2021年
No.11
Filters applied: from 2021/9/1 - 2021/9/30
1. Nat Genet. 2021 Sep;53(9):1348-1359. doi: 10.1038/s41588-021-00920-0. Epub 2021 Sep 6.
Genomic and evolutionary classification of lung cancer in never smokers.
Zhang T(1), Joubert P(2), Ansari-Pour N(3), Zhao W(1), Hoang PH(1), Lokanga
R(4), …
Author information:
(1)Division of Cancer Epidemiology and Genetics, National Cancer Institute,
Bethesda, MD, USA.
(2)Institut Universitaire de Cardiologie et de Pneumologie de Québec, Laval
University, Quebec City, Quebec, Canada.
(3)Big Data Institute, Nuffield Department of Medicine, University of Oxford,
Oxford, UK.
…
Comment in
Lancet Oncol. 2021 Oct;22(10):1363.
Lung cancer in never smokers (LCINS) is a common cause of cancer mortality but
its genomic landscape is poorly characterized. Here high-coverage whole-genome
sequencing of 232 LCINS showed 3 subtypes defined by copy number aberrations.
The dominant subtype (piano), which is rare in lung cancer in smokers, features
somatic UBA1 mutations, germline AR variants and stem cell-like properties,
including low mutational burden, high intratumor heterogeneity, long telomeres,
frequent KRAS mutations and slow growth, as suggested by the occurrence of
cancer drivers' progenitor cells many years before tumor diagnosis. The other
subtypes are characterized by specific amplifications and EGFR mutations
(mezzo-forte) and whole-genome doubling (forte). No strong tobacco smoking
signatures were detected, even in cases with exposure to secondhand tobacco
smoke. Genes within the receptor tyrosine kinase-Ras pathway had distinct
impacts on survival; five genomic alterations independently doubled mortality.
These findings create avenues for personalized treatment in LCINS.
© 2021. This is a U.S. government work and not under copyright protection in the
U.S.; foreign copyright protection may apply.
DOI: 10.1038/s41588-021-00920-0
PMCID: PMC8432745
PMID: 34493867 [Indexed for MEDLINE]
2. Nature. 2021 Sep;597(7878):732-737. doi: 10.1038/s41586-021-03898-1. Epub 2021
Sep 15.
Structure-based classification predicts drug response in EGFR-mutant NSCLC.
Robichaux JP(1), Le X(1), Vijayan RSK(2), Hicks JK(3), Heeke S(1), Elamin YY(1),
Lin HY(4), Udagawa H(1), Skoulidis F(1), Tran H(1), Varghese S(1), He J(1),
Zhang F(1), Nilsson MB(1), Hu L(1), Poteete A(1), Rinsurongkawong W(5), Zhang
X(6), Ren C(6), Liu X(1)(7), Hong L(1), Zhang J(1), Diao L(8), Madison R(9),
Schrock AB(9), Saam J(10), Raymond V(10), Fang B(6), Wang J(8), Ha MJ(4), Cross
JB(2), Gray JE(11), Heymach JV(12).
Author information:
(1)Department of Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer
Center, Houston, TX, USA.
(2)Institute for Applied Cancer Science, MD Anderson Cancer Center, Houston, TX,
USA.
(3)Department of Individualized Cancer Management, Moffitt Cancer Center, Tampa,
FL, USA.
…
Comment in
Cancer Cell. 2021 Nov 8;39(11):1455-1457.
Epidermal growth factor receptor (EGFR) mutations typically occur in exons 18-21
and are established driver mutations in non-small cell lung cancer (NSCLC)1-3.
Targeted therapies are approved for patients with 'classical' mutations and a
small number of other mutations4-6. However, effective therapies have not been
identified for additional EGFR mutations. Furthermore, the frequency and effects
of atypical EGFR mutations on drug sensitivity are unknown1,3,7-10. Here we
characterize the mutational landscape in 16,715 patients with EGFR-mutant NSCLC,
and establish the structure-function relationship of EGFR mutations on drug
sensitivity. We found that EGFR mutations can be separated into four distinct
subgroups on the basis of sensitivity and structural changes that
retrospectively predict patient outcomes following treatment with EGFR
inhibitors better than traditional exon-based groups. Together, these data
delineate a structure-based approach for defining functional groups of EGFR
mutations that can effectively guide treatment and clinical trial choices for
patients with EGFR-mutant NSCLC and suggest that a structure-function-based
approach may improve the prediction of drug sensitivity to targeted therapies in
oncogenes with diverse mutations.
© 2021. The Author(s).
DOI: 10.1038/s41586-021-03898-1
PMCID: PMC8481125
PMID: 34526717
3. N Engl J Med. 2021 Sep 18. doi: 10.1056/NEJMoa2112431. Online ahead of print.
Trastuzumab Deruxtecan in HER2-Mutant Non-Small-Cell Lung Cancer.
Li BT(1), Smit EF(1), Goto Y(1), Nakagawa K(1), Udagawa H(1), Mazières J(1),
Nagasaka M(1), Bazhenova L(1), Saltos AN(1), Felip E(1), Pacheco JM(1), Pérol
M(1), Paz-Ares L(1), Saxena K(1), Shiga R(1), Cheng Y(1), Acharyya S(1), Vitazka
P(1), Shahidi J(1), Planchard D(1), Jänne PA(1); DESTINY-Lung01 Trial
Investigators.
Author information:
(1)From Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine, New
York (B.T.L.); the Netherlands Cancer Institute, Amsterdam (E.F.S); the National
Cancer Center Hospital, Tokyo (Y.G.), Kindai University Hospital, Osaka (K.N.),
and the National Cancer Center East, Kashiwa (H.U.) - all in Japan; Centre
Hospitalier Universitaire, Toulouse (J.M.), Centre Léon Bérard, Lyon (M.P.), and
the Department of Medical Oncology, Thoracic Group, Gustave Roussy, Villejuif
(D.P.) - all in France; Karmanos Cancer Institute, Detroit (M.N.); the
University of California, San Diego, Moores Cancer Center, San Diego (L.B.);
Moffitt Cancer Center, Tampa, FL (A.N.S.); Vall d'Hebron University Hospital and
Vall d'Hebron Institute of Oncology, Barcelona (E.F.); University of Colorado,
Aurora (J.M.P.); Hospital Universitario 12 de Octubre, H12O-Centro Nacional de
Investigaciones Oncológicas (CNIO) Lung Cancer Clinical Research Unit, and
Complutense University, Madrid (L.P.-A.); Daiichi Sankyo, Basking Ridge, NJ
(K.S., R.S., Y.C., S.A., P.V., J.S.); and Dana-Farber Cancer Institute and the
Belfer Center for Applied Cancer Science, Boston (P.A.J.).
Comment in
Nat Rev Clin Oncol. 2021 Dec;18(12):748.
BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-targeted therapies
have not been approved for patients with non-small-cell lung cancer (NSCLC). The
efficacy and safety of trastuzumab deruxtecan (formerly DS-8201), a HER2
antibody-drug conjugate, in patients with HER2-mutant NSCLC have not been
investigated extensively.
METHODS: We conducted a multicenter, international, phase 2 study in which
trastuzumab deruxtecan (6.4 mg per kilogram of body weight) was administered to
patients who had metastatic HER2-mutant NSCLC that was refractory to standard
treatment. The primary outcome was objective response as assessed by independent
central review. Secondary outcomes included the duration of response,
progression-free survival, overall survival, and safety. Biomarkers of HER2
alterations were assessed.
RESULTS: A total of 91 patients were enrolled. The median duration of follow-up
was 13.1 months (range, 0.7 to 29.1). Centrally confirmed objective response
occurred in 55% of the patients (95% confidence interval [CI], 44 to 65). The
median duration of response was 9.3 months (95% CI, 5.7 to 14.7). Median
progression-free survival was 8.2 months (95% CI, 6.0 to 11.9), and median
overall survival was 17.8 months (95% CI, 13.8 to 22.1). The safety profile was
generally consistent with those from previous studies; grade 3 or higher
drug-related adverse events occurred in 46% of patients, the most common event
being neutropenia (in 19%). Adjudicated drug-related interstitial lung disease
occurred in 26% of patients and resulted in death in 2 patients. Responses were
observed across different HER2 mutation subtypes, as well as in patients with no
detectable HER2 expression or HER2 amplification.
CONCLUSIONS: Trastuzumab deruxtecan showed durable anticancer activity in
patients with previously treated HER2-mutant NSCLC. The safety profile included
interstitial lung disease that was fatal in two cases. Observed toxic effects
were generally consistent with those in previously reported studies. (Funded by
Daiichi Sankyo and AstraZeneca; DESTINY-Lung01 ClinicalTrials.gov number,
NCT03505710.).
Copyright © 2021 Massachusetts Medical Society.
DOI: 10.1056/NEJMoa2112431
PMID: 34534430
4. Lancet. 2021 Oct 9;398(10308):1344-1357. doi: 10.1016/S0140-6736(21)02098-5.
Epub 2021 Sep 20.
Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA
non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label,
phase 3 trial.
Felip E(1), Altorki N(2), Zhou C(3), Csőszi T(4), Vynnychenko I(5), Goloborodko
O(6), Luft A(7), Akopov A(8), Martinez-Marti A(9), Kenmotsu H(10), Chen YM(11),
Chella A(12), Sugawara S(13), Voong D(14), Wu F(15), Yi J(14), Deng Y(14),
McCleland M(14), Bennett E(14), Gitlitz B(14), Wakelee H(16); IMpower010
Investigators.
Author information:
(1)Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital,
Barcelona, Spain. Electronic address: efelip@vhio.net.
(2)Division of Thoracic Surgery, Weill Cornell Medicine, New York-Presbyterian
Hospital, New York, NY, USA.
(3)Department of Oncology, Tongji University Affiliated Shanghai Pulmonary
Hospital, Shanghai, China.
…
Erratum in
Lancet. 2021 Sep 23;:
Comment in
Lancet. 2021 Oct 9;398(10308):1281-1283.
BACKGROUND: Novel adjuvant strategies are needed to optimise outcomes after
complete surgical resection in patients with early-stage non-small-cell lung
cancer (NSCLC). We aimed to evaluate adjuvant atezolizumab versus best
supportive care after adjuvant platinum-based chemotherapy in these patients.
METHODS: IMpower010 was a randomised, multicentre, open-label, phase 3 study
done at 227 sites in 22 countries and regions. Eligible patients were 18 years
or older with completely resected stage IB (tumours ≥4 cm) to IIIA NSCLC per the
Union Internationale Contre le Cancer and American Joint Committee on Cancer
staging system (7th edition). Patients were randomly assigned (1:1) by a
permuted-block method (block size of four) to receive adjuvant atezolizumab
(1200 mg every 21 days; for 16 cycles or 1 year) or best supportive care
(observation and regular scans for disease recurrence) after adjuvant
platinum-based chemotherapy (one to four cycles). The primary endpoint,
investigator-assessed disease-free survival, was tested hierarchically first in
the stage II-IIIA population subgroup whose tumours expressed PD-L1 on 1% or
more of tumour cells (SP263), then all patients in the stage II-IIIA population,
and finally the intention-to-treat (ITT) population (stage IB-IIIA). Safety was
evaluated in all patients who were randomly assigned and received atezolizumab
or best supportive care. IMpower010 is registered with ClinicalTrials.gov,
NCT02486718 (active, not recruiting).
FINDINGS: Between Oct 7, 2015, and Sept 19, 2018, 1280 patients were enrolled
after complete resection. 1269 received adjuvant chemotherapy, of whom 1005
patients were eligible for randomisation to atezolizumab (n=507) or best
supportive care (n=498); 495 in each group received treatment. After a median
follow-up of 32·2 months (IQR 27·4-38·3) in the stage II-IIIA population,
atezolizumab treatment improved disease-free survival compared with best
supportive care in patients in the stage II-IIIA population whose tumours
expressed PD-L1 on 1% or more of tumour cells (HR 0·66; 95% CI 0·50-0·88;
p=0·0039) and in all patients in the stage II-IIIA population (0·79; 0·64-0·96; p=0·020). In the ITT population, HR for disease-free survival was 0·81
(0·67-0·99; p=0·040). Atezolizumab-related grade 3 and 4 adverse events occurred in 53 (11%) of 495 patients and grade 5 events in four patients (1%).
INTERPRETATION: IMpower010 showed a disease-free survival benefit with
atezolizumab versus best supportive care after adjuvant chemotherapy in patients
with resected stage II-IIIA NSCLC, with pronounced benefit in the subgroup whose
tumours expressed PD-L1 on 1% or more of tumour cells, and no new safety
signals. Atezolizumab after adjuvant chemotherapy offers a promising treatment
option for patients with resected early-stage NSCLC.
FUNDING: F Hoffmann-La Roche and Genentech.
Copyright © 2021 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S0140-6736(21)02098-5
PMID: 34555333 [Indexed for MEDLINE]
5. Annu Rev Pharmacol Toxicol. 2022 Jan 6;62:197-210. doi:
10.1146/annurev-pharmtox-041921-074800. Epub 2021 Sep 30.
Emerging Therapeutics, Technologies, and Drug Development Strategies to Address
Patient Nonadherence and Improve Tuberculosis Treatment.
Garcia-Cremades M(1), Solans BP(1), Strydom N(1), Vrijens B(2)(3), Pillai
GC(4)(5), Shaffer C(1), Thomas B(6), Savic RM(1).
Author information:
(1)Department of Bioengineering and Therapeutic Sciences, University of
California, San Francisco, California 94158, USA; email: rada.savic@ucsf.edu.
(2)AARDEX Group, B-4102 Liège Science Park, Belgium.
(3)Department of Public Health, University of Liège, B-4000 Liège, Belgium.
(4)Division of Clinical Pharmacology, University of Cape Town, 7925 Observatory,
South Africa.
(5)CP+ Associates GmbH, 4102 Basel, Switzerland.
(6)The Arcady Group, Richmond, Virginia 23226, USA.
Imperfect medication adherence remains the biggest predictor of treatment
failure for patients with tuberculosis. Missed doses during treatment lead to
relapse, tuberculosis resistance, and further spread of disease. Understanding
individual patient phenotypes, population pharmacokinetics, resistance
development, drug distribution to tuberculosis lesions, and pharmacodynamics at
the site of infection is necessary to fully measure the impact of adherence on
patient outcomes. To decrease the impact of expected variabilityin drug intake
on tuberculosis outcomes, an improvement in patient adherence and new forgiving
regimens that protect against missed doses are needed. In this review, we
summarize emerging technologies to improve medication adherence in clinical
practice and provide suggestions on how digital adherence technologies can be
incorporated in clinical trials and practice and the drug development pipeline
that will lead to more forgiving regimens and benefit patients suffering from
tuberculosis.
DOI: 10.1146/annurev-pharmtox-041921-074800
PMID: 34591605
6. Lancet Oncol. 2021 Oct;22(10):1448-1457. doi: 10.1016/S1470-2045(21)00401-0.
Epub 2021 Sep 13.
Stereotactic ablative radiotherapy for operable stage I non-small-cell lung
cancer (revised STARS): long-term results of a single-arm, prospective trial
with prespecified comparison to surgery.
Chang JY(1), Mehran RJ(2), Feng L(3), Verma V(4), Liao Z(4), Welsh JW(4), Lin
SH(4), O'Reilly MS(4), Jeter MD(4), Balter PA(5), McRae SE(6), Berry D(3),
Heymach JV(7), Roth JA(2); STARS Lung Cancer Trials Group.
Collaborators: Antonoff M, Hofstetter W, Rajaram R, Rice D, Sepesi B, Swisher S,
Vaporciyan A, Walsh G, DeGraaf C, Correa A, Chen A, Gandhi S, Komaki R, Lee P,
Nguyen QN, Ning M, Gao S, Pollard-Larkin J, Nitsch P, Sadagopan R, Wang X.
Author information:
(1)Department of Radiation Oncology, The University of Texas MD Anderson Cancer
Center, Houston, TX, USA. Electronic address: jychang@mdanderson.org.
(2)Department of Thoracic and Cardiovascular Surgery, The University of Texas MD
Anderson Cancer Center, Houston, TX, USA.
(3)Department of Biostatistics, The University of Texas MD Anderson Cancer
Center, Houston, TX, USA.
…
Comment in
Lancet Oncol. 2021 Dec;22(12):e534.
Lancet Oncol. 2021 Dec;22(12):e535.
Lancet Oncol. 2021 Dec;22(12):e536.
Lancet Oncol. 2021 Dec;22(12):e537-e538.
BACKGROUND: A previous pooled analysis of the STARS and ROSEL trials showed
higher survival after stereotactic ablative radiotherapy (SABR) than with
surgery for operable early-stage non-small-cell lung cancer (NSCLC), but that
analysis had notable limitations. This study reports long-term results of the
revised STARS trial, in which the SABR group was re-accrued with a larger sample
size, along with a protocol-specified propensity-matched comparison with a
prospectively registered, contemporary institutional cohort of patients who
underwent video-assisted thoracoscopic surgical lobectomy with mediastinal lymph
node dissection (VATS L-MLND).
METHODS: This single-arm prospective trial was done at the University of Texas
MD Anderson Cancer Center (Houston, TX, USA) and enrolled patients aged 18 years
or older with a Zubrod performance status of 0-2, newly diagnosed and
histologically confirmed NSCLC with N0M0 disease (squamous cell, adenocarcinoma,
large cell, or NSCLC not otherwise specified), and a tumour diameter of 3 cm or
less. This trial did not include patients from the previous pooled analysis.
SABR dosing was 54 Gy in three fractions (for peripheral lesions) or 50 Gy in
four fractions (for central tumours; simultaneous integrated boost to gross
tumour totalling 60 Gy). The primary endpoint was the 3-year overall survival.
For the propensity-matching analysis, we used a surgical cohort from the MD
Anderson Department of Thoracic and Cardiovascular Surgery's prospectively
registered, institutional review board-approved database of all patients with
clinical stage I NSCLC who underwent VATS L-MLND during the period of enrolment
in this trial. Non-inferiority could be claimed if the 3-year overall survival
rate after SABR was lower than that after VATS L-MLND by 12% or less and the
upper bound of the 95% CI of the hazard ratio (HR) was less than 1·965.
Propensity matching consisted of determining a propensity score using a
multivariable logistic regression model including several covariates (age,
tumour size, histology, performance status, and the interaction of age and sex);
based on the propensity scores, one patient in the SABR group was randomly
matched with one patient in the VATS L-MLND group using a 5:1 digit greedy match
algorithm. This study is registered with ClinicalTrials.gov, NCT02357992.
FINDINGS: Between Sept 1, 2015, and Jan 31, 2017, 80 patients were enrolled and
included in efficacy and safety analyses. Median follow-up time was 5·1 years
(IQR 3·9-5·8). Overall survival was 91% (95% CI 85-98) at 3 years and 87%
(79-95) at 5 years. SABR was tolerated well, with no grade 4-5 toxicity and one
(1%) case each of grade 3 dyspnoea, grade 2 pneumonitis, and grade 2 lung
fibrosis. No serious adverse events were recorded. Overall survival in the
propensity-matched VATS L-MLND cohort was 91% (95% CI 85-98) at 3 years and 84%
(76-93) at 5 years. Non-inferiority was claimed since the 3-year overall
survival after SABR was not lower than that observed in the VATS L-MLND group.
There was no significant difference in overall survival between the two patient
cohorts (hazard ratio 0·86 [95% CI 0·45-1·65], p=0·65) from a multivariable
analysis.
INTERPRETATION: Long-term survival after SABR is non-inferior to VATS L-MLND for
operable stage IA NSCLC. SABR remains promising for such cases but
multidisciplinary management is strongly recommended.
FUNDING: Varian Medical Systems and US National Cancer Institute (National
Institutes of Health).
Copyright © 2021 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1470-2045(21)00401-0
PMCID: PMC8521627
PMID: 34529930 [Indexed for MEDLINE]
7. Lancet Infect Dis. 2022 Jan;22(1):e2-e12. doi: 10.1016/S1473-3099(21)00403-5.
Epub 2021 Sep 7.
100 years of Mycobacterium bovis bacille Calmette-Guérin.
Lange C(1), Aaby P(2), Behr MA(3), Donald PR(4), Kaufmann SHE(5), Netea MG(6),
Mandalakas AM(7).
Author information:
(1)Division of Clinical Infectious Diseases, Medical Clinic, Research Center
Borstel, Borstel, Germany; German Center for Infection Research (DZIF)
Tuberculosis Unit, Borstel, Germany; Respiratory Medicine and International
Health, University of Lübeck, Lübeck, Germany; Global TB Program, Baylor College
of Medicine and Texas Children's Hospital, Houston, TX, USA. Electronic address:
clange@fz-borstel.de.
(2)Bandim Health Project, Indepth Network, Bissau, Guinea-Bissau; Bandim Health
Project, Southern Danish University, Copenhagen, Denmark.
(3)McGill International TB Centre and Department of Medicine, McGill University,
Montreal, QC, Canada.
…
Mycobacterium bovis bacille Calmette-Guérin (BCG), an experimental vaccine
designed to protect cattle from bovine tuberculosis, was administered for the
first time to a newborn baby in Paris in 1921. Over the past century, BCG has
saved tens of millions of lives and has been given to more humans than any other
vaccine. It remains the sole tuberculosis vaccine licensed for use in humans.
BCG provides long-lasting strong protection against miliary and meningeal
tuberculosis in children, but it is less effective for the prevention of
pulmonary tuberculosis, especially in adults. Evidence mainly from the past two
decades suggests that BCG has non-specific benefits against non-tuberculous
infections in newborn babies and in older adults, and offers immunotherapeutic
benefit in certain malignancies such as non-muscle invasive bladder cancer.
However, as a live attenuated vaccine, BCG can cause localised or disseminated
infections in immunocompromised hosts, which can also occur following
intravesical installation of BCG for the treatment of bladder cancer. The legacy
of BCG includes fundamental discoveries about tuberculosis-specific and
non-specific immunity and the demonstration that tuberculosis is a
vaccine-preventable disease, providing a foundation for new vaccines to hasten
tuberculosis elimination.
Copyright © 2022 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1473-3099(21)00403-5
PMID: 34506734 [Indexed for MEDLINE]
8. Autophagy. 2021 Sep;17(9):2629-2638. doi: 10.1080/15548627.2020.1825273. Epub
2020 Oct 4.
Neutrophil autophagy during human active tuberculosis is modulated by SLAMF1.
Pellegrini JM(1)(2), Sabbione F(3), Morelli MP(1)(2), Tateosian NL(1)(2),
Castello FA(1)(2), Amiano NO(1)(2), Palmero D(4), Levi A(4), Ciallella L(4),
Colombo MI(5), Trevani AS(3), García VE(1)(2).
Author information:
(1)Departamento de Química Biológica. Facultad de Ciencias Exactas y Naturales,
UBA, Buenos Aires, Argentina.
(2)Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales
(IQUIBICEN), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos
Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires,
Argentina.
(3)Laboratorio de Inmunidad Innata, Instituto de Medicina Experimental
(IMEX)-CONICET,Academia Nacional de Medicina, Buenos Aires, Argentina.
(4)Hospital F.J. Muñiz, Uspallata 2272, (C1282AEN) Buenos Aires, Argentina.
(5)Instituto de Histología y Embriología de Mendoza, Facultad de Ciencias
Médicas, Universidad Nacional de Cuyo-CONICET, Mendoza, Argentina.
Neutrophils infected with Mycobacterium tuberculosis (Mtb) predominate in
tuberculosis patients' lungs. Neutrophils phagocytose the pathogen, but the
mechanism of pathogen elimination is controversial. Macroautophagy/autophagy, a
crucial mechanism for several neutrophil functions, can be modulated by
immunological mediators. The costimulatory molecule SLAMF1 can act as a
microbial sensor in macrophages being also able to interact with
autophagy-related proteins. Here, we demonstrate for the first time that human
neutrophils express SLAMF1 upon Mtb-stimulation. Furthermore, SLAMF1 was found
colocalizing with LC3B+ vesicles, and activation of SLAMF1 increased neutrophil
autophagy induced by Mtb. Finally, tuberculosis patients' neutrophils displayed
reduced levels of SLAMF1 and lower levels of autophagy against Mtb as compared
to healthy controls. Altogether, these results indicate that SLAMF1 participates
in neutrophil autophagy during active tuberculosis.Abbreviations: AFB: acid-fast
bacilli; BafA1: bafilomycin A1; CLL: chronic lymphocytic leukemia; DPI:
diphenyleneiodonium; EVs: extracellular vesicles; FBS: fetal bovine serum; HD:
healthy donors; HR: high responder (tuberculosis patient); IFNG: interferon
gamma; IL1B: interleukin 1 beta; IL17A: interleukin 17A; IL8: interleukin 8; LR:
low responder (tuberculosis patient); mAb: monoclonal antibody; MAP1LC3/LC3:
microtubule associated protein 1 light chain 3; MAPK: mitogen-activated protein
kinase; MAPK1/ERK2: mitogen-activated protein kinase 1; MAPK14/p38:
mitogen-activated protein kinase 14; Mtb: Mycobacterium tuberculosis; Mtb-Ag:
Mycobacterium tuberculosis, Strain H37Rv, whole cell lysate; NETs: neutrophils
extracellular traps; PPD: purified protein derivative; ROS: reactive oxygen
species; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3;
SLAMF1: signaling lymphocytic activation molecule family member 1; TB:
tuberculosis; TLR: toll like receptor.
DOI: 10.1080/15548627.2020.1825273
PMCID: PMC8496709
PMID: 32954947
9. Lancet Infect Dis. 2021 Sep;21(9):e272-e280. doi: 10.1016/S1473-3099(21)00077-3.
Barriers and enablers to implementing tuberculosis control strategies in EU and
European Economic Area countries: a systematic review.
Conroy O(1), Wurie F(2), Collin SM(2), Edmunds M(2), de Vries G(3), Lönnroth
K(4), Abubakar I(5), Anderson SR(2), Zenner D(6).
Author information:
(1)TB Unit, National Infection Service, Public Health England, London, UK.
Electronic address: olivia.conroy@PHE.gov.uk.
(2)TB Unit, National Infection Service, Public Health England, London, UK.
(3)KNCV Tuberculosis Foundation, The Hague, Netherlands.
(4)Department of Public Health Sciences, Karolinska Institute, Stockholm,
Sweden.
(5)Institute for Global Health, University College London, London, UK.
(6)TB Unit, National Infection Service, Public Health England, London, UK;
Institute for Global Health, University College London, London, UK.
Meeting the 2035 WHO targets of reducing tuberculosis incidence by 90% from 2015
levels requires the implementation of country-specific tuberculosis control
strategies. This systematic review aims to identify factors that facilitate or
impede the implementation of such strategies in EU and European Economic Area
(EEA) settings. Focusing on providers of care, health system constraints, and
social and political factors, this Review complements available evidence on the
accessibility of tuberculosis services to recipients of care. Databases were
searched for EU and EEA articles published between Jan 1, 1997, and Nov 6, 2020,
that presented empirical data on tuberculosis policies, strategies, guidelines,
or interventions. 2061 articles were screened and 65 were included. The most
common barrier to tuberculosis control strategies described the divergence of
health-care practices from guidelines, often related to inadequate knowledge or
perceived usefulness of the guidelines by clinicians. The most commonly
identified enabler to tuberculosis control strategies was the documented
positive attitudes of health-care workers towards tuberculosis programmes.
Divergence between clinical practice and guidelines was described in most EU and
EEA settings, indicating the need for a focused review of guideline adherence.
Strengths of this study involve its broad inclusion criteria and wide range of
tuberculosis control strategies analysed.
Copyright © 2021 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1473-3099(21)00077-3
PMID: 34450080 [Indexed for MEDLINE]
10. Nat Rev Clin Oncol. 2021 Sep;18(9):547-557. doi: 10.1038/s41571-021-00501-4.
Epub 2021 Apr 28.
Evolution of systemic therapy for stages I-III non-metastatic non-small-cell
lung cancer.
Chaft JE(#)(1), Rimner A(#)(2), Weder W(3), Azzoli CG(4), Kris MG(5), Cascone
T(6).
Author information:
(1)Thoracic Oncology Service, Department of Medicine, Memorial Sloan Kettering
Cancer Center, New York, NY and Weill Cornell Medical College, New York, NY,
USA. chaftj@mskcc.org.
(2)Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New
York, NY, USA.
(3)Thoracic Surgery, Klinik Bethanien Zurich, Zurich, Switzerland.
…
The treatment goal for patients with early-stage lung cancer is cure.
Multidisciplinary discussions of surgical resectability and medical operability
determine the modality of definitive local treatment (surgery or radiotherapy)
and the associated systemic therapies to further improve the likelihood of cure.
Trial evidence supports cisplatin-based adjuvant therapy either after surgical
resection or concurrently with radiotherapy. Consensus guidelines support
neoadjuvant chemotherapy in lieu of adjuvant chemotherapy and carboplatin-based
regimens for patients who are ineligible for cisplatin. The incorporation of
newer agents, now standard for patients with stage IV lung cancer, into the
curative therapy paradigm has lagged owing to inefficient trial designs, the
lengthy follow-up needed to assess survival end points and a developmental focus
on the advanced-stage disease setting. Surrogate end points, such as
pathological response, are being studied and might shorten trial durations. In
2018, the anti-PD-L1 antibody durvalumab was approved for patients with stage
III lung cancer after concurrent chemoradiotherapy. Since then, the study of
targeted therapies and immunotherapies in patients with early-stage lung cancer
has rapidly expanded. In this Review, we present the current considerations in
the treatment of patients with early-stage lung cancer and explore the current
and future state of clinical research to develop systemic therapies for
non-metastatic lung cancer.
© 2021. Springer Nature Limited.
DOI: 10.1038/s41571-021-00501-4
PMID: 33911215 [Indexed for MEDLINE]
11. Am J Respir Crit Care Med. 2021 Sep 1;204(5):583-595. doi:
10.1164/rccm.202101-0032OC.
Micro-Computed Tomography Analysis of the Human Tuberculous Lung Reveals
Remarkable Heterogeneity in Three-dimensional Granuloma Morphology.
Wells G(1), Glasgow JN(2), Nargan K(1), Lumamba K(1), Madansein R(3), Maharaj
K(3), Hunter RL(4), Naidoo T(5), Coetzer L(6), le Roux S(6), du Plessis A(6),
Steyn AJC(1)(2)(7).
Author information:
(1)Africa Health Research Institute, University of KwaZulu-Natal, Durban, South
Africa.
(2)Department of Microbiology and.
(3)Department of Cardiothoracic Surgery, Nelson Mandela School of Medicine,
University of KwaZulu-Natal, Durban, South Africa.
(4)Department of Pathology and Laboratory Medicine, University of Texas Health
Sciences Center at Houston, Houston, Texas.
(5)Department of Anatomical Pathology, National Health Laboratory Service,
Inkosi Albert Luthuli Central Hospital, Durban, South Africa; and.
(6)Computed Tomography Scanner Facility, Central Analytical Facilities,
Stellenbosch University, Stellenbosch, South Africa.
(7)Centers for AIDS Research and Free Radical Biology, University of Alabama at
Birmingham, Birmingham, Alabama.
Comment in
Am J Respir Crit Care Med. 2021 Sep 1;204(5):505-507.
Rationale: Our current understanding of tuberculosis (TB) pathophysiology is
limited by a reliance on animal models, the paucity of human TB lung tissue, and
traditional histopathological analysis, a destructive two-dimensional approach
that provides limited spatial insight. Determining the three-dimensional (3D)
structure of the necrotic granuloma, a characteristic feature of TB, will more
accurately inform preventive TB strategies.Objectives: To ascertain the 3D shape
of the human tuberculous granuloma and its spatial relationship with airways and
vasculature within large lung tissues.Methods: We characterized the 3D
microanatomical environment of human tuberculous lungs by using micro computed
tomography, histopathology, and immunohistochemistry. By using 3D segmentation
software, we accurately reconstructed TB granulomas, vasculature, and airways in
three dimensions and confirmed our findings by using histopathology and
immunohistochemistry.Measurements and Main Results: We observed marked
heterogeneity in the morphology, volume, and number of TB granulomas in human
lung sections. Unlike depictions of granulomas as simple spherical structures,
human necrotic granulomas exhibit complex, cylindrical, branched morphologies
that are connected to the airways and shaped by the bronchi. The use of 3D
imaging of human TB lung sections provides unanticipated insight into the
spatial organization of TB granulomas in relation to the airways and
vasculature.Conclusions: Our findings highlight the likelihood that a single,
structurally complex lesion could be mistakenly viewed as multiple independent
lesions when evaluated in two dimensions. In addition, the lack of
vascularization within obstructed bronchi establishes a paradigm for
antimycobacterial drug tolerance. Lastly, our results suggest that bronchogenic
spread of Mycobacterium tuberculosis reseeds the lung.
DOI: 10.1164/rccm.202101-0032OC
PMCID: PMC8491258
PMID: 34015247 [Indexed for MEDLINE]
12. J Clin Oncol. 2021 Sep 1;39(25):2791-2802. doi: 10.1200/JCO.20.03307. Epub 2021 Jun 2.
Clinicopathologic Features and Response to Therapy of NRG1 Fusion-Driven Lung
Cancers: The eNRGy1 Global Multicenter Registry.
Drilon A(1), Duruisseaux M(2)(3)(4), Han JY(5), Ito M(6)(7)(8), Falcon C(1),
Yang SR(1), Murciano-Goroff YR(9), Chen H(10)(11), Okada M(8), Molina MA(12),
…
Author information:
(1)Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New
York, NY.
(2)Respiratory Department, Louis Pradel Hospital, Hospices Civils de Lyon Cancer
Institute, Lyon, France.
(3)Anticancer Antibodies Laboratory, Cancer Research Center of Lyon, Lyon,
France.
…
PURPOSE: Although NRG1 fusions are oncogenic drivers across multiple tumor types
including lung cancers, these are difficult to study because of their rarity.
The global eNRGy1 registry was thus established to characterize NRG1
fusion-positive lung cancers in the largest and most diverse series to date.
METHODS: From June 2018 to February 2020, a consortium of 22 centers from nine
countries in Europe, Asia, and the United States contributed data from patients
with pathologically confirmed NRG1 fusion-positive lung cancers. Profiling
included DNA-based and/or RNA-based next-generation sequencing and fluorescence
in situ hybridization. Anonymized clinical, pathologic, molecular, and response
(RECIST v1.1) data were centrally curated and analyzed.
RESULTS: Although the typified never smoking (57%), mucinous adenocarcinoma
(57%), and nonmetastatic (71%) phenotype predominated in 110 patients with NRG1
fusion-positive lung cancer, further diversity, including in smoking history
(43%) and histology (43% nonmucinous and 6% nonadenocarcinoma), was elucidated.
RNA-based testing identified most fusions (74%). Molecularly, six (of 18) novel
5' partners, 20 unique epidermal growth factor domain-inclusive chimeric events,
and heterogeneous 5'/3' breakpoints were found. Platinum-doublet and
taxane-based (post-platinum-doublet) chemotherapy achieved low objective
response rates (ORRs 13% and 14%, respectively) and modest progression-free
survival medians (PFS 5.8 and 4.0 months, respectively). Consistent with a low
programmed death ligand-1 expressing (28%) and low tumor mutational burden
(median: 0.9 mutations/megabase) immunophenotype, the activity of
chemoimmunotherapy and single-agent immunotherapy was poor (ORR 0%/PFS 3.3
months and ORR 20%/PFS 3.6 months, respectively). Afatinib achieved an ORR of
25%, not contingent on fusion type, and a 2.8-month median PFS.
CONCLUSION: NRG1 fusion-positive lung cancers were molecularly, pathologically,
and clinically more heterogeneous than previously recognized. The activity of
cytotoxic, immune, and targeted therapies was disappointing. Further research
examining NRG1-rearranged tumor biology is needed to develop new therapeutic
strategies.
DOI: 10.1200/JCO.20.03307
PMCID: PMC8407651
PMID: 34077268 [Indexed for MEDLINE]
13. Am J Respir Crit Care Med. 2021 Sep 15;204(6):713-722. doi:
10.1164/rccm.202009-3527OC.
Evidence-based Definition for Extensively Drug-Resistant Tuberculosis.
Roelens M(1), Battista Migliori G(2), Rozanova L(1), Estill J(1)(3), Campbell
JR(4)(5), Cegielski JP(6), Tiberi S(7)(8), Palmero D(9), Fox GJ(10),
Guglielmetti L(11)(12), Sotgiu G(13), Brust JCM(14), Bang D(15)(16), Lienhardt
C(17)(18), Lange C(19)(20)(21), Menzies D(4)(5), Keiser O(1), Raviglione M(22).
Author information:
(1)Institute of Global Health, Faculty of Medicine, University of Geneva,
Geneva, Switzerland.
(2)Istituti Clinici Scientifici Maugeri, Istituto di Ricovero e Cura a Carattere
Scientifico, Tradate, Italy.
(3)Institute of Mathematical Statistics and Actuarial Science, University of
Bern, Bern, Switzerland.
…
Comment in
Am J Respir Crit Care Med. 2021 Sep 15;204(6):629-631.
Rationale: Until 2020, extensively drug-resistant tuberculosis (XDR-TB) was
defined as TB with resistance to rifampicin and isoniazid (multidrug-resistant
TB [MDR-TB]), any fluoroquinolone (FQ), and any second-line injectable drug
(SLID). In 2019, the World Health Organization issued new recommendations for
treating patients with drug-resistant TB, substantially limiting the role of
SLIDs in MDR-TB treatment and thus putting the definition of XDR-TB into
question. Objectives: To propose an up-to-date definition for XDR-TB. Methods:
We used a large data set to assess treatment outcomes for patients with MDR-TB
exposed to any type of longer regimen. We included patients with
bacteriologically confirmed MDR-TB and known FQ and SLID resistance results. We
performed logistic regression to estimate the adjusted odds ratios (aORs) for an
unfavorable treatment outcome (failure, relapse, death, loss to follow-up), and
estimates were stratified by the resistance pattern (FQ and/or SLID) and group A
drug use (moxifloxacin/levofloxacin, linezolid, and/or bedaquiline).
Measurements and Main Results: We included 11,666 patients with MDR-TB; 4,653
(39.9%) had an unfavorable treatment outcome. Resistance to FQs increased the
odds of an unfavorable treatment outcome (aOR, 1.91; 95% confidence interval
[CI], 1.63-2.23). Administration of bedaquiline and/or linezolid improved
treatment outcomes regardless of resistance to FQs and/or SLIDs. Among patients
with XDR-TB, compared with persons receiving no group A drug, aORs for an
unfavorable outcome were 0.37 (95% CI, 0.20-0.69) with linezolid only, 0.40 (95%
CI, 0.21-0.77) with bedaquiline only, and 0.21 (95% CI, 0.12-0.38) with both.
Conclusions: Our study supports a new definition of XDR-TB as MDR-TB and
additional resistance to FQ plus bedaquiline and/or linezolid and helps assess
the adequacy of this definition for surveillance and treatment choice.
DOI: 10.1164/rccm.202009-3527OC
PMID: 34107231 [Indexed for MEDLINE]
14. Cancer Discov. 2022 Jan;12(1):74-89. doi: 10.1158/2159-8290.CD-21-0715. Epub
2021 Sep 21.
Efficacy and Safety of Patritumab Deruxtecan (HER3-DXd) in EGFR
Inhibitor-Resistant, EGFR-Mutated Non-Small Cell Lung Cancer.
Jänne PA(1), Baik C(2), Su WC(3), Johnson ML(4), Hayashi H(5), Nishio M(6), Kim
DW(7), Koczywas M(8), Gold KA(9), Steuer CE(10), Murakami H(11), Yang JC(12),
Kim SW(13), Vigliotti M(14), Shi R(14), Qi Z(14), Qiu Y(14), Zhao L(14),
Sternberg D(14), Yu C(14), Yu HA(15).
Author information:
(1)Dana-Farber Cancer Institute, Boston, Massachusetts.
Pasi_Janne@dfci.harvard.edu.
(2)Seattle Cancer Care Alliance, Seattle, Washington.
(3)National Cheng Kung University Hospital, Tainan, Taiwan.
…
Comment in
Cancer Discov. 2022 Jan;12(1):16-19.
Comment on
Cancer Discov. 2022 Jan;12(1):16-19.
Receptor tyrosine-protein kinase ERBB3 (HER3) is expressed in most EGFR-mutated
lung cancers but is not a known mechanism of resistance to EGFR inhibitors.
HER3-DXd is an antibody-drug conjugate consisting of a HER3 antibody attached to
a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker.
This phase I, dose escalation/expansion study included patients with locally
advanced or metastatic EGFR-mutated non-small cell lung cancer (NSCLC) with
prior EGFR tyrosine kinase inhibitor (TKI) therapy. Among 57 patients receiving
HER3-DXd 5.6 mg/kg intravenously once every 3 weeks, the confirmed objective
response rate by blinded independent central review (Response Evaluation
Criteria in Solid Tumors v1.1) was 39% [95% confidence interval (CI),
26.0-52.4], and median progression-free survival was 8.2 (95% CI, 4.4-8.3)
months. Responses were observed in patients with known and unknown EGFR TKI
resistance mechanisms. Clinical activity was observed across a broad range of
HER3 membrane expression. The most common grade ≥3 treatment-emergent adverse
events were hematologic toxicities. HER3-DXd has clinical activity in EGFR
TKI-resistant cancers independent of resistance mechanisms, providing an
approach to treat a broad range of drug-resistant cancers. SIGNIFICANCE: In
metastatic EGFR-mutated NSCLC, after disease progression on EGFR TKI therapy,
treatment approaches include genotype-directed therapy targeting a known
resistance mechanism or chemotherapy. HER3-DXd demonstrated clinical activity
spanning known and unknown EGFR TKI resistance mechanisms. HER3-DXd could
present a future treatment option agnostic to the EGFR TKI resistance
mechanism.See related commentary by Lim et al., p. 16.This article is
highlighted in the In This Issue feature, p. 1.
©2021 The Authors; Published by the American Association for Cancer Research.
DOI: 10.1158/2159-8290.CD-21-0715
PMID: 34548309
15. Nat Commun. 2021 Sep 20;12(1):5548. doi: 10.1038/s41467-021-25867-y.
Isonicotinylation is a histone mark induced by the anti-tuberculosis first-line
drug isoniazid.
Jiang Y(1), Li Y(1), Liu C(1), Zhang L(1), Lv D(1), Weng Y(2), Cheng Z(2), Chen
X(3), Zhan J(1), Zhang H(4).
Author information:
(1)Program for Cancer and Cell Biology, Department of Human Anatomy, Histology
and Embryology, PKU International Cancer Institute, MOE Key Laboratory of
Carcinogenesis and Translational Research and State Key Laboratory of Natural
and Biomimetic Drugs, Peking University Health Science Center, Beijing, PR
China.
(2)Jingjie PTM BioLab Co. Ltd., Hangzhou Economic and Technological Development
Area, Hangzhou, PR China.
(3)Department of Microbiology & Infectious Disease Center, Peking University
Health Science Center, Beijing, PR China.
…
Isoniazid (INH) is a first-line anti-tuberculosis drug used for nearly 70 years.
However, the mechanism underlying the side effects of INH has remained elusive.
Here, we report that INH and its metabolites induce a post-translational
modification (PTM) of histones, lysine isonicotinylation (Kinic), also called
4-picolinylation, in cells and mice. INH promotes the biosynthesis of
isonicotinyl-CoA (Inic-CoA), a co-factor of intracellular isonicotinylation.
Mass spectrometry reveals 26 Kinic sites in histones in HepG2 cells.
Acetyltransferases CREB-binding protein (CBP) and P300 catalyse histone Kinic,
while histone deacetylase HDAC3 functions as a deisonicotinylase. Notably, MNase
sensitivity assay and RNA-seq analysis show that histone Kinic relaxes chromatin
structure and promotes gene transcription. INH-mediated histone Kinic
upregulates PIK3R1 gene expression and activates the PI3K/Akt/mTOR signalling
pathway in liver cancer cells, linking INH to tumourigenicity in the liver. We
demonstrate that Kinic is a histone acylation mark with a pyridine ring, which
may have broad biological effects. Therefore, INH-induced isonicotinylation
potentially accounts for the side effects in patients taking INH long-term for
anti-tuberculosis therapy, and this modification may increase the risk of cancer
in humans.
© 2021. The Author(s).
DOI: 10.1038/s41467-021-25867-y
PMCID: PMC8452692
PMID: 34545082 [Indexed for MEDLINE]
16. J Exp Med. 2021 Sep 6;218(9):e20210332. doi: 10.1084/jem.20210332. Epub 2021 Jul 16.
Genetic models of latent tuberculosis in mice reveal differential influence of
adaptive immunity.
Su H(1), Lin K(1), Tiwari D(1), Healy C(1), Trujillo C(1), Liu Y(1), Ioerger
TR(2), Schnappinger D(1), Ehrt S(1).
Author information:
(1)Department of Microbiology and Immunology, Weill Cornell Medicine, New York,
NY.
(2)Department of Computer Science and Engineering, Texas A&M University, College
Station, TX.
Studying latent Mycobacterium tuberculosis (Mtb) infection has been limited by
the lack of a suitable mouse model. We discovered that transient depletion of
biotin protein ligase (BPL) and thioredoxin reductase (TrxB2) results in latent
infections during which Mtb cannot be detected but that relapse in a subset of
mice. The immune requirements for Mtb control during latency, and the frequency
of relapse, were strikingly different depending on how latency was established.
TrxB2 depletion resulted in a latent infection that required adaptive immunity
for control and reactivated with high frequency, whereas latent infection after
BPL depletion was independent of adaptive immunity and rarely reactivated. We
identified immune signatures of T cells indicative of relapse and demonstrated
that BCG vaccination failed to protect mice from TB relapse. These reproducible
genetic latency models allow investigation of the host immunological
determinants that control the latent state and offer opportunities to evaluate
therapeutic strategies in settings that mimic aspects of latency and TB relapse
in humans.
© 2021 Su et al.
DOI: 10.1084/jem.20210332
PMCID: PMC8289691
PMID: 34269789 [Indexed for MEDLINE]
17. J Exp Med. 2021 Sep 6;218(9):e20210615. doi: 10.1084/jem.20210615. Epub 2021 Jul 22.
Single cell analysis of M. tuberculosis phenotype and macrophage lineages in the
infected lung.
Pisu D(1), Huang L(1)(2), Narang V(3), Theriault M(1), Lê-Bury G(1), Lee B(3),
Lakudzala AE(4), Mzinza DT(4), Mhango DV(4), Mitini-Nkhoma SC(4), Jambo
KC(4)(5), Singhal A(3)(6), Mwandumba HC(4)(5), Russell DG(1).
Author information:
(1)Microbiology and Immunology, College of Veterinary Medicine, Cornell
University, Ithaca, NY.
(2)Microbiology and Immunology, University of Arkansas for Medical Sciences,
Little Rock, AR.
(3)Singapore Immunology Network, Agency for Science, Technology and Research,
Singapore.
(4)Malawi Liverpool Wellcome Trust Clinical Research Program, University of
Malawi College of Medicine, Blantyre, Malawi.
(5)Department of Clinical Sciences, Liverpool School of Tropical Medicine,
Liverpool, UK.
(6)A*STAR Infectious Diseases Laboratories, Agency for Science, Technology and
Research, Singapore.
In this study, we detail a novel approach that combines bacterial fitness
fluorescent reporter strains with scRNA-seq to simultaneously acquire the host
transcriptome, surface marker expression, and bacterial phenotype for each
infected cell. This approach facilitates the dissection of the functional
heterogeneity of M. tuberculosis-infected alveolar (AMs) and interstitial
macrophages (IMs) in vivo. We identify clusters of pro-inflammatory AMs
associated with stressed bacteria, in addition to three different populations of
IMs with heterogeneous bacterial phenotypes. Finally, we show that the main
macrophage populations in the lung are epigenetically constrained in their
response to infection, while inter-species comparison reveals that most AMs
subsets are conserved between mice and humans. This conceptual approach is
readily transferable to other infectious disease agents with the potential for
an increased understanding of the roles that different host cell populations
play during the course of an infection.
© 2021 Pisu et al.
DOI: 10.1084/jem.20210615
PMCID: PMC8302446
PMID: 34292313 [Indexed for MEDLINE]
18. J Exp Med. 2021 Oct 4;218(10):e20210915. doi: 10.1084/jem.20210915. Epub 2021
Sep 7.
Blood transcriptomics reveal the evolution and resolution of the immune response
in tuberculosis.
Tabone O(#)(1), Verma R(#)(2), Singhania A(1), Chakravarty P(3), Branchett
WJ(1), Graham CM(1), Lee J(2), Trang T(4), Reynier F(4), Leissner P(4), Kaiser
K(5), Rodrigue M(6), Woltmann G(2), Haldar P(#)(2), O'Garra A(#)(1)(7).
Author information:
(1)Laboratory of Immunoregulation and Infection, The Francis Crick Institute,
London, UK.
(2)Department of Respiratory Sciences, National Institute for Health Research
Respiratory Biomedical Research Centre, University of Leicester, UK.
(3)Bioinformatics Core, The Francis Crick Institute, London, UK.
…
Blood transcriptomics have revealed major characteristics of the immune response
in active TB, but the signature early after infection is unknown. In a unique
clinically and temporally well-defined cohort of household contacts of active TB
patients that progressed to TB, we define minimal changes in gene expression in
incipient TB increasing in subclinical and clinical TB. While increasing with
time, changes in gene expression were highest at 30 d before diagnosis, with
heterogeneity in the response in household TB contacts and in a published cohort
of TB progressors as they progressed to TB, at a bulk cohort level and in
individual progressors. Blood signatures from patients before and during anti-TB
treatment robustly monitored the treatment response distinguishing early and
late responders. Blood transcriptomics thus reveal the evolution and resolution
of the immune response in TB, which may help in clinical management of the
disease.
© 2021 Tabone et al.
DOI: 10.1084/jem.20210915
PMCID: PMC8493863
PMID: 34491266 [Indexed for MEDLINE]
19. J Clin Oncol. 2021 Sep 10;39(26):2872-2880. doi: 10.1200/JCO.21.00276. Epub 2021 Jul 12.
SAKK 16/14: Durvalumab in Addition to Neoadjuvant Chemotherapy in Patients With
Stage IIIA(N2) Non-Small-Cell Lung Cancer-A Multicenter Single-Arm Phase II
Trial.
Rothschild SI(1), Zippelius A(1), Eboulet EI(2), Savic Prince S(3), Betticher
D(4), Bettini A(4), Früh M(5)(6), Joerger M(5), Lardinois D(7), Gelpke H(8),
Mauti LA(9), Britschgi C(10), Weder W(11), Peters S(12), Mark M(13), Cathomas
R(13), Ochsenbein AF(6), Janthur WD(14), Waibel C(15), Mach N(16), Froesch
P(17), Buess M(18), Bohanes P(19), Godar G(2), Rusterholz C(2), Gonzalez M(20),
Pless M(9); Swiss Group for Clinical Cancer Research (SAKK).
Author information:
(1)Department of Medical Oncology and Comprehensive Cancer Center, University
Hospital Basel, Basel, Switzerland.
(2)SAKK Coordinating Center, Bern, Switzerland.
(3)Pathology, Institute of Medical Genetics and Pathology, University Hospital
Basel, Basel, Switzerland.
…
Comment in
J Clin Oncol. 2021 Sep 10;39(26):2855-2858.
PURPOSE: For patients with resectable stage IIIA(N2) non-small-cell lung cancer,
neoadjuvant chemotherapy with cisplatin and docetaxel followed by surgery
resulted in a 1-year event-free survival (EFS) rate of 48% in the SAKK 16/00
trial and is an accepted standard of care. We investigated the additional
benefit of perioperative treatment with durvalumab.
METHODS: Neoadjuvant treatment consisted of three cycles of cisplatin 100 mg/m2
and docetaxel 85 mg/m2 once every 3 weeks followed by two doses of durvalumab
750 mg once every 2 weeks. Durvalumab was continued for 1 year after surgery.
The primary end point was 1-year EFS. The hypothesis for statistical
considerations was an improvement of 1-year EFS from 48% to 65%.
RESULTS: Sixty-eight patients were enrolled, 67 were included in the full
analysis set. Radiographic response rate was 43% (95% CI, 31 to 56) after
neoadjuvant chemotherapy and 58% (95% CI, 45 to 71) after sequential neoadjuvant
immunotherapy. Fifty-five patients were resected, of which 34 (62%) achieved a
major pathologic response (MPR; ≤ 10% viable tumor cells) and 10 (18%) among
them a complete pathologic response. Postoperative nodal downstaging (ypN0-1)
was observed in 37 patients (67%). Fifty-one (93%) resected patients had an R0
resection. There was no significant effect of pretreatment PD-L1 expression on
MPR or nodal downstaging. The 1-year EFS rate was 73% (two-sided 90% CI, 63 to
82). Median EFS and overall survival were not reached after 28.6 months of
median follow-up. Fifty-nine (88%) patients had an adverse event grade ≥ 3
including two fatal adverse events that were judged not to be treatment-related.
CONCLUSION: The addition of perioperative durvalumab to neoadjuvant chemotherapy
in patients with stage IIIA(N2) non-small-cell lung cancer is safe and exceeds
historical data of chemotherapy alone with a high MPR and an encouraging 1-year
EFS rate of 73%.
DOI: 10.1200/JCO.21.00276
PMID: 34251873 [Indexed for MEDLINE]
20. J Clin Invest. 2021 Sep 1;131(17):e137407. doi: 10.1172/JCI137407.
TREM-2 promotes Th1 responses by interacting with the CD3ζ-ZAP70 complex
following Mycobacterium tuberculosis infection.
Wu Y(1)(2)(3)(4), Wu M(1), Ming S(1)(2)(5), Zhan X(1), Hu S(1), Li X(1)(2), Yin
H(1)(2), Cao C(1)(2), Liu J(1)(2), Li J(1)(2), Wu Z(6), Zhou J(6), Liu L(5),
Gong S(4), He D(7), Huang X(1)(2)(3)(4)(5).
Author information:
(1)Center for Infection and Immunity, The Fifth Affiliated Hospital of Sun
Yat-sen University, Zhuhai, Guangdong Province, China.
(2)Guangdong Provincial Engineering Research Center of Molecular Imaging,
Guangdong Provincial Key Laboratory of Biomedical Imaging, and Department of
Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University,
Zhuhai, China.
(3)Southern Marine Science and Engineering Guangdong Laboratory, Zhuhai,
Guangdong Province, China.
…
Triggering receptor expressed on myeloid cells 2 (TREM-2) is a modulator of
pattern recognition receptors on innate immune cells that regulates the
inflammatory response. However, the role of TREM-2 in in vivo models of
infection and inflammation remains controversial. Here, we demonstrated that
TREM-2 expression on CD4+ T cells was induced by Mycobacterium tuberculosis
infection in both humans and mice and positively associated with T cell
activation and an effector memory phenotype. Activation of TREM-2 in CD4+ T
cells was dependent on interaction with the putative TREM-2 ligand expressed on
DCs. Unlike the observation in myeloid cells that TREM-2 signals through DAP12,
in CD4+ T cells, TREM-2 interacted with the CD3ζ-ZAP70 complex as well as with
the IFN-γ receptor, leading to STAT1/-4 activation and T-bet transcription. In
addition, an infection model using reconstituted Rag2-/- mice (with TREM-2-KO
vs. WT cells or TREM-2+ vs. TREM-2-CD4+ T cells) or CD4+ T cell-specific TREM-2
conditional KO mice demonstrated that TREM-2 promoted a Th1-mediated host
defense against M. tuberculosis infection. Taken together, these findings reveal
a critical role of TREM-2 in evoking proinflammatory Th1 responses that may
provide potential therapeutic targets for infectious and inflammatory diseases.
DOI: 10.1172/JCI137407
PMCID: PMC8409584
PMID: 34623322 [Indexed for MEDLINE]
21. Nat Commun. 2021 Sep 2;12(1):5236. doi: 10.1038/s41467-021-25537-z.
The cryo-EM structure of the bd oxidase from M. tuberculosis reveals a unique
structural framework and enables rational drug design to combat TB.
Safarian S(1), Opel-Reading HK(2), Wu D(3), Mehdipour AR(4), Hards K(5), Harold
LK(5), Radloff M(3), Stewart I(6), Welsch S(7), Hummer G(4)(8), Cook GM(5),
Krause KL(2), Michel H(9).
Author information:
(1)Department of Molecular Membrane Biology, Max Planck Institute of Biophysics,
Frankfurt/Main, Germany. schara.safarian@biophys.mpg.de.
(2)Department of Biochemistry, University of Otago, Dunedin, New Zealand.
(3)Department of Molecular Membrane Biology, Max Planck Institute of Biophysics,
Frankfurt/Main, Germany.
…
New drugs are urgently needed to combat the global TB epidemic. Targeting
simultaneously multiple respiratory enzyme complexes of Mycobacterium
tuberculosis is regarded as one of the most effective treatment options to
shorten drug administration regimes, and reduce the opportunity for the
emergence of drug resistance. During infection and proliferation, the cytochrome
bd oxidase plays a crucial role for mycobacterial pathophysiology by maintaining
aerobic respiration at limited oxygen concentrations. Here, we present the
cryo-EM structure of the cytochrome bd oxidase from M. tuberculosis at 2.5 Å. In
conjunction with atomistic molecular dynamics (MD) simulation studies we
discovered a previously unknown MK-9-binding site, as well as a unique disulfide
bond within the Q-loop domain that defines an inactive conformation of the
canonical quinol oxidation site in Actinobacteria. Our detailed insights into
the long-sought atomic framework of the cytochrome bd oxidase from M.
tuberculosis will form the basis for the design of highly specific drugs to act
on this enzyme.
© 2021. The Author(s).
DOI: 10.1038/s41467-021-25537-z
PMCID: PMC8413341
PMID: 34475399 [Indexed for MEDLINE]
22. J Clin Oncol. 2021 Sep 22:JCO2101113. doi: 10.1200/JCO.21.01113. Online ahead of print.
Poziotinib for Patients With HER2 Exon 20 Mutant Non-Small-Cell Lung Cancer:
Results From a Phase II Trial.
Elamin YY(1), Robichaux JP(1), Carter BW(2), Altan M(1), Gibbons DL(1), Fossella
FV(1), Lam VK(1)(3), Patel AB(4), Negrao MV(1), Le X(1), Mott FE(1), Zhang J(1),
Feng L(5), Blumenschein G Jr(1), Tsao AS(1), Heymach JV(1).
Author information:
(1)Department of Thoracic/Head and Neck Medical Oncology, The University of
Texas MD Anderson Cancer Center, Houston, TX.
(2)Department of Thoracic Imaging, The University of Texas MD Anderson Cancer
Center, Houston, TX.
(3)Department of Medicine, Johns Hopkins Sidney Kimmel Cancer Center, Baltimore,
MD.
(4)Department of Dermatology, The University of Texas MD Anderson Cancer Center,
Houston, TX.
(5)Department of Biostatistics, The University of Texas MD Anderson Cancer
Center, Houston, TX.
PURPOSE: Targeted therapies against non-small-cell lung cancer (NSCLC) harboring
HER2 mutations remain an unmet need. In this study, we assessed the efficacy and
safety of poziotinib in patients with HER2 exon 20 mutant advanced NSCLC in a
single-arm, open-label, phase II study.
PATIENTS AND METHODS: Patients with advanced HER2 exon 20 mutant NSCLC were
enrolled to receive poziotinib at a dose of 16 mg/d for 28-day cycles. The
primary end point was objective response rate per RECIST version 1.1.
Confirmatory scans were performed at least 28 days from initial radiologic
response.
RESULTS: Thirty patients received poziotinib treatment. At baseline, 90% of
patients received prior platinum-based chemotherapy and 53% had two lines or
more prior systemic therapies. As of data cutoff on March 1, 2021, the confirmed
objective response rate was 27% (95% CI, 12 to 46). Responses were observed
across HER2 exon 20 mutation subtypes. The median duration of response was 5.0
months (95% CI, 4.0 to not estimable). The median progression-free survival was
5.5 months (95% CI, 4.0 to 7.0). The median overall survival was 15 months (95%
CI, 9.0 to not estimable). The most common grade 3 treatment-related adverse
events were skin rash (47%) and diarrhea (20%). There was one possible
treatment-related death because of pneumonitis.
CONCLUSION: Poziotinib showed promising antitumor activity in patients with HER2
exon 20 mutant NSCLC including patients who had previously received
platinum-based chemotherapy.
DOI: 10.1200/JCO.21.01113
PMID: 34550757
23. Nat Commun. 2021 Sep 14;12(1):5431. doi: 10.1038/s41467-021-25787-x.
Multi-region exome sequencing reveals the intratumoral heterogeneity of
surgically resected small cell lung cancer.
Zhou H(#)(1), Hu Y(#)(2), Luo R(#)(3), Zhao Y(#)(1), Pan H(#)(4), Ji L(#)(5),
Zhou T(1), Zhang L(6), Long H(6), Fu J(6), Wen Z(6), Wang S(6), Wang X(6), Lin
P(6), Yang H(6), Wang J(6), Song M(5), Yi X(5), Yang L(5), Xia X(5), Guan Y(5),
Fang W(1), Yang Y(1), Hong S(1), Huang Y(1), Li P(5), Zhang Y(7), Zhou N(8).
Author information:
(1)Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State
Key Laboratory of Oncology in South China, Collaborative Innovation Center for
Cancer Medicine, Guangzhou, China.
(2)Department of Thoracic Surgery, Sun Yat-Sen University Cancer Center, State
Key Laboratory of Oncology in South China, Collaborative Innovation Center for
Cancer Medicine, Guangdong Esophageal Cancer Institute (GECI), Guangzhou, China.
(3)Department of Pathology, Sun Yat-Sen University Cancer Center, State Key
Laboratory of Oncology in South China, Collaborative Innovation Center for
Cancer Medicine, Guangzhou, China.
…
Small cell lung cancer (SCLC) is a highly malignant tumor which is eventually
refractory to any treatment. Intratumoral heterogeneity (ITH) may contribute to
treatment failure. However, the extent of ITH in SCLC is still largely unknown.
Here, we subject 120 tumor samples from 40 stage I-III SCLC patients to
multi-regional whole-exome sequencing. The most common mutant genes are TP53
(88%) and RB1 (72%). We observe a medium level of mutational heterogeneity
(0.30, range 0.0~0.98) and tumor mutational burden (TMB, 10.2 mutations/Mb,
range 1.1~51.7). Our SCLC samples also exhibit somatic copy number variation
(CNV) across all patients, with an average CNV ITH of 0.49 (range 0.02~0.99). In
terms of mutation distribution, ITH, TMB, mutation clusters, and gene
signatures, patients with combined SCLC behave roughly the same way as patients
with pure SCLC. This condition also exists in smoking patients and patients with
EGFR mutations. A higher TMB per cluster is associated with better disease-free
survival while single-nucleotide variant ITH is linked to worse overall
survival, and therefore these features may be used as prognostic biomarkers for
SCLC. Together, these findings demonstrate the intratumoral genetic
heterogeneity of surgically resected SCLC and provide insights into resistance
to treatment.
© 2021. The Author(s).
DOI: 10.1038/s41467-021-25787-x
PMCID: PMC8440529
PMID: 34521849 [Indexed for MEDLINE]
