2022年
No.7
Filters applied: from 2022/7/1 - 2022/7/31.
1. Mol Cell. 2022 Jul 29:S1097-2765(22)00602-5. doi: 10.1016/j.molcel.2022.06.019.
Online ahead of print.
HelR is a helicase-like protein that protects RNA polymerase from rifamycin
antibiotics.
Surette MD(1), Waglechner N(2), Koteva K(1), Wright GD(3).
Author information:
(1)David Braley Center for Antibiotic Discovery, M.G. DeGroote Institute for
Infectious Disease Research, Department of Biochemistry and Biomedical Sciences,
McMaster University, Hamilton, ON L8S 4L8, Canada.
(2)Toronto Invasive Bacterial Diseases Network, Mount Sinai Hospital, Toronto,
ON M5G 1X5, Canada.
(3)David Braley Center for Antibiotic Discovery, M.G. DeGroote Institute for
Infectious Disease Research, Department of Biochemistry and Biomedical Sciences,
McMaster University, Hamilton, ON L8S 4L8, Canada. Electronic address:
wrightge@mcmaster.ca.
Rifamycin antibiotics such as rifampin are potent inhibitors of prokaryotic RNA
polymerase (RNAP) used to treat tuberculosis and other bacterial infections.
Although resistance arises in the clinic principally through mutations in RNAP,
many bacteria possess highly specific enzyme-mediated resistance mechanisms that
modify and inactivate rifamycins. The expression of these enzymes is controlled
by a 19-bp cis-acting rifamycin-associated element (RAE). Guided by the presence
of RAE sequences, we identify a helicase-like protein, HelR, in Streptomyces
venezuelae that confers broad-spectrum rifamycin resistance. We show that HelR
also promotes tolerance to rifamycins, enabling bacterial evasion of the toxic
properties of these antibiotics. HelR forms a complex with RNAP and rescues
transcription inhibition by displacing rifamycins from RNAP, thereby providing
resistance by target protection . Furthermore, HelRs are broadly distributed in
Actinobacteria, including several opportunistic Mycobacterial pathogens,
offering yet another challenge for developing new rifamycin antibiotics.
Copyright © 2022 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.molcel.2022.06.019
PMID: 35907401
2. Mol Cell. 2022 Jul 21:S1097-2765(22)00652-9. doi: 10.1016/j.molcel.2022.06.034.
Online ahead of print.
Mycobacterium abscessus HelR interacts with RNA polymerase to confer intrinsic
rifamycin resistance.
Hurst-Hess KR(1), Saxena A(2), Rudra P(1), Yang Y(1), Ghosh P(3).
Author information:
(1)Division of Genetics, Wadsworth Center, New York State Department of Health,
Albany, NY 12208, USA.
(2)School of Public Health, University at Albany, Albany, NY 12208, USA.
(3)Division of Genetics, Wadsworth Center, New York State Department of Health,
Albany, NY 12208, USA; School of Public Health, University at Albany, Albany, NY
12208, USA. Electronic address: pallavi.ghosh@health.ny.gov.
Rifampicin (RIF), the frontline drug against M. tuberculosis, is completely
ineffective against M. abscessus, partially due to the presence of an
ADP-ribosyltransferase (Arr) that inactivates RIF. Using RNA-seq, we show that
exposure of M. abscessus to sublethal doses of RIF and Rifabutin (RBT), a close
analog of RIF, results in an ∼25-fold upregulation of Mab_helR in laboratory and
clinical isolates. An isogenic deletion in Mab_helR results in RIF/RBT
hypersensitivity, and overexpression of Mab_helR confers RIF tolerance in
M. tuberculosis. We demonstrate an increased HelR-RNAP association in
RIF-exposed bacteria and a MabHelR-mediated dissociation of RNAP from stalled
initiation complexes in vitro. Finally, we show that the tip of the PCh-loop of
Mab_helR, present in proximity to RIF, is critical for conferring RIF resistance
but dispensable for dissociation of stalled RNAP complexes, suggesting that
HelR-mediated RIF resistance requires a step in addition to displacement of
RIF-stalled RNAP.
Copyright © 2022 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.molcel.2022.06.034
PMID: 35905736
3. Am J Respir Crit Care Med. 2022 Jul 28. doi: 10.1164/rccm.202204-0727OC. Online
ahead of print.
A Risk-Stratifieed Approach for Never- and Ever-Smokers in Lung Cancer
Screening: A Prospective Cohort Study in China.
Wang F(1), Tan F(2), Shen S(3), Wu Z(4), Cao W(4), Yu Y(4), Dong X(4), Xia C(4),
Tang W(5), Xu Y(4), Qin C(4), Zhu M(6), Li J(4), Yang Z(4), Zheng Y(4), Luo
Z(4), Zhao L(4), Li J(7), Ren J(7), Shi J(7), Huang Y(8), Wu N(7), Shen H(6),
Chen W(7), Li N(7)(9), He J(10).
Author information:
(1)Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing,
China.
(2)Chinese Academy of Medical Sciences and Peking Union Medical College,
Department of Thoracic Surgery, National Clinical Research Center for Cancer,
Beijing, China.
(3)Nanjing Medical University, Biostatistics, Nanjing, China.
…
RATIONALE: Over 40% lung cancer cases occurred in never-smokers in China.
However, high-risk never-smokers were precluded benefiting from the lung cancer
screening as most screening guidelines did not consider them.
OBJECTIVES: We sought to develop and validate prediction models for three-year
lung cancer risks for never- and ever-smokers (China NCC-LCm2021 models).
METHODS: 425 626 never-smokers and 128 952 ever-smokers from the National Lung
Cancer Screening program were used as the training cohort and analyzed using
multivariable Cox models. Models were validated in two independent prospective
cohorts: one included 369 650 never-smokers and 107 678 ever-smokers (841 and
421 lung cancers), and the other included 286 327 never-smokers and 78 469
ever-smokers (503 and 127 lung cancers).
MEASUREMENTS AND RESULTS: The areas under the receiver operating characteristic
curves (AUC) in the two validation cohorts were 0.698 and 0.673 for
never-smokers, and 0.728 and 0.752 for ever-smokers. Our models had higher AUCs
than other existing models and were well calibrated in the validation cohort.
The China NCC-LCm2021 ≥0.47% threshold was suggested for never-smokers and
≥0.51% for ever-smokers. Moreover, we provided a range of threshold options with
corresponding expected screening outcomes, screening target, and screening
efficiency.
CONCLUSION: The construction of the China NCC-LCm2021 models can accurately
reflect individuals' risk of lung cancer, regardless of smoking status. Our
models can significantly increase the feasibility of conducting centralized lung
cancer screening programs, because we provided justified thresholds to define
the high-risk population of lung cancer and threshold options to adapt different
configuration of medical resources.
DOI: 10.1164/rccm.202204-0727OC
PMID: 35900139
4. Cancer Discov. 2022 Jul 27:CD-22-0111. doi: 10.1158/2159-8290.CD-22-0111. Online
ahead of print.
AXL and error-prone DNA replication confer drug resistance and offer strategies
to treat EGFR-mutant lung cancer.
Noronha A(1), Belugali Nataraj N(2), Sang Lee J(3), Zhitomirsky B(4), Oren Y(5),
Oster S(6), Lindzen M(1), Mukherjee S(1), Will R(7), Ghosh S(8), Simoni-Nieves
A(9), Verma A(10), Chatterjee R(10), Borgoni S(11), Robinson W(12), Sinha S(13),
Brandis A(1), Kerr DL(14), Wu W(15), Sekar A(9), Giri S(2), Chung Y(3),
Drago-Garcia D(2), Danysh BP(16), Lauriola M(17), Fiorentino M(17), Ardizzoni
A(18), Oren M(1), Blakely CM(19), Ezike J(4), Wiemann S(7), Parida L(20), Bivona
TG(19), Aqeilan RI(6), Brugge JS(21), Regev A(22), Getz G(23), Ruppin E(24),
Yarden Y(2).
Author information:
(1)Weizmann Institute of Science, Rehovot, Israel.
(2)Weizmann Institute of Science, Rehovot, Israel, Israel.
(3)Sungkyunkwan University, Suwon, Korea (South), Republic of.
…
Anti-cancer therapies have been limited by emergence of mutations and other
adaptations. In bacteria, antibiotics activate the SOS response, which mobilizes
error-prone factors that allow for continuous replication at the cost of
mutagenesis. We investigated whether treatment of lung cancer with EGFR
inhibitors (EGFRi) similarly engages hypermutators. In cycling drug-tolerant
persister (DTP) cells and in EGFRi-treated patients presenting residual disease
we observed upregulation of GAS6, while ablation of GAS6's receptor, AXL,
eradicated resistance. Reciprocally, AXL overexpression enhanced DTP survival
and accelerated the emergence of T790M, an EGFR mutation typical to resistant
cells. Mechanistically, AXL induces low-fidelity DNA polymerases and activates
their organizer, RAD18, by promoting neddylation. Metabolomics uncovered another
hypermutator, AXL-driven activation of MYC and increased purine synthesis that
is unbalanced by pyrimidines. Aligning anti-AXL combination treatments with the
transition from DTPs to resistant cells cured patient-derived xenografts. Hence,
similar to bacteria, tumors tolerate therapy by engaging pharmacologically
targetable endogenous mutators.
DOI: 10.1158/2159-8290.CD-22-0111
PMID: 35895872
5. Nat Commun. 2022 Jul 23;13(1):4261. doi: 10.1038/s41467-022-31926-9.
Development of a nanoparticle-based immunotherapy targeting PD-L1 and PLK1 for
lung cancer treatment.
Reda M(1)(2), Ngamcherdtrakul W(1), Nelson MA(1), Siriwon N(2), Wang R(1)(2),
Zaidan HY(1), Bejan DS(1), Reda S(1), Hoang NH(2), Crumrine NA(1), Rehwaldt
JPC(1), Bindal A(2), Mills GB(3)(4), Gray JW(2)(4), Yantasee W(5)(6)(7).
Author information:
(1)PDX Pharmaceuticals, Inc., Portland, OR, USA.
(2)Department of Biomedical Engineering, Oregon Health and Science University,
Portland, OR, USA.
(3)Department of Cell, Developmental & Cancer Biology, Oregon Health and Science
University, Portland, OR, USA.
…
Immune checkpoint inhibitors (ICIs) targeting PD-L1 and PD-1 have improved
survival in a subset of patients with advanced non-small cell lung cancer
(NSCLC). However, only a minority of NSCLC patients respond to ICIs,
highlighting the need for superior immunotherapy. Herein, we report on a
nanoparticle-based immunotherapy termed ARAC (Antigen Release Agent and
Checkpoint Inhibitor) designed to enhance the efficacy of PD-L1 inhibitor. ARAC
is a nanoparticle co-delivering PLK1 inhibitor (volasertib) and PD-L1 antibody.
PLK1 is a key mitotic kinase that is overexpressed in various cancers including
NSCLC and drives cancer growth. Inhibition of PLK1 selectively kills cancer
cells and upregulates PD-L1 expression in surviving cancer cells thereby
providing opportunity for ARAC targeted delivery in a feedforward manner. ARAC
reduces effective doses of volasertib and PD-L1 antibody by 5-fold in a
metastatic lung tumor model (LLC-JSP) and the effect is mainly mediated by
CD8+ T cells. ARAC also shows efficacy in another lung tumor model (KLN-205),
which does not respond to CTLA-4 and PD-1 inhibitor combination. This study
highlights a rational combination strategy to augment existing therapies by
utilizing our nanoparticle platform that can load multiple cargo types at once.
© 2022. The Author(s).
DOI: 10.1038/s41467-022-31926-9
PMCID: PMC9308817
PMID: 35871223 [Indexed for MEDLINE]
6. ACS Nano. 2022 Jul 21. doi: 10.1021/acsnano.2c04159. Online ahead of print.
An Osimertinib-Perfluorocarbon Nanoemulsion with Excellent Targeted Therapeutic
Efficacy in Non-small Cell Lung Cancer: Achieving Intratracheal and Intravenous
Administration.
Yang J(1)(2), Li Y(1)(2), Sun J(1)(2), Zou H(1)(2), Sun Y(1)(2), Luo J(1)(2),
Xie Q(1)(2), A R(1)(2), Wang H(1)(2), Li X(1)(2), Wang K(1)(2), Yang L(1)(2), Ma
T(3), Wu L(1)(2), Sun X(1)(2).
Author information:
(1)NHC and CAMS Key Laboratory of Molecular Probe and Targeted Theranostics,
Molecular Imaging Research Center (MIRC), Harbin Medical University, 150028
Harbin, Heilongjiang, China.
(2)Department of Nuclear Medicine, the Fourth Hospital of Harbin Medical
University, 150028 Harbin, Heilongjiang, China.
(3)Shenzhen Key Laboratory of Ultrasound Imaging and Therapy, Shenzhen
Institutes of Advanced Technology, Chinese Academy of Sciences, 518055 Shenzhen,
Guangdong, China.
Low accumulation of anticancer drugs in tumors and serious systemic toxicity
remain the main challenges to the clinical efficiency of pharmaceuticals.
Pulmonary delivery of nanoscale-based drug delivery systems offered a strategy
to increase antitumor activity with minimal adverse exposure. Herein, we report
an osimertinib-loaded perfluoro-15-crown-5-ether (AZD9291-PFCE) nanoemulsion,
through intratracheal and intravenous delivery, synergizes with 19F magnetic
resonance imaging (19F MRI)-guided low-intensity focused ultrasound (LIFU) for
lung cancer therapy. Pulmonary delivery of AZD9291-PFCE nanoemulsion in
orthotopic lung carcinoma models achieves quick distribution of the nanoemulsion
in lung tissues and tumors without short-term and long-term toxic effects.
Furthermore, LIFU can trigger drug release from the AZD9291-PFCE nanoemulsion
and specifically increases tumor vascular and tumor tissue permeability. 19F MRI
was applied to quantify nanoemulsion accumulation in tumors in real time after
LIFU irradiation. We validate the treatment effect of AZD9291-PFCE nanoemulsion
in resected human lung cancer tissues, proving the translational potential to
enhance clinical outcomes of lung cancer therapy. Thus, this work presents a
promising pulmonary nanoemulsion delivery system of osimertinib (AZD9291) for
targeted therapy of lung cancer without severe side effects.
DOI: 10.1021/acsnano.2c04159
PMID: 35863049
7. J Clin Invest. 2022 Jul 21:e161564. doi: 10.1172/JCI161564. Online ahead of
print.
Isoniazid and rifapentine treatment effectively reduces persistent M.
tuberculosis infection in macaque lungs.
Sharan R(1), Ganatra SR(1), Singh DK(1), Cole J(1), Foreman TW(2), Thippeshappa
R(1), Peloquin CA(3), Shivanna V(1), Gonzalez O(1), Day CL(4), Gandhi NR(5),
Dick EJ Jr(1), Hall-Ursone S(1), Mehra S(1), Schlesinger LS(1), Rengarajan J(6),
Kaushal D(1).
Author information:
(1)Southwest National Primate Research Center, Texas Biomedical Research
Institute, San Antonio, United States of America.
(2)Division of Bacteriology and Parasitology, Tulane National Primate Research
Center, Covington, United States of America.
(3)College of Pharmacy, University of Florida, Gainesville, United States of
America.
…
Once-weekly oral dose of isoniazid and rifapentine for 12 weeks (3HP) is
recommended by CDC for treatment of latent tuberculosis infection (LTBI). The
aim of this study is to assess 3HP-mediated clearance of Mtb bacteria in
macaques with asymptomatic LTBI. Twelve Indian rhesus macaques were infected
with low dose (~10 CFU) of Mtb CDC1551 via aerosol. Six animals were treated
with 3HP and six were left untreated. The animals were imaged via positron
emissions tomography - computed tomography (PET/CT) at frequent intervals. Upon
treatment completion, all animals except one were coinfected with simian
immunodeficiency virus to assess reactivation of LTBI to active TB disease. Four
of six treated macaques showed no evidence of persistent bacilli or
extrapulmonary spread until study end-point. PET/CT demonstrated the presence of
significantly more granulomas in untreated animals relative to the treated
group. The untreated animals harbored persistent bacilli and demonstrated TB
reactivation following SIV coinfection while none of the treated animals
reactivated to active TB disease (ATB). 3HP treatment effectively reduced
persistent infection with Mtb and prevented reactivation of TB disease in
latently infected macaques.
DOI: 10.1172/JCI161564
PMID: 35862216
8. Am J Respir Crit Care Med. 2022 Jul 18. doi: 10.1164/rccm.202110-2358OC. Online
ahead of print.
Transcriptional Circuitry of NKX2-1 and SOX1 Defines an Unrecognized Lineage
Subtype of Small Cell Lung Cancer.
Kong R(1), Patel AS(2), Sato T(3), Jiang F(4), Yoo S(4), Bao L(5), Sinha A(4),
Tian Y(4), Fridrikh M(4), Liu S(4), Feng J(6), He X(7), Jiang J(8), Ma Y(8),
Grullon K(4), Yang D(9), Powell CA(10), Beasley MB(11), Zhu J(4), Snyder EL(12),
Li S(8), Watanabe H(13).
Author information:
(1)The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
(2)New York University Langone Medical Center, New York, New York, United
States.
(3)Keio University School of Medicine, Shinjuku-ku, Japan.
…
Rationale: The current molecular classification of small cell lung cancer (SCLC)
based on expression of four lineage transcription factors still leaves its major
subtype SCLC-A as a heterogeneous group, necessitating more precise
characterization of lineage subclasses. Objectives: To refine the current SCLC
classification with epigenomic profiles and to identify features of the
re-defined SCLC subtypes. Methods: We performed unsupervised clustering of
epigenomic profiles on 25 SCLC cell lines. Functional significance of NKX2-1 was
evaluated by cell growth, apoptosis and xenograft using CRISPR-Cas9-mediated
deletion. NKX2-1 specific cistromic profiles were determined by ChIP-seq and its
functional transcriptional partners were determined using co-immunoprecipitation
followed by mass-spectrometry. Rb1fl/flTrp53fl/fl and
Rb1fl/flTrp53fl/flNkx2-1fl/fl mouse models were engineered to explore the
function of Nkx2-1 in SCLC tumorigenesis. Epigenomic landscapes of 6 human SCLC
specimens and 20 tumors from 2 mouse models were characterized. Measurements and
Main Results: We identified an epigenomic subcluster of the major SCLC-A
subtype: SCLC-Aα and SCLC-Aσ. SCLC-Aα was characterized by the presence of a
super-enhancer at the NKX2-1 locus, which was observed in human SCLC specimens
and a murine SCLC model. We found NKX2-1, a dual lung and neural lineage factor,
is uniquely relevant in SCLC-Aα. Additionally, we found maintenance of this
neural identity in SCLC-Aα is mediated by collaborative transcriptional activity
with another neuronal transcriptional factor SOX1. Conclusions: We
comprehensively describe additional epigenomic heterogeneity of the major SCLC-A
subtype, and define SCLC-Aα subtype by the core regulatory circuitry of NKX2-1
and SOX1 super-enhancers and their functional collaborations to maintain
neuronal linage state.
DOI: 10.1164/rccm.202110-2358OC
PMID: 35848993
9. Immunol Rev. 2022 Aug;309(1):97-122. doi: 10.1111/imr.13116. Epub 2022 Jul 12.
Transcriptomics for child and adolescent tuberculosis.
Kaforou M(1), Broderick C(1), Vito O(1), Levin M(1), Scriba TJ(2), Seddon
JA(1)(3).
Author information:
(1)Department of Infectious Disease, Imperial College London, London, UK.
(2)South African Tuberculosis Vaccine Initiative, Institute of Infectious
Disease and Molecular Medicine and Division of Immunology, Department of
Pathology, University of Cape Town, Cape Town, South Africa.
(3)Desmond Tutu TB Centre, Department of Paediatrics and Child Health,
Stellenbosch University, Cape Town, South Africa.
Tuberculosis (TB) in humans is caused by Mycobacterium tuberculosis (Mtb). It is
estimated that 70 million children (<15 years) are currently infected with Mtb,
with 1.2 million each year progressing to disease. Of these, a quarter die. The
risk of progression from Mtb infection to disease and from disease to death is
dependent on multiple pathogen and host factors. Age is a central component in
all these transitions. The natural history of TB in children and adolescents is
different to adults, leading to unique challenges in the development of
diagnostics, therapeutics, and vaccines. The quantification of RNA
transcripts in specific cells or in the peripheral blood, using high-throughput
methods, such as microarray analysis or RNA-Sequencing, can shed light into the
host immune response to Mtb during infection and disease, as well as
understanding treatment response, disease severity, and vaccination, in a global
hypothesis-free manner. Additionally, gene expression profiling can be used for
biomarker discovery, to diagnose disease, predict future disease progression and
to monitor response to treatment. Here, we review the role of transcriptomics in
children and adolescents, focused mainly on work done in blood, to understand
disease biology, and to discriminate disease states to assist clinical
decision-making. In recent years, studies with a specific pediatric and
adolescent focus have identified blood gene expression markers with diagnostic
or prognostic potential that meet or exceed the current sensitivity and
specificity targets for diagnostic tools. Diagnostic and prognostic gene
expression signatures identified through high-throughput methods are currently
being translated into diagnostic tests.
© 2022 The Authors. Immunological Reviews published by John Wiley & Sons Ltd.
DOI: 10.1111/imr.13116
PMID: 35818983 [Indexed for MEDLINE]
10. J Natl Cancer Inst. 2022 Jul 12:djac127. doi: 10.1093/jnci/djac127. Online ahead
of print.
A Randomized Trial of Telephone-Based Smoking Cessation Treatment in the Lung
Cancer Screening Setting.
Taylor KL(1), Williams RM(1), Li T(2), Luta G(2), Smith L(1), Davis KM(1),
Stanton C(3), Niaura R(4), Abrams D(4), Lobo T(1), Mandelblatt J(1), Jayasekera
J(1), Meza R(5), Jeon J(5), Cao P(5), Anderson ED(6); Georgetown Lung Screening,
Tobacco, and Health Trial.
Collaborators: Anderson R, Anderson S, Batlle J, Breece CJ, Campos C, Charles L,
Cordon M, Deros DE, Dornelas E, Dunlap D, Ebner J, Eyestone E, Mph SF, Frey J,
Friberg J, Galleno L, Geronimo MM, Gould D, Hagerman C, Harper H, Harris M,
Howell J, Hutchison S, Kao JC, Kim E, Borondy-Kitts A, Leon Y, McKee A, McKee B,
Parikh V, Pless M, Ramsaier M, Regis S, Rojas N, Ruiz D, Salner A, Stephens J,
Yang F.
Author information:
(1)Cancer Prevention and Control Program, Lombardi Comprehensive Cancer Center,
Georgetown University Medical Center, Washington, DC, USA.
(2)Department of Biostatistics, Bioinformatics, and Biomathematics, Georgetown
University Medical Center, Washington, DC, USA.
(3)Behavioral Health, Westat, Rockville, MD, USA.
(4)School of Global Public Health, New York University, NY, NY, USA.
(5)Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA.
(6)Department of Pulmonary and Sleep Medicine, Georgetown University Medical
Center, Washington, DC, USA.
BACKGROUND: Lung cancer mortality is reduced via low-dose CT screening and
treatment of early-stage disease. Evidence-based smoking cessation treatment in
the lung screening setting can further reduce mortality. We report the results
of a cessation trial from the NCI's SCALE collaboration.
METHODS: Eligible patients (N = 818) aged 50-80 were randomized (May
2017-January 2021) to the Intensive vs. Minimal arms (8 vs. 3 phone sessions
plus 8 vs. 2 weeks of nicotine patches, respectively). Bio-verified (primary)
and self-reported 7-day abstinence rates were assessed 3-, 6-, and 12-months
post-randomization. Logistic regression analyses evaluated the effects of study
arm. All statistical tests were two-sided.
RESULTS: Participants reported 48.0 (SD = 17.2) pack-years and 51.6% were not
ready to quit in < 30 days. Self-reported 3-month quit rates were significantly
higher in the Intensive vs. Minimal arm (14.3% vs. 7.9%; OR = 2.00, 95%
confidence interval [CI] = 1.26,3.18). Bio-verified abstinence was lower but
with similar relative differences between arms (9.1% vs. 3.9%; OR = 2.70, 95%
CI = 1.44, 5.08). Compared to the Minimal arm, the Intensive arm was more
effective among those with greater nicotine dependence (OR = 3.47, 95%
CI = 1.55, 7.76), normal screening results (OR = 2.58, 95% CI = 1.32, 5.03),
high engagement in counseling (OR = 3.03, 95% CI = 1.50, 6.14) and patch use
(OR = 2.81, 95% CI = 1.39, 5.68). Abstinence rates did not differ significantly
between arms at 6-months (OR = 1.2, 95% CI = 0.68, 2.11) or 12-months (OR = 1.4,
95% CI = 0.82, 2.42).
CONCLUSIONS: Delivering intensive telephone counseling and nicotine replacement
with lung screening is an effective strategy to increase short-term smoking
cessation. Methods to maintain short-term effects are needed. Even with modest
quit rates, integrating cessation treatment into lung screening programs may
have a large impact on tobacco-related mortality.
© The Author(s) 2022. Published by Oxford University Press. All rights reserved.
For permissions, please email: journals.permissions@oup.com.
DOI: 10.1093/jnci/djac127
PMID: 35818122
11. J Clin Oncol. 2022 Jul 11:JCO2200824. doi: 10.1200/JCO.22.00824. Online ahead of print.
Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations: ASCO
Living Guideline.
Singh N(1), Temin S(2), Baker S Jr(3), Blanchard E(4), Brahmer JR(5), Celano
P(6), Duma N(7), Ellis PM(8), Elkins IB(9), Haddad RY(10), Hesketh PJ(11), Jain
D(12), Johnson DH(13), Leighl NB(14), Mamdani H(15), Masters G(16), Moffitt
PR(17), Phillips T(18), Riely GJ(19), Robinson AG(20), Rosell R(21), Schiller
JH(22), Schneider BJ(23), Spigel DR(24), Jaiyesimi IA(25).
Author information:
(1)Postgraduate Institute of Medical Education and Research, Chandigarh, India.
(2)American Society of Clinical Oncology, Alexandria, VA.
(3)Virginia Commonwealth University, Richmond, VA.
…
PURPOSE: To provide evidence-based recommendations updating the 2021 ASCO and
Ontario Health (Cancer Care Ontario) guideline on systemic therapy for patients
with stage IV non-small-cell lung cancer (NSCLC) with driver alterations.
METHODS: ASCO updated recommendations on the basis of an ongoing systematic
review of randomized control trials from 2020 to 2021.
RESULTS: This guideline update reflects changes in evidence since the previous
update. Two studies provide the evidence base. Outcomes of interest include
efficacy and safety.
RECOMMENDATIONS: For patients with an anaplastic lymphoma kinase rearrangement,
a performance status (PS) of 0-2, and previously untreated NSCLC, clinicians
should offer alectinib or brigatinib or lorlatinib. For patients with an
anaplastic lymphoma kinase rearrangement, a PS of 0-2, and previously untreated
NSCLC, if alectinib, brigatinib, or lorlatinib are not available, clinicians
should offer ceritinib or crizotinib. For patients with a RET rearrangement, a
PS of 0-2, and previously untreated NSCLC, clinicians may offer selpercatinib or
pralsetinib. In second line, for patients with a RET rearrangement who have not
received RET-targeted therapy, clinicians may offer selpercatinib or
pralsetinib.Additional information is available at
www.asco.org/thoracic-cancer-guidelines.
DOI: 10.1200/JCO.22.00824
PMID: 35816666
12. Nat Commun. 2022 Jul 2;13(1):3817. doi: 10.1038/s41467-022-31236-0.
A convolutional neural network highlights mutations relevant to antimicrobial
resistance in Mycobacterium tuberculosis.
Green AG(#)(1), Yoon CH(#)(1)(2), Chen ML(1)(3), Ektefaie Y(1), Fina M(4),
Freschi L(1), Gröschel MI(1), Kohane I(1), Beam A(#)(5)(6), Farhat M(#)(7)(8).
Author information:
(1)Department of Biomedical Informatics, Harvard Medical School, 25 Shattuck St,
Boston, MA, 02115, USA.
(2)Big Data Institute, Nuffield Department of Population Health, University of
Oxford, Oxford, OX37LF, UK.
(3)Stanford University School of Medicine, 291 Campus Dr, Stanford, CA, 94305,
USA.
…
Long diagnostic wait times hinder international efforts to address antibiotic
resistance in M. tuberculosis. Pathogen whole genome sequencing, coupled with
statistical and machine learning models, offers a promising solution. However,
generalizability and clinical adoption have been limited by a lack of
interpretability, especially in deep learning methods. Here, we present two deep
convolutional neural networks that predict antibiotic resistance phenotypes of
M. tuberculosis isolates: a multi-drug CNN (MD-CNN), that predicts resistance to
13 antibiotics based on 18 genomic loci, with AUCs 82.6-99.5% and higher
sensitivity than state-of-the-art methods; and a set of 13 single-drug CNNs
(SD-CNN) with AUCs 80.1-97.1% and higher specificity than the previous
state-of-the-art. Using saliency methods to evaluate the contribution of input
sequence features to the SD-CNN predictions, we identify 18 sites in the genome
not previously associated with resistance. The CNN models permit functional
variant discovery, biologically meaningful interpretation, and clinical
applicability.
© 2022. The Author(s).
DOI: 10.1038/s41467-022-31236-0
PMCID: PMC9250494
PMID: 35780211 [Indexed for MEDLINE]
13. J Clin Oncol. 2022 Jul 20;40(21):2295-2306. doi: 10.1200/JCO.22.00912. Epub 2022
Jun 3.
Phase II Randomized Study of Ramucirumab and Pembrolizumab Versus Standard of
Care in Advanced Non-Small-Cell Lung Cancer Previously Treated With
Immunotherapy-Lung-MAP S1800A.
Reckamp KL(1), Redman MW(2), Dragnev KH(3), Minichiello K(2), Villaruz LC(4),
Faller B(5)(6), Al Baghdadi T(5)(7), Hines S(6), Everhart L(7), Highleyman L(7),
Papadimitrakopoulou V(8), Gandara DR(9), Kelly K(9), Herbst RS(10).
Author information:
(1)Cedars-Sinai Medical Center, Los Angeles, CA.
(2)SWOG Statistics and Data Management Center, Fred Hutchinson Cancer Research
Center, Seattle, WA.
(3)Dartmouth-Hitchcock Norris Cotton Cancer Center, Alliance for Clinical Trials
in Oncology, Lebanon, NH.
…
Comment in
2285.
PURPOSE: Resistance to immune checkpoint inhibition (ICI) in advanced
non-small-cell lung cancer (NSCLC) represents a major unmet need. Combining ICI
with vascular endothelial growth factor (VEGF)/VEGF receptor inhibition has
yielded promising results in multiple tumor types.
METHODS: In this randomized phase II Lung-MAP nonmatch substudy (S1800A),
patients ineligible for a biomarker-matched substudy with NSCLC previously
treated with ICI and platinum-based chemotherapy and progressive disease at
least 84 days after initiation of ICI were randomly assigned to receive
ramucirumab plus pembrolizumab (RP) or investigator's choice standard of care
(SOC: docetaxel/ramucirumab, docetaxel, gemcitabine, and pemetrexed). With a
goal of 130 eligible patients, the primary objective was to compare overall
survival (OS) using a one-sided 10% level using the better of a standard
log-rank (SLR) and weighted log-rank (WLR; G[rho = 0, gamma = 1]) test.
Secondary end points included objective response, duration of response,
investigator-assessed progression-free survival, and toxicity.
RESULTS: Of 166 patients enrolled, 136 were eligible (69 RP; 67 SOC). OS was
significantly improved with RP (hazard ratio [80% CI]: 0.69 [0.51 to 0.92]; SLR
one-sided P = .05; WLR one-sided P = .15). The median (80% CI) OS was 14.5 (13.9
to 16.1) months for RP and 11.6 (9.9 to 13.0) months for SOC. OS benefit for RP
was seen in most subgroups. Investigator-assessed progression-free survival
(hazard ratio [80% CI]: 0.86 [0.66 to 1.14]; one-sided SLR, P = .25 and .14 for
WLR) and response rates (22% RP v 28% SOC, one-sided P = .19) were similar
between arms. Grade ≥ 3 treatment-related adverse events occurred in 42% of
patients in the RP group and 60% on SOC.
CONCLUSION: This randomized phase II trial demonstrated significantly improved
OS with RP compared with SOC in patients with advanced NSCLC previously treated
with ICI and chemotherapy. The safety was consistent with known toxicities of
both drugs. These data warrant further evaluation.
DOI: 10.1200/JCO.22.00912
PMCID: PMC9287284
PMID: 35658002 [Indexed for MEDLINE]
14. Am J Respir Crit Care Med. 2022 Jul 15;206(2):206-216. doi:
10.1164/rccm.202110-2378OC.
Aerosolization of Mycobacterium tuberculosis by Tidal Breathing.
Dinkele R(1)(2), Gessner S(1)(2), McKerry A(3), Leonard B(3), Leukes J(3),
Seldon R(3), Warner DF(1)(2)(4), Wood R(2)(3).
Author information:
(1)South African Medical Research Council/National Health Laboratory
Services/University of Cape Town Molecular Mycobacteriology Research Unit &
Department of Science and Innovation, National Research Foundation Centre of
Excellence for Biomedical Tuberculosis Research, Department of Pathology.
(2)Institute of Infectious Diseases and Molecular Medicine.
(3)Desmond Tutu Health Foundation, University of Cape Town, Cape Town, South
Africa.
(4)Wellcome Centre for Infectious Diseases Research in Africa, Faculty of Health
Sciences, and.
Comment in
Am J Respir Crit Care Med. 2022 Jul 15;206(2):141-143.
Rationale: Interrupting tuberculosis (TB) transmission requires an improved
understanding of how and when the causative organism, Mycobacterium tuberculosis
(Mtb), is aerosolized. Although cough is commonly assumed to be the dominant
source of Mtb aerosols, recent evidence of cough-independent Mtb release implies
the contribution of alternative mechanisms. Objectives: To compare the
aerosolization of Mtb bacilli and total particulate matter from patients with TB
during three separate respiratory maneuvers: tidal breathing (TiBr), FVC, and
cough. Methods: Bioaerosol sampling and Mtb enumeration by live-cell,
fluorescence microscopy were combined with real-time measurement of CO2
concentration and total particle counts from 38 patients with GeneXpert-positive
TB before treatment initiation. Measurements and Main Results: For all
maneuvers, the proportions of particles detected across five size categories
were similar, with most particles falling between 0.5-5 μm. Although total
particle counts were 4.8-fold greater in cough samples than either TiBr or FVC,
all three maneuvers returned similar rates of positivity for Mtb. No correlation
was observed between total particle production and Mtb count. Instead, for total
Mtb counts, the variability between individuals was greater than the variability
between sampling maneuvers. Finally, when modelled using 24-hour breath and
cough frequencies, our data indicate that TiBr might contribute more than 90% of
the daily aerosolized Mtb among symptomatic patients with TB. Conclusions:
Assuming the number of viable Mtb organisms released offers a reliable proxy of
patient infectiousness, our observations imply that TiBr and interindividual
variability in Mtb release might be significant contributors to TB transmission
among active cases.
DOI: 10.1164/rccm.202110-2378OC
PMID: 35584342 [Indexed for MEDLINE]
15. J Clin Invest. 2022 Jul 1;132(13):e145099. doi: 10.1172/JCI145099.
Deficiency of the splicing factor RBM10 limits EGFR inhibitor response in
EGFR-mutant lung cancer.
Nanjo S(1)(2)(3), Wu W(1)(2), Karachaliou N(4), Blakely CM(1)(2), Suzuki J(5),
Chou YT(1)(2), Ali SM(6), Kerr DL(1)(2), Olivas VR(1)(2), Shue J(1)(2), Rotow
J(1)(2), Mayekar MK(1)(2), Haderk F(1)(2), Chatterjee N(1)(2), Urisman A(7), Yeo
JC(8), Skanderup AJ(8), Tan AC(9), Tam WL(8)(10), Arrieta O(11), Hosomichi
K(12), Nishiyama A(3), Yano S(3), Kirichok Y(5), Tan DS(9), Rosell R(4), Okimoto
RA(1)(2), Bivona TG(1)(2)(13).
Author information:
(1)Department of Medicine and.
(2)Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco,
California, USA.
(3)Division of Medical Oncology, Kanazawa University Cancer Research Institute,
Kanazawa, Japan.
…
Molecularly targeted cancer therapy has improved outcomes for patients with
cancer with targetable oncoproteins, such as mutant EGFR in lung cancer. Yet,
the long-term survival of these patients remains limited, because treatment
responses are typically incomplete. One potential explanation for the lack of
complete and durable responses is that oncogene-driven cancers with activating
mutations of EGFR often harbor additional co-occurring genetic alterations. This
hypothesis remains untested for most genetic alterations that co-occur with
mutant EGFR. Here, we report the functional impact of inactivating genetic
alterations of the mRNA splicing factor RNA-binding motif 10 (RBM10) that
co-occur with mutant EGFR. RBM10 deficiency decreased EGFR inhibitor efficacy in
patient-derived EGFR-mutant tumor models. RBM10 modulated mRNA alternative
splicing of the mitochondrial apoptotic regulator Bcl-x to regulate tumor cell
apoptosis during treatment. Genetic inactivation of RBM10 diminished EGFR
inhibitor-mediated apoptosis by decreasing the ratio of (proapoptotic) Bcl-xS to
(antiapoptotic) Bcl-xL isoforms of Bcl-x. RBM10 deficiency was a biomarker of
poor response to EGFR inhibitor treatment in clinical samples. Coinhibition of
Bcl-xL and mutant EGFR overcame the resistance induced by RBM10 deficiency. This
study sheds light on the role of co-occurring genetic alterations and on the
effect of splicing factor deficiency on the modulation of sensitivity to
targeted kinase inhibitor cancer therapy.
DOI: 10.1172/JCI145099
PMCID: PMC9246391
PMID: 35579943 [Indexed for MEDLINE]
16. Cancer Discov. 2022 Jul 6;12(7):1690-1701. doi: 10.1158/2159-8290.CD-21-1486.
Longitudinal Undetectable Molecular Residual Disease Defines Potentially Cured
Population in Localized Non-Small Cell Lung Cancer.
Zhang JT(#)(1), Liu SY(#)(1), Gao W(#)(2), Liu SM(#)(3)(4), Yan HH(1), Ji L(2),
Chen Y(1), Gong Y(2), Lu HL(1), Lin JT(1), Yin K(1), Jiang BY(1), Nie Q(1), Liao
RQ(1), Dong S(1), Guan Y(2), Dai P(2), Zhang XC(1), Yang JJ(1), Tu HY(1), Xia
X(2), Yi X(2), Zhou Q(1), Zhong WZ(1), Yang XN(1), Wu YL(1).
Author information:
(1)Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital,
Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China.
(2)Geneplus-Beijing Institute, Beijing, China.
(3)Department of Hematology, First Affiliated Hospital, Institute of Hematology,
School of Medicine; Key Laboratory for Regenerative Medicine of Ministry of
Education, Jinan University, Guangzhou, Guangdong, China.
(4)Chinese Thoracic Oncology Group (CTONG), Guangzhou, Guangdong, China.
(#)Contributed equally
The efficacy and potential limitations of molecular residual disease (MRD)
detection urgently need to be fully elucidated in a larger population of
non-small cell lung cancer (NSCLC). We enrolled 261 patients with stages I to
III NSCLC who underwent definitive surgery, and 913 peripheral blood samples
were successfully detected by MRD assay. Within the population, only six
patients (3.2%) with longitudinal undetectable MRD recurred, resulting in a
negative predictive value of 96.8%. Longitudinal undetectable MRD may define the
patients who were cured. The peak risk of developing detectable MRD was
approximately 18 months after landmark detection. Correspondingly, the positive
predictive value of longitudinal detectable MRD was 89.1%, with a median lead
time of 3.4 months. However, brain-only recurrence was less commonly detected by
MRD (n = 1/5, 20%). Further subgroup analyses revealed that patients with
undetectable MRD might not benefit from adjuvant therapy. Together, these
results expound the value of MRD in NSCLC.
SIGNIFICANCE: This study confirms the prognostic value of MRD detection in
patients with NSCLC after definitive surgery, especially in those with
longitudinal undetectable MRD, which might represent the potentially cured
population regardless of stage and adjuvant therapy. Moreover, the risk of
developing detectable MRD decreased stepwise after 18 months since landmark
detection. This article is highlighted in the In This Issue feature, p. 1599.
©2022 The Authors; Published by the American Association for Cancer Research.
DOI: 10.1158/2159-8290.CD-21-1486
PMID: 35543554 [Indexed for MEDLINE]
17. Lancet Infect Dis. 2022 Jul;22(7):1042-1051. doi: 10.1016/S1473-3099(21)00811-2. Epub 2022 May 2.
Treatment outcomes 24 months after initiating short, all-oral
bedaquiline-containing or injectable-containing rifampicin-resistant
tuberculosis treatment regimens in South Africa: a retrospective cohort study.
Ndjeka N(1), Campbell JR(2), Meintjes G(3), Maartens G(3), Schaaf HS(4), Hughes
J(4), Padanilam X(5), Reuter A(6), Romero R(7), Ismail F(8), Enwerem M(9),
Ferreira H(10), Conradie F(11), Naidoo K(12), Menzies D(2).
Author information:
(1)National Department of Health, Tuberculosis Control and Management Cluster,
Pretoria, South Africa; Nelson R Mandela School of Medicine, University of
KwaZulu Natal, Durban, South Africa. Electronic address:
norbert.ndjeka@health.gov.za.
(2)Department of Epidemiology, Biostatistics, and Occupational Health and the
McGill International TB Centre, McGill University, and The Montreal Chest
Institute, McGill University Health Centre, Montreal, QC, Canada.
(3)Department of Medicine and Wellcome Centre for Infectious Diseases Research
in Africa, Institute of Infectious Disease and Molecular Medicine, University of
Cape Town, South Africa.
…
Comment in
Lancet Infect Dis. 2022 Jul;22(7):923-924.
BACKGROUND: There is a need for short and safe all-oral treatment of
rifampicin-resistant tuberculosis. We compared outcomes up to 24 months after
treatment initiation for patients with rifampicin-resistant tuberculosis in
South Africa treated with a short, all-oral bedaquiline-containing regimen
(bedaquiline group), or a short, injectable-containing regimen (injectable
group).
METHODS: Patients with rifampicin-resistant tuberculosis, aged 18 years or
older, eligible for a short regimen starting treatment between Jan 1 and Dec 31,
2017, with a bedaquiline-containing or WHO recommended injectable-containing
treatment regimen of 9-12 months, registered in the drug-resistant tuberculosis
database (EDRWeb), and with known age, sex, HIV status, and national
identification number were eligible for study inclusion; patients receiving
linezolid, carbapenems, terizidone or cycloserine, delamanid, or
para-aminosalicylic acid were excluded. Bedaquiline was given at a dose of 400
mg once daily for two weeks followed by 200 mg three times a week for 22 weeks.
To compare regimens, patients were exactly matched on HIV and ART status,
previous tuberculosis treatment history, and baseline acid-fast bacilli smear
and culture result, while propensity score matched on age, sex, province of
treatment, and isoniazid-susceptibility status. We did binomial linear
regression to estimate adjusted risk differences (aRD) and 95% CIs for 24-month
outcomes, which included: treatment success (ie, cure or treatment completion
without evidence of recurrence) versus all other outcomes, survival versus
death, disease free survival versus survival with treatment failure or
recurrence, and loss to follow-up versus all other outcomes.
FINDINGS: Overall, 1387 (14%) of 10152 patients with rifampicin-resistant
tuberculosis treated during 2017 met inclusion criteria; 688 in the bedaquiline
group and 699 in the injectable group. Four patients (1%) had treatment failure
or recurrence, 44 (6%) were lost to follow-up, and 162 (24%) died in the
bedaquiline group, compared with 17 (2%), 87 (12%), and 199 (28%), respectively,
in the injectable group. In adjusted analyses, treatment success was 14% (95% CI
8-20) higher in the bedaquiline group than in the injectable group (70% vs 57%);
loss to follow-up was 4% (1-8) lower in the bedaquiline group (6% vs 12%); and
disease-free survival was 2% (0-5) higher in the bedaquiline group (99% vs 97%).
The bedaquiline group had 8% (4-11) lower risk of mortality during treatment
(17·0% vs 22·4%), but there was no difference in mortality post-treatment.
INTERPRETATION: Patients in the bedaquiline group experienced significantly
higher rates of treatment success at 24 months. This finding supports the use of
short bedaquiline-containing regimens in eligible patients.
FUNDING: WHO Global TB Programme.
TRANSLATION: For the French translation of the abstract see Supplementary
Materials section.
This is an Open Access article published under the CC BY 3.0 IGO license which
permits unrestricted use, distribution, and reproduction in any medium, provided
the original work is properly cited. In any use of this article, there should be
no suggestion that WHO endorses any specific organisation, products or services.
The use of the WHO logo is not permitted. This notice should be preserved along
with the article's original URL.
DOI: 10.1016/S1473-3099(21)00811-2
PMCID: PMC9217754
PMID: 35512718 [Indexed for MEDLINE]
18. Am J Respir Crit Care Med. 2022 Jul 1;206(1):94-104. doi:
10.1164/rccm.202112-2747OC.
Response to Hypoxia and the Ensuing Dysregulation of Inflammation Impacts
Mycobacterium tuberculosis Pathogenicity.
Bucşan AN(1), Veatch A(1), Singh DK(2), Akter S(3), Golden NA(1), Kirkpatrick
M(1), Threeton B(1), Moodley C(1), Ahmed M(3), Doyle LA(1), Russell-Lodrigue
K(1), Norton EB(4), Didier PJ(1), Roy CJ(1)(2), Abramovitch RB(5), Mehra
S(1)(2), Khader SA(3), Kaushal D(1)(2).
Author information:
(1)Tulane National Primate Research Center, Tulane University Health Sciences
Center, Covington, Louisiana.
(2)Southwest National Primate Research Center, Texas Biomedical Research
Institute, San Antonio, Texas.
(3)Department of Molecular Microbiology, Washington University in St. Louis
School of Medicine, St. Louis, Missouri.
(4)Department of Microbiology and Immunology, Tulane University School of
Medicine, New Orleans, Louisiana; and.
(5)Department of Microbiology and Molecular Genetics, Michigan State University,
East Lansing, Michigan.
Comment in
Am J Respir Crit Care Med. 2022 Jul 1;206(1):10-12.
Rationale: Different Mycobacterium tuberculosis (Mtb) strains exhibit variable
degrees of virulence in humans and animal models. Differing stress response
strategies used by different strains of Mtb could influence virulence.
Objectives: We compared the virulence of two strains of Mtb with use in animal
model research: CDC1551 and Erdman. Methods: Rhesus macaques, which develop
human-like tuberculosis attributes and pathology, were infected with a high dose
of either strain via aerosol, and virulence was compared by bacterial burden and
pathology. Measurements and Main Results: Infection with Erdman resulted in
significantly shorter times to euthanasia and higher bacterial burdens and
greater systemic inflammation and lung pathology relative to those infected with
CDC1551. Macaques infected with Erdman also exhibited significantly higher early
inflammatory myeloid cell influx to the lung, greater macrophage and T cell
activity, and higher expression of lung remodeling (extracellular matrix) genes,
consistent with greater pathology. Expression of NOTCH4 (neurogenic locus notch
homolog 4) signaling, which is induced in response to hypoxia and promotes
undifferentiated cellular state, was also higher in Erdman-infected lungs. The
granulomas generated by Erdman, and not CDC1551, infection appeared to have
larger regions of necrosis, which is strongly associated with hypoxia. To better
understand the mechanisms of differential hypoxia induction by these strains, we
subjected both to hypoxia in vitro. Erdman induced higher concentrations of DosR
regulon relative to CDC1551. The DosR regulon is the global regulator of
response to hypoxia in Mtb and critical for its persistence in granulomas.
Conclusions: Our results show that the response to hypoxia is a critical
mediator of virulence determination in Mtb, with potential impacts on bacillary
persistence, reactivation, and efficiency of therapeutics.
DOI: 10.1164/rccm.202112-2747OC
PMID: 35412961 [Indexed for MEDLINE]
19. Cancer Discov. 2022 Jul 6;12(7):1676-1689. doi: 10.1158/2159-8290.CD-21-1615.
Sunvozertinib, a Selective EGFR Inhibitor for Previously Treated Non-Small Cell
Lung Cancer with EGFR Exon 20 Insertion Mutations.
Wang M(#)(1), Yang JC(#)(2), Mitchell PL(3), Fang J(4), Camidge DR(5), Nian
W(6), Chiu CH(7), Zhou J(8), Zhao Y(9), Su WC(10), Yang TY(11), Zhu VW(12),
Millward M(13), Fan Y(14), Huang WT(15), Cheng Y(16), Jiang L(17), Brungs D(18),
Bazhenova L(19), Lee CK(20), Gao B(21), Xu Y(1), Hsu WH(22), Zheng L(23), Jänne
PA(24).
Author information:
(1)Department of Respiratory and Critical Care Medicine, Peking Union Medical
College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical
College, No. 1 Shuaifuyuan, Dongcheng District, Beijing, China.
(2)National Taiwan University Hospital and National Taiwan University Cancer
Center, Taipei, Taiwan.
(3)Austin Hospital, Heidelberg, Melbourne, Victoria, Australia.
…
Epidermal growth factor receptor exon 20 insertion mutations (EGFRexon20ins) are
detected in approximately 2% of patients with non-small cell lung cancer
(NSCLC). Due to a lack of effective therapy, the prognosis of these patients is
typically poor. Sunvozertinib (DZD9008) was designed as an oral, potent,
irreversible, and selective EGFR tyrosine kinase inhibitor, showing activity
against EGFRexon20ins and other mutations. In both cell lines and xenograft
models, sunvozertinib shows potent antitumor activity. In the two ongoing phase
I clinical studies, sunvozertinib was tolerated up to 400 mg once daily. The
most common drug-related adverse events included diarrhea and skin rash.
Antitumor efficacy was observed at the doses of 100 mg and above in patients
with EGFRexon20ins NSCLC across different subtypes, with prior amivantamab
treatment as well as with baseline brain metastasis. The median duration of
response has not been reached.
SIGNIFICANCE: We report the discovery and early clinical development of
sunvozertinib, a potential treatment option for the unmet medical need of
EGFRexon20ins NSCLC. This article is highlighted in the In This Issue feature,
p. 1599.
©2022 The Authors; Published by the American Association for Cancer Research.
DOI: 10.1158/2159-8290.CD-21-1615
PMCID: PMC9262839
PMID: 35404393 [Indexed for MEDLINE]
20. J Clin Oncol. 2022 Jul 1;40(19):2094-2105. doi: 10.1200/JCO.21.02496. Epub 2022
Mar 8.
Lung Cancer Diagnosed Through Screening, Lung Nodule, and Neither Program: A
Prospective Observational Study of the Detecting Early Lung Cancer (DELUGE) in
the Mississippi Delta Cohort.
Osarogiagbon RU(1), Liao W(1), Faris NR(1), Meadows-Taylor M(1), Fehnel C(1),
Lane J(1), Williams SC(1), Patel AA(1), Akinbobola OA(1), Pacheco A(1), Epperson
A(1), Luttrell J(1), McCoy D(1), McHugh L(1), Signore R(1), Bishop AM(1), Tonkin
K(1)(2), Optican R(1)(2), Wright J(1)(3), Robbins T(1), Ray MA(4), Smeltzer
MP(4).
Author information:
(1)Multidisciplinary Thoracic Oncology Program, Baptist Cancer Center, Memphis,
TN.
(2)Mid-South Imaging and Therapeutics, Memphis, TN.
(3)Memphis Lung Physicians, Memphis, TN.
(4)Division of Epidemiology, Biostatistics, and Environmental Health, School of
Public Health, University of Memphis, Memphis, TN.
Comment in
2074.
PURPOSE: Lung cancer screening saves lives, but implementation is challenging.
We evaluated two approaches to early lung cancer detection-low-dose computed
tomography screening (LDCT) and program-based management of incidentally
detected lung nodules.
METHODS: A prospective observational study enrolled patients in the early
detection programs. For context, we compared them with patients managed in a
Multidisciplinary Care Program. We compared clinical stage distribution,
surgical resection rates, 3- and 5-year survival rates, and eligibility for LDCT
screening of patients diagnosed with lung cancer.
RESULTS: From 2015 to May 2021, 22,886 patients were enrolled: 5,659 in LDCT,
15,461 in Lung Nodule, and 1,766 in Multidisciplinary Care. Of 150, 698, and
1,010 patients diagnosed with lung cancer in the respective programs, 61%, 60%,
and 44% were diagnosed at clinical stage I or II, whereas 19%, 20%, and 29% were
stage IV (P = .0005); 47%, 42%, and 32% had curative-intent surgery (P < .0001);
aggregate 3-year overall survival rates were 80% (95% CI, 73 to 88) versus 64%
(60 to 68) versus 49% (46 to 53); 5-year overall survival rates were 76% (67 to
87) versus 60% (56 to 65) versus 44% (40 to 48), respectively. Only 46% of 1,858
patients with lung cancer would have been deemed eligible for LDCT by US
Preventive Services Task Force (USPSTF) 2013 criteria, and 54% by 2021 criteria.
Even if all eligible patients by USPSTF 2021 criteria had been enrolled into
LDCT, the Nodule Program would have detected 20% of the stage I-II lung cancer
in the entire cohort.
CONCLUSION: LDCT and Lung Nodule Programs are complementary, expanding access to
early lung cancer detection and curative treatment to different-risk
populations. Implementing Lung Nodule Programs may alleviate emerging
disparities in access to early lung cancer detection.
DOI: 10.1200/JCO.21.02496
PMCID: PMC9242408
PMID: 35258994 [Indexed for MEDLINE]
21. Lancet Infect Dis. 2022 Jul;22(7):e191-e196. doi: 10.1016/S1473-3099(21)00808-2. Epub 2022 Mar 3.
25 years of surveillance of drug-resistant tuberculosis: achievements,
challenges, and way forward.
Dean AS(1), Tosas Auguet O(2), Glaziou P(2), Zignol M(2), Ismail N(2), Kasaeva
T(2), Floyd K(2).
Author information:
(1)Global TB Programme, World Health Organization, Geneva, Switzerland.
Electronic address: deanan@who.int.
(2)Global TB Programme, World Health Organization, Geneva, Switzerland.
Comment in
Lancet Infect Dis. 2022 Jun;22(6):760.
Tuberculosis is second only to COVID-19 as a cause of death from a single
infectious agent. In 2020, almost 10 million people were estimated to have
developed tuberculosis and it caused 1·5 million deaths. Around a quarter of
deaths caused by antimicrobial resistance are due to rifampicin-resistant
tuberculosis. Antimicrobial resistance surveillance systems for many bacterial
pathogens are still in the early stages of implementation in many countries, and
do not yet allow for the estimation of disease burden at the national level. In
this Personal View, we present the achievements, challenges, and way forward for
the oldest and largest global antimicrobial resistance surveillance system.
Hosted by WHO since 1994, the Global Project on Anti-Tuberculosis Drug
Resistance Surveillance has served as a platform for the evaluation of the
trends in anti-tuberculosis drug resistance for over 25 years at country,
regional, and global levels. With an estimated 465 000 incident cases of
multidrug-resistant and rifampicin-resistant tuberculosis in 2019,
drug-resistant tuberculosis remains a public health crisis. The COVID-19
pandemic has reversed years of progress in providing essential tuberculosis
services and reducing disease burden. The number of people diagnosed with
drug-resistant tuberculosis has dropped by 22% since before the pandemic, and
the number of patients provided with treatment for drug-resistant tuberculosis
has dropped by 15%. Now more than ever, closing gaps in the detection of
drug-resistant tuberculosis requires investment in research and development of
new diagnostic tools and their rollout, expansion of sample transport systems,
and the implementation of data connectivity solutions.
Copyright © 2022 World Health Organization. Published by Elsevier Ltd. All
rights reserved. Published by Elsevier Ltd.. All rights reserved.
DOI: 10.1016/S1473-3099(21)00808-2
PMCID: PMC8893725
PMID: 35248168 [Indexed for MEDLINE]
