 76 weeks; any death, bacteriological failure

or recurrence, and major treatment change were considered unfavourable outcomes.

All comparisons used groups of participants randomly assigned concurrently. For

non-inferiority to be shown, the upper boundary of the 95% CI should be less

than 10% in both modified intention-to-treat (mITT) and per-protocol analyses,

with prespecified tests for superiority done if non-inferiority was shown. This

trial is registered with ISRCTN, ISRCTN18148631.

FINDINGS: Between March 28, 2016, and Jan 28, 2020, 1436 participants were

screened and 588 were randomly assigned. Of 517 participants in the mITT

population, 133 (71%) of 187 on the control regimen and 162 (83%) of 196 on the

oral regimen had a favourable outcome: a difference of 11·0% (95% CI 2·9-19·0),

adjusted for HIV status and randomisation protocol (p<0·0001 for

non-inferiority). By 76 weeks, 108 (53%) of 202 participants on the control

regimen and 106 (50%) of 211 allocated to the oral regimen had an adverse event

of grade 3 or 4; five (2%) participants on the control regimen and seven (3%) on

the oral regimen had died. Hearing loss (Brock grade 3 or 4) was more frequent

in participants on the control regimen than in those on the oral regimen (18

[9%] vs four [2%], p=0·0015). Of 134 participants in the mITT population who

were allocated to the 6-month regimen, 122 (91%) had a favourable outcome

compared with 87 (69%) of 127 participants randomly assigned concurrently to the

control regimen (adjusted difference 22·2%, 95% CI 13·1-31·2); six (4%) of 143

participants on the 6-month regimen had grade 3 or 4 hearing loss.

INTERPRETATION: Both bedaquiline-containing regimens, a 9-month oral regimen and

a 6-month regimen with 8 weeks of second-line injectable, had superior efficacy

compared with a 9-month injectable-containing regimen, with fewer cases of

hearing loss.

FUNDING: USAID and Janssen Research & Development.

Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open

Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All

rights reserved.

DOI: 10.1016/S0140-6736(22)02078-5

PMID: 36368336 [Indexed for MEDLINE]

3. Cell. 2022 Nov 23;185(24):4507-4525.e18. doi: 10.1016/j.cell.2022.10.019. Epub

2022 Nov 9.

An ancestral mycobacterial effector promotes dissemination of infection.

Saelens JW(1), Sweeney MI(1), Viswanathan G(1), Xet-Mull AM(1), Jurcic Smith

KL(1), Sisk DM(1), Hu DD(2), Cronin RM(3), Hughes EJ(1), Brewer WJ(1), Coers

J(4), Champion MM(5), Champion PA(6), Lowe CB(1), Smith CM(1), Lee S(7), Stout

JE(8), Tobin DM(9).

Author information:

(1)Department of Molecular Genetics and Microbiology, Duke University School of

Medicine, Durham, NC 27710, USA.

(2)Department of Chemistry and Biochemistry, University of Notre Dame, Notre

Dame, IN 46556, USA.

(3)Department of Biological Sciences, University of Notre Dame, Notre Dame, IN

46556, USA.

…

The human pathogen Mycobacterium tuberculosis typically causes lung disease but

can also disseminate to other tissues. We identified a M. tuberculosis (Mtb)

outbreak presenting with unusually high rates of extrapulmonary dissemination

and bone disease. We found that the causal strain carried an ancestral

full-length version of the type VII-secreted effector EsxM rather than the

truncated version present in other modern Mtb lineages. The ancestral EsxM

variant exacerbated dissemination through enhancement of macrophage motility,

increased egress of macrophages from established granulomas, and alterations in

macrophage actin dynamics. Reconstitution of the ancestral version of EsxM in an

attenuated modern strain of Mtb altered the migratory mode of infected

macrophages, enhancing their motility. In a zebrafish model, full-length EsxM

promoted bone disease. The presence of a derived nonsense variant in EsxM

throughout the major Mtb lineages 2, 3, and 4 is consistent with a role for EsxM

in regulating the extent of dissemination.

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

DOI: 10.1016/j.cell.2022.10.019

PMCID: PMC9691622

PMID: 36356582 [Indexed for MEDLINE]

4. Cancer Cell. 2022 Nov 11:S1535-6108(22)00521-9. doi:

10.1016/j.ccell.2022.10.024. Online ahead of print.

Understanding NSCLC, one cell at a time.

Ballesteros I(1), Cerezo-Wallis D(2), Hidalgo A(3).

Author information:

(1)Area of Cell & Developmental Biology, Centro Nacional de Investigaciones

Cardiovasculares Carlos III, Madrid, Spain.

(2)Vascular Biology and Therapeutics Program and Department of Immunobiology,

Yale University School of Medicine, New Haven, CT, USA.

(3)Area of Cell & Developmental Biology, Centro Nacional de Investigaciones

Cardiovasculares Carlos III, Madrid, Spain; Vascular Biology and Therapeutics

Program and Department of Immunobiology, Yale University School of Medicine, New

Haven, CT, USA. Electronic address: ahidalgo@cnic.es.

Lung cancers are very heterogeneous, a feature that in part emanates from the

tumor microenvironment. In this issue, Salcher et al. provide a comprehensive

analysis of hundreds of patients with non-small cell lung cancer (NSCLC) at the

single-cell level to discover extreme immune diversity and define neutrophil

populations associated with treatment outcome.

Copyright © 2022 Elsevier Inc. All rights reserved.

DOI: 10.1016/j.ccell.2022.10.024

PMID: 36400019

5. Nat Med. 2022 Nov;28(11):2353-2363. doi: 10.1038/s41591-022-02047-z. Epub 2022

Nov 10.

Overall survival with circulating tumor DNA-guided therapy in advanced

non-small-cell lung cancer.

Jee J(1), Lebow ES(1), Yeh R(1), Das JP(1), Namakydoust A(1), Paik PK(1)(2),

Chaft JE(1)(2), Jayakumaran G(1), Rose Brannon A(1), Benayed R(1), Zehir A(1),

…

Author information:

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

(2)Weill Cornell Medicine, Cornell University, New York, NY, USA.

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

Guangdong Academy of Medical Sciences, Guangzhou, China.

…

Comment in

    Nat Med. 2022 Nov;28(11):2255-2256.

Circulating tumor DNA (ctDNA) sequencing guides therapy decisions but has been

studied mostly in small cohorts without sufficient follow-up to determine its

influence on overall survival. We prospectively followed an international cohort

of 1,127 patients with non-small-cell lung cancer and ctDNA-guided therapy.

ctDNA detection was associated with shorter survival (hazard ratio (HR), 2.05;

95% confidence interval (CI), 1.74-2.42; P < 0.001) independently of

clinicopathologic features and metabolic tumor volume. Among the 722 (64%)

patients with detectable ctDNA, 255 (23%) matched to targeted therapy by ctDNA

sequencing had longer survival than those not treated with targeted therapy (HR,

0.63; 95% CI, 0.52-0.76; P < 0.001). Genomic alterations in ctDNA not detected

by time-matched tissue sequencing were found in 25% of the patients. These

ctDNA-only alterations disproportionately featured subclonal drivers of

resistance, including RICTOR and PIK3CA alterations, and were associated with

short survival. Minimally invasive ctDNA profiling can identify heterogeneous

drivers not captured in tissue sequencing and expand community access to

life-prolonging therapy.

© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.

DOI: 10.1038/s41591-022-02047-z

PMID: 36357680 [Indexed for MEDLINE]

6. Cancer Cell. 2022 Nov 14;40(11):1279-1293. doi: 10.1016/j.ccell.2022.09.018.

Epub 2022 Oct 20.

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 [Indexed for MEDLINE]

7. 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]

8. Nat Med. 2022 Nov;28(11):2374-2380. doi: 10.1038/s41591-022-01977-y. Epub 2022

Aug 25.

Cemiplimab plus chemotherapy versus chemotherapy alone in non-small cell lung

cancer: a randomized, controlled, double-blind phase 3 trial.

Gogishvili M(1), Melkadze T(2), Makharadze T(3), Giorgadze D(4), Dvorkin M(5),

Penkov K(6), Laktionov K(7), Nemsadze G(8), Nechaeva M(9), Rozhkova I(10),

Kalinka E(11), Gessner C(12)(13), Moreno-Jaime B(14), Passalacqua R(15), Li

S(16), McGuire K(16), Kaul M(16), Paccaly A(16), Quek RGW(16), Gao B(16),

Seebach F(16), Weinreich DM(16), Yancopoulos GD(16), Lowy I(16), Gullo G(16),

Rietschel P(16).

Author information:

(1)High Technology Medical Centre, University Clinic Ltd., Tbilisi, Georgia.

mirandagogishvili@yahoo.com.

(2)Acad. F. Todua Medical Center, Tbilisi, Georgia.

(3)LTD High Technology Hospital Med Center, Batumi, Georgia.

…

First-line cemiplimab (anti-programmed cell death-1 (PD-1)) monotherapy has

previously shown significant improvement in overall survival (OS) and

progression-free survival (PFS) versus chemotherapy in patients with advanced

non-small cell lung cancer (aNSCLC) and PD-ligand 1 (PD-L1) expression ≥50%.

EMPOWER-Lung 3 ( NCT03409614 ), a double-blind, placebo-controlled, phase 3

study, examined cemiplimab plus platinum-doublet chemotherapy as first-line

treatment for aNSCLC, irrespective of PD-L1 expression or histology. In this

study, 466 patients with stage III/IV aNSCLC without EGFR, ALK or ROS1 genomic

tumor aberrations were randomized (2:1) to receive cemiplimab 350 mg (n = 312)

or placebo (n = 154) every 3 weeks for up to 108 weeks in combination with four

cycles of platinum-doublet chemotherapy (followed by pemetrexed maintenance as

indicated). In total, 57.1% (266/466 patients) had non-squamous NSCLC, and 85.2%

(397/466 patients) had stage IV disease. The primary endpoint was OS. The trial

was stopped early per recommendation of the independent data monitoring

committee, based on meeting preset OS efficacy criteria: median OS was

21.9 months (95% confidence interval (CI), 15.5-not evaluable) with cemiplimab

plus chemotherapy versus 13.0 months (95% CI, 11.9-16.1) with placebo plus

chemotherapy (hazard ratio (HR) = 0.71; 95% CI, 0.53-0.93; P = 0.014). Grade ≥3

adverse events occurred with cemiplimab plus chemotherapy (43.6%, 136/312

patients) and placebo plus chemotherapy (31.4%, 48/153 patients). Cemiplimab is

only the second anti-PD-1/PD-L1 agent to show efficacy in aNSCLC as both

monotherapy and in combination with chemotherapy for both squamous and

non-squamous histologies.

© 2022. The Author(s).

DOI: 10.1038/s41591-022-01977-y

PMCID: PMC9671806

PMID: 36008722 [Indexed for MEDLINE]

9. Nat Rev Microbiol. 2022 Nov;20(11):685-701. doi: 10.1038/s41579-022-00731-y.

Epub 2022 Apr 27.

Anti-tuberculosis treatment strategies and drug development: challenges and

priorities.

Dartois VA(1), Rubin EJ(2).

Author information:

(1)Center for Discovery and Innovation, and Hackensack Meridian School of

Medicine, Department of Medical Sciences, Hackensack Meridian Health, Nutley,

NJ, USA. veronique.dartois@hmh-cdi.org.

(2)Harvard T.H. Chan School of Public Health, Department of Immunology and

Infectious Diseases, Boston, MA, USA.

Despite two decades of intensified research to understand and cure tuberculosis

disease, biological uncertainties remain and hamper progress. However, owing to

collaborative initiatives including academia, the pharmaceutical industry and

non-for-profit organizations, the drug candidate pipeline is promising. This

exceptional success comes with the inherent challenge of prioritizing multidrug

regimens for clinical trials and revamping trial designs to accelerate regimen

development and capitalize on drug discovery breakthroughs. Most wanted are

markers of progression from latent infection to active pulmonary disease,

markers of drug response and predictors of relapse, in vitro tools to uncover

synergies that translate clinically and animal models to reliably assess the

treatment shortening potential of new regimens. In this Review, we highlight the

benefits and challenges of 'one-size-fits-all' regimens and treatment duration

versus individualized therapy based on disease severity and host and pathogen

characteristics, considering scientific and operational perspectives.

© 2022. Springer Nature Limited.

DOI: 10.1038/s41579-022-00731-y

PMCID: PMC9045034

PMID: 35478222 [Indexed for MEDLINE]

10. J Natl Cancer Inst. 2022 Nov 29:djac208. doi: 10.1093/jnci/djac208. Online ahead of print.

Association between imaging surveillance frequency and outcomes following

surgical treatment of early-stage lung cancer.

Heiden BT(1), Eaton DB(2), Chang SH(2)(3), Yan Y(2)(3), Schoen MW(2)(4), Thomas

TS(2)(5), Patel MR(2), Kreisel D(1)(2), Nava RG(1)(2), Meyers BF(1), Kozower

BD(1), Puri V(1)(2).

Author information:

(1)Division of Cardiothoracic Surgery, Department of Surgery, Washington

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

(2)VA St. Louis Health Care System, St. Louis, MO, USA.

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

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

(4)Division of Hematology and Medical Oncology, Department of Internal Medicine,

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

(5)Divisions of Hematology & Oncology, Department of Medicine, Washington

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

BACKGROUND: Recent studies have suggested that more frequent post-operative

surveillance imaging via computed tomography (CT) following lung cancer

resection may not improve outcomes. We sought to validate these findings using a

uniquely compiled dataset from the Veterans Health Administration, the largest

integrated healthcare system in the United States.

METHODS: We performed a retrospective cohort study of Veterans with pathologic

stage I non-small cell lung cancer (NSCLC) receiving surgery (2006-2016). We

assessed the relationship between surveillance frequency (chest CT scans within

2 years after surgery) and recurrence-free survival and overall survival.

RESULTS: Among 6171 patients, 3047 (49.4%) and 3124 (50.6%) underwent

low-frequency (<2 scans/year; every 6-12 months) and high-frequency (≥2

scans/year; every 3-6 months) surveillance, respectively. Factors associated

with high-frequency surveillance included being a former smoker (vs. current,

adjusted odds ratio [aOR] 1.18, 95% CI 1.05-1.33), receiving a wedge resection

(vs. lobectomy, aOR 1.21, 95% CI 1.05-1.39), and having follow-up with an

oncologist (aOR 1.58, 95% CI 1.42-1.77), whereas African American race was

associated with low-frequency surveillance (vs. White race, aOR 0.64, 95% CI

0.54-0.75). With a median (IQR) follow-up of 7.3 (3.4-12.5) years, recurrence

was detected in 1360 (22.0%) patients. High-frequency surveillance was not

associated with longer recurrence-free survival (adjusted hazard ratio [aHR],

0.93; 95% CI, 0.83-1.04, p = 0.22) or overall survival (aHR, 1.04; 95% CI,

0.96-1.12, p = 0.35).

CONCLUSIONS: We found that high-frequency surveillance does not improve outcomes

in surgically treated stage I NSCLC. Future lung cancer treatment guidelines

should consider less frequent surveillance imaging in patients with stage I

disease.

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

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

DOI: 10.1093/jnci/djac208

PMID: 36442509

11. PLoS Biol. 2022 Nov 28;20(11):e3001906. doi: 10.1371/journal.pbio.3001906.

eCollection 2022 Nov.

The Mycobacterium tuberculosis PE15/PPE20 complex transports calcium across the

outer membrane.

Boradia V(1), Frando A(1), Grundner C(1)(2)(3).

Author information:

(1)Center for Global Infectious Disease Research, Seattle Children's Research

Institute, Seattle, Washington, United States of America.

(2)Department of Pediatrics, University of Washington, Seattle, Washington,

United States of America.

(3)Department of Global Health, University of Washington, Seattle, Washington,

United States of America.

The mechanisms by which nutrients traverse the Mycobacterium tuberculosis (Mtb)

outer membrane remain mostly unknown and, in the absence of classical porins,

likely involve specialized transport systems. Calcium ions (Ca2+) are an

important nutrient and serve as a second messenger in eukaryotes, but whether

bacteria have similar Ca2+ signaling systems is not well understood. To

understand the basis for Ca2+ transport and signaling in Mtb, we determined

Mtb's transcriptional response to Ca2+. Overall, only few genes changed

expression, suggesting a limited role of Ca2+ as a transcriptional regulator.

However, 2 of the most strongly down-regulated genes were the pe15 and ppe20

genes that code for members of a large family of proteins that localize to the

outer membrane and comprise many intrinsically disordered proteins. PE15 and

PPE20 formed a complex and PPE20 directly bound Ca2+. Ca2+-associated phenotypes

such as increased ATP consumption and biofilm formation were reversed in a

pe15/ppe20 knockout (KO) strain, suggesting a direct role in Ca2+ homeostasis.

To test whether the PE15/PPE20 complex has a role in Ca2+ transport across the

outer membrane, we created a fluorescence resonance energy transfer (FRET)-based

Ca2+ reporter strain. A pe15/ppe20 KO in the FRET background showed a specific

and selective loss of Ca2+ influx that was dependent on the presence of an

intact outer cell wall. These data show that PE15/PPE20 form a Ca2+-binding

protein complex that selectively imports Ca2+, show a distinct transport

function for an intrinsically disordered protein, and support the emerging idea

of a general family-wide role of PE/PPE proteins as idiosyncratic transporters

across the outer membrane.

Copyright: © 2022 Boradia et al. This is an open access article distributed

under the terms of the Creative Commons Attribution License, which permits

unrestricted use, distribution, and reproduction in any medium, provided the

original author and source are credited.

DOI: 10.1371/journal.pbio.3001906

PMCID: PMC9731449

PMID: 36441815 [Indexed for MEDLINE]

12. J Clin Invest. 2022 Nov 22:e153470. doi: 10.1172/JCI153470. Online ahead of

print.

Oncogenic KRAS signaling drives evasion of innate immune surveillance in lung

adenocarcinoma by activating CD47.

Hu H(1), Cheng R(1), Wang Y(1), Wang X(2), Wu J(1), Kong Y(2), Zhan S(1), Zhou

Z(1), Zhu H(2), Yu R(1), Liang G(1), Wang Q(1), Zhu X(1), Zhang CY(1), Yin R(2),

Yan C(1), Chen X(1).

Author information:

(1)State Key Laboratory of Pharmaceutical Sciences, School of Life Sciences,

Nanjing University, Nanjing, China.

(2)Department of Thoracic Surgery, Jiangsu Cancer Hospital, Nanjing, China.

KRAS is one of the most frequently activated oncogenes in human cancers. While

the role of KRAS mutation in tumorigenesis and tumor maintenance has been

extensively studied, the relationship between KRAS and the tumor immune

microenvironment is not fully understood. Herein, we identified a novel role of

KRAS in driving tumor evasion from innate immune surveillance. In lung

adenocarcinoma patient samples and Kras-driven genetic mouse models of lung

cancer, mutant KRAS activated the expression of cluster of differentiation 47

(CD47), an antiphagocytic signal in cancer cells, leading to decreased

phagocytosis of cancer cells by macrophages. Mechanistically, mutant KRAS

activated PI3K-STAT3 signaling, which restrained miR-34a expression and relieved

the post-transcriptional repression of miR-34a on CD47. In three independent

lung cancer patient cohorts, KRAS mutation status positively correlated with

CD47 expression. Therapeutically, disruption of the KRAS-CD47 signaling axis

with KRAS siRNA, the KRASG12C inhibitor AMG 510 or miR-34a mimic suppressed CD47

expression, enhanced the phagocytic capacity of macrophages and restored innate

immune surveillance. Our results revealed a direct mechanistic link between

active KRAS and innate immune evasion and identified CD47 as a major effector

underlying KRAS-mediated immunosuppressive tumor microenvironment.

DOI: 10.1172/JCI153470

PMID: 36413402

13. Nat Commun. 2022 Nov 18;13(1):7068. doi: 10.1038/s41467-022-34853-x.

A comprehensive update to the Mycobacterium tuberculosis H37Rv reference genome.

Chitale P(1)(2), Lemenze AD(3), Fogarty EC(4)(5), Shah A(1)(6), Grady C(1)(2),

Odom-Mabey AR(7)(8), Johnson WE(1)(2)(9), Yang JH(1)(6), Eren AM(10)(11), Brosch

R(12), Kumar P(1)(2), Alland D(13)(14).

Author information:

(1)Ray V. Lourenco Center for the Study of Emerging and Re-emerging Pathogens,

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

(2)Public Health Research Institute, Rutgers University - New Jersey Medical

School, Newark, NJ, USA.

(3)Department of Pathology, Immunology and Laboratory Medicine, New Jersey

Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA.

…

Erratum in

    Nat Commun. 2022 Dec 7;13(1):7538.

H37Rv is the most widely used Mycobacterium tuberculosis strain, and its genome

is globally used as the M. tuberculosis reference sequence. Here, we present

Bact-Builder, a pipeline that uses consensus building to generate complete and

accurate bacterial genome sequences and apply it to three independently cultured

and sequenced H37Rv aliquots of a single laboratory stock. Two of the 4,417,942

base-pair long H37Rv assemblies are 100% identical, with the third differing by

a single nucleotide. Compared to the existing H37Rv reference, the new sequence

contains ~6.4 kb additional base pairs, encoding ten new regions that include

insertions in PE/PPE genes and new paralogs of esxN and esxJ, which are

differentially expressed compared to the reference genes. New sequencing and de

novo assemblies with Bact-Builder confirm that all 10 regions, plus small

additional polymorphisms, are also present in the commonly used H37Rv strains

NR123, TMC102, and H37Rv1998. Thus, Bact-Builder shows promise as an improved

method to perform accurate and reproducible de novo assemblies of bacterial

genomes, and our work provides important updates to the primary M. tuberculosis

reference genome.

© 2022. The Author(s).

DOI: 10.1038/s41467-022-34853-x

PMCID: PMC9673877

PMID: 36400796 [Indexed for MEDLINE]

14. Lancet Infect Dis. 2022 Nov 14:S1473-3099(22)00668-5. doi:

10.1016/S1473-3099(22)00668-5. Online ahead of print.

Effect of systematic tuberculosis detection on mortality in young children with

severe pneumonia in countries with high incidence of tuberculosis: a

stepped-wedge cluster-randomised trial.

Marcy O(1), Wobudeya E(2), Font H(3), Vessière A(3), Chabala C(4), Khosa C(5),

Taguebue JV(6), Moh R(7), Mwanga-Amumpaire J(8), Lounnas M(9), Mulenga V(4),

…

Author information:

(1)Inserm UMR 1219, IRD EMR 271, University of Bordeaux, Bordeaux, France.

Electronic address: olivier.marcy@u-bordeaux.fr.

(2)Makerere University-Johns Hopkins University Research Collaboration, Kampala,

Uganda.

(3)Inserm UMR 1219, IRD EMR 271, University of Bordeaux, Bordeaux, France.

…

BACKGROUND: Tuberculosis diagnosis might be delayed or missed in children with

severe pneumonia because this diagnosis is usually only considered in cases of

prolonged symptoms or antibiotic failure. Systematic tuberculosis detection at

hospital admission could increase case detection and reduce mortality.

METHODS: We did a stepped-wedge cluster-randomised trial in 16 hospitals from

six countries (Cambodia, Cameroon, Côte d'Ivoire, Mozambique, Uganda, and

Zambia) with high incidence of tuberculosis. Children younger than 5 years with

WHO-defined severe pneumonia received either the standard of care (control

group) or standard of care plus Xpert MTB/RIF Ultra (Xpert Ultra; Cepheid,

Sunnyvale, CA, USA) on nasopharyngeal aspirate and stool samples (intervention

group). Clusters (hospitals) were progressively switched from control to

intervention at 5-week intervals, using a computer-generated random sequence,

stratified on incidence rate of tuberculosis at country level, and masked to

teams until 5 weeks before switch. We assessed the effect of the intervention on

primary (12-week all-cause mortality) and secondary (including tuberculosis

diagnosis) outcomes, using generalised linear mixed models. The primary analysis

was by intention to treat. We described outcomes in children with severe acute

malnutrition in a post hoc analysis. This study is registered with

ClinicalTrials.gov (NCT03831906) and the Pan African Clinical Trial Registry

(PACTR202101615120643).

FINDINGS: From March 21, 2019, to March 30, 2021, we enrolled 1401 children in

the control group and 1169 children in the intervention group. In the

intervention group, 1140 (97·5%) children had nasopharyngeal aspirates and 942

(80·6%) had their stool collected; 24 (2·1%) had positive Xpert Ultra. At 12

weeks, 110 (7·9%) children in the control group and 91 (7·8%) children in the

intervention group had died (adjusted odds ratio [OR] 0·986, 95% CI 0·597-1·630, p=0·957),

 and 74 (5·3%) children in the control group and 88 (7·5%) children in the intervention group

 had tuberculosis diagnosed (adjusted OR 1·238, 95% CI 0·696-2·202, p=0·467). 

In children with severe acute malnutrition, 57 (23·8%) of 240 children in the control group 

and 53 (17·8%) of 297 children in the intervention group died, and 36 (15·0%) of 240 children

 in the control group and 56 (18·9%) of 297 children in the intervention group were diagnosed with

tuberculosis. The main adverse events associated with nasopharyngeal aspirates

were samples with blood in 312 (27·3%) of 1147 children with nasopharyngeal

aspirates attempted, dyspnoea or SpO2 less than 95% in 134 (11·4%) of children,

and transient respiratory distress or SpO2 less than 90% in 59 (5·2%) children.

There was no serious adverse event related to nasopharyngeal aspirates reported

during the trial.

INTERPRETATION: Systematic molecular tuberculosis detection at hospital

admission did not reduce mortality in children with severe pneumonia. High

treatment and microbiological confirmation rates support more systematic use of

Xpert Ultra in this group, notably in children with severe acute malnutrition.

FUNDING: Unitaid and L'Initiative.

TRANSLATION: For the French translation of the abstract see Supplementary

Materials section.

Copyright © 2022 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1473-3099(22)00668-5

PMID: 36395782

15. J Clin Invest. 2022 Nov 15;132(22):e161308. doi: 10.1172/JCI161308.

BCL6 is regulated by the MAPK/ELK1 axis and promotes KRAS-driven lung cancer.

Li K(1)(2)(3), Liu Y(1), Ding Y(1), Zhang Z(1), Feng J(1), Hu J(1), Chen J(1),

Lian Z(1), Chen Y(4), Hu K(3), Chen Z(5), Cai Z(4), Liu M(1), Pang X(1).

Author information:

(1)Changning Maternity and Infant Health Hospital and Shanghai Key Laboratory of

Regulatory Biology and School of Life Sciences and.

(2)Joint Translational Science and Technology Research Institute, East China

Normal University, Shanghai, China.

(3)Cancer Institute, Fudan University Shanghai Cancer Center, Department of

Oncology, Shanghai Medical College, Fudan University, Shanghai, China.

(4)Department of Biochemistry and Molecular Biology, School of Medicine, Tongji

University, Shanghai, China.

(5)Medical Research Institute, Wuhan University, Wuhan, China.

Mutational activation of KRAS is a common oncogenic event in lung cancer, yet

effective therapies are still lacking. Here, we identify B cell lymphoma 6

(BCL6) as a lynchpin in KRAS-driven lung cancer. BCL6 expression was increased

upon KRAS activation in lung tumor tissue in mice and was positively correlated

with the expression of KRAS-GTP, the active form of KRAS, in various human

cancer cell lines. Moreover, BCL6 was highly expressed in human KRAS-mutant lung

adenocarcinomas and was associated with poor patient survival. Mechanistically,

the MAPK/ERK/ELK1 signaling axis downstream of mutant KRAS directly regulated

BCL6 expression. BCL6 maintained the global expression of prereplication complex

components; therefore, BCL6 inhibition induced stalling of the replication fork,

leading to DNA damage and growth arrest in KRAS-mutant lung cancer cells.

Importantly, BCL6-specific knockout in lungs significantly reduced the tumor

burden and mortality in the LSL-KrasG12D/+ lung cancer mouse model. Likewise,

pharmacological inhibition of BCL6 significantly impeded the growth of

KRAS-mutant lung cancer cells both in vitro and in vivo. In summary, our

findings reveal a crucial role of BCL6 in promoting KRAS-addicted lung cancer

and suggest BCL6 as a therapeutic target for the treatment of this intractable

disease.

DOI: 10.1172/JCI161308

PMCID: PMC9663163

PMID: 36377663 [Indexed for MEDLINE]

16. Nat Commun. 2022 Nov 14;13(1):6944. doi: 10.1038/s41467-022-34627-5.

A fluorogenic probe for predicting treatment response in non-small cell lung

cancer with EGFR-activating mutations.

Deng H(#)(1)(2)(3), Lei Q(#)(4)(5)(6), Wang C(#)(4), Wang Z(4)(6), Chen H(5)(6),

Wang G(5), Yang N(5), Huang D(7), Yu Q(5), Yao M(6), Xiao X(6), Zhu G(6), Cheng

C(6), Li Y(6), Li F(7), Tian P(8), Li W(9)(10)(11).

Author information:

(1)Department of Respiratory and Critical Care Medicine, West China Hospital,

Sichuan University, Chengdu, Sichuan, China. huideng0923@hotmail.com.

(2)Targeted Tracer Research and Development Laboratory, Precision Medicine Key

Laboratory of Sichuan Province, Precision Medicine Research Center, West China

Hospital, Sichuan University, Chengdu, Sichuan, China. huideng0923@hotmail.com.

(3)Institute of Respiratory Health, Frontiers Science Center for Disease-related

Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan,

China. huideng0923@hotmail.com.

…

Therapeutic responses of non-small cell lung cancer (NSCLC) to epidermal growth

factor receptor (EGFR) - tyrosine kinase inhibitors (TKIs) are known to be

associated with EGFR mutations. However, a proportion of NSCLCs carrying EGFR

mutations still progress on EGFR-TKI underlining the imperfect correlation.

Structure-function-based approaches have recently been reported to perform

better in retrospectively predicting patient outcomes following EGFR-TKI

treatment than exon-based method. Here, we develop a multicolor

fluorescence-activated cell sorting (FACS) with an EGFR-TKI-based fluorogenic

probe (HX103) to profile active-EGFR in tumors. HX103-based FACS shows an

overall agreement with gene mutations of 82.6%, sensitivity of 81.8% and

specificity of 83.3% for discriminating EGFR-activating mutations from wild-type

in surgical specimens from NSCLC patients. We then translate HX103 to the

clinical studies for prediction of EGFR-TKI sensitivity. When integrating

computed tomography imaging with HX103-based FACS, we find a high correlation

between EGFR-TKI therapy response and probe labeling. These studies demonstrate

HX103-based FACS provides a high predictive performance for response to

EGFR-TKI, suggesting the potential utility of an EGFR-TKI-based probe in

precision medicine trials to stratify NSCLC patients for EGFR-TKI treatment.

© 2022. The Author(s).

DOI: 10.1038/s41467-022-34627-5

PMCID: PMC9663578

PMID: 36376325 [Indexed for MEDLINE]

17. Am J Respir Crit Care Med. 2022 Nov 8. doi: 10.1164/rccm.202109-2019OC. Online ahead of print.

Multi-Dimensional Cell-free DNA Fragmentomic Assay for Detection of Early-Stage

Lung Cancer.

Wang S(1), Meng F(2), Li M(1), Bao H(3), Chen X(4), Zhu M(2), Liu R(4), Xu X(4),

Yang S(4), Wu X(5), Shao Y(6), Xu L(7), Yin R(8).

Author information:

(1)Jiangsu Cancer Institute and Hospital, 26481, Nanjing, Jiangsu, China.

(2)Nanjing Medical University, Nanjing, China.

(3)Geneseeq Tech Inc, Nanjing, China.

(4)Geneseeq Research Institute, Nanjing Geneseeq Technology Inc., Nanjing,

China.

(5)Geneseeq Technology Inc., R&D, Toronto, Ontario, Canada.

(6)Geneseeq Technology Inc., Translational Medicine Research Institute, Toronto,

Ontario, Canada.

(7)Jiangsu Key Laboratory of Molecular and Translational Cancer Research,

Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated

Cancer Hospital of Nanjing Medical University, Nanjing, China.

(8)Jiangsu Cancer Hospital, 26481, Nanjing, China; rong_yin@njmu.edu.cn.

RATIONALE: Cell-free DNA (cfDNA) analysis holds promise for early detection of

lung cancer and benefits patients with higher survival. However, the detection

sensitivity of previous cfDNA-based studies was still low to suffice the

clinical use, especially for early-stage tumors.

OBJECTIVES: Establish an accurate and affordable approach for early-stage lung

cancer detection by integrating cfDNA fragmentomics and machine learning models.

METHODS: This study included 350 non-cancer and 432 cancer participants. The

participants' plasma cfDNA samples were profiled by whole-genome sequencing.

Multiple cfDNA features and machine learning models were compared in the

training cohort to achieve an optimal model. Model performance was evaluated in

three validation cohorts.

MEASUREMENTS AND MAIN RESULTS: A stacked ensemble model integrating five cfDNA

features and five machine learning algorithms constructed in the training cohort

(cancer: 113, healthy: 113) outperformed all the models built on individual

feature-algorithm combinations. This integrated model yielded superior

sensitivities of 91.4% at 95.7% specificity for Cohort Validation I [Area Under

the Curve (AUC): 0.984], 84.7% at 98.6% specificity for Validation II (AUC:

0.987), and 92.5% at 94.2% specificity for Additional Validation (AUC: 0.974),

respectively. The model's high performance remained consistent when sequencing

depth was down to 0.5× (AUC: 0.966-0.971). Furthermore, our model is sensitive

to identifying early pathological features (83.2% sensitivity for stage I, 85.0%

sensitivity for<1cm tumor at the 0.66 cutoff).

CONCLUSIONS: We have established a stacked ensemble model using cfDNA

fragmentomics features and achieved superior sensitivity for detecting

early-stage lung cancer, which could promote early diagnosis and benefit more

patients. This article is open access and distributed under the terms of the

Creative Commons Attribution Non-Commercial No Derivatives License 4.0

(http://creativecommons.org/licenses/by-nc-nd/4.0/).

DOI: 10.1164/rccm.202109-2019OC

PMID: 36346614

18. J Natl Cancer Inst. 2022 Nov 8:djac203. doi: 10.1093/jnci/djac203. Online ahead of print.

Disparity in checkpoint inhibitor utilization among commercially insured adult

patients with metastatic lung cancer.

Li M(1), Liao K(1), Chen AJ(2), Cascone T(3), Shen Y(4), Lu Q(5), Shih YT(1).

Author information:

(1)Section of Cancer Economics and Policy, Department of Health Services

Research, University of Texas MD Anderson Cancer Center, Houston, USA.

(2)Sol Price School of Public Policy, University of Southern California, Los

Angeles, USA.

(3)Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD

Anderson Cancer Center, Houston, USA.

(4)Department of Biostatistics, University of Texas MD Anderson Cancer Center,

Houston, USA.

(5)Department of Health Disparities Research, University of Texas MD Anderson

Cancer Center, Houston, USA.

BACKGROUND: There is a lack of evidence from nationwide sample on the disparity

of initiating immune checkpoint inhibitors (ICIs) after metastatic lung cancer

diagnosis.

METHODS: We identified metastatic lung cancer patients diagnosed between 2015

and 2020 from a large nationwide commercial claims database. We analyzed the

time from metastatic lung cancer diagnosis to ICI therapy using Cox proportional

hazard models. Independent variables included county-level measures (quintiles

of percentage of racialized population, quintiles of percentage of population

below poverty, urbanity, and density of medical oncologists) and patient

characteristics (age, sex, Charlson comorbidity index, Medicare Advantage, and

year of diagnosis). All tests were two-sided.

RESULTS: A total of 17,022 patients were included. Counties with a larger

proportion of racialized population appeared to be more urban, have a greater

percentage of its residents in poverty, and have a higher density of medical

oncologists. In Cox analysis, the adjusted hazard ratio of the second, third,

fourth, and highest quintile of percentage of racialized population were 0.89

(95% confidence interval [CI]: 0.82-0.98), 0.85 (95% CI: 0.78-0.93), 0.78 (95%

CI: 0.71-0.86), and 0.71 (95% CI: 0.62-0.81), respectively, compared to counties

in the lowest quintile. The slower ICI therapy initiation was driven by counties

with the highest percentage of Hispanic population and other non-Black

racialized groups.

CONCLUSIONS: Commercially insured patients with metastatic lung cancer who lived

in counties with greater percentage of racialized population had slower

initiation of ICI therapy after lung cancer diagnosis, despite greater density

of oncologists in their neighborhood.

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

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

DOI: 10.1093/jnci/djac203

PMID: 36346180

19. Nat Commun. 2022 Nov 4;13(1):6623. doi: 10.1038/s41467-022-34428-w.

Tumor factors stimulate lysosomal degradation of tumor antigens and undermine

their cross-presentation in lung cancer.

Lu Z(#)(1), Chen J(#)(1), Yu P(#)(1), Atherton MJ(2), Gui J(1), Tomar VS(1),

Middleton JD(3), Sullivan NT(4), Singhal S(4), George SS(5), Woolfork AG(6),

Weljie AM(6), Hai T(3), Eruslanov EB(4), Fuchs SY(7).

Author information:

(1)Department of Biomedical Sciences, School of Veterinary Medicine, University

of Pennsylvania, Philadelphia, PA, 19104, USA.

(2)Department of Clinical Sciences & Advanced Medicine, School of Veterinary

Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.

(3)Department of Biological Chemistry and Pharmacology, The Ohio State

University, Columbus, OH, 43210, USA.

…

Activities of dendritic cells (DCs) that present tumor antigens are often

suppressed in tumors. Here we report that this suppression is induced by tumor

microenvironment-derived factors, which activate the activating transcription

factor-3 (ATF3) transcription factor and downregulate cholesterol 25-hydroxylase

(CH25H). Loss of CH25H in antigen presenting cells isolated from human lung

tumors is associated with tumor growth and lung cancer progression. Accordingly,

mice lacking CH25H in DCs exhibit an accelerated tumor growth, decreased

infiltration and impaired activation of intratumoral CD8+ T cells. These mice do

not establish measurable long-term immunity against malignant cells that undergo

chemotherapy-induced immunogenic cell death. Mechanistically, downregulation of

CH25H stimulates membrane fusion between endo-phagosomes and lysosomes,

accelerates lysosomal degradation and restricts cross-presentation of tumor

antigens in the intratumoral DCs. Administration of STING agonist MSA-2 reduces

the lysosomal activity in DCs, restores antigen cross presentation, and

increases therapeutic efficacy of PD-1 blockade against tumour challenge in a

CH25H-dependent manner. These studies highlight the importance of downregulation

of CH25H in DCs for tumor immune evasion and resistance to therapy.

© 2022. The Author(s).

DOI: 10.1038/s41467-022-34428-w

PMCID: PMC9636202

PMID: 36333297 [Indexed for MEDLINE]

20. Nat Commun. 2022 Nov 3;13(1):6594. doi: 10.1038/s41467-022-34061-7.

Inflammation and immune activation are associated with risk of Mycobacterium

tuberculosis infection in BCG-vaccinated infants.

Satti I(1), Wittenberg RE(#)(1), Li S(#)(1), Harris SA(1), Tanner R(1), Cizmeci

D(1), Jacobs A(1)(2), Williams N(3), Mulenga H(4), Fletcher HA(5), Scriba TJ(4),

Tameris M(4), Hatherill M(4), McShane H(6).

Author information:

(1)Jenner Institute, Nuffield Department of Medicine, University of Oxford,

Oxford, OX3 7DQ, UK.

(2)Wellcome Centre for Infectious Diseases Research in Africa, University of

Cape Town, Observatory, Cape Town, South Africa.

(3)Nuffield Department of Primary Care Health Sciences, University of Oxford,

Radcliffe Observatory Quarter, Woodstock Road, Oxford, OX2 6GG, UK.

…

Tuberculosis vaccine development is hindered by the lack of validated immune

correlates of protection. Exploring immune correlates of risk of disease and/or

infection in prospective samples can inform this field. We investigate whether

previously identified immune correlates of risk of TB disease also associate

with increased risk of M.tb infection in BCG-vaccinated South African infants,

who became infected with M.tb during 2-3 years of follow-up. M.tb infection is

defined by conversion to positive reactivity in the QuantiFERON test. We

demonstrate that inflammation and immune activation are associated with risk of

M.tb infection. Ag85A-specific IgG is elevated in infants that were subsequently

infected with M.tb, and this is coupled with upregulated gene expression of

immunoglobulin-associated genes and type-I interferon. Plasma levels of

IFN-[Formula: see text]2, TNF-[Formula: see text], CXCL10 (IP-10) and complement

C2 are also higher in infants that were subsequently infected with M.tb.

© 2022. The Author(s).

DOI: 10.1038/s41467-022-34061-7

PMCID: PMC9632577

PMID: 36329009 [Indexed for MEDLINE]

21. J Clin Oncol. 2022 Nov 3:JCO2200975. doi: 10.1200/JCO.22.00975. Online ahead of print.

Durvalumab With or Without Tremelimumab in Combination With Chemotherapy as

First-Line Therapy for Metastatic Non-Small-Cell Lung Cancer: The Phase III

POSEIDON Study.

Johnson ML(1), Cho BC(2), Luft A(3), Alatorre-Alexander J(4), Geater SL(5),

Laktionov K(6), Kim SW(7), Ursol G(8), Hussein M(9), Lim FL(10), Yang CT(11),

Araujo LH(12), Saito H(13), Reinmuth N(14), Shi X(15), Poole L(16), Peters

S(17), Garon EB(18), Mok T(19); POSEIDON investigators.

Author information:

(1)Sarah Cannon Research Institute, Tennessee Oncology, PLLC, Nashville, TN.

(2)Yonsei Cancer Center, Seoul, South Korea.

(3)Leningrad Regional Clinical Hospital, St Petersburg, Russia.

…

PURPOSE: The open-label, phase III POSEIDON study evaluated tremelimumab plus

durvalumab and chemotherapy (T + D + CT) and durvalumab plus chemotherapy (D +

CT) versus chemotherapy alone (CT) in first-line metastatic non-small-cell lung

cancer (mNSCLC).

METHODS: Patients (n = 1,013) with EGFR/ALK wild-type mNSCLC were randomly

assigned (1:1:1) to tremelimumab 75 mg plus durvalumab 1,500 mg and

platinum-based chemotherapy for up to four 21-day cycles, followed by durvalumab

once every 4 weeks until progression and one additional tremelimumab dose;

durvalumab plus chemotherapy for up to four 21-day cycles, followed by

durvalumab once every 4 weeks until progression; or chemotherapy for up to six

21-day cycles (with or without maintenance pemetrexed; all arms). Primary end

points were progression-free survival (PFS) and overall survival (OS) for D + CT

versus CT. Key alpha-controlled secondary end points were PFS and OS for T + D +

CT versus CT.

RESULTS: PFS was significantly improved with D + CT versus CT (hazard ratio

[HR], 0.74; 95% CI, 0.62 to 0.89; P = .0009; median, 5.5 v 4.8 months); a trend

for improved OS did not reach statistical significance (HR, 0.86; 95% CI, 0.72

to 1.02; P = .0758; median, 13.3 v 11.7 months; 24-month OS, 29.6% v 22.1%). PFS

(HR, 0.72; 95% CI, 0.60 to 0.86; P = .0003; median, 6.2 v 4.8 months) and OS

(HR, 0.77; 95% CI, 0.65 to 0.92; P = .0030; median, 14.0 v 11.7 months; 24-month

OS, 32.9% v 22.1%) were significantly improved with T + D + CT versus CT.

Treatment-related adverse events were maximum grade 3/4 in 51.8%, 44.6%, and

44.4% of patients receiving T + D + CT, D + CT, and CT, respectively; 15.5%,

14.1%, and 9.9%, respectively, discontinued treatment because of

treatment-related adverse events.

CONCLUSION: D + CT significantly improved PFS versus CT. A limited course of

tremelimumab added to durvalumab and chemotherapy significantly improved OS and

PFS versus CT, without meaningful additional tolerability burden, representing a

potential new option in first-line mNSCLC.

DOI: 10.1200/JCO.22.00975

PMID: 36327426

22. J Exp Med. 2023 Jan 2;220(1):e20220484. doi: 10.1084/jem.20220484. Epub 2022 Nov 3.

Inherited human ITK deficiency impairs IFN-γ immunity and underlies tuberculosis.

Ogishi M(1)(2), Yang R(#)(1), Rodriguez R(#)(3)(4), Golec DP(#)(5), Martin

E(3)(4), Philippot Q(4)(6), Bohlen J(4)(6), Pelham SJ(1), Arias AA(1)(7)(8),

Khan T(9), Ata M(9), Al Ali F(9), Rozenberg F(10), Kong XF(1), Chrabieh M(4)(6),

…

Author information:

(1)St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller

Branch, Rockefeller University, New York, NY.

(2)The David Rockefeller Graduate Program, Rockefeller University, New York, NY.

(3)Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection,

INSERM UMR1163, Paris, France.

…

Inborn errors of IFN-γ immunity can underlie tuberculosis (TB). We report three

patients from two kindreds without EBV viremia or disease but with severe TB and

inherited complete ITK deficiency, a condition associated with severe EBV

disease that renders immunological studies challenging. They have CD4+ αβ T

lymphocytopenia with a concomitant expansion of CD4-CD8- double-negative (DN) αβ and Vδ2- γδ T 

lymphocytes, both displaying a unique CD38+CD45RA+T-bet+EOMES- phenotype. Itk-deficient mice 

recapitulated an expansion of the γδ T and DN αβ T lymphocyte populations in the thymus and spleen,

respectively. Moreover, the patients' T lymphocytes secrete small amounts of IFN-γ in response to 

TCR crosslinking, mitogens, or forced synapse formation with autologous B

lymphocytes. Finally, the patients' total lymphocytes secrete small amounts of

IFN-γ, and CD4+, CD8+, DN αβ T, Vδ2+ γδ T, and MAIT cells display impaired IFN-γ production

 in response to BCG. Inherited ITK deficiency undermines the

development and function of various IFN-γ-producing T cell subsets, thereby

underlying TB.

© 2022 Ogishi et al.

DOI: 10.1084/jem.20220484

PMCID: PMC9641312

PMID: 36326697 [Indexed for MEDLINE]

23. J Natl Cancer Inst. 2022 Nov 2:djac205. doi: 10.1093/jnci/djac205. Online ahead of print.

Predictors of Survival to Immunotherapy and Chemoimmunotherapy in Non-Small Cell

Lung Cancer: A Meta-Analysis.

Di Federico A(1)(2), De Giglio A(1)(2), Gelsomino F(1)(2), Sperandi F(1),

Melotti B(1), Ardizzoni A(1)(2).

Author information:

(1)Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna,

Bologna, Italy.

(2)Department of Experimental, Diagnostic and Specialty Medicine (DIMES),

University of Bologna, Bologna, Italy.

BACKGROUND: many patients with non-small cell lung cancer (NSCLC) derive poor

benefit from immunotherapy (IO). For some of them, adding chemotherapy (CT) can

improve the outcomes, but the reliability of PD-L1 expression as the only

biomarker to distinguish these patients is unsatisfactory. We sought to detect

clinicopathological and molecular predictive factors of survival that might be

added to PD-L1 expression in the selection of patients that should receive IO

alone or chemoimmunotherapy (CIT).

METHODS: We conducted a systematic search of randomized controlled clinical

trials (RCT) investigating IO, alone or plus CT, versus CT alone in

treatment-naïve advanced NSCLC patients. Meta-analyses and meta-regression

analyses were performed to investigate IO alone versus CT, CIT versus CT, and IO

alone versus CIT.

RESULTS: 14367 patients with advanced NSCLC across 25 RCT were included.

Squamous histology, male sex, current/former smoker status, PD-L1 expression

≥50%, and high tumor mutational burden (TMB) correlated with improved survival

with IO alone compared to CT. Conversely, female sex, no smoking history,

negative PD-L1 expression, and low TMB correlated with unsatisfactory outcomes

with IO alone versus CT, but not with CIT versus CT. CIT improved survival

versus IO alone in female patients, never smokers, in those having a PD-L1

expression ≥1% (but not with PD-L1 ≥50%) or a low TMB, and in patients with

central nervous system metastasis.

CONCLUSION: these findings suggest some clinicopathological and molecular

features that, added to PD-L1 expression, could help in the selection of the

most appropriate first-line IO-based treatment for advanced NSCLC patients.

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

DOI: 10.1093/jnci/djac205

PMID: 36322815

24. J Clin Invest. 2022 Nov 1;132(21):e157873. doi: 10.1172/JCI157873.

Stromal structure remodeling by B lymphocytes limits T cell activation in lymph

nodes of Mycobacterium tuberculosis-infected mice.

Daniel L(1)(2)(3), Bhattacharyya ND(1)(2)(3), Counoupas C(2)(3)(4), Cai Y(5),

Chen X(5), Triccas JA(2)(3)(4)(6), Britton WJ(2)(6)(7), Feng CG(1)(2)(3)(6).

Author information:

(1)Immunology and Host Defence Group, School of Medical Sciences, Faculty of

Medicine and Health.

(2)Centenary Institute.

(3)Charles Perkins Centre, and.

…

An effective adaptive immune response depends on the organized architecture of

secondary lymphoid organs, including the lymph nodes (LNs). While the cellular

composition and microanatomy of LNs under steady state are well defined, the

impact of chronic tissue inflammation on the structure and function of draining

LNs is incompletely understood. Here we showed that Mycobacterium tuberculosis

infection remodeled LN architecture by increasing the number and paracortical

translocation of B cells. The formation of paracortical B lymphocyte and CD35+

follicular dendritic cell clusters dispersed CCL21-producing fibroblastic

reticular cells and segregated pathogen-containing myeloid cells from

antigen-specific CD4+ T cells. Depletion of B cells restored the chemokine and

lymphoid structure and reduced bacterial burdens in LNs of the chronically

infected mice. Importantly, this remodeling process impaired activation of naive

CD4+ T cells in response to mycobacterial and unrelated antigens during chronic

tuberculosis infection. Our studies reveal a mechanism in the regulation of LN

microanatomy during inflammation and identify B cells as a critical element

limiting the T cell response to persistent intracellular infection in LNs.

DOI: 10.1172/JCI157873

PMCID: PMC9621141

PMID: 36317628 [Indexed for MEDLINE]

25. Ann Intern Med. 2022 Nov;175(11):1501-1505. doi: 10.7326/M22-1325. Epub 2022 Oct 11.

Characteristics of Persons Screened for Lung Cancer in the United States : A

Cohort Study.

Silvestri GA(1), Goldman L(2), Burleson J(2), Gould M(3), Kazerooni EA(4),

Mazzone PJ(5), Rivera MP(6), Doria-Rose VP(7), Rosenthal LS(8), Simanowith M(2),

Smith RA(8), Tanner NT(1), Fedewa S(9).

Author information:

(1)Division of Pulmonary Medicine, Thoracic Oncology Research Group, Hollings

Cancer Center, Medical University of South Carolina, Charleston, South Carolina

(G.A.S., N.T.T.).

(2)American College of Radiology, Reston, Virginia (L.G., J.B., M.S.).

(3)Department of Health Systems Science, Kaiser Permanente Bernard J. Tyson

School of Medicine, Pasadena, California (M.G.).

…

Comment in

    Ann Intern Med. 2022 Nov;175(11):1608-1609.

BACKGROUND: Lung cancer screening (LCS) with low-dose computed tomography (LDCT)

was recommended by the U.S. Preventive Services Task Force (USPSTF) in 2013,

making approximately 8 million Americans eligible for screening. The demographic

characteristics and adherence of persons screened in the United States have not

been reported at the population level.

OBJECTIVE: To define sociodemographic characteristics and adherence among

persons screened and entered into the American College of Radiology's Lung

Cancer Screening Registry (LCSR).

DESIGN: Cohort study.

SETTING: United States, 2015 to 2019.

PARTICIPANTS: Persons receiving a baseline LDCT for LCS from 3625 facilities

reporting to the LCSR.

MEASUREMENTS: Age, sex, and smoking status distributions (percentages) were

computed among persons who were screened and among respondents in the 2015

National Health Interview Survey (NHIS) who were eligible for screening. The

prevalence between the LCSR and the NHIS was compared with prevalence ratios

(PRs) and 95% CIs. Adherence to annual screening was defined as having a

follow-up test within 11 to 15 months of an initial LDCT.

RESULTS: Among 1 159 092 persons who were screened, 90.8% (n = 1 052 591) met

the USPSTF eligibility criteria. Compared with adults from the NHIS who met the

criteria (n = 1257), screening recipients in the LCSR were older (34.7% vs.

44.8% were aged 65 to 74 years; PR, 1.29 [95% CI, 1.20 to 1.39]), more likely to

be female (41.8% vs. 48.1%; PR, 1.15 [CI, 1.08 to 1.23]), and more likely to

currently smoke (52.3% vs. 61.4%; PR, 1.17 [CI, 1.11 to 1.23]). Only 22.3% had a

repeated annual LDCT. If follow-up was extended to 24 months and more than 24

months, 34.3% and 40.3% were adherent, respectively.

LIMITATIONS: Underreporting of LCS and missing data may skew demographic

characteristics of persons reported to be screened. Underreporting of adherence

may result in underestimates of follow-up.

CONCLUSION: Approximately 91% of persons who had LCS met USPSTF eligibility

criteria. In addition to continuing to target all eligible adults, men, those

who formerly smoked, and younger eligible patients may be less likely to be

screened. Adherence to annual follow-up screening was poor, potentially limiting

screening effectiveness.

PRIMARY FUNDING SOURCE: None.

DOI: 10.7326/M22-1325

PMID: 36215712 [Indexed for MEDLINE]

26. J Exp Med. 2022 Nov 7;219(11):e20220504. doi: 10.1084/jem.20220504. Epub 2022

Sep 7.

GPX4 regulates cellular necrosis and host resistance in Mycobacterium

tuberculosis infection.

Amaral EP(1), Foreman TW(2), Namasivayam S(1), Hilligan KL(1), Kauffman KD(2),

Barbosa Bomfim CC(1), Costa DL(3), Barreto-Duarte B(4)(5)(6), Gurgel-Rocha

C(7)(8), Santana MF(9)(10)(11), Cordeiro-Santos M(10)(11)(12), Du Bruyn E(13),

Riou C(13), Aberman K(1), Wilkinson RJ(13)(14)(15), Barber DL(2), Mayer-Barber

KD(16), Andrade BB(4)(5)(6)(17)(18)(19)(20), Sher A(1).

Author information:

(1)Immunobiology Section, Laboratory of Parasitic Diseases, National Institute

of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD.

(2)T Lymphocyte Biology Section, Laboratory of Parasitic Diseases, National

Institute of Allergy and Infectious Disease, National Institutes of Health,

Bethesda, MD.

(3)Departmento de Bioquímica e Imunologia, Programa de Pós-Graduação em

Imunologia Básica e Aplicada, Faculdade de Medicina de Ribeirão Preto,

Universidade de São Paulo, Ribeirão Preto, Brazil.

…

Cellular necrosis during Mycobacterium tuberculosis (Mtb) infection promotes

both immunopathology and bacterial dissemination. Glutathione peroxidase-4

(Gpx4) is an enzyme that plays a critical role in preventing iron-dependent

lipid peroxidation-mediated cell death (ferroptosis), a process previously

implicated in the necrotic pathology seen in Mtb-infected mice. Here, we

document altered GPX4 expression, glutathione levels, and lipid peroxidation in

patients with active tuberculosis and assess the role of this pathway in mice

genetically deficient in or overexpressing Gpx4. We found that Gpx4-deficient

mice infected with Mtb display substantially increased lung necrosis and

bacterial burdens, while transgenic mice overexpressing the enzyme show

decreased bacterial loads and necrosis. Moreover, Gpx4-deficient macrophages

exhibited enhanced necrosis upon Mtb infection in vitro, an outcome suppressed

by the lipid peroxidation inhibitor, ferrostatin-1. These findings provide

support for the role of ferroptosis in Mtb-induced necrosis and implicate the

Gpx4/GSH axis as a target for host-directed therapy of tuberculosis.

© 2022 Amaral et al.

DOI: 10.1084/jem.20220504

PMCID: PMC9458471

PMID: 36069923 [Indexed for MEDLINE]

27. Nat Chem Biol. 2022 Nov;18(11):1236-1244. doi: 10.1038/s41589-022-01102-7. Epub 2022 Aug 22.

Evybactin is a DNA gyrase inhibitor that selectively kills Mycobacterium

tuberculosis.

Imai Y(#)(1)(2), Hauk G(#)(3), Quigley J(1), Liang L(1), Son S(1), Ghiglieri

M(1), Gates MF(1), Morrissette M(1), Shahsavari N(1), Niles S(1), Baldisseri

D(4), Honrao C(5), Ma X(5), Guo JJ(5)(6), Berger JM(7), Lewis K(8).

Author information:

(1)Antimicrobial Discovery Center, Department of Biology, Northeastern

University, Boston, MA, USA.

(2)Department of Biomolecular Innovation, Institute for Biomedical Sciences,

Shinshu University, Nagano, Japan.

(3)Department of Biophysics and Biophysical Chemistry, Johns Hopkins University

School of Medicine, Baltimore, MD, USA.

(4)Bruker Biospin Corporation, Billerica, MA, USA.

(5)Center for Drug Discovery, Department of Pharmaceutical Sciences,

Northeastern University, Boston, MA, USA.

(6)Barnett Institute for Chemical and Biological Analysis, Department of

Chemistry and Chemical Biology, Northeastern University, Boston, MA, USA.

(7)Department of Biophysics and Biophysical Chemistry, Johns Hopkins University

School of Medicine, Baltimore, MD, USA. jmberger@jhmi.edu.

(8)Antimicrobial Discovery Center, Department of Biology, Northeastern

University, Boston, MA, USA. k.lewis@northeastern.edu.

(#)Contributed equally

The antimicrobial resistance crisis requires the introduction of novel

antibiotics. The use of conventional broad-spectrum compounds selects for

resistance in off-target pathogens and harms the microbiome. This is especially

true for Mycobacterium tuberculosis, where treatment requires a 6-month course

of antibiotics. Here we show that a novel antimicrobial from Photorhabdus

noenieputensis, which we named evybactin, is a potent and selective antibiotic

acting against M. tuberculosis. Evybactin targets DNA gyrase and binds to a site

overlapping with synthetic thiophene poisons. Given the conserved nature of DNA

gyrase, the observed selectivity against M. tuberculosis is puzzling. We found

that evybactin is smuggled into the cell by a promiscuous transporter of

hydrophilic compounds, BacA. Evybactin is the first, but likely not the only,

antimicrobial compound found to employ this unusual mechanism of selectivity.

© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.

DOI: 10.1038/s41589-022-01102-7

PMID: 35996001 [Indexed for MEDLINE]

28. J Natl Cancer Inst. 2022 Nov 14;114(11):1449-1467. doi: 10.1093/jnci/djac154.

Facilitators and Barriers to Implementation of Lung Cancer Screening: A

Framework-Driven Systematic Review.

Sedani AE(1), Davis OC(2), Clifton SC(3), Campbell JE(1), Chou AF(4).

Author information:

(1)Department of Biostatistics and Epidemiology, Hudson College of Public

Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.

(2)College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma

City, OK, USA.

(3)Robert M. Bird Health Sciences Library, University of Oklahoma Health

Sciences Center, Oklahoma City, OK, USA.

(4)Department of Family and Preventive Medicine, College of Medicine, University

of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.

BACKGROUND: The purpose of this study is to undertake a comprehensive systematic

review to describe multilevel factors (barriers and facilitators) that may

influence the implementation of low-dose chest computed tomography for lung

cancer screening in the United States.

METHODS: Systematic literature searches were performed using 6 online databases

and citation indexes for peer-reviewed studies, for articles published from 2013

to 2021. Studies were classified into 3 perspectives, based on the study's unit

of analysis: system, health-care provider, and patient. Barriers and

facilitators identified for each study included in our final review were then

coded and categorized using the Consolidate Framework for Implementation

Research domains.

RESULTS: At the system level, the 2 most common constructs were external policy

and incentives and executing the implementation process. At the provider level,

the most common constructs were evidence strength and quality of the

intervention characteristics, patient needs and resources, implementation

climate, and an individual's knowledge and beliefs about the intervention. At

the patient level, the most common constructs were patient needs and resources,

individual's knowledge and beliefs about the intervention, and engaging in the

implementation process. These constructs can act as facilitators or barriers to

lung cancer screening implementation.

CONCLUSIONS: Applying the Consolidate Framework for Implementation Research

domains and constructs to understand and specify factors facilitating uptake of

lung cancer screening as well as cataloging the lessons learned from previous

efforts helps inform the development and implementation processes of lung cancer

screening programs in the community setting.

REGISTRATION: PROSPERO, CRD42021247677.

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

DOI: 10.1093/jnci/djac154

PMCID: PMC9664175

PMID: 35993616 [Indexed for MEDLINE]

29. J Clin Oncol. 2022 Nov 1;40(31):3587-3592. doi: 10.1200/JCO.21.02911. Epub 2022 Aug 12.

Updated Analysis of NEJ009: Gefitinib-Alone Versus Gefitinib Plus Chemotherapy

for Non-Small-Cell Lung Cancer With Mutated EGFR.

Miyauchi E(1), Morita S(2), Nakamura A(3), Hosomi Y(4), Watanabe K(5), Ikeda

S(6), Seike M(7), Fujita Y(8), Minato K(9), Ko R(10), Harada T(11), Hagiwara

K(12), Kobayashi K(13), Nukiwa T(14), Inoue A(15); North-East Japan Study Group.

Author information:

(1)Department of Respiratory Medicine, Tohoku University Hospital, Sendai,

Japan.

(2)Department of Biomedical Statistics and Bioinformatics, Kyoto University

Graduate School of Medicine, Kyoto, Japan.

(3)Department of Respiratory Medicine, Sendai Kosei Hospital, Sendai, Japan.

…

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 coprimary 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.In a randomized, open-label, phase

III NEJ009 study, gefitinib plus chemotherapy significantly improved

progression-free survival (PFS) and overall survival (OS) compared with

gefitinib-alone in patients with untreated non-small-cell lung cancer harboring

mutations in epidermal growth factor receptor. Herein, we report the updated

survival outcome and long-term tolerability. Patients were randomly assigned to

gefitinib (gefitinib 250 mg orally, once daily) and gefitinib combined with

carboplatin plus pemetrexed (GCP in a 3-week cycle for six cycles followed by

concurrent gefitinib and pemetrexed maintenance) groups. At the data cutoff (May

22, 2020), GCP demonstrated significantly better PFS2 (hazard ratio, 0.77; 95%

CI, 0.62 to 0.97; P = .027) than gefitinib. However, the updated median OS was

38.5 months (95% CI, 31.1 to 47.1) and 49.0 months (95% CI, 41.8 to 56.7) in the

gefitinib and GCP groups, respectively (hazard ratio, 0.82; 95% CI, 0.64 to

1.06; P = .127). The OS in both groups was similar for the overall patient

population. No severe adverse events occurred since the first report. This

updated analysis revealed that the GCP regimen improved PFS and PFS2 with an

acceptable safety profile compared with gefitinib-alone. GCP is more efficient

than gefitinib monotherapy as a first-line treatment for non-small-cell lung

cancer with epidermal growth factor receptor mutations.

DOI: 10.1200/JCO.21.02911

PMCID: PMC9622660

PMID: 35960896 [Indexed for MEDLINE]

30. Lancet Infect Dis. 2022 Nov;22(11):1617-1625. doi:

10.1016/S1473-3099(22)00425-X. Epub 2022 Aug 4.

Nationwide tuberculosis outbreak in the USA linked to a bone graft product: an

outbreak report.

Schwartz NG(1), Hernandez-Romieu AC(2), Annambhotla P(3), Filardo TD(4),

Althomsons SP(5), Free RJ(3), Li R(2), Wyatt Wilson W(2), Deutsch-Feldman M(4),

Drees M(6), Hanlin E(7), White K(8), Lehman KA(9), Thacker TC(9), Brubaker

SA(10), Clark B(10), Basavaraju SV(3), Benowitz I(3), Burton Glowicz J(3), Cowan

LS(5), Starks AM(5), Bamrah Morris S(5), LoBue P(5), Stewart RJ(5), Wortham

JM(5), Haddad MB(5); Bone Allograft Tuberculosis Investigators.

Author information:

(1)Division of Tuberculosis Elimination, National Center for HIV, Viral

Hepatitis, STD, and TB Prevention, US Centers for Disease Control and

Prevention, Atlanta, GA, USA; Epidemic Intelligence Service, US Centers for

Disease Control and Prevention, Atlanta, GA, USA. Electronic address:

nschwartz@cdc.gov.

(2)Epidemic Intelligence Service, US Centers for Disease Control and Prevention,

Atlanta, GA, USA; Division of Healthcare Quality Promotion, National Center for

Emerging and Zoonotic Infectious Diseases, US Centers for Disease Control and

Prevention, Atlanta, GA, USA.

(3)Division of Healthcare Quality Promotion, National Center for Emerging and

Zoonotic Infectious Diseases, US Centers for Disease Control and Prevention,

Atlanta, GA, USA.

…

Comment in

    Lancet Infect Dis. 2022 Nov;22(11):1522-1523.

BACKGROUND: Mycobacterium tuberculosis transmission through solid organ

transplantation has been well described, but transmission through transplanted

tissues is rare. We investigated a tuberculosis outbreak in the USA linked to a

bone graft product containing live cells derived from a single deceased donor.

METHODS: In this outbreak report, we describe the management and severity of the

outbreak and identify opportunities to improve tissue transplant safety in the

USA. During early June, 2021, the US Centers for Disease Control and Prevention

(CDC) worked with state and local health departments and health-care facilities

to locate and sequester unused units from the recalled lot and notify, evaluate,

and treat all identified product recipients. Investigators from CDC and the US

Food and Drug Administration (FDA) reviewed donor screening and tissue

processing. Unused product units from the recalled and other donor lots were

tested for the presence of M tuberculosis using real-time PCR (rt PCR) assays

and culture. M tuberculosis isolates from unused product and recipients were

compared using phylogenetic analysis.

FINDINGS: The tissue donor (a man aged 80 years) had unrecognised risk factors,

symptoms, and signs consistent with tuberculosis. Bone was procured from the

deceased donor and processed into 154 units of bone allograft product containing

live cells, which were distributed to 37 hospitals and ambulatory surgical

centres in 20 US states between March 1 and April 2, 2021. From March 3 to June

1, 2021, 136 (88%) units were implanted into 113 recipients aged 24-87 years in

18 states (some individuals received multiple units). The remaining 18 units

(12%) were located and sequestered. 87 (77%) of 113 identified product

recipients had microbiological or imaging evidence of tuberculosis disease.

Eight product recipients died 8-99 days after product implantation (three deaths

were attributed to tuberculosis after recognition of the outbreak). All 105

living recipients started treatment for tuberculosis disease at a median of 69

days (IQR 56-81) after product implantation. M tuberculosis was detected in all

eight sequestered unused units tested from the recalled donor lot, but not in

lots from other donors. M tuberculosis isolates from unused product and

recipients were more than 99·99% genetically identical.

INTERPRETATION: Donor-derived transmission of M tuberculosis via bone allograft

resulted in substantial morbidity and mortality. All prospective tissue and

organ donors should be routinely assessed for tuberculosis risk factors and

clinical findings. When these are present, laboratory testing for M tuberculosis

should be strongly considered.

FUNDING: None.

Copyright © 2022 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1473-3099(22)00425-X

PMCID: PMC9605268

PMID: 35934016 [Indexed for MEDLINE]

31. J Clin Oncol. 2022 Nov 20;40(33):3808-3816. doi: 10.1200/JCO.21.02986. Epub 2022 Jun 27.

Antibody Response to COVID-19 mRNA Vaccine in Patients With Lung Cancer After

Primary Immunization and Booster: Reactivity to the SARS-CoV-2 WT Virus and

Omicron Variant.

Valanparambil RM(1)(2), Carlisle J(3), Linderman SL(1)(2), Akthar A(1)(2),

Millett RL(3), Lai L(1)(4)(5), Chang A(1)(2)(3)(6), McCook-Veal AA(7),

…

Author information:

(1)Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA.

(2)Department of Microbiology and Immunology, Emory University, Atlanta, GA.

(3)Winship Cancer Institute, Atlanta, GA.

…

Update of

    medRxiv. 2022 Jan 23;:

PURPOSE: To examine COVID-19 mRNA vaccine-induced binding and neutralizing

antibody responses in patients with non-small-cell lung cancer (NSCLC) to

SARS-CoV-2 614D (wild type [WT]) strain and variants of concern after the

primary 2-dose and booster vaccination.

METHODS: Eighty-two patients with NSCLC and 53 healthy volunteers who received

SARS-CoV-2 mRNA vaccines were included in the study. Blood was collected

longitudinally, and SARS-CoV-2-specific binding and neutralizing antibody

responses were evaluated by Meso Scale Discovery assay and live virus Focus

Reduction Neutralization Assay, respectively.

RESULTS: A majority of patients with NSCLC generated binding and neutralizing

antibody titers comparable with the healthy vaccinees after mRNA vaccination,

but a subset of patients with NSCLC (25%) made poor responses, resulting in

overall lower (six- to seven-fold) titers compared with the healthy cohort (P =

< .0001). Although patients age > 70 years had lower immunoglobulin G titers (P

= < .01), patients receiving programmed death-1 monotherapy, chemotherapy, or a

combination of both did not have a significant impact on the antibody response.

Neutralizing antibody titers to the B.1.617.2 (Delta), B.1.351 (Beta), and in

particular, B.1.1.529 (Omicron) variants were significantly lower (P = < .0001)

compared with the 614D (WT) strain. Booster vaccination led to a significant

increase (P = .0001) in the binding and neutralizing antibody titers to the WT

and Omicron variant. However, 2-4 months after the booster, we observed a five-

to seven-fold decrease in neutralizing titers to WT and Omicron viruses.

CONCLUSION: A subset of patients with NSCLC responded poorly to the SARS-CoV-2

mRNA vaccination and had low neutralizing antibodies to the B.1.1.529 Omicron

variant. Booster vaccination increased binding and neutralizing antibody titers

to Omicron, but antibody titers declined after 3 months. These data highlight

the concern for patients with cancer given the rapid spread of SARS-CoV-2

Omicron variant.

DOI: 10.1200/JCO.21.02986

PMCID: PMC9671759

PMID: 35759727 [Indexed for MEDLINE]

32. Am J Respir Crit Care Med. 2022 Nov 1;206(9):1153-1162. doi:

10.1164/rccm.202201-0114OC.

Solid Fuel, Secondhand Smoke, and Lung Cancer Mortality: A Prospective Cohort of

323,794 Chinese Never-Smokers.

Cheng ES(1)(2), Chan KH(3)(4), Weber M(2), Steinberg J(2), Young J(1)(2),

Canfell K(2)(5), Yu XQ(2).

Author information:

(1)Sydney School of Public Health and.

(2)the Daffodil Centre, the University of Sydney, Sydney, New South Wales,

Australia.

(3)Oxford British Heart Foundation Centre of Research Excellence and.

(4)Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield

Department of Population Health, University of Oxford, Oxford, United Kingdom;

and.

(5)Prince of Wales Clinical School, University of New South Wales, Sydney, New

South Wales, Australia.

Comment in

    Am J Respir Crit Care Med. 2022 Nov 1;206(9):1065-1067.

Rationale: Household air pollution and secondhand tobacco smoke are known

carcinogens for lung cancer, but large-scale estimates of the relationship with

lung cancer mortality are lacking. Objectives: Using the large-scale cohort

China Kadoorie Biobank, we prospectively investigated associations between these

two risk factors and lung cancer death among never-smokers. Methods: The Biobank

recruited 512,715 adults aged 30-79 years from 10 regions in China during

2004-2008. Self-reported never-smoking participants were followed up to December

31, 2016, with linkage to mortality data. Total duration of exposure to

household air pollution was calculated from self-reported domestic solid fuel

use. Exposure to secondhand tobacco smoke was ascertained using exposure at home

and/or other places. Hazard ratios and 95% confidence intervals for associations

between these two exposures and lung cancer death were estimated using Cox

regression, adjusting for key confounders. Measurements and Main Results: There

were 979 lung cancer deaths among 323,794 never-smoking participants without a

previous cancer diagnosis during 10.2 years of follow-up. There was a log-linear

positive association between exposure to household air pollution and lung cancer

death, with a 4% increased risk per 5-year increment of exposure (hazard

ratio = 1.04; 95% confidence interval = 1.01-1.06; P trend = 0.0034), and

participants with 40.1-50.0 years of exposure had the highest risk compared with

the never-exposed (hazard ratio = 1.53; 95% confidence interval = 1.13-2.07).

The association was largely consistent across various subgroups. No significant

association was found between secondhand smoke and lung cancer death.

Conclusions: This cohort study provides new prospective evidence suggesting that

domestic solid fuel use is associated with lung cancer death among

never-smokers.

DOI: 10.1164/rccm.202201-0114OC

PMCID: PMC9704832

PMID: 35616543 [Indexed for MEDLINE]

33. J Clin Oncol. 2022 Nov 1;40(31):3593-3602. doi: 10.1200/JCO.21.02278. Epub 2022 May 23.

Post Hoc Analysis of Lorlatinib Intracranial Efficacy and Safety in Patients

With ALK-Positive Advanced Non-Small-Cell Lung Cancer From the Phase III CROWN

Study.

Solomon BJ(1), Bauer TM(2), Ignatius Ou SH(3), Liu G(4), Hayashi H(5), Bearz

A(6), Penkov K(7), Wu YL(8), Arrieta O(9), Jassem J(10), Calella AM(11), Peltz

G(12), Polli A(11), Thurm H(13), Mok T(14).

Author information:

(1)Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.

(2)Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN.

(3)University of California Irvine School of Medicine, Orange, CA.

…

Comment in

    J Clin Oncol. 2022 Nov 1;40(31):3564-3568.

PURPOSE: Lorlatinib significantly improved progression-free survival (PFS)

versus crizotinib and showed robust intracranial activity in patients with

previously untreated advanced ALK-positive non-small-cell lung cancer (NSCLC) in

the phase III CROWN trial. Here, we report post hoc efficacy outcomes in

patients with and without brain metastases at baseline, and present data on the

incidence and management of CNS adverse events (AEs) in CROWN.

METHODS: Eligible patients were randomly assigned 1:1 to first-line lorlatinib

(100 mg once daily) or crizotinib (250 mg twice a day); no crossover between

treatment arms was permitted. Tumor assessments, including CNS magnetic

resonance imaging, were performed at screening and then at 8-week intervals.

Regular assessments of patient-reported outcomes were conducted.

RESULTS: PFS by blinded independent central review was improved with lorlatinib

versus crizotinib in patients with and without brain metastases at baseline

(12-month PFS rates: 78% v 22% and 78% v 45%, respectively). Lorlatinib was

associated with lower 12-month cumulative incidence of CNS progression versus

crizotinib in patients with (7% v 72%) and without (1% v 18%) brain metastases

at baseline. In total, 35% of patients had CNS AEs with lorlatinib, most of

grade 1 severity. Occurrence of CNS AEs did not result in a clinically

meaningful difference in patient-reported quality of life. At analysis, 56% of

CNS AEs had resolved (33% without intervention; 17% with lorlatinib dose

modification), and 38% were unresolved; most required no intervention.

Lorlatinib dose modification did not notably influence PFS.

CONCLUSION: First-line lorlatinib improved PFS outcomes and reduced CNS

progression versus crizotinib in patients with advanced ALK-positive

non-small-cell lung cancer with or without brain metastases at baseline. Half of

all CNS AEs resolved without intervention or with lorlatinib dose modification.

DOI: 10.1200/JCO.21.02278

PMCID: PMC9622589

PMID: 35605188 [Indexed for MEDLINE]