2021年
No.8
Medical Abstracts
Filters applied: from 2021/7/1 - 2021/7/31
Key words: tuberculosis ; lung cancer
1. Cell. 2021 Aug 19;184(17):4579-4592.e24. doi: 10.1016/j.cell.2021.06.033. Epub
2021 Jul 22.
Genome-wide gene expression tuning reveals diverse vulnerabilities of
M.tuberculosis.
Bosch B(1), DeJesus MA(1), Poulton NC(1), Zhang W(2), Engelhart CA(3), Zaveri
A(3), Lavalette S(3), Ruecker N(3), Trujillo C(3), Wallach JB(3), Li S(1), Ehrt
S(3), Chait BT(2), Schnappinger D(4), Rock JM(5).
Author information:
(1)Laboratory of Host-Pathogen Biology, The Rockefeller University, New York, NY
10065, USA.
(2)Laboratory of Mass Spectrometry and Gaseous Ion Chemistry, The Rockefeller
University, New York, NY 10065, USA.
(3)Department of Microbiology and Immunology, Weill Cornell Medicine, New York,
NY 10065, USA.
(4)Department of Microbiology and Immunology, Weill Cornell Medicine, New York,
NY 10065, USA. Electronic address: dis2003@med.cornell.edu.
(5)Laboratory of Host-Pathogen Biology, The Rockefeller University, New York, NY
10065, USA. Electronic address: rock@rockefeller.edu.
Antibacterial agents target the products of essential genes but rarely achieve
complete target inhibition. Thus, the all-or-none definition of essentiality
afforded by traditional genetic approaches fails to discern the most attractive
bacterial targets: those whose incomplete inhibition results in major fitness
costs. In contrast, gene "vulnerability" is a continuous, quantifiable trait
that relates the magnitude of gene inhibition to the effect on bacterial
fitness. We developed a CRISPR interference-based functional genomics method to
systematically titrate gene expression in Mycobacterium tuberculosis (Mtb) and
monitor fitness outcomes. We identified highly vulnerable genes in various
processes, including novel targets unexplored for drug discovery. Equally
important, we identified invulnerable essential genes, potentially explaining
failed drug discovery efforts. Comparison of vulnerability between the reference
and a hypervirulent Mtb isolate revealed incomplete conservation of
vulnerability and that differential vulnerability can predict differential
antibacterial susceptibility. Our results quantitatively redefine essential
bacterial processes and identify high-value targets for drug development.
Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.cell.2021.06.033
PMCID: PMC8382161
PMID: 34297925
2. Nature. 2021 Jul;595(7868):578-584. doi: 10.1038/s41586-021-03651-8. Epub 2021
Jun 16.
Tissue-resident macrophages provide a pro-tumorigenic niche to early NSCLC
cells.
Casanova-Acebes M(1)(2)(3)(4), Dalla E(#)(5)(6)(7)(8), Leader AM(#)(9)(10)(11),
LeBerichel J(#)(9)(10)(11), Nikolic J(12), Morales BM(13), Brown M(13), Chang
C(9)(10)(11), Troncoso L(9)(10)(11), Chen ST(9)(10)(11), Sastre-Perona
A(14)(15), Park MD(9)(10)(11), Tabachnikova A(9)(10)(11), Dhainaut
M(10)(11)(16), Hamon P(9)(10)(11), Maier B(9)(10)(11)(17), Sawai CM(18),
Agulló-Pascual E(19), Schober M(14), Brown BD(10)(11)(16)(20), Reizis B(21),
Marron T(9)(10)(11)(5)(22), Kenigsberg E(10)(20), Moussion C(13), Benaroch
P(12), Aguirre-Ghiso JA(9)(10)(11)(5)(6)(7)(8), Merad M(23)(24)(25)(26).
Author information:
(1)Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai,
New York, NY, USA. mcasanova@cnio.es.
(2)Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New
York, NY, USA. mcasanova@cnio.es.
(3)Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York,
NY, USA. mcasanova@cnio.es.
…
Comment in
Nat Immunol. 2021 Sep;22(9):1078-1079.
Macrophages have a key role in shaping the tumour microenvironment (TME), tumour
immunity and response to immunotherapy, which makes them an important target for
cancer treatment1,2. However, modulating macrophages has proved extremely
difficult, as we still lack a complete understanding of the molecular and
functional diversity of the tumour macrophage compartment. Macrophages arise
from two distinct lineages. Tissue-resident macrophages self-renew locally,
independent of adult haematopoiesis3-5, whereas short-lived monocyte-derived
macrophages arise from adult haematopoietic stem cells, and accumulate mostly in
inflamed lesions1. How these macrophage lineages contribute to the TME and
cancer progression remains unclear. To explore the diversity of the macrophage
compartment in human non-small cell lung carcinoma (NSCLC) lesions, here we
performed single-cell RNA sequencing of tumour-associated leukocytes. We
identified distinct populations of macrophages that were enriched in human and
mouse lung tumours. Using lineage tracing, we discovered that these macrophage
populations differ in origin and have a distinct temporal and spatial
distribution in the TME. Tissue-resident macrophages accumulate close to tumour
cells early during tumour formation to promote epithelial-mesenchymal transition
and invasiveness in tumour cells, and they also induce a potent regulatory T
cell response that protects tumour cells from adaptive immunity. Depletion of
tissue-resident macrophages reduced the numbers and altered the phenotype of
regulatory T cells, promoted the accumulation of CD8+ T cells and reduced tumour
invasiveness and growth. During tumour growth, tissue-resident macrophages
became redistributed at the periphery of the TME, which becomes dominated by
monocyte-derived macrophages in both mouse and human NSCLC. This study
identifies the contribution of tissue-resident macrophages to early lung cancer
and establishes them as a target for the prevention and treatment of early lung
cancer lesions.
© 2021. The Author(s), under exclusive licence to Springer Nature Limited.
DOI: 10.1038/s41586-021-03651-8
PMID: 34135508
3. CA Cancer J Clin. 2021 Jul;71(4):299-314. doi: 10.3322/caac.21671. Epub 2021 May
20.
Racial and socioeconomic disparities in lung cancer screening in the United
States: A systematic review.
Sosa E(1), D'Souza G(2), Akhtar A(2), Sur M(1), Love K(3), Duffels J(3), Raz
DJ(2), Kim JY(2), Sun V(1)(2), Erhunmwunsee L(1)(2).
Author information:
(1)Department of Populations Sciences, City of Hope National Medical Center,
Duarte, California.
(2)Department of Surgery, City of Hope Comprehensive Cancer Center, Duarte,
California.
(3)Division of Library Services, City of Hope National Medical Center, Duarte,
California.
Nonsmall cell lung cancer (NSCLC) is the leading cause of cancer deaths. Lung
cancer screening (LCS) reduces NSCLC mortality; however, a lack of diversity in
LCS studies may limit the generalizability of the results to marginalized groups
who face higher risk for and worse outcomes from NSCLC. Identifying sources of
inequity in the LCS pipeline is essential to reduce disparities in NSCLC
outcomes. The authors searched 3 major databases for studies published from
January 1, 2010 to February 27, 2020 that met the following criteria: 1)
included screenees between ages 45 and 80 years who were current or former
smokers, 2) written in English, 3) conducted in the United States, and 4)
discussed socioeconomic and race-based LCS outcomes. Eligible studies were
assessed for risk of bias. Of 3721 studies screened, 21 were eligible. Eligible
studies were evaluated, and their findings were categorized into 3 themes
related to LCS disparities faced by Black and socioeconomically disadvantaged
individuals: 1) eligibility; 2) utilization, perception, and utility; and 3)
postscreening behavior and care. Disparities in LCS exist along racial and
socioeconomic lines. There are several steps along the LCS pipeline in which
Black and socioeconomically disadvantaged individuals miss the potential
benefits of LCS, resulting in increased mortality. This study identified
potential sources of inequity that require further investigation. The authors
recommend the implementation of prospective trials that evaluate eligibility
criteria for underserved groups and the creation of interventions focused on
improving utilization and follow-up care to decrease LCS disparities.
© 2021 The Authors. CA: A Cancer Journal for Clinicians published by Wiley
Periodicals LLC on behalf of American Cancer Society.
DOI: 10.3322/caac.21671
PMCID: PMC8266751
PMID: 34015860
4. Cancer Cell. 2021 Jul 20:S1535-6108(21)00382-2. doi:
10.1016/j.ccell.2021.07.005. Online ahead of print.
Bevacizumab plus erlotinib in Chinese patients with untreated, EGFR-mutated,
advanced NSCLC (ARTEMIS-CTONG1509): A multicenter phase 3 study.
Zhou Q(1), Xu CR(1), Cheng Y(2), Liu YP(3), Chen GY(4), Cui JW(5), Yang N(6),
Song Y(7), Li XL(8), Lu S(9), Zhou JY(10), Ma ZY(11), Yu SY(12), Huang C(13),
Shu YQ(14), Wang Z(1), Yang JJ(1), Tu HY(1), Zhong WZ(1), Wu YL(15).
Author information:
(1)Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer,
Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital and
Guangdong Academy of Medical Sciences, Guangzhou, China.
(2)Department of Thoracic Oncology, Jilin Provincial Tumor Hospital, Changchun,
China.
(3)Department of Medical Oncology, First Hospital of China Medical University,
Shenyang, China.
…
Dual inhibition of epidermal growth factor receptor (EGFR) and vascular
endothelial growth factor (VEGF) pathways may delay therapeutic resistance in
advanced non-small cell lung cancer (NSCLC). This phase 3 study investigated the
efficacy and safety of an erlotinib plus bevacizumab regimen in untreated
patients with advanced NSCLC. In total, 311 patients received bevacizumab plus
erlotinib (n = 157) or erlotinib only (n = 154). Progression-free survival (PFS)
was 17.9 months (95% confidence interval [CI], 15.2-19.9) for bevacizumab plus
erlotinib and 11.2 months (95% CI, 9.7-13.8) for erlotinib only (hazard ratio
[HR] = 0.55; 95% CI, 0.41-0.73; p < 0.001). A brain metastases subgroup treated
with bevacizumab plus erlotinib also showed improved PFS (HR = 0.48; 95% CI,
0.27-0.84; p = 0.008). Grade ≥3 treatment-related adverse events occurred in 86
(54.8%) and 40 (26.1%) patients, respectively. Bevacizumab plus erlotinib
significantly improved PFS in patients with untreated metastatic EGFR-mutated
NSCLC, including those with brain metastases at baseline.
Copyright © 2021 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ccell.2021.07.005
PMID: 34388377
5. Cancer Cell. 2021 Jul 27:S1535-6108(21)00383-4. doi:
10.1016/j.ccell.2021.07.006. Online ahead of print.
Targeting Aurora B kinase prevents and overcomes resistance to EGFR inhibitors
in lung cancer by enhancing BIM- and PUMA-mediated apoptosis.
Tanaka K(1), Yu HA(2), Yang S(1), Han S(1), Selcuklu SD(1), Kim K(3), Ramani
S(1), Ganesan YT(1), Moyer A(4), Sinha S(1), Xie Y(5), Ishizawa K(1),
Osmanbeyoglu HU(6), Lyu Y(7), Roper N(8), Guha U(9), Rudin CM(10), Kris MG(2),
Hsieh JJ(7), Cheng EH(11).
Author information:
(1)Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer
Center, New York, NY 10065, USA.
(2)Thoracic Oncology Service, Department of Medicine, Memorial Sloan Kettering
Cancer Center, Department of Medicine, Weill Cornell Medical College, New York,
NY 10065, USA.
(3)Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
10065, USA.
…
The clinical success of EGFR inhibitors in EGFR-mutant lung cancer is limited by
the eventual development of acquired resistance. We hypothesize that enhancing
apoptosis through combination therapies can eradicate cancer cells and reduce
the emergence of drug-tolerant persisters. Through high-throughput screening of
a custom library of ∼1,000 compounds, we discover Aurora B kinase inhibitors as
potent enhancers of osimertinib-induced apoptosis. Mechanistically, Aurora B
inhibition stabilizes BIM through reduced Ser87 phosphorylation, and
transactivates PUMA through FOXO1/3. Importantly, osimertinib resistance caused
by epithelial-mesenchymal transition (EMT) activates the ATR-CHK1-Aurora B
signaling cascade and thereby engenders hypersensitivity to respective kinase
inhibitors by activating BIM-mediated mitotic catastrophe. Combined inhibition
of EGFR and Aurora B not only efficiently eliminates cancer cells but also
overcomes resistance beyond EMT.
Copyright © 2021 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ccell.2021.07.006
PMID: 34388376
6. Lancet Oncol. 2021 Jul;22(7):959-969. doi: 10.1016/S1470-2045(21)00247-3. Epub
2021 Jun 9.
Pralsetinib for RET fusion-positive non-small-cell lung cancer (ARROW): a
multi-cohort, open-label, phase 1/2 study.
Gainor JF(1), Curigliano G(2), Kim DW(3), Lee DH(4), Besse B(5), Baik CS(6),
Doebele RC(7), Cassier PA(8), Lopes G(9), Tan DSW(10), Garralda E(11), Paz-Ares
LG(12), Cho BC(13), Gadgeel SM(14), Thomas M(15), Liu SV(16), Taylor MH(17),
Mansfield AS(18), Zhu VW(19), Clifford C(20), Zhang H(21), Palmer M(22), Green
J(23), Turner CD(23), Subbiah V(24).
Author information:
(1)Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
Electronic address: jgainor@partners.org.
(2)Department of Oncology and Hemato-Oncology, University of Milan and European
Institute of Oncology, IRCCS, Milan, Italy.
(3)Department of Internal Medicine, Seoul National University College of
Medicine and Seoul National University Hospital, Seoul, South Korea.
…
Erratum in
Lancet Oncol. 2021 Aug;22(8):e347.
BACKGROUND: Oncogenic alterations in RET have been identified in multiple tumour
types, including 1-2% of non-small-cell lung cancers (NSCLCs). We aimed to
assess the safety, tolerability, and antitumour activity of pralsetinib, a
highly potent, oral, selective RET inhibitor, in patients with RET
fusion-positive NSCLC.
METHODS: ARROW is a multi-cohort, open-label, phase 1/2 study done at 71 sites
(community and academic cancer centres) in 13 countries (Belgium, China, France,
Germany, Hong Kong, Italy, Netherlands, Singapore, South Korea, Spain, Taiwan,
the UK, and the USA). Patients aged 18 years or older with locally advanced or
metastatic solid tumours, including RET fusion-positive NSCLC, and an Eastern
Cooperative Oncology Group performance status of 0-2 (later limited to 0-1 in a
protocol amendment) were enrolled. In phase 2, patients received 400 mg
once-daily oral pralsetinib, and could continue treatment until disease
progression, intolerance, withdrawal of consent, or investigator decision. Phase
2 primary endpoints were overall response rate (according to Response Evaluation
Criteria in Solid Tumours version 1·1 and assessed by blinded independent
central review) and safety. Tumour response was assessed in patients with RET
fusion-positive NSCLC and centrally adjudicated baseline measurable disease who
had received platinum-based chemotherapy or were treatment-naive because they
were ineligible for standard therapy. This ongoing study is registered with
ClinicalTrials.gov, NCT03037385, and enrolment of patients with treatment-naive
RET fusion-positive NSCLC was ongoing at the time of this interim analysis.
FINDINGS: Of 233 patients with RET fusion-positive NSCLC enrolled between March
17, 2017, and May 22, 2020 (data cutoff), 92 with previous platinum-based
chemotherapy and 29 who were treatment-naive received pralsetinib before July
11, 2019 (efficacy enrolment cutoff); 87 previously treated patients and 27
treatment-naive patients had centrally adjudicated baseline measurable disease.
Overall responses were recorded in 53 (61%; 95% CI 50-71) of 87 patients with
previous platinum-based chemotherapy, including five (6%) patients with a
complete response; and 19 (70%; 50-86) of 27 treatment-naive patients, including
three (11%) with a complete response. In 233 patients with RET fusion-positive
NSCLC, common grade 3 or worse treatment-related adverse events were neutropenia
(43 patients [18%]), hypertension (26 [11%]), and anaemia (24 [10%]); there were
no treatment-related deaths in this population.
INTERPRETATION: Pralsetinib is a new, well-tolerated, promising, once-daily oral
treatment option for patients with RET fusion-positive NSCLC.
FUNDING: Blueprint Medicines.
Copyright © 2021 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1470-2045(21)00247-3
PMID: 34118197 [Indexed for MEDLINE]
7. Nat Med. 2021 Jul;27(7):1171-1177. doi: 10.1038/s41591-021-01358-x. Epub 2021
May 24.
Prisons as ecological drivers of fitness-compensated multidrug-resistant
Mycobacterium tuberculosis.
Gygli SM(#)(1)(2), Loiseau C(#)(1)(2), Jugheli L(1)(2)(3), Adamia N(3), Trauner
A(1)(2), Reinhard M(1)(2), Ross A(1)(2), Borrell S(1)(2), Aspindzelashvili R(3),
Maghradze N(1)(2)(3), Reither K(1)(2), Beisel C(4), Tukvadze N(1)(2)(3),
Avaliani Z(3), Gagneux S(5)(6).
Author information:
(1)Swiss Tropical and Public Health Institute, Basel, Switzerland.
(2)University of Basel, Basel, Switzerland.
(3)National Center for Tuberculosis and Lung Diseases (NCTLD), Tbilisi, Georgia.
(4)Department of Biosystems Science and Engineering, ETH Zürich, Basel,
Switzerland.
(5)Swiss Tropical and Public Health Institute, Basel, Switzerland.
sebastien.gagneux@swisstph.ch.
(6)University of Basel, Basel, Switzerland. sebastien.gagneux@swisstph.ch.
(#)Contributed equally
Erratum in
Nat Med. 2021 Jun 1;:
Multidrug-resistant tuberculosis (MDR-TB) accounts for one third of the annual
deaths due to antimicrobial resistance1. Drug resistance-conferring mutations
frequently cause fitness costs in bacteria2-5. Experimental work indicates that
these drug resistance-related fitness costs might be mitigated by compensatory
mutations6-10. However, the clinical relevance of compensatory evolution remains
poorly understood. Here we show that, in the country of Georgia, during a 6-year
nationwide study, 63% of MDR-TB was due to patient-to-patient transmission.
Compensatory mutations and patient incarceration were independently associated
with transmission. Furthermore, compensatory mutations were overrepresented
among isolates from incarcerated individuals that also frequently spilled over
into the non-incarcerated population. As a result, up to 31% of MDR-TB in
Georgia was directly or indirectly linked to prisons. We conclude that prisons
fuel the epidemic of MDR-TB in Georgia by acting as ecological drivers of
fitness-compensated strains with high transmission potential.
© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.
DOI: 10.1038/s41591-021-01358-x
PMID: 34031604
8. Mol Aspects Med. 2021 Jul 31:101002. doi: 10.1016/j.mam.2021.101002. Online
ahead of print.
Protein synthesis in Mycobacterium tuberculosis as a potential target for
therapeutic interventions.
Kumar N(1), Sharma S(1), Kaushal PS(2).
Author information:
(1)Structural Biology & Translation Regulation Laboratory, Regional Centre for
Biotechnology, NCR Biotech Science Cluster, Faridabad, 121 001, India.
(2)Structural Biology & Translation Regulation Laboratory, Regional Centre for
Biotechnology, NCR Biotech Science Cluster, Faridabad, 121 001, India.
Electronic address: prem.kaushal@rcb.res.in.
Mycobacterium tuberculosis (Mtb) causes one of humankind's deadliest diseases,
tuberculosis. Mtb protein synthesis machinery possesses several unique
species-specific features, including its ribosome that carries two mycobacterial
specific ribosomal proteins, bL37 and bS22, and ribosomal RNA segments. Since
the protein synthesis is a vital cellular process that occurs on the ribosome, a
detailed knowledge of the structure and function of mycobacterial ribosomes is
essential to understand the cell's proteome by translation regulation. Like in
many bacterial species such as Bacillus subtilis and Streptomyces coelicolor,
two distinct populations of ribosomes have been identified in Mtb. Under
low-zinc conditions, Mtb ribosomal proteins S14, S18, L28, and L33 are replaced
with their non-zinc binding paralogues. Depending upon the nature of
physiological stress, species-specific modulation of translation by stress
factors and toxins that interact with the ribosome have been reported. In
addition, about one-fourth of messenger RNAs in mycobacteria have been reported
to be leaderless, i.e., without 5' UTR regions. However, the mechanism by which
they are recruited to the Mtb ribosome is not understood. In this review, we
highlight the mycobacteria-specific features of the translation apparatus and
propose exploiting these features to improve the efficacy and specificity of
existing antibiotics used to treat tuberculosis.
Copyright © 2021 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.mam.2021.101002
PMID: 34344520
9. 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.
…
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
10. Nat Commun. 2021 Jul 16;12(1):4360. doi: 10.1038/s41467-021-24537-3.
Glucocorticoid receptor triggers a reversible drug-tolerant dormancy state with
acquired therapeutic vulnerabilities in lung cancer.
Prekovic S(#)(1), Schuurman K(#)(2), Mayayo-Peralta I(2), Manjón AG(3), Buijs
M(2), Yavuz S(2), Wellenstein MD(4), Barrera A(5), Monkhorst K(6), Huber
A(2)(7), Morris B(8), Lieftink C(8), Chalkiadakis T(2), Alkan F(2), Silva J(2),
Győrffy B(9)(10), Hoekman L(11), van den Broek B(12), Teunissen H(13), Debets
DO(14), Severson T(2), Jonkers J(15), Reddy T(5), de Visser KE(4), Faller W(2),
Beijersbergen R(8), Altelaar M(11)(14), de Wit E(13), Medema R(3), Zwart
W(16)(17).
Author information:
(1)Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute,
Amsterdam, The Netherlands. s.prekovic@nki.nl.
(2)Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute,
Amsterdam, The Netherlands.
(3)Division of Cell Biology, Oncode Institute, The Netherlands Cancer Institute,
Amsterdam, The Netherlands.
…
The glucocorticoid receptor (GR) regulates gene expression, governing aspects of
homeostasis, but is also involved in cancer. Pharmacological GR activation is
frequently used to alleviate therapy-related side-effects. While prior studies
have shown GR activation might also have anti-proliferative action on tumours,
the underpinnings of glucocorticoid action and its direct effectors in
non-lymphoid solid cancers remain elusive. Here, we study the mechanisms of
glucocorticoid response, focusing on lung cancer. We show that GR activation
induces reversible cancer cell dormancy characterised by anticancer drug
tolerance, and activation of growth factor survival signalling accompanied by
vulnerability to inhibitors. GR-induced dormancy is dependent on a single
GR-target gene, CDKN1C, regulated through chromatin looping of a GR-occupied
upstream distal enhancer in a SWI/SNF-dependent fashion. These insights
illustrate the importance of GR signalling in non-lymphoid solid cancer biology,
particularly in lung cancer, and warrant caution for use of glucocorticoids in
treatment of anticancer therapy related side-effects.
© 2021. The Author(s).
DOI: 10.1038/s41467-021-24537-3
PMCID: PMC8285479
PMID: 34272384 [Indexed for MEDLINE]
11. 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
12. PLoS Med. 2021 Jul 14;18(7):e1003717. doi: 10.1371/journal.pmed.1003717.
eCollection 2021 Jul.
Evaluating the impact of the nationwide public-private mix (PPM) program for
tuberculosis under National Health Insurance in South Korea: A difference in
differences analysis.
Yu S(1)(2)(3), Sohn H(4), Kim HY(2)(3), Kim H(1)(5), Oh KH(1)(6), Kim HJ(1),
Chung H(2)(3), Choi H(1)(7).
Author information:
(1)Korean Institute of Tuberculosis, Korean National Tuberculosis Association,
Cheongju, Republic of Korea.
(2)School of Health Policy & Management, College of Health Science, Korea
University, Seoul, Republic of Korea.
(3)BK21 FOUR R&E Center for Learning Health Systems, Korea University, Seoul,
Republic of Korea.
…
BACKGROUND: Public-private mix (PPM) programs on tuberculosis (TB) have a
critical role in engaging and integrating the private sector into the national
TB control efforts in order to meet the End TB Strategy targets. South Korea's
PPM program can provide important insights on the long-term impact and policy
gaps in the development and expansion of PPM as a nationwide program.
METHODS AND FINDINGS: Healthcare is privatized in South Korea, and a majority
(80.3% in 2009) of TB patients sought care in the private sector. Since 2009,
South Korea has rapidly expanded its PPM program coverage under the National
Health Insurance (NHI) scheme as a formal national program with dedicated PPM
nurses managing TB patients in both the private and public sectors. Using the
difference in differences (DID) analytic framework, we compared relative changes
in TB treatment outcomes-treatment success (TS) and loss to follow-up (LTFU)-in
the private and public sector between the 2009 and 2014 TB patient cohorts.
Propensity score matching (PSM) using the kernel method was done to adjust for
imbalances in the covariates between the 2 population cohorts. The 2009 cohort
included 6,195 (63.0% male, 37.0% female; mean age: 42.1) and 27,396 (56.1%
male, 43.9% female; mean age: 45.7) TB patients in the public and private
sectors, respectively. The 2014 cohort included 2,803 (63.2% male, 36.8% female;
mean age: 50.1) and 29,988 (56.5% male, 43.5% female; mean age: 54.7) patients.
In both the private and public sectors, the proportion of patients with transfer
history decreased (public: 23.8% to 21.7% and private: 20.8% to 17.6%), and
bacteriological confirmed disease increased (public: 48.9% to 62.3% and private:
48.8% to 58.1%) in 2014 compared to 2009. After expanding nationwide PPM,
absolute TS rates improved by 9.10% (87.5% to 93.4%) and by 13.6% (from 70.3% to
83.9%) in the public and private sectors. Relative to the public, the private
saw 4.1% (95% confidence interval [CI] 2.9% to 5.3%, p-value < 0.001) and -8.7%
(95% CI -9.7% to -7.7%, p-value<0.001) higher rates of improvement in TS and
reduction in LTFU. Treatment outcomes did not improve in patients who
experienced at least 1 transfer during their TB treatment. Study limitations
include non-longitudinal nature of our original dataset, inability to assess the
regional disparities, and verify PPM program's impact on TB mortality.
CONCLUSIONS: We found that the nationwide scale-up of the PPM program was
associated with improvements in TB treatment outcomes in the private sector in
South Korea. Centralized financial governance and regulatory mechanisms were
integral in facilitating the integration of highly diverse South Korean private
sector into the national TB control program and scaling up of the PPM
intervention nationwide. However, TB care gaps continued to exist for patients
who transferred at least once during their treatment. These programmatic gaps
may be improved through reducing administrative hurdles and making programmatic
amendments that can help facilitate management TB patients between institutions
and healthcare sectors, as well as across administrative regions.
DOI: 10.1371/journal.pmed.1003717
PMCID: PMC8318235
PMID: 34260579
13. Immunity. 2021 Aug 10;54(8):1758-1771.e7. doi: 10.1016/j.immuni.2021.06.009.
Epub 2021 Jul 12.
Macrophage and neutrophil death programs differentially confer resistance to
tuberculosis.
Stutz MD(1), Allison CC(1), Ojaimi S(1), Preston SP(1), Doerflinger M(1),
Arandjelovic P(1), Whitehead L(1), Bader SM(1), Batey D(1), Asselin-Labat ML(1),
Herold MJ(1), Strasser A(1), West NP(2), Pellegrini M(3).
Author information:
(1)The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052,
Australia; Department of Medical Biology, The University of Melbourne,
Parkville, VIC 3010, Australia.
(2)School of Chemistry and Molecular Bioscience, The University of Queensland,
St Lucia, QLD 4072, Australia.
(3)The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052,
Australia; Department of Medical Biology, The University of Melbourne,
Parkville, VIC 3010, Australia. Electronic address: pellegrini@wehi.edu.au.
Comment in
Immunity. 2021 Aug 10;54(8):1625-1627.
Apoptosis can potently defend against intracellular pathogens by directly
killing microbes and eliminating their replicative niche. However, the reported
ability of Mycobacterium tuberculosis to restrict apoptotic pathways in
macrophages in vitro has led to apoptosis being dismissed as a host-protective
process in tuberculosis despite a lack of in vivo evidence. Here we define
crucial in vivo functions of the death receptor-mediated and BCL-2-regulated
apoptosis pathways in mediating protection against tuberculosis by eliminating
distinct populations of infected macrophages and neutrophils and priming T cell
responses. We further show that apoptotic pathways can be targeted
therapeutically with clinical-stage compounds that antagonize inhibitor of
apoptosis (IAP) proteins to promote clearance of M. tuberculosis in mice. These
findings reveal that any inhibition of apoptosis by M. tuberculosis is
incomplete in vivo, advancing our understanding of host-protective responses to
tuberculosis (TB) and revealing host pathways that may be targetable for
treatment of disease.
Copyright © 2021 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.immuni.2021.06.009
PMID: 34256013
14. Am J Respir Crit Care Med. 2021 Jul 12. doi: 10.1164/rccm.202011-4063OC. Online
ahead of print.
Air Pollution, Genetic Factors and the Risk of Lung Cancer: A Prospective Study
in the UK Biobank.
Huang Y(1), Zhu M(1)(2)(3), Ji M(1), Fan J(1), Xie J(1), Wei X(1), Jiang X(1),
Xu J(4), Chen L(4), Yin R(3), Wang Y(1)(3), Dai J(1)(2), Jin G(1)(2), Xu L(3),
Hu Z(1)(2), Ma H(1)(5), Shen H(1)(2)(6).
Author information:
(1)Nanjing Medical University School of Public Health, 572407, Department of
Epidemiology, Center for Global Health, Nanjing, China.
(2)Nanjing Medical University, 12461, Jiangsu Key Lab of Cancer Biomarkers,
Prevention and Treatment, Collaborative Innovation Center for Cancer
Personalized Medicine, Nanjing, China.
(3)Jiangsu Institute of Cancer Research, 26481, Department of Thoracic Surgery,
Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Jiangsu
Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University,
Nanjing, China.
…
Rationale: Both genetic and environmental factors contribute to lung cancer, but
the degree to which air pollution modifies the impact of genetic susceptibility
on lung cancer remains unknown. Objectives: To investigate whether air pollution
and genetic factors jointly contribute to incident lung cancer. Methods: We
analyzed data from 455,974 participants (53% women) without previous cancer at
baseline in the UK Biobank. The concentrations of particulate matter (PM2.5,
PMcoarse and PM10), nitrogen dioxide (NO2), and nitrogen oxides (NOx) were
estimated by land-use regression models, and the association between air
pollutants and incident lung cancer was investigated using a Cox proportional
hazard model. Furthermore, we constructed a polygenic risk score and evaluated
whether air pollutants modified the effect of genetic susceptibility on the
development of lung cancer. Measurements and Main Results: The results showed
significant associations between the risk of lung cancer and PM2.5 (hazard ratio
[HR]: 1.63, 95% confidence interval [CI]: 1.33-2.01; per 5 μg/m3), PM10 (1.53,
1.20-1.96; per 10 μg/m3), NO2 (1.10, 1.05-1.15; per 10 μg/m3), and NOx (1.13,
1.07-1.18; per 20 μg/m3). There were additive interactions between air
pollutants and the genetic risk. Compared with participants with low genetic
risk and low air pollution, those with high air pollution and high genetic risk
had the highest risk of lung cancer (PM2.5: HR: 1.71, 95% CI:1.45-2.02; PM10:
1.77, 1.50-2.10; NO2: 1.77, 1.42-2.22; NOx: 1.67, 1.43-1.95). Conclusion:
Long-term exposure to air pollution may increase the risk of lung cancer,
especially in those with high genetic risk.
DOI: 10.1164/rccm.202011-4063OC
PMID: 34252012
15. 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.
…
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
16. J Clin Invest. 2021 Jul 15;131(14):e140073. doi: 10.1172/JCI140073.
Monocyte metabolic transcriptional programs associate with resistance to
tuberculin skin test/interferon-γ release assay conversion.
Simmons JD(1), Van PT(2), Stein CM(3)(4), Chihota V(5)(6), Ntshiqa T(6),
Maenetje P(6), Peterson GJ(1), Reynolds A(1), Benchek P(3), Velen K(6), Fielding
KL(5)(7), Grant AD(5)(7)(8), Graustein AD(1), Nguyen FK(1), Seshadri C(1),
Gottardo R(2), Mayanja-Kizza H(9), Wallis RS(6), Churchyard G(6), Boom WH(4),
Hawn TR(1).
Author information:
(1)TB Research and Training Center, Department of Medicine, University of
Washington, Seattle, Washington, USA.
(2)Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
(3)Department of Population & Quantitative Health Sciences and.
…
After extensive exposure to Mycobacterium tuberculosis (Mtb), most individuals
acquire latent Mtb infection (LTBI) defined by a positive tuberculin skin test
(TST) or interferon-γ release assay (IGRA). To identify mechanisms of resistance
to Mtb infection, we compared transcriptional profiles from highly exposed
contacts who resist TST/IGRA conversion (resisters, RSTRs) and controls with
LTBI using RNAseq. Gene sets related to carbon metabolism and free fatty acid
(FFA) transcriptional responses enriched across 2 independent cohorts suggesting
RSTR and LTBI monocytes have distinct activation states. We compared
intracellular Mtb replication in macrophages treated with FFAs and found that
palmitic acid (PA), but not oleic acid (OA), enhanced Mtb intracellular growth.
This PA activity correlated with its inhibition of proinflammatory cytokines in
Mtb-infected cells. Mtb growth restriction in PA-treated macrophages was
restored by activation of AMP kinase (AMPK), a central host metabolic regulator
known to be inhibited by PA. Finally, we genotyped AMPK variants and found 7
SNPs in PRKAG2, which encodes the AMPK-γ subunit, that strongly associated with
RSTR status. Taken together, RSTR and LTBI phenotypes are distinguished by FFA
transcriptional programs and by genetic variation in a central metabolic
regulator, which suggests immunometabolic pathways regulate TST/IGRA conversion.
DOI: 10.1172/JCI140073
PMCID: PMC8279582
PMID: 34111032
17. Autophagy. 2021 Jul 7:1-19. doi: 10.1080/15548627.2021.1938912. Online ahead of print.
M. tuberculosis PknG manipulates host autophagy flux to promote pathogen
intracellular survival.
Ge P(1)(2), Lei Z(1)(2), Yu Y(1)(2), Lu Z(1)(2), Qiang L(1)(2), Chai Q(1), Zhang
Y(1), Zhao D(1)(2), Li B(1), Pang Y(3), Liu CH(1)(2), Wang J(1).
Author information:
(1)CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of
Microbiology, Center for Biosafety Mega-Science, Chinese Academy of Sciences,
Beijing, China.
(2)Savaid Medical School, University of Chinese Academy of Sciences, Beijing,
China.
(3)Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest
Hospital, Capital Medical University, Beijing, China.
The eukaryotic-type protein kinase G (PknG), one of the eleven eukaryotic type
serine-threonine protein kinase (STPK) in Mycobacterium tuberculosis (Mtb), is
involved in mycobacterial survival within macrophages, presumably by suppressing
phagosome and autophagosome maturation, which makes PknG an attractive drug
target. However, the exact mechanism by which PknG inhibits pathogen clearance
during mycobacterial infection remains largely unknown. Here, we show that PknG
promotes macroautophagy/autophagy induction but inhibits autophagosome
maturation, causing an overall effect of blocked autophagy flux and enhanced
pathogen intracellular survival. PknG prevents the activation of AKT (AKT
serine/threonine kinase) via competitively binding to its pleckstrin homology
(PH) domain, leading to autophagy induction. Remarkably, PknG could also inhibit
autophagosome maturation to block autophagy flux via targeting host small GTPase
RAB14. Specifically, PknG directly interacts with RAB14 to block RAB14-GTP
hydrolysis. Furthermore, PknG phosphorylates TBC1D4/AS160 (TBC1 domain family
member 4) to suppress its GTPase-activating protein (GAP) activity toward RAB14.
In macrophages and in vivo, PknG promotes Mtb intracellular survival through
blocking autophagy flux, which is dependent on RAB14. Taken together, our data
unveil a dual-functional bacterial effector that tightly regulates host
autophagy flux to benefit pathogen intracellular survival.Abbreviations: AKT:
AKT serine/threonine kinase; ATG5: autophagy related 5; BMDMs: bone
marrow-derived macrophages; DTT: dithiothreitol; FBS: fetal calf serum; GAP:
GTPase-activating protein; MOI: multiplicity of infection; Mtb: Mycobacterium
tuberculosis; MTOR: mechanistic target of rapamycin kinase; OADC: oleic
acid-albumin-dextrose-catalase; PC, phosphatidylcholine; PH: pleckstrin
homology; PI3K: phosphoinositide 3-kinase; PknG: protein kinase G;
PtdIns(3,4,5)P3: phosphatidylinositol(3,4,5)-trisphosphate; SQSTM1: sequestosome
1; STPK: serine-threonine protein kinase; TB: tuberculosis; TBC1D4: TBC1 domain
family member 4; TPR: tetratricopeptide repeat; ULK1: unc-51 like autophagy
activating kinase 1; WT: wild-type.
DOI: 10.1080/15548627.2021.1938912
PMID: 34092182
18. J Clin Oncol. 2021 Jul 20;39(21):2339-2349. doi: 10.1200/JCO.21.00174. Epub 2021
Apr 19.
Five-Year Outcomes With Pembrolizumab Versus Chemotherapy for Metastatic
Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score ≥ 50.
Reck M(1), Rodríguez-Abreu D(2), Robinson AG(3), Hui R(4), Csőszi T(5), Fülöp
A(6), Gottfried M(7), Peled N(8), Tafreshi A(9), Cuffe S(10), O'Brien M(11), Rao
S(12), Hotta K(13), Leal TA(14), Riess JW(15), Jensen E(16), Zhao B(16),
Pietanza MC(16), Brahmer JR(17).
Author information:
(1)Lung Clinic Grosshansdorf, Airway Research Center North (ARCN), member of the
German Center for Lung Research (DZL), Grosshansdorf, Germany.
(2)Complejo Hospitalario Universitario Insular Materno-Infantil de Gran Canaria,
Universidad de Las Palmas de Gran Canaria, Las Palmas, Spain.
(3)Cancer Centre of Southeastern Ontario at Kingston General Hospital, Kingston,
ON, Canada.
…
Comment in 2321.
PURPOSE: We report the first 5-year follow-up of any first-line phase III
immunotherapy trial for non-small-cell lung cancer (NSCLC). KEYNOTE-024
(ClinicalTrials.gov identifier: NCT02142738) is an open-label, randomized
controlled trial of pembrolizumab compared with platinum-based chemotherapy in
patients with previously untreated NSCLC with a programmed death ligand-1
(PD-L1) tumor proportion score of at least 50% and no sensitizing EGFR or ALK
alterations. Previous analyses showed pembrolizumab significantly improved
progression-free survival and overall survival (OS).
METHODS: Eligible patients were randomly assigned (1:1) to pembrolizumab (200 mg
once every 3 weeks for up to 35 cycles) or platinum-based chemotherapy. Patients
in the chemotherapy group with progressive disease could cross over to
pembrolizumab. The primary end point was progression-free survival; OS was a
secondary end point.
RESULTS: Three hundred five patients were randomly assigned: 154 to
pembrolizumab and 151 to chemotherapy. Median (range) time from randomization to
data cutoff (June 1, 2020) was 59.9 (55.1-68.4) months. Among patients initially
assigned to chemotherapy, 99 received subsequent anti-PD-1 or PD-L1 therapy,
representing a 66.0% effective crossover rate. Median OS was 26.3 months (95%
CI, 18.3 to 40.4) for pembrolizumab and 13.4 months (9.4-18.3) for chemotherapy
(hazard ratio, 0.62; 95% CI, 0.48 to 0.81). Kaplan-Meier estimates of the 5-year
OS rate were 31.9% for the pembrolizumab group and 16.3% for the chemotherapy
group. Thirty-nine patients received 35 cycles (ie, approximately 2 years) of
pembrolizumab, 82.1% of whom were still alive at data cutoff (approximately 5
years). Toxicity did not increase with longer treatment exposure.
CONCLUSION: Pembrolizumab provides a durable, clinically meaningful long-term OS
benefit versus chemotherapy as first-line therapy for metastatic NSCLC with
PD-L1 tumor proportion score of at least 50%.
DOI: 10.1200/JCO.21.00174
PMCID: PMC8280089
PMID: 33872070
19. Lancet Infect Dis. 2021 Jul;21(7):984-992. doi: 10.1016/S1473-3099(20)30919-1.
Epub 2021 Feb 25.
Quantifying the global number of tuberculosis survivors: a modelling study.
Dodd PJ(1), Yuen CM(2), Jayasooriya SM(3), van der Zalm MM(4), Seddon JA(5).
Author information:
(1)School of Health and Related Research, University of Sheffield, Sheffield,
UK. Electronic address: p.j.dodd@sheffield.ac.uk.
(2)Harvard Medical School, Harvard University, Boston, MA, USA; Division of
Global Health Equity, Brigham and Women's Hospital, Boston, MA, USA.
(3)Academic Unit of Primary Care, University of Sheffield, Sheffield, UK.
(4)Desmond Tutu TB Centre, Department of Paediatrics and Child Health,
Stellenbosch University, Cape Town, South Africa.
(5)Desmond Tutu TB Centre, Department of Paediatrics and Child Health,
Stellenbosch University, Cape Town, South Africa; Section of Paediatric
Infectious Diseases, Department of Infectious Diseases, Imperial College London,
London, UK.
BACKGROUND: People who survive tuberculosis face clinical and societal
consequences after recovery, including increased risks of recurrent
tuberculosis, premature death, reduced lung function, and ongoing stigma. To
describe the size of this issue, we aimed to estimate the number of individuals
who developed first-episode tuberculosis between 1980 and 2019, the number who
survived to 2020, and the number who have been treated within the past 5 years
or 2 years.
METHODS: In this modelling study, we estimated the number of people who survived
treated tuberculosis using country-level WHO data on tuberculosis case
notifications, excluding those who died during treatment. We estimated the
number of individuals surviving untreated tuberculosis using the difference
between WHO country-level incidence estimates and notifications, applying
published age-stratified and HIV-stratified case fatality ratios. To estimate
survival with time, post-tuberculosis life tables were developed for each
country-year by use of UN World Population Prospects 2019 mortality rates and
published post-tuberculosis mortality hazard ratios.
FINDINGS: Between 1980 and 2019, we estimate that 363 million people (95%
uncertainty interval [UI] 287 million-438 million) developed tuberculosis, of
whom 172 million (169 million-174 million) were treated. Individuals who
developed tuberculosis between 1980 and 2019 had lived 3480 million life-years
(95% UI 3040 million-3920 million) after tuberculosis by 2020, with survivors
younger than 15 years at the time of tuberculosis development contributing 12%
(95% UI 7-17) of these life-years. We estimate that 155 million tuberculosis
survivors (95% UI 138 million-171 million) were alive in 2020, the largest
proportion (47% [37-57]) of whom were in the WHO South-East Asia region. Of the
tuberculosis survivors who were alive in 2020, we estimate that 18% (95% UI
16-20) were treated in the past 5 years and 8% (7-9) were treated in the past 2
years.
INTERPRETATION: The number of tuberculosis survivors alive in 2020 is more than
ten times the estimated annual tuberculosis incidence. Interventions to
alleviate respiratory morbidity, screen for and prevent recurrent tuberculosis,
and reduce stigma should be immediately prioritised for recently treated
tuberculosis survivors.
FUNDING: UK Medical Research Council, the UK Department for International
Development, the National Institute for Health Research, and the European and
Developing Countries Clinical Trials Partnership.
Copyright © 2021 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1473-3099(20)30919-1
PMID: 33640076 [Indexed for MEDLINE]
20. Lancet Infect Dis. 2021 Jul;21(7):975-983. doi: 10.1016/S1473-3099(20)30770-2.
Epub 2021 Feb 12.
QT effects of bedaquiline, delamanid, or both in patients with
rifampicin-resistant tuberculosis: a phase 2, open-label, randomised, controlled
trial.
Dooley KE(1), Rosenkranz SL(2), Conradie F(3), Moran L(4), Hafner R(5), von
Groote-Bidlingmaier F(6), Lama JR(7), Shenje J(8), De Los Rios J(7), Comins
K(6), Morganroth J(9), Diacon AH(10), Cramer YS(2), Donahue K(11), Maartens
G(12); AIDS Clinical Trials Group (ACTG) A5343 DELIBERATE Study Team.
Collaborators: Alli O, Gottesman J, Guevara M, Hikuam C, Hovind L, Karlsson M,
McClaren J, McIlleron H, Murtaugh W, Rolls B, Shahkolahi A, Stone L, Tegha G,
Tenai J, Upton C, Wimbish C.
Author information:
(1)Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic
address: kdooley1@jhmi.edu.
(2)Frontier Science Foundation, Brookline, MA, USA.
(3)University of Witwatersrand, Johannesburg, South Africa.
…
Comment in
Lancet Infect Dis. 2021 Jul;21(7):894-895.
BACKGROUND: Bedaquiline and delamanid are the first drugs of new classes
registered for tuberculosis treatment in 40 years. Each can prolong the QTc
interval, with maximum effects occurring weeks after drug initiation. The
cardiac safety and microbiological activity of these drugs when co-administered
are not well-established. Our aim was to characterise the effects of
bedaquiline, delamanid, or both on the QTc interval, longitudinally over 6
months of multidrug treatment, among patients with multidrug-resistant or
rifampicin-resistant tuberculosis taking multidrug background therapy.
METHODS: ACTG A5343 is a phase 2, open-label, randomised, controlled trial in
which adults with multidrug-resistant or rifampicin-resistant tuberculosis
receiving multidrug background treatment were randomly assigned 1:1:1 by
centrally, computer-generated randomisation, by means of permuted blocks to
receive bedaquiline, delamanid, or both for 24 weeks. Participants were enrolled
at TASK in Cape Town and the South African Tuberculosis Vaccine Initiative in
Worcester, both in South Africa, and Hospital Maria Auxiliadora in Peru.
Individuals with QTc greater than 450 ms were excluded. HIV-positive
participants received dolutegravir-based antiretroviral therapy. Clofazimine was
disallowed, and levofloxacin replaced moxifloxacin. ECG in triplicate and sputum
cultures were done fortnightly. The primary endpoint was mean QTcF change from
baseline (averaged over weeks 8-24); cumulative culture conversation at week
8-24 was an exploratory endpoint. Analyses included all participants who
initiated study tuberculosis treatment (modified intention-to-treat population).
This trial is registered with ClinicalTrials.gov, NCT02583048 and is ongoing.
FINDINGS: Between Aug 26, 2016 and July 13, 2018, of 174 screened, 84
participants (28 in each treatment group, and 31 in total with HIV) were
enrolled. Two participants did not initiate study treatment (one in the
delamanid group withdrew consent and one in the bedaquiline plus delamanid
group) did not meet the eligibility criterion). Mean change in QTc from baseline
was 12·3 ms (95% CI 7·8-16·7; bedaquiline), 8·6 ms (4·0-13·1; delamanid), and
20·7 ms (16·1-25·3) (bedaquiline plus delamanid). There were no grade 3 or 4
adverse QTc prolongation events and no deaths during study treatment. Cumulative
culture conversion by week 8 was 21 (88%) of 24 (95% CI 71-97; bedaquiline), 20
(83%) of 24 (65-95; delamanid), and 19 (95%) of 20 (79-100; bedaquiline plus
delamanid) and was 92% (77-99) for bedaquiline, 91% (76-99), for delamanid, and
95% (79-100) for bedaquiline plus delamanid at 24 weeks.
INTERPRETATION: Combining bedaquiline and delamanid has a modest, no more than
additive, effect on the QTc interval, and initial microbiology data are
encouraging. This study provides supportive evidence for use of these agents
together in patients with multidrug-resistant or rifampicin-resistant
tuberculosis with normal baseline QTc values.
FUNDING: Division of AIDS, National Institutes of Health.
Copyright © 2021 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1473-3099(20)30770-2
PMCID: PMC8312310
PMID: 33587897 [Indexed for MEDLINE]
21. J Clin Oncol. 2021 Jul 20;39(21):2327-2338. doi: 10.1200/JCO.20.03579. Epub 2021
Jan 29.
Pembrolizumab Plus Ipilimumab or Placebo for Metastatic Non-Small-Cell Lung
Cancer With PD-L1 Tumor Proportion Score ≥ 50%: Randomized, Double-Blind Phase
III KEYNOTE-598 Study.
Boyer M(1), Şendur MAN(2), Rodríguez-Abreu D(3), Park K(4), Lee DH(5), Çiçin
I(6), Yumuk PF(7), Orlandi FJ(8), Leal TA(9), Molinier O(10), Soparattanapaisarn
N(11), Langleben A(12), Califano R(13), Medgyasszay B(14), Hsia TC(15), Otterson
GA(16), Xu L(17), Piperdi B(17), Samkari A(17), Reck M(18); KEYNOTE-598
Investigators.
Author information:
(1)Chris O'Brien Lifehouse, Camperdown, NSW, Australia.
(2)Ankara Yıldırım Beyazıt University, Faculty of Medicine and Ankara City
Hospital, Ankara, Turkey.
(3)Complejo Hospitalario Universitario Insular Materno-Infantil de Gran Canaria,
Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain.
…
Comment in
Nat Rev Clin Oncol. 2021 Apr;18(4):194.
PURPOSE: Pembrolizumab monotherapy is standard first-line therapy for metastatic
non-small-cell lung cancer (NSCLC) with programmed death ligand 1 (PD-L1) tumor
proportion score (TPS) ≥ 50% without actionable driver mutations. It is not
known whether adding ipilimumab to pembrolizumab improves efficacy over
pembrolizumab alone in this population.
METHODS: In the randomized, double-blind, phase III KEYNOTE-598 trial
(ClinicalTrials.gov identifier: NCT03302234), eligible patients with previously
untreated metastatic NSCLC with PD-L1 TPS ≥ 50% and no sensitizing EGFR or ALK
aberrations were randomly allocated 1:1 to ipilimumab 1 mg/kg or placebo every 6
weeks for up to 18 doses; all participants received pembrolizumab 200 mg every 3
weeks for up to 35 doses. Primary end points were overall survival and
progression-free survival.
RESULTS: Of the 568 participants, 284 were randomly allocated to each group.
Median overall survival was 21.4 months for pembrolizumab-ipilimumab versus 21.9
months for pembrolizumab-placebo (hazard ratio, 1.08; 95% CI, 0.85 to 1.37; P =
.74). Median progression-free survival was 8.2 months for
pembrolizumab-ipilimumab versus 8.4 months for pembrolizumab-placebo (hazard
ratio, 1.06; 95% CI, 0.86 to 1.30; P = .72). Grade 3-5 adverse events occurred
in 62.4% of pembrolizumab-ipilimumab recipients versus 50.2% of
pembrolizumab-placebo recipients and led to death in 13.1% versus 7.5%. The
external data and safety monitoring committee recommended that the study be
stopped for futility and that participants discontinue ipilimumab and placebo.
CONCLUSION: Adding ipilimumab to pembrolizumab does not improve efficacy and is
associated with greater toxicity than pembrolizumab monotherapy as first-line
treatment for metastatic NSCLC with PD-L1 TPS ≥ 50% and no targetable EGFR or
ALK aberrations. These data do not support use of pembrolizumab-ipilimumab in
place of pembrolizumab monotherapy in this population.
DOI: 10.1200/JCO.20.03579
PMID: 33513313
