2021年
No.4
Medical Abstracts
Filters applied: from 2021/3/1 - 2021/3/31.
1. Cell. 2021 Apr 1;184(7):1757-1774.e14. doi: 10.1016/j.cell.2021.02.046. Epub
2021 Mar 23.
A non-canonical type 2 immune response coordinates tuberculous granuloma
formation and epithelialization.
Cronan MR(1), Hughes EJ(2), Brewer WJ(3), Viswanathan G(3), Hunt EG(3), Singh
B(4), Mehra S(5), Oehlers SH(6), Gregory SG(7), Kaushal D(4), Tobin DM(8).
Author information:
(1)Department of Molecular Genetics and Microbiology, Duke University School of
Medicine, Durham, NC 27710, USA. Electronic address: cronan@mpiib-berlin.mpg.de.
(2)Department of Molecular Genetics and Microbiology, Duke University School of
Medicine, Durham, NC 27710, USA; University Program in Genetics and Genomics,
Duke University School of Medicine, Durham, NC 27710, USA.
(3)Department of Molecular Genetics and Microbiology, Duke University School of
Medicine, Durham, NC 27710, USA.
…
The central pathogen-immune interface in tuberculosis is the granuloma, a
complex host immune structure that dictates infection trajectory and physiology.
Granuloma macrophages undergo a dramatic transition in which entire epithelial
modules are induced and define granuloma architecture. In tuberculosis,
relatively little is known about the host signals that trigger this transition.
Using the zebrafish-Mycobacterium marinum model, we identify the basis of
granuloma macrophage transformation. Single-cell RNA-sequencing analysis of
zebrafish granulomas and analysis of Mycobacterium tuberculosis-infected
macaques reveal that, even in the presence of robust type 1 immune responses,
countervailing type 2 signals associate with macrophage epithelialization. We
find that type 2 immune signaling, mediated via stat6, is absolutely required
for epithelialization and granuloma formation. In mixed chimeras, stat6 acts
cell autonomously within macrophages, where it is required for epithelioid
transformation and incorporation into necrotic granulomas. These findings
establish the signaling pathway that produces the hallmark structure of
mycobacterial infection.
Copyright © 2021 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.cell.2021.02.046
PMID: 33761328
2. JAMA. 2021 Mar 9;325(10):962-970. doi: 10.1001/jama.2021.1117.
Screening for Lung Cancer: US Preventive Services Task Force Recommendation
Statement.
US Preventive Services Task Force, Krist AH(1)(2), Davidson KW(3), Mangione
CM(4), Barry MJ(5), Cabana M(6), Caughey AB(7), Davis EM(8), Donahue KE(9),
Doubeni CA(10), Kubik M(11), Landefeld CS(12), Li L(13), Ogedegbe G(14), Owens
DK(15), Pbert L(16), Silverstein M(17), Stevermer J(18), Tseng CW(19)(20), Wong
JB(21).
Author information:
(1)Fairfax Family Practice Residency, Fairfax, Virginia.
(2)Virginia Commonwealth University, Richmond.
(3)Feinstein Institute for Medical Research at Northwell Health, Manhasset, New
York.
…
Comment in
JAMA. 2021 Mar 9;325(10):939-941.
Summary for patients in
JAMA. 2021 Mar 9;325(10):1016.
IMPORTANCE: Lung cancer is the second most common cancer and the leading cause
of cancer death in the US. In 2020, an estimated 228?820 persons were diagnosed
with lung cancer, and 135?720 persons died of the disease. The most important
risk factor for lung cancer is smoking. Increasing age is also a risk factor for
lung cancer. Lung cancer has a generally poor prognosis, with an overall 5-year
survival rate of 20.5%. However, early-stage lung cancer has a better prognosis
and is more amenable to treatment.
OBJECTIVE: To update its 2013 recommendation, the US Preventive Services Task
Force (USPSTF) commissioned a systematic review on the accuracy of screening for
lung cancer with low-dose computed tomography (LDCT) and on the benefits and
harms of screening for lung cancer and commissioned a collaborative modeling
study to provide information about the optimum age at which to begin and end
screening, the optimal screening interval, and the relative benefits and harms
of different screening strategies compared with modified versions of
multivariate risk prediction models.
POPULATION: This recommendation statement applies to adults aged 50 to 80 years
who have a 20 pack-year smoking history and currently smoke or have quit within
the past 15 years.
EVIDENCE ASSESSMENT: The USPSTF concludes with moderate certainty that annual
screening for lung cancer with LDCT has a moderate net benefit in persons at
high risk of lung cancer based on age, total cumulative exposure to tobacco
smoke, and years since quitting smoking.
RECOMMENDATION: The USPSTF recommends annual screening for lung cancer with LDCT
in adults aged 50 to 80 years who have a 20 pack-year smoking history and
currently smoke or have quit within the past 15 years. Screening should be
discontinued once a person has not smoked for 15 years or develops a health
problem that substantially limits life expectancy or the ability or willingness
to have curative lung surgery. (B recommendation) This recommendation replaces
the 2013 USPSTF statement that recommended annual screening for lung cancer with
LDCT in adults aged 55 to 80 years who have a 30 pack-year smoking history and
currently smoke or have quit within the past 15 years.
DOI: 10.1001/jama.2021.1117
PMID: 33687470 [Indexed for MEDLINE]
3. Nat Med. 2021 Mar;27(3):504-514. doi: 10.1038/s41591-020-01224-2. Epub 2021 Feb
18.
Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell
lung cancer: the phase 2 randomized NEOSTAR trial.
Cascone T(1), William WN Jr(2)(3), Weissferdt A(4)(5), Leung CH(6), Lin HY(6),
Pataer A(5), Godoy MCB(7), Carter BW(7), Federico L(8), Reuben A(2), …
Author information:
(1)Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson
Cancer Center, Houston, TX, USA. tcascone@mdanderson.org.
(2)Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson
Cancer Center, Houston, TX, USA.
(3)Oncology Center, Hospital BP, a Beneficencia Portuguesa de São Paulo, São
Paulo, Brazil.
…
Ipilimumab improves clinical outcomes when combined with nivolumab in metastatic
non-small cell lung cancer (NSCLC), but its efficacy and impact on the immune
microenvironment in operable NSCLC remain unclear. We report the results of the
phase 2 randomized NEOSTAR trial (NCT03158129) of neoadjuvant nivolumab or
nivolumab + ipilimumab followed by surgery in 44 patients with operable NSCLC,
using major pathologic response (MPR) as the primary endpoint. The MPR rate for
each treatment arm was tested against historical controls of neoadjuvant
chemotherapy. The nivolumab + ipilimumab arm met the prespecified primary
endpoint threshold of 6 MPRs in 21 patients, achieving a 38% MPR rate (8/21). We
observed a 22% MPR rate (5/23) in the nivolumab arm. In 37 patients resected on
trial, nivolumab and nivolumab + ipilimumab produced MPR rates of 24% (5/21) and
50% (8/16), respectively. Compared with nivolumab, nivolumab + ipilimumab
resulted in higher pathologic complete response rates (10% versus 38%), less
viable tumor (median 50% versus 9%), and greater frequencies of effector,
tissue-resident memory and effector memory T cells. Increased abundance of gut
Ruminococcus and Akkermansia spp. was associated with MPR to dual therapy. Our
data indicate that neoadjuvant nivolumab + ipilimumab-based therapy enhances
pathologic responses, tumor immune infiltrates and immunologic memory, and
merits further investigation in operable NSCLC.
DOI: 10.1038/s41591-020-01224-2
PMID: 33603241
4. Cancer Cell. 2021 Mar 8;39(3):346-360.e7. doi: 10.1016/j.ccell.2020.12.014. Epub
2021 Jan 21.
Patterns of transcription factor programs and immune pathway activation define
four major subtypes of SCLC with distinct therapeutic vulnerabilities.
Gay CM(1), Stewart CA(1), Park EM(1), Diao L(2), Groves SM(3), Heeke S(1), Nabet
BY(4), Fujimoto J(5), Solis LM(5), Lu W(5), Xi Y(2), Cardnell RJ(1), Wang Q(2),
Fabbri G(6), Cargill KR(1), Vokes NI(1), Ramkumar K(1), Zhang B(1), Della Corte
CM(7), Robson P(8), Swisher SG(9), Roth JA(9), Glisson BS(1), Shames DS(4),
Wistuba II(5), Wang J(2), Quaranta V(3), Minna J(10), Heymach JV(1), Byers
LA(11).
Author information:
(1)Department of Thoracic/Head & Neck Medical Oncology, the University of Texas
MD Anderson Cancer Center, Houston, TX, USA.
(2)Department of Bioinformatics and Computational Biology, the University of
Texas MD Anderson Cancer Center, Houston, TX, USA.
(3)Department of Biochemistry, Vanderbilt University Medical Center, Nashville,
TN, USA.
…
Despite molecular and clinical heterogeneity, small cell lung cancer (SCLC) is
treated as a single entity with predictably poor results. Using tumor expression
data and non-negative matrix factorization, we identify four SCLC subtypes
defined largely by differential expression of transcription factors ASCL1,
NEUROD1, and POU2F3 or low expression of all three transcription factor
signatures accompanied by an Inflamed gene signature (SCLC-A, N, P, and I,
respectively). SCLC-I experiences the greatest benefit from the addition of
immunotherapy to chemotherapy, while the other subtypes each have distinct
vulnerabilities, including to inhibitors of PARP, Aurora kinases, or BCL-2.
Cisplatin treatment of SCLC-A patient-derived xenografts induces intratumoral
shifts toward SCLC-I, supporting subtype switching as a mechanism of acquired
platinum resistance. We propose that matching baseline tumor subtype to therapy,
as well as manipulating subtype switching on therapy, may enhance depth and
duration of response for SCLC patients.
Copyright © 2020 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ccell.2020.12.014
PMID: 33482121
5. Lancet Infect Dis. 2021 Mar 23:S1473-3099(20)30792-1. doi:
10.1016/S1473-3099(20)30792-1. Online ahead of print.
Food for thought: addressing undernutrition to end tuberculosis.
Sinha P(1), Lönnroth K(2), Bhargava A(3), Heysell SK(4), Sarkar S(5), Salgame
P(6), Rudgard W(7), Boccia D(8), Van Aartsen D(4), Hochberg NS(9).
Author information:
(1)Section of Infectious Diseases, Department of Medicine, Boston University
School of Medicine, Boston University, MA, USA. Electronic address:
sinha.pranay@pm.me.
(2)Department of Global Public Health, Karolinska Institutet, Stockholm, Sweden.
(3)Department of Medicine, Yenepoya Medical College, and Center for Nutrition
Studies, Yenepoya (Deemed to be University), Mangalore, India; Department of
Medicine, McGill University, Montreal, QC, Canada.
…
Tuberculosis is the leading cause of deaths from an infectious disease
worldwide. WHO's End TB Strategy is falling short of several 2020 targets.
Undernutrition is the leading population-level risk factor for tuberculosis.
Studies have consistently found that undernutrition is associated with increased
tuberculosis incidence, increased severity, worse treatment outcomes, and
increased mortality. Modelling studies support implementing nutritional
interventions for people living with tuberculosis and those at risk of
tuberculosis disease to ensure the success of the End TB Strategy. In this
Personal View, we highlight nutrition-related immunocompromisation, implications
of undernutrition for tuberculosis treatment and prevention, the role of
nutritional supplementation, pharmacokinetics and pharmacodynamics of
antimycobacterial medications in undernourished people with tuberculosis, and
the role of social protection interventions in addressing undernutrition as a
tuberculosis risk factor. To catalyse action on this insufficiently addressed
accelerant of the global tuberculosis epidemic, research should be prioritised
to understand the immunological pathways that are impaired by nutrient
deficiencies, develop tools to diagnose clinical and subclinical tuberculosis in
people who are undernourished, and understand how nutritional status affects the
efficacy of tuberculosis vaccine and therapy. Through primary research,
modelling, and implementation research, policy change should also be
accelerated, particularly in countries with a high burden of tuberculosis.
Copyright © 2021 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1473-3099(20)30792-1
PMID: 33770535
6. Lancet Infect Dis. 2021 Mar 23:S1473-3099(20)30732-5. doi:
10.1016/S1473-3099(20)30732-5. Online ahead of print.
Measuring health-care delays among privately insured patients with tuberculosis
in the USA: an observational cohort study.
El Halabi J(1), Palmer N(1), McDuffie M(1), Golub JJ(2), Fox K(1), Kohane I(1),
Farhat MR(3).
Author information:
(1)Department of Biomedical Informatics, Harvard Medical School, Boston, MA,
USA.
(2)Center for Tuberculosis Research, Johns Hopkins University, Baltimore, MD,
USA.
(3)Department of Biomedical Informatics, Harvard Medical School, Boston, MA,
USA; Division of Pulmonary and Critical Care Medicine, Massachusetts General
Hospital, Boston, MA, USA. Electronic address: maha_farhat@hms.harvard.edu.
BACKGROUND: A high index of suspicion is needed to initiate appropriate testing
for tuberculosis due to its protean symptoms, yet health-care providers in
low-incidence settings are becoming less familiar with the disease as rates
decline. We aimed to estimate delays in tuberculosis diagnosis and treatment at
the US national level between 2008 and 2016.
METHODS: In this retrospective observational cohort study, we repurposed private
insurance claims data provided by Aetna (Connecticut, USA), to measure
health-care delays in tuberculosis diagnosis in the USA in 2008-16. Active
tuberculosis was determined by diagnosis codes and the filling of
anti-tuberculosis treatment prescriptions. Health-care delays were defined as
the duration between the first health-care visit for a tuberculosis symptom and
the initiation of anti-tuberculosis treatment. We assessed if delays varied over
time, and by patient and system variables, using multivariable regression. We
estimated household tuberculosis transmission and respiratory complications
after treatment initiation.
FINDINGS: We confirmed 738 active tuberculosis cases (incidence 1·45 per 100 000
person-years) with a median health-care delay of 24 days (IQR 10-45).
Multivariable regression analysis showed that longer delays were associated with
older age (8·4% per 10 year increase [95% CI 4·0 to 13·1]; p<0·0086) and non-HIV
immunosuppression (19·2% [15·1 to 60·0]; p=0·0432). Presenting with three or
more symptoms was associated with a shorter delay (-22·5% [-39·1 to -2·0];
p=0·0415), relative to presenting with one symptom, as did use of chest imaging
(-24·9% [-37·9 to -8·9]; p<0·0098), tuberculosis nucleic acid amplification
tests (-19·2% [-32·7 to -3·1]; p=0·0241), and care by a tuberculosis specialist
provider (-17·2% [-33·1 to -22·3]; p<0·0087). Longer delays were associated with
an increased rate of respiratory complications even after controlling for
patient characteristics, and an increased rate of secondary tuberculosis among
dependents.
INTERPRETATION: In the USA, the median health-care delay for privately insured
patients with tuberculosis exceeds WHO-recommended levels of 21 days (3 weeks).
The results suggest the need for health-care provider education on best
practices in tuberculosis diagnosis, including the use of molecular tests and
the maintenance of a high index of suspicion for the disease.
FUNDING: US National Institutes of Health.
Copyright © 2021 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1473-3099(20)30732-5
PMID: 33770534
7. Am J Respir Crit Care Med. 2021 Mar 24. doi: 10.1164/rccm.202011-4239PP. Online
ahead of print.
Latent Tuberculosis: Two Centuries of Confusion.
Behr MA(1), Kaufmann E(2), Duffin J(3), Edelstein PH(4), Ramakrishnan L(5).
Author information:
(1)McGill University, 5620, Division of Infectious Diseases, Montreal, Quebec,
Canada; marcel.behr@mcgill.ca.
(2)McGill University, 5620, Montreal, Quebec, Canada.
(3)Queen's University, 4257, Kingston, Ontario, Canada.
(4)University of Pennsylvania, 6572, Philadelphia, Pennsylvania, United States.
(5)Cambridge University, 2152, Department of Medicine, Cambridge, United Kingdom
of Great Britain and Northern Ireland.
The term latent tuberculosis (TB) was coined two centuries ago to describe
post-mortem tuberculous pathology in the absence of ante-mortem tuberculosis
manifestations. However, the meaning of the term has changed with each passing
century, engendering confusion. In the early 20th century, with the advent of
microbiological assays for live tubercle bacteria, latent TB switched from the
host to refer to the bacteria from post-mortem tissues of nontuberculous hosts.
Then in the late 20th century, the definition of latent TB infection returned to
the host, this time referring to those with immunoreactivity to Mycobacterium
tuberculosis antigens. Based on this new definition, latent TB infection is
unique among bacterial infectious diseases, in that supportive evidence of the
infection state is sought by the absence of the causative bacterium and its
clinical manifestations. The use of indirect bedside and laboratory tests to
denote infection creates clinical and research confusion, as the tests for
immunoreactivity suffer from recognized limitations in sensitivity and
specificity. We propose that the concept of latent TB infection be separated
from that of tuberculous immunoreactivity in the interest of correct diagnosis
and focused treatment, correct formulation and interpretation of research
questions and better allocation of programmatic resources for TB elimination. To
this end, we suggest new terminology to course-correct our thinking about
tuberculous infection (TBI) which is subdivided into tuberculous infection-no
disease (TBInd) and the long-accepted term for the disease, tuberculosis (TB).
DOI: 10.1164/rccm.202011-4239PP
PMID: 33761302
8. Nat Commun. 2021 Mar 19;12(1):1780. doi: 10.1038/s41467-021-22057-8.
Clinical impact of subclonal EGFR T790M mutations in advanced-stage EGFR-mutant
non-small-cell lung cancers.
Vaclova T(1), Grazini U(2), Ward L(3), O'Neill D(3), Markovets A(4), Huang X(5),
Chmielecki J(4), Hartmaier R(4), Thress KS(4)(6), Smith PD(2), Barrett JC(4),
Downward J(7), de Bruin EC(8).
Author information:
(1)Translational Medicine, Oncology R&D, AstraZeneca, Cambridge, UK.
(2)Bioscience, Oncology R&D, AstraZeneca, Cambridge, UK.
(3)Discovery Science, BioPharmaceutical R&D, AstraZeneca, Cambridge, UK.
(4)Translational Medicine, Oncology R&D, AstraZeneca, Boston, MA, USA.
(5)Biometrics Oncology, Oncology R&D, AstraZeneca, Cambridge, UK.
(6)Global Marketing Diagnostics, Oncology Business, AstraZeneca, Gaithersburg,
MD, USA.
(7)Oncogene Biology, Francis Crick Institute, London, UK.
(8)Translational Medicine, Oncology R&D, AstraZeneca, Cambridge, UK.
elza.de-bruin@astrazeneca.com.
Advanced non-small-cell lung cancer (NSCLC) patients with EGFR T790M-positive
tumours benefit from osimertinib, an epidermal growth factor receptor-tyrosine
kinase inhibitor (EGFR-TKI). Here we show that the size of the EGFR
T790M-positive clone impacts response to osimertinib. T790M subclonality, as
assessed by a retrospective NGS analysis of 289 baseline plasma ctDNA samples
from T790M-positive advanced NSCLC patients from the AURA3 phase III trial, is
associated with shorter progression-free survival (PFS), both in the osimertinib
and the chemotherapy-treated patients. Both baseline and longitudinal ctDNA
profiling indicate that the T790M subclonal tumours are enriched for PIK3CA
alterations, which we demonstrate to confer resistance to osimertinib in vitro
that can be partially reversed by PI3K pathway inhibitors. Overall, our results
elucidate the impact of tumour heterogeneity on response to osimertinib in
advanced stage NSCLC patients and could help define appropriate combination
therapies in these patients.
DOI: 10.1038/s41467-021-22057-8
PMID: 33741979 [Indexed for MEDLINE]
9. Immunol Rev. 2021 Mar 12. doi: 10.1111/imr.12959. Online ahead of print.
The double-edged sword of Tregs in M tuberculosis, M avium, and M absessus
infection.
Verma D(1), Chan ED(2)(3)(4), Ordway DJ(1).
Author information:
(1)Mycobacteria Research Laboratory, Department of Microbiology, Immunology, and
Pathology, Colorado State University, Fort Collins, CO, USA.
(2)Department of Medicine, Rocky Mountain Regional Veterans Affairs Medical
Center, Denver, CO, USA.
(3)Departments of Medicine and Academic Affairs, National Jewish Health, Denver,
CO, USA.
(4)Division of Pulmonary Sciences and Critical Care Medicine, University of
Colorado Anschutz Medical Campus, Denver, CO, USA.
Immunity against different Mycobacteria species targeting the lung requires
distinctly different pulmonary immune responses for bacterial clearance. Many
parameters of acquired and regulatory immune responses differ quantitatively and
qualitatively from immunity during infection with Mycobacteria species.
Nontuberculosis Mycobacteria species (NTM) Mycobacterium avium- (M avium),
Mycobacterium abscessus-(M abscessus), and the Mycobacteria species
Mycobacterium tuberculosis-(Mtb). Herein, we discuss the potential implications
of acquired and regulatory immune responses in the context of animal and human
studies, as well as future directions for efforts to treat Mycobacteria
diseases.
© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
DOI: 10.1111/imr.12959
PMID: 33713043
10. Cell Host Microbe. 2021 Mar 5:S1931-3128(21)00084-6. doi:
10.1016/j.chom.2021.02.005. Online ahead of print.
TGFβ restricts expansion, survival, and function of T cells within the
tuberculous granuloma.
Gern BH(1), Adams KN(2), Plumlee CR(2), Stoltzfus CR(3), Shehata L(3), Moguche
AO(3), Busman-Sahay K(4), Hansen SG(4), Axthelm MK(4), Picker LJ(4), Estes
JD(4), Urdahl KB(5), Gerner MY(6).
Author information:
(1)Center for Global Infectious Disease Research, Seattle Children's Research
Institute, Seattle, WA 98109, USA; Department of Pediatrics, University of
Washington, Seattle, WA 98195, USA.
(2)Center for Global Infectious Disease Research, Seattle Children's Research
Institute, Seattle, WA 98109, USA.
(3)Department of Immunology, University of Washington, Seattle, WA 98109, USA.
…
CD4 T cell effector function is required for optimal containment of
Mycobacterium tuberculosis (Mtb) infection. IFN? produced by CD4 T cells is a
key cytokine that contributes to protection. However, lung-infiltrating CD4
T cells have a limited ability to produce IFN?, and IFN? plays a lesser
protective role within the lung than at sites of Mtb dissemination. In a murine
infection model, we observed that IFN? production by Mtb-specific CD4 T cells is
rapidly extinguished within the granuloma but not within unaffected lung
regions, suggesting localized immunosuppression. We identified a signature of
TGFβ signaling within granuloma-infiltrating T cells in both mice and rhesus
macaques. Selective blockade of TGFβ signaling in T cells resulted in an
accumulation of terminally differentiated effector CD4 T cells, improved IFN?
production within granulomas, and reduced bacterial burdens. These findings
uncover a spatially localized immunosuppressive mechanism associated with Mtb
infection and provide potential targets for host-directed therapy.
Copyright © 2021. Published by Elsevier Inc.
DOI: 10.1016/j.chom.2021.02.005
PMID: 33711270
11. Immunol Rev. 2021 Mar 12. doi: 10.1111/imr.12965. Online ahead of print.
BCG-induced protection against Mycobacterium tuberculosis infection: Evidence,
mechanisms, and implications for next-generation vaccines.
Foster M(1), Hill PC(2), Setiabudiawan TP(3), Koeken VACM(3)(4), Alisjahbana
B(5), van Crevel R(3).
Author information:
(1)Department of Microbiology and Immunology, University of Otago, Dunedin, New
Zealand.
(2)Centre for International Health, University of Otago, Dunedin, New Zealand.
(3)Department of Internal Medicine and Radboud Center for Infectious Diseases
(RCI), Radboud University Medical Center, Nijmegen, The Netherlands.
(4)Department of Computational Biology for Individualised Infection Medicine,
Centre for Individualised Infection Medicine (CiiM) & TWINCORE, Joint Ventures
between The Helmholtz-Centre for Infection Research (HZI) and The Hannover
Medical School (MHH), Hannover, Germany.
(5)Tuberculosis Working Group, Faculty of Medicine, Universitas Padjadjaran,
Bandung, Indonesia.
The tuberculosis (TB) vaccine Bacillus Calmette-Guérin (BCG) was introduced 100
years ago, but as it provides insufficient protection against TB disease,
especially in adults, new vaccines are being developed and evaluated. The
discovery that BCG protects humans from becoming infected with Mycobacterium
tuberculosis (Mtb) and not just from progressing to TB disease provides
justification for considering Mtb infection as an endpoint in vaccine trials.
Such trials would require fewer participants than those with disease as an
endpoint. In this review, we first define Mtb infection and disease phenotypes
that can be used for mechanistic studies and/or endpoints for vaccine trials.
Secondly, we review the evidence for BCG-induced protection against Mtb
infection from observational and BCG re-vaccination studies, and discuss
limitations and variation of this protection. Thirdly, we review possible
underlying mechanisms for BCG efficacy against Mtb infection, including
alternative T cell responses, antibody-mediated protection, and innate immune
mechanisms, with a specific focus on BCG-induced trained immunity, which
involves epigenetic and metabolic reprogramming of innate immune cells. Finally,
we discuss the implications for further studies of BCG efficacy against Mtb
infection, including for mechanistic research, and their relevance to the design
and evaluation of new TB vaccines.
© 2021 The Authors. Immunological Reviews published by John Wiley & Sons Ltd.
DOI: 10.1111/imr.12965
PMID: 33709421
12. Nat Commun. 2021 Mar 11;12(1):1606. doi: 10.1038/s41467-021-21748-6.
Biofilm formation in the lung contributes to virulence and drug tolerance of
Mycobacterium tuberculosis.
Chakraborty P(1), Bajeli S(1), Kaushal D(2), Radotra BD(3), Kumar A(4)(5).
Author information:
(1)Council of Scientific and Industrial Research, Institute of Microbial
Technology, Chandigarh, India.
(2)Southwest National Primate Research Center, Texas Biomedical Research
Institute, San Antonio, TX, USA.
(3)Department of Histopathology, Postgraduate Institute of Medical Education and
Research, Chandigarh, India.
(4)Council of Scientific and Industrial Research, Institute of Microbial
Technology, Chandigarh, India. ashwanik@imtech.res.in.
(5)Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar
Pradesh, India. ashwanik@imtech.res.in.
Tuberculosis is a chronic disease that displays several features commonly
associated with biofilm-associated infections: immune system evasion, antibiotic
treatment failures, and recurrence of infection. However, although Mycobacterium
tuberculosis (Mtb) can form cellulose-containing biofilms in vitro, it remains
unclear whether biofilms are formed during infection in vivo. Here, we
demonstrate the formation of Mtb biofilms in animal models of infection and in
patients, and that biofilm formation can contribute to drug tolerance. First, we
show that cellulose is also a structural component of the extracellular matrix
of in vitro biofilms of fast and slow-growing nontuberculous mycobacteria. Then,
we use cellulose as a biomarker to detect Mtb biofilms in the lungs of
experimentally infected mice and non-human primates, as well as in lung tissue
sections obtained from patients with tuberculosis. Mtb strains defective in
biofilm formation are attenuated for survival in mice, suggesting that biofilms
protect bacilli from the host immune system. Furthermore, the administration of
nebulized cellulase enhances the antimycobacterial activity of isoniazid and
rifampicin in infected mice, supporting a role for biofilms in phenotypic drug
tolerance. Our findings thus indicate that Mtb biofilms are relevant to human
tuberculosis.
DOI: 10.1038/s41467-021-21748-6
PMCID: PMC7952908
PMID: 33707445 [Indexed for MEDLINE]
13. Cancer Discov. 2021 Mar 11:candisc.1385.2020. doi: 10.1158/2159-8290.CD-20-1385. Online ahead of print.
Genetic determinants of EGFR-Driven Lung Cancer Growth and Therapeutic Response
In Vivo.
Foggetti G(1), Li C(2), Cai H(3), Hellyer JA(4), Lin WY(3), Ayeni D(5), Hastings
K(6), Choi J(7), Wurtz A(8), Andrejka L(9), Maghini DG(10), Rashleigh N(8), Levy
S(8), Homer R(11), Gettinger SN(12), Diehn M(13), Wakelee HA(14), Petrov DA(15),
Winslow MM(3), Politi K(16).
Author information:
(1)Medical Oncology, Yale School of Medicine.
(2)Biology, Stanford University.
(3)Department of Genetics, Stanford University School of Medicine.
…
In lung adenocarcinoma, oncogenic EGFR mutations co-occur with many tumor
suppressor gene alterations, however the extent to which these contribute to
tumor growth and response to therapy in vivo remains largely unknown. By
quantifying the effects of inactivating ten putative tumor suppressor genes in a
mouse model of EGFR-driven Trp53-deficient lung adenocarcinoma, we found that
Apc, Rb1, or Rbm10 inactivation strongly promoted tumor growth. Unexpectedly,
inactivation of Lkb1 or Setd2 - the strongest drivers of growth in a Kras-driven
model - reduced EGFR-driven tumor growth. These results are consistent with
mutational frequencies in human EGFR- and KRAS-driven lung adenocarcinomas.
Furthermore, Keap1 inactivation reduced the sensitivity of EGFR-driven tumors to
the EGFR inhibitor osimertinib and mutations in the KEAP1 pathway were
associated with decreased time on tyrosine kinase inhibitor treatment in
patients. Our study highlights how the impact of genetic alterations differ
across oncogenic contexts and that the fitness landscape shifts upon treatment.
Copyright ©2021, American Association for Cancer Research.
DOI: 10.1158/2159-8290.CD-20-1385
PMID: 33707235
14. Am J Respir Crit Care Med. 2021 Mar 11. doi: 10.1164/rccm.202007-2634OC. Online
ahead of print.
Glycemic Trajectories After Tuberculosis Diagnosis and Treatment Outcomes of New
Tuberculosis Patients: A Prospective Study in Eastern China.
Liu Q(1), You N(1), Pan H(2), Shen Y(3), Lu P(4), Wang J(5), Lu W(1), Zhu L(6),
Martinez L(7).
Author information:
(1)Center for Disease Control and Prevention of Jiangsu Province, Department of
Chronic Communicable Disease, Nanjing, China.
(2)The Third People's Hospital of Zhenjiang Affiliated to Jiangsu University,
Department of Tuberculosis, Zhenjiang, China.
(3)University of Georgia, Department of Epidemiology and Biostatistics, Athens,
Georgia, United States.
…
Rationale Newly diagnosed tuberculosis patients often have inconsistent glycemic
measurements during and after treatment. Distinct glycemic trajectories after
tuberculosis diagnosis are not well characterized and whether patients with
stress hyperglycemia have poor treatment outcomes is not known. Objectives To
identify distinct glycemic trajectories from tuberculosis diagnosis to
post-treatment and to assess the relationship between glycemic trajectories and
tuberculosis treatment outcomes. Methods Newly diagnosed, drug-susceptible
tuberculosis patients with at least three fasting plasma glucose (FPG) tests at
tuberculosis diagnosis and during the 3rd and 6th month of treatment were
identified and included from Jiangsu Province, China. Patients were also given
an additional FPG test at two and four months post-treatment. Measurements and
Main Results Several distinct glycemic trajectories from tuberculosis diagnosis
to post-treatment were found including consistently normal glycemic testing
(43%), transient hyperglycemia (24%), erratic glycemic instability (12%),
diabetes (16%), and consistently hyperglycemic but without diabetes (6%).
Compared to participants with a consistently normal glycemic trajectory,
patients were more likely to fail treatment if they had transient hyperglycemia
(Adjusted Odds Ratio [AOR], 4.20; 95% CI, 1.57-11.25, P=0.004) or erratic
glycemic instability (AOR, 5.98; 95% CI, 2.00-17.87; P=0.001). Patients living
with diabetes also had higher risk of treatment failure (AOR, 6.56; 95%
Confidence Interval [CI], 2.22-19.35, P=0.001), and this was modified by
glycemic control and metformin use. Conclusions Among tuberculosis patients
without diabetes, glycemic changes were common and may represent an important
marker for patient response to tuberculosis treatment.
DOI: 10.1164/rccm.202007-2634OC
PMID: 33705666
15. J Clin Oncol. 2021 Mar 8:JCO2002212. doi: 10.1200/JCO.20.02212. Online ahead of print.
Nivolumab and Ipilimumab as Maintenance Therapy in Extensive-Disease Small-Cell
Lung Cancer: CheckMate 451.
Owonikoko TK(1), Park K(2), Govindan R(3), Ready N(4), Reck M(5), Peters S(6),
Dakhil SR(7), Navarro A(8), Rodríguez-Cid J(9), Schenker M(10), Lee JS(11),
Gutierrez V(12), Percent I(13), Morgensztern D(3), Barrios CH(14), Greillier
L(15), Baka S(16), Patel M(17), Lin WH(18), Selvaggi G(18), Baudelet C(18),
Baden J(18), Pandya D(18), Doshi P(18), Kim HR(19).
Author information:
(1)Winship Cancer Institute of Emory University, Atlanta, GA.
(2)Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul,
South Korea.
(3)Alvin J Siteman Cancer Center at Washington University School of Medicine, St
Louis, MO.
…
PURPOSE: In extensive-disease small-cell lung cancer (ED-SCLC), response rates
to first-line platinum-based chemotherapy are robust, but responses lack
durability. CheckMate 451, a double-blind phase III trial, evaluated nivolumab
plus ipilimumab and nivolumab monotherapy as maintenance therapy following
first-line chemotherapy for ED-SCLC.
METHODS: Patients with ED-SCLC, Eastern Cooperative Oncology Group performance
status 0-1, and no progression after ≤ 4 cycles of first-line chemotherapy were
randomly assigned (1:1:1) to nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once
every 3 weeks for 12 weeks followed by nivolumab 240 mg once every 2 weeks,
nivolumab 240 mg once every 2 weeks, or placebo for ≤ 2 years or until
progression or unacceptable toxicity. Primary end point was overall survival
(OS) with nivolumab plus ipilimumab versus placebo. Secondary end points were
hierarchically tested.
RESULTS: Overall, 834 patients were randomly assigned. The minimum follow-up was
8.9 months. OS was not significantly prolonged with nivolumab plus ipilimumab
versus placebo (hazard ratio [HR], 0.92; 95% CI, 0.75 to 1.12; P = .37; median,
9.2 v 9.6 months). The HR for OS with nivolumab versus placebo was 0.84 (95% CI,
0.69 to 1.02); the median OS for nivolumab was 10.4 months. Progression-free
survival HRs versus placebo were 0.72 for nivolumab plus ipilimumab (95% CI,
0.60 to 0.87) and 0.67 for nivolumab (95% CI, 0.56 to 0.81). A trend toward OS
benefit with nivolumab plus ipilimumab was observed in patients with tumor
mutational burden ≥ 13 mutations per megabase. Rates of grade 3-4
treatment-related adverse events were nivolumab plus ipilimumab (52.2%),
nivolumab (11.5%), and placebo (8.4%).
CONCLUSION: Maintenance therapy with nivolumab plus ipilimumab did not prolong
OS for patients with ED-SCLC who did not progress on first-line chemotherapy.
There were no new safety signals.
DOI: 10.1200/JCO.20.02212
PMID: 33683919
16. J Clin Oncol. 2021 Apr 10;39(11):1253-1263. doi: 10.1200/JCO.20.03025. Epub 2021
Mar 1.
Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Locally
Advanced or Metastatic ROS1 Fusion-Positive Non-Small-Cell Lung Cancer.
Dziadziuszko R(1), Krebs MG(2), De Braud F(3)(4), Siena S(3)(5), Drilon A(6),
Doebele RC(7), Patel MR(8), Cho BC(9), Liu SV(10), Ahn MJ(11), Chiu CH(12),
Farago AF(13), Lin CC(14), Karapetis CS(15), Li YC(16), Day BM(17), Chen D(17),
Wilson TR(17), Barlesi F(18)(19).
Author information:
(1)Medical University of Gdańsk, Gdańsk, Poland.
(2)Division of Cancer Sciences, Faculty of Biology, Medicine and Health, The
University of Manchester and The Christie NHS Foundation Trust, Manchester
Academic Health Science Centre, Manchester, United Kingdom.
(3)Department of Oncology and Hematology-Oncology, Università degli Studi di
Milano, Milan, Italy.
…
PURPOSE: Genetic rearrangements of the tyrosine receptor kinase ROS
proto-oncogene 1 (ROS1) are oncogenic drivers in non-small-cell lung cancer
(NSCLC). We report the results of an updated integrated analysis of three phase
I or II clinical trials (ALKA-372-001, STARTRK-1, and STARTRK-2) of the ROS1
tyrosine kinase inhibitor, entrectinib, in ROS1 fusion-positive NSCLC.
METHODS: The efficacy-evaluable population included adults with locally advanced
or metastatic ROS1 fusion-positive NSCLC with or without CNS metastases who
received entrectinib ≥ 600 mg orally once per day. Co-primary end points were
objective response rate (ORR) assessed by blinded independent central review and
duration of response (DoR). Secondary end points included progression-free
survival (PFS), overall survival (OS), intracranial ORR, intracranial DoR,
intracranial PFS, and safety.
RESULTS: In total, 161 patients with a follow-up of ≥ 6 months were evaluable.
The median treatment duration was 10.7 months (IQR, 6.4-17.7). The ORR was 67.1%
(n = 108, 95% CI, 59.3 to 74.3), and responses were durable (12-month DoR rate,
63%, median DoR 15.7 months). The 12-month PFS rate was 55% (median PFS 15.7
months), and the 12-month OS rate was 81% (median OS not estimable). In 24
patients with measurable baseline CNS metastases by blinded independent central
review, the intracranial ORR was 79.2% (n = 19; 95% CI, 57.9 to 92.9), the
median intracranial PFS was 12.0 months (95% CI, 6.2 to 19.3), and the median
intracranial DoR was 12.9 months (12-month rate, 55%). The safety profile in
this updated analysis was similar to that reported in the primary analysis, and
no new safety signals were found.
CONCLUSION: Entrectinib continued to demonstrate a high level of clinical
benefit for patients with ROS1 fusion-positive NSCLC, including patients with
CNS metastases.
DOI: 10.1200/JCO.20.03025
PMID: 33646820
17. J Clin Oncol. 2021 Mar 20;39(9):1040-1091. doi: 10.1200/JCO.20.03570. Epub 2021
Feb 16.
Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations: ASCO
and OH (CCO) Joint Guideline Update.
Hanna NH(1), Robinson AG(2), Temin S(3), Baker S Jr(4), Brahmer JR(5), Ellis
PM(6), Gaspar LE(7)(8), Haddad RY(9), Hesketh PJ(10), Jain D(11), Jaiyesimi
I(12), Johnson DH(13), Leighl NB(14), Moffitt PR(15), Phillips T(16), Riely
GJ(17), Rosell R(18), Schiller JH(19), Schneider BJ(20), Singh N(21), Spigel
DR(22), Tashbar J(23), Masters G(24).
Author information:
(1)Indiana University Simon Comprehensive Cancer Center, Indianapolis, IN.
(2)Kingston General Hospital, School of Medicine, Queen's University, ON,
Canada.
(3)American Society of Clinical Oncology, Alexandria, VA.
…
PURPOSE: To provide evidence-based recommendations updating the 2017 ASCO
guideline on systemic therapy for patients with stage IV non-small-cell lung
cancer (NSCLC) with driver alterations. A guideline update for systemic therapy
for patients with stage IV NSCLC without driver alterations was published
separately.
METHODS: The American Society of Clinical Oncology and Ontario Health (Cancer
Care Ontario) NSCLC Expert Panel updated recommendations based on a systematic
review of randomized controlled trials (RCTs) from December 2015 to January 2020
and meeting abstracts from ASCO 2020.
RESULTS: This guideline update reflects changes in evidence since the previous
update. Twenty-seven RCTs, 26 observational studies, and one meta-analysis
provide the evidence base (total 54). Outcomes of interest included efficacy and
safety. Additional literature suggested by the Expert Panel is discussed.
RECOMMENDATIONS: All patients with nonsquamous NSCLC should have the results of
testing for potentially targetable mutations (alterations) before implementing
therapy for advanced lung cancer, regardless of smoking status recommendations,
when possible, following other existing high-quality testing guidelines. Most
patients should receive targeted therapy for these alterations: Targeted
therapies against ROS-1 fusions, BRAF V600e mutations, RET fusions, MET exon 14
skipping mutations, and NTRK fusions should be offered to patients, either as
initial or second-line therapy when not given in the first-line setting. New or
revised recommendations include the following: Osimertinib is the optimal
first-line treatment for patients with activating epidermal growth factor
receptor mutations (exon 19 deletion, exon 21 L858R, and exon 20 T790M);
alectinib or brigatinib is the optimal first-line treatment for patients with
anaplastic lymphoma kinase fusions. For the first time, to our knowledge, the
guideline includes recommendations regarding RET, MET, and NTRK alterations.
Chemotherapy is still an option at most stages.Additional information is
available at www.asco.org/thoracic-cancer-guidelines.
DOI: 10.1200/JCO.20.03570
PMID: 33591844
18. Immunity. 2021 Mar 9;54(3):526-541.e7. doi: 10.1016/j.immuni.2021.01.003. Epub
2021 Jan 29.
Early innate and adaptive immune perturbations determine long-term severity of
chronic virus and Mycobacterium tuberculosis coinfection.
Xu W(1), Snell LM(1), Guo M(2), Boukhaled G(1), Macleod BL(1), Li M(3), Tullius
MV(4), Guidos CJ(5), Tsao MS(1), Divangahi M(6), Horwitz MA(7), Liu J(8), Brooks
DG(9).
Author information:
(1)Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G
2M9, Canada.
(2)Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G
2M9, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S
1A8, Canada.
(3)Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G
2M9, Canada; Department of Molecular Genetics, University of Toronto, Toronto,
ON M5S 1A8, Canada.
…
Chronic viral infections increase severity of Mycobacterium tuberculosis (Mtb)
coinfection. Here, we examined how chronic viral infections alter the pulmonary
microenvironment to foster coinfection and worsen disease severity. We developed
a coordinated system of chronic virus and Mtb infection that induced central
clinical manifestations of coinfection, including increased Mtb burden,
extra-pulmonary dissemination, and heightened mortality. These disease states
were not due to chronic virus-induced immunosuppression or exhaustion; rather,
increased amounts of the cytokine TNFα initially arrested pulmonary Mtb growth,
impeding dendritic cell mediated antigen transportation to the lymph node and
subverting immune-surveillance, allowing bacterial sanctuary. The cryptic Mtb
replication delayed CD4 T cell priming, redirecting T helper (Th) 1 toward Th17
differentiation and increasing pulmonary neutrophilia, which diminished
long-term survival. Temporally restoring CD4 T cell induction overcame these
diverse disease sequelae to enhance Mtb control. Thus, Mtb co-opts TNFα from the
chronic inflammatory environment to subvert immune-surveillance, avert early
immune function, and foster long-term coinfection.
Copyright © 2021 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.immuni.2021.01.003
PMCID: PMC7946746
PMID: 33515487
19. Lancet Infect Dis. 2021 Mar;21(3):354-365. doi: 10.1016/S1473-3099(20)30914-2.
Epub 2021 Jan 25.
Biomarker-guided tuberculosis preventive therapy (CORTIS): a randomised
controlled trial.
Scriba TJ(1), Fiore-Gartland A(2), Penn-Nicholson A(1), Mulenga H(1), Kimbung
Mbandi S(1), Borate B(2), Mendelsohn SC(1), Hadley K(1), Hikuam C(1), Kaskar
M(1), Musvosvi M(1), Bilek N(1), Self S(2), Sumner T(3), White RG(3), Erasmus
M(1), Jaxa L(1), Raphela R(1), Innes C(4), Brumskine W(4), Hiemstra A(5),
Malherbe ST(5), Hassan-Moosa R(6), Tameris M(1), Walzl G(5), Naidoo K(6),
Churchyard G(7), Hatherill M(8); CORTIS-01 Study Team.
Author information:
(1)South African Tuberculosis Vaccine Initiative, Institute of Infectious
Disease and Molecular Medicine, Division of Immunology, Department of Pathology,
University of Cape Town, Cape Town, South Africa.
(2)Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research
Center, Seattle, WA, USA.
(3)TB Modelling Group, TB Centre, Centre for Mathematical Modelling of
Infectious Diseases, Department of Infectious Disease Epidemiology, London
School of Hygiene & Tropical Medicine, London, UK.
…
Comment in
Lancet Infect Dis. 2021 Mar;21(3):299-300.
BACKGROUND: Targeted preventive therapy for individuals at highest risk of
incident tuberculosis might impact the epidemic by interrupting transmission. We
tested performance of a transcriptomic signature of tuberculosis (RISK11) and
efficacy of signature-guided preventive therapy in parallel, using a hybrid
three-group study design.
METHODS: Adult volunteers aged 18-59 years were recruited at five geographically
distinct communities in South Africa. Whole blood was sampled for RISK11 by
quantitative RT-PCR assay from eligible volunteers without HIV, recent previous
tuberculosis (ie, <3 years before screening), or comorbidities at screening.
RISK11-positive participants were block randomised (1:2; block size 15) to
once-weekly, directly-observed, open-label isoniazid and rifapentine for 12
weeks (ie, RISK11 positive and 3HP positive), or no treatment (ie, RISK11
positive and 3HP negative). A subset of eligible RISK11-negative volunteers were
randomly assigned to no treatment (ie, RISK11 negative and 3HP negative).
Diagnostic discrimination of prevalent tuberculosis was tested in all
participants at baseline. Thereafter, prognostic discrimination of incident
tuberculosis was tested in the untreated RISK11-positive versus RISK11-negative
groups, and treatment efficacy in the 3HP-treated versus untreated
RISK11-positive groups, during active surveillance through 15 months. The
primary endpoint was microbiologically confirmed pulmonary tuberculosis. The
primary outcome measures were risk ratio [RR] for tuberculosis of
RISK11-positive to RISK11-negative participants, and treatment efficacy. This
trial is registered with ClinicalTrials.gov, NCT02735590.
FINDINGS: 20?207 volunteers were screened, and 2923 participants were enrolled,
including RISK11-positive participants randomly assigned to 3HP (n=375) or no
3HP (n=764), and 1784 RISK11-negative participants. Cumulative probability of
prevalent or incident tuberculosis disease was 0·066 (95% CI 0·049 to 0·084) in
RISK11-positive (3HP negative) participants and 0·018 (0·011 to 0·025) in
RISK11-negative participants (RR 3·69, 95% CI 2·25-6·05) over 15 months.
Tuberculosis prevalence was 47 (4·1%) of 1139 versus 14 (0·78%) of 1984 in
RISK11-positive compared with RISK11-negative participants, respectively
(diagnostic RR 5·13, 95% CI 2·93 to 9·43). Tuberculosis incidence over 15 months
was 2·09 (95% CI 0·97 to 3·19) vs 0·80 (0·30 to 1·30) per 100 person years in
RISK11-positive (3HP-negative) participants compared with RISK11-negative
participants (cumulative incidence ratio 2·6, 95% CI 1·2 to 5·9). Serious
adverse events related to 3HP included one hospitalisation for seizures
(unintentional isoniazid overdose) and one death of unknown cause (possibly
temporally related). Tuberculosis incidence over 15 months was 1·94 (95% CI 0·35
to 3·50) versus 2·09 (95% CI 0·97 to 3·19) per 100 person-years in 3HP-treated
RISK11-positive participants compared with untreated RISK11-positive
participants (efficacy 7·0%, 95% CI -145 to 65).
INTERPRETATION: The RISK11 signature discriminated between individuals with
prevalent tuberculosis, or progression to incident tuberculosis, and individuals
who remained healthy, but provision of 3HP to signature-positive individuals
after exclusion of baseline disease did not reduce progression to tuberculosis
over 15 months.
FUNDING: Bill and Melinda Gates Foundation, South African Medical Research
Council.
Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open
Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All
rights reserved.
DOI: 10.1016/S1473-3099(20)30914-2
PMCID: PMC7907670
PMID: 33508224 [Indexed for MEDLINE]
20. Lancet Infect Dis. 2021 Mar;21(3):366-375. doi: 10.1016/S1473-3099(20)30928-2.
Epub 2021 Jan 25.
Transcriptomic signatures for diagnosing tuberculosis in clinical practice: a
prospective, multicentre cohort study.
Hoang LT(1), Jain P(1), Pillay TD(1), Tolosa-Wright M(1), Niazi U(2), Takwoingi
Y(3), Halliday A(4), Berrocal-Almanza LC(1), Deeks JJ(3), Beverley P(1), Kon
OM(5), Lalvani A(6).
Author information:
(1)Tuberculosis Research Centre, National Heart and Lung Institute, Imperial
College London, London, UK.
(2)Guy's and St Thomas' National Health Service Foundation Trust and King's
College London National Institute for Health Research Biomedical Research Centre
Translational Bioinformatics Platform, Guy's Hospital, London, UK.
(3)Test Evaluation Research Group, Institute of Applied Health Research,
University of Birmingham, Birmingham, UK; National Institute of Health Research
Birmingham Biomedical Research Centre, University Hospitals Birmingham National
Health Service Foundation Trust and University of Birmingham, Birmingham, UK.
…
BACKGROUND: Blood transcriptomic signatures for diagnosis of tuberculosis have
shown promise in case-control studies, but none have been prospectively designed
or validated in adults presenting with the full clinical spectrum of suspected
tuberculosis, including extrapulmonary tuberculosis and common differential
diagnoses that clinically resemble tuberculosis. We aimed to evaluate the
diagnostic accuracy of transcriptomic signatures in patients presenting with
clinically suspected tuberculosis in routine practice.
METHODS: The Validation of New Technologies for Diagnostic Evaluation of
Tuberculosis (VANTDET) study was nested within a prospective, multicentre cohort
study in secondary care in England (IDEA 11/H0722/8). Patients (aged ≥16 years)
suspected of having tuberculosis in the routine clinical inpatient and
outpatient setting were recruited at ten National Health Service hospitals in
England for IDEA and were included in VANTDET if they provided consent for
genomic analysis. Patients had whole blood taken for microarray analysis to
measure abundance of transcripts and were followed up for 6-12 months to
determine final diagnoses on the basis of predefined diagnostic criteria. The
diagnostic accuracy of six signatures derived from the cohort and three
previously published transcriptomic signatures with potentially high diagnostic
performance were assessed by calculating area under the receiver-operating
characteristic curves (AUC-ROCs), sensitivities, and specificities.
FINDINGS: Between Nov 25, 2011, and Dec 31, 2013, 1162 participants were
enrolled. 628 participants (aged ≥16 years) were included in the analysis, of
whom 212 (34%) had culture-confirmed tuberculosis, 89 (14%) had highly probable
tuberculosis, and 327 (52%) had tuberculosis excluded. The novel signature with
highest performance for identifying all active tuberculosis gave an AUC-ROC of
0·87 (95% CI 0·81-0·92), sensitivity of 77% (66-87), and specificity of 84%
(74-91). The best-performing published signature gave an AUC-ROC of 0·83
(0·80-0·86), sensitivity of 78% (73-83), and specificity of 76% (70-80). For
detecting highly probable tuberculosis, the best novel signature yielded results
of 0·86 (0·71-0·95), 77% (56-94%), and 77% (57-95%). None of the relevant
cohort-derived or previously published signatures achieved the WHO-defined
targets of paired sensitivity and specificity for a non-sputum-based diagnostic
test.
INTERPRETATION: In a clinically representative cohort in routine practice in a
low-incidence setting, transcriptomic signatures did not have adequate accuracy
for diagnosis of tuberculosis, including in patients with highly probable
tuberculosis where the unmet need is greatest. These findings suggest that
transcriptomic signatures have little clinical utility for diagnostic assessment
of suspected tuberculosis.
FUNDING: National Institute for Health Research.
Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open
Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd..
All rights reserved.
DOI: 10.1016/S1473-3099(20)30928-2
PMCID: PMC7907671
PMID: 33508221 [Indexed for MEDLINE]
21. J Clin Oncol. 2021 Mar 10;39(8):931-939. doi: 10.1200/JCO.20.03364. Epub 2021
Jan 27.
Radiation Therapy for Small-Cell Lung Cancer: ASCO Guideline Endorsement of an
ASTRO Guideline.
Daly ME(1), Ismaila N(2), Decker RH(3), Higgins K(4), Owen D(5), Saxena A(6),
Franklin GE(7), Donaldson D(8), Schneider BJ(9).
Author information:
(1)University of California, Davis, CA.
(2)American Society of Clinical Oncology, Alexandria, VA.
(3)Yale School of Medicine, New Haven, CT.
(4)Emory University School of Medicine, Atlanta, GA.
(5)Mayo Clinic, Rochester, MN.
(6)Weill Cornell Medicine, New York, NY.
(7)New Mexico Cancer Center, Albuquerque, NM.
(8)Dusty Joy Foundation, High Point, NC.
(9)University of Michigan School of Medicine, Ann Arbor, MI.
PURPOSE: The American Society for Radiation Oncology (ASTRO) produced an
evidence-based guideline on radiation therapy (RT) for small-cell lung cancer
(SCLC). Because of the relevance of this topic to ASCO membership, ASCO reviewed
the guideline, applying a set of procedures and policies used to critically
examine guidelines developed by other organizations.
METHODS: The ASTRO guideline on RT for SCLC was reviewed for developmental rigor
by methodologists. Then, an ASCO Expert Panel reviewed the content and the
recommendations.
RESULTS: The ASCO Expert Panel determined that the recommendations from ASTRO
guideline on RT for SCLC, published in June 2020, are clear, thorough, and based
upon the most relevant scientific evidence. ASCO endorsed ASTRO guideline on RT
for SCLC with a few discussion points.
RECOMMENDATIONS: Recommendations addressed thoracic radiotherapy for
limited-stage SCLC, role of stereotactic body radiotherapy in stage I or II
node-negative SCLC, prophylactic cranial radiotherapy, and thoracic
consolidation for extensive-stage SCLC.Additional information is available at
www.asco.org/thoracic-cancer-guidelines.
DOI: 10.1200/JCO.20.03364
PMID: 33502911
22. J Clin Oncol. 2021 Mar 1;39(7):723-733. doi: 10.1200/JCO.20.01605. Epub 2021 Jan 15.
Five-Year Outcomes From the Randomized, Phase III Trials CheckMate 017 and 057:
Nivolumab Versus Docetaxel in Previously Treated Non-Small-Cell Lung Cancer.
Borghaei H(1), Gettinger S(2), Vokes EE(3), Chow LQM(4), Burgio MA(5), de Castro
Carpeno J(6), Pluzanski A(7), Arrieta O(8), Frontera OA(9), Chiari R(10), Butts
C(11), Wójcik-Tomaszewska J(12), Coudert B(13), Garassino MC(14), Ready N(15),
Felip E(16), García MA(17), Waterhouse D(18), Domine M(19), Barlesi F(20),
Antonia S(21), Wohlleber M(22), Gerber DE(23), Czyzewicz G(24), Spigel DR(25),
Crino L(5), Eberhardt WEE(26), Li A(27), Marimuthu S(27), Brahmer J(28).
Author information:
(1)Fox Chase Cancer Center, Philadelphia, PA.
(2)Yale Comprehensive Cancer Center, New Haven, CT.
(3)Univeristy of Chicago Medicine and Biologic Sciences Division, Chicago, IL.
…
Erratum in
J Clin Oncol. 2021 Apr 1;39(10):1190.
PURPOSE: Immunotherapy has revolutionized the treatment of advanced
non-small-cell lung cancer (NSCLC). In two phase III trials (CheckMate 017 and
CheckMate 057), nivolumab showed an improvement in overall survival (OS) and
favorable safety versus docetaxel in patients with previously treated, advanced
squamous and nonsquamous NSCLC, respectively. We report 5-year pooled efficacy
and safety from these trials.
METHODS: Patients (N = 854; CheckMate 017/057 pooled) with advanced NSCLC, ECOG
PS ≤ 1, and progression during or after first-line platinum-based chemotherapy
were randomly assigned 1:1 to nivolumab (3 mg/kg once every 2 weeks) or
docetaxel (75 mg/m2 once every 3 weeks) until progression or unacceptable
toxicity. The primary end point for both trials was OS; secondary end points
included progression-free survival (PFS) and safety. Exploratory landmark
analyses were investigated.
RESULTS: After the minimum follow-up of 64.2 and 64.5 months for CheckMate 017
and 057, respectively, 50 nivolumab-treated patients and nine docetaxel-treated
patients were alive. Five-year pooled OS rates were 13.4% versus 2.6%,
respectively; 5-year PFS rates were 8.0% versus 0%, respectively.
Nivolumab-treated patients without disease progression at 2 and 3 years had an
82.0% and 93.0% chance of survival, respectively, and a 59.6% and 78.3% chance
of remaining progression-free at 5 years, respectively. Treatment-related
adverse events (TRAEs) were reported in 8 of 31 (25.8%) nivolumab-treated
patients between 3-5 years of follow-up, seven of whom experienced new events;
one (3.2%) TRAE was grade 3, and there were no grade 4 TRAEs.
CONCLUSION: At 5 years, nivolumab continued to demonstrate a survival benefit
versus docetaxel, exhibiting a five-fold increase in OS rate, with no new safety
signals. These data represent the first report of 5-year outcomes from
randomized phase III trials of a programmed death-1 inhibitor in previously
treated, advanced NSCLC.
DOI: 10.1200/JCO.20.01605
PMID: 33449799
23. J Clin Oncol. 2021 Mar 1;39(7):713-722. doi: 10.1200/JCO.20.01820. Epub 2020 Dec 17.
Gefitinib Versus Vinorelbine Plus Cisplatin as Adjuvant Treatment for Stage
II-IIIA (N1-N2) EGFR-Mutant NSCLC: Final Overall Survival Analysis of CTONG1104
Phase III Trial.
Zhong WZ(1), Wang Q(2), Mao WM(3), Xu ST(2), Wu L(4), Wei YC(5), Liu YY(6), Chen
C(7), Cheng Y(8), Yin R(9), Yang F(10), Ren SX(11), Li XF(12), Li J(13), Huang
C(14), Liu ZD(15), Xu S(16), Chen KN(17), Xu SD(18), Liu LX(19), Yu P(20), Wang
BH(21), Ma HT(22), Yang JJ(1), Yan HH(1), Yang XN(1), Liu SY(1), Zhou Q(1), Wu
YL(1).
Author information:
(1)Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, and
Guangdong Academy of Medical Sciences, Guangzhou, China.
(2)Fudan University Affiliated Zhongshan Hospital, Shanghai, China.
(3)Zhejiang Cancer Hospital, Hangzhou, China.
…
PURPOSE: ADJUVANT-CTONG1104 (ClinicalTrials.gov identifier: NCT01405079), a
randomized phase III trial, showed that adjuvant gefitinib treatment
significantly improved disease-free survival (DFS) versus vinorelbine plus
cisplatin (VP) in patients with epidermal growth factor receptor (EGFR)
mutation-positive resected stage II-IIIA (N1-N2) non-small-cell lung cancer
(NSCLC). Here, we report the final overall survival (OS) results.
METHODS: From September 2011 to April 2014, 222 patients from 27 sites were
randomly assigned 1:1 to adjuvant gefitinib (n = 111) or VP (n = 111). Patients
with resected stage II-IIIA (N1-N2) NSCLC and EGFR-activating mutation were
enrolled, receiving gefitinib for 24 months or VP every 3 weeks for four cycles.
The primary end point was DFS (intention-to-treat [ITT] population). Secondary
end points included OS, 3-, 5-year (y) DFS rates, and 5-year OS rate. Post hoc
analysis was conducted for subsequent therapy data.
RESULTS: Median follow-up was 80.0 months. Median OS (ITT) was 75.5 and 62.8
months with gefitinib and VP, respectively (hazard ratio [HR], 0.92; 95% CI,
0.62 to 1.36; P = .674); respective 5-year OS rates were 53.2% and 51.2% (P =
.784). Subsequent therapy was administered upon progression in 68.4% and 73.6%
of patients receiving gefitinib and VP, respectively. Subsequent targeted
therapy contributed most to OS (HR, 0.23; 95% CI, 0.14 to 0.38) compared with no
subsequent therapy. Updated 3y DFS rates were 39.6% and 32. 5% with gefitinib
and VP (P = .316) and 5y DFS rates were 22. 6% and 23.2% (P = .928),
respectively.
CONCLUSION: Adjuvant therapy with gefitinib in patients with early-stage NSCLC
and EGFR mutation demonstrated improved DFS over standard of care chemotherapy.
Although this DFS advantage did not translate to a significant OS difference, OS
with adjuvant gefitinib was one of the longest observed in this patient group
compared with historic data.
DOI: 10.1200/JCO.20.01820
PMID: 33332190
24. Lancet Infect Dis. 2021 Mar;21(3):376-384. doi: 10.1016/S1473-3099(20)30598-3.
Epub 2020 Dec 11.
Comparing accuracy of lipoarabinomannan urine tests for diagnosis of pulmonary
tuberculosis in children from four African countries: a cross-sectional study.
Nkereuwem E(1), Togun T(2), Gomez MP(1), Székely R(3), Macé A(3), Jobe D(1),
Schumacher SG(3), Kampmann B(4), Denkinger CM(5); Reach4KidsAfrica (R4KA)
Consortium.
Author information:
(1)Vaccines and Immunity Theme, Medical Research Council Unit The Gambia at
London School of Hygiene & Tropical Medicine, Banjul, The Gambia.
(2)Vaccines and Immunity Theme, Medical Research Council Unit The Gambia at
London School of Hygiene & Tropical Medicine, Banjul, The Gambia; Faculty of
Infectious and Tropical Diseases, London, UK.
(3)FIND (Foundation for Innovative New Diagnostics), Geneva, Switzerland.
…
Comment in
Lancet Infect Dis. 2021 Mar;21(3):302-303.
BACKGROUND: A sensitive and specific non-sputum-based test would be
groundbreaking for the diagnosis of childhood tuberculosis. We assessed side by
side the diagnostic accuracy of the urine-based lipoarabinomannan assays
Fujifilm SILVAMP TB LAM (FujiLAM) and Alere Determine TB LAM Ag (AlereLAM) for
detection of childhood tuberculosis.
METHODS: In this cross-sectional study, we tested urine samples from children
younger than 15 years with presumed pulmonary tuberculosis. Children were
consecutively recruited from four dedicated outpatient childhood tuberculosis
clinics in The Gambia, Mali, Nigeria, and Tanzania. Biobanked urine samples were
thawed and tested using FujiLAM and AlereLAM assays. We measured diagnostic
performance against a microbiological reference standard (confirmed
tuberculosis) and a composite reference standard (confirmed and unconfirmed
tuberculosis). Sensitivity and specificity were estimated with bivariate
random-effects meta-analyses.
FINDINGS: Between July 1, 2017, and Dec 1, 2018, we obtained and stored urine
samples from 415 children. 63 (15%) children had confirmed tuberculosis, 113
(27%) had unconfirmed tuberculosis, and 239 (58%) were unlikely to have
tuberculosis. 61 children were HIV-positive (prevalence 15%). Using the
microbiological reference standard, the sensitivity of FujiLAM was 64·9% (95% CI
43·7-85·2; positive in 40 of 63 confirmed samples) and the sensitivity of
AlereLAM was 30·7% (8·6-61·6; 19 of 63). The specificity of FujiLAM was 83·8%
(95% CI 76·5-89·4; negative in 297 of 352 unconfirmed and unlikely samples) and
the specificity of AlereLAM was 87·8% (79·0-93·7; 312 of 352). Against the
composite reference standard, both assays had decreased sensitivity; the
sensitivity of FujiLAM was 32·9% (95% CI 24·6-41·9; positive in 58 of 176
confirmed and unconfirmed samples) and the sensitivity of AlereLAM was 20·2%
(12·3-29·4; 36 of 176). The specificity of FujiLAM was 83·3% (95% CI 71·8-91·7;
negative in 202 of 239 unlikely samples) and the specificity of AlereLAM was
90·0% (81·6-95·6; 216 of 239).
INTERPRETATION: By comparison with AlereLAM, FujiLAM showed higher sensitivity
and similar specificity. FujiLAM could potentially add value to the rapid
diagnosis of tuberculosis in children.
FUNDING: German Federal Ministry of Education and Research, the Global Health
Innovative Technology Fund, the UK Research and Innovation Global Challenges
Research Fund, and the UK Medical Research Council.
Copyright © 2021 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1473-3099(20)30598-3
PMID: 33316214 [Indexed for MEDLINE]
