2021年
No. 5
Medical Abstracts
Filters applied: from 2021/4/1 - 2021/4/30
1. Science. 2021 Apr 30;372(6541):eabb8699. doi: 10.1126/science.abb8699.
Stepwise pathogenic evolution of Mycobacterium abscessus.
Bryant JM(1)(2), Brown KP(1)(3), Burbaud S(1), Everall I(1)(4), Belardinelli
JM(5), Rodriguez-Rincon D(1), Grogono DM(1)(3), Peterson CM(5), Verma D(5),
Evans IE(1)(3), Ruis C(1)(2), Weimann A(1)(2), Arora D(1), Malhotra S(6)(7),
Bannerman B(1)(2), Passemar C(1), Templeton K(8), MacGregor G(8), Jiwa K(9),
Fisher AJ(9), Blundell TL(6), Ordway DJ(5), Jackson M(5), Parkhill J(10)(11),
Floto RA(12)(2)(3).
Author information:
(1)Molecular Immunity Unit, University of Cambridge Department of Medicine, MRC
Laboratory of Molecular Biology, Cambridge, UK.
(2)University of Cambridge Centre for AI in Medicine, Cambridge, UK.
(3)Cambridge Centre for Lung Infection, Royal Papworth Hospital, Cambridge, UK.
…
Comment in
Science. 2021 Apr 30;372(6541):465-466.
Although almost all mycobacterial species are saprophytic environmental
organisms, a few, such as Mycobacterium tuberculosis, have evolved to cause
transmissible human infection. By analyzing the recent emergence and spread of
the environmental organism M. abscessus through the global cystic fibrosis
population, we have defined key, generalizable steps involved in the pathogenic
evolution of mycobacteria. We show that epigenetic modifiers, acquired through
horizontal gene transfer, cause saltational increases in the pathogenic
potential of specific environmental clones. Allopatric parallel evolution during
chronic lung infection then promotes rapid increases in virulence through
mutations in a discrete gene network; these mutations enhance growth within
macrophages but impair fomite survival. As a consequence, we observe constrained
pathogenic evolution while person-to-person transmission remains indirect, but
postulate accelerated pathogenic adaptation once direct transmission is
possible, as observed for M. tuberculosis Our findings indicate how key
interventions, such as early treatment and cross-infection control, might
restrict the spread of existing mycobacterial pathogens and prevent new,
emergent ones.
Copyright © 2021 The Authors, some rights reserved; exclusive licensee American
Association for the Advancement of Science. No claim to original U.S. Government
Works.
DOI: 10.1126/science.abb8699
PMCID: PMC7611193
PMID: 33926925 [Indexed for MEDLINE]
2. Nature. 2021 Apr;592(7855):629-633. doi: 10.1038/s41586-021-03430-5. Epub 2021
Apr 7.
Evaluating eligibility criteria of oncology trials using real-world data and AI.
Liu R(1), Rizzo S(2), Whipple S(2), Pal N(2), Pineda AL(2), Lu M(2), Arnieri
B(2), Lu Y(3), Capra W(2), Copping R(4), Zou J(5)(6)(7)(8).
Author information:
(1)Department of Electrical Engineering, Stanford University, Stanford, CA, USA.
(2)Genentech, South San Francisco, CA, USA.
(3)Department of Biomedical Data Science, Stanford University, Stanford, CA,
USA.
(4)Genentech, South San Francisco, CA, USA. copping.ryan@gene.com.
(5)Department of Electrical Engineering, Stanford University, Stanford, CA, USA.
jamesz@stanford.edu.
(6)Department of Biomedical Data Science, Stanford University, Stanford, CA,
USA. jamesz@stanford.edu.
(7)Department of Computer Science, Stanford University, Stanford, CA, USA.
jamesz@stanford.edu.
(8)Chan Zuckerberg Biohub, San Francisco, CA, USA. jamesz@stanford.edu.
Comment in
Nature. 2021 Apr;592(7855):512-513.
There is a growing focus on making clinical trials more inclusive but the design
of trial eligibility criteria remains challenging1-3. Here we systematically
evaluate the effect of different eligibility criteria on cancer trial
populations and outcomes with real-world data using the computational framework
of Trial Pathfinder. We apply Trial Pathfinder to emulate completed trials of
advanced non-small-cell lung cancer using data from a nationwide database of
electronic health records comprising 61,094 patients with advanced
non-small-cell lung cancer. Our analyses reveal that many common criteria,
including exclusions based on several laboratory values, had a minimal effect on
the trial hazard ratios. When we used a data-driven approach to broaden
restrictive criteria, the pool of eligible patients more than doubled on average
and the hazard ratio of the overall survival decreased by an average of 0.05.
This suggests that many patients who were not eligible under the original trial
criteria could potentially benefit from the treatments. We further support our
findings through analyses of other types of cancer and patient-safety data from
diverse clinical trials. Our data-driven methodology for evaluating eligibility
criteria can facilitate the design of more-inclusive trials while maintaining
safeguards for patient safety.
DOI: 10.1038/s41586-021-03430-5
PMID: 33828294
3. 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
PMCID: PMC8055144
PMID: 33761328
4. Annu Rev Immunol. 2021 Apr 26;39:611-637. doi:
10.1146/annurev-immunol-093019-010426. Epub 2021 Feb 26.
The Innate Immune Response to Mycobacterium tuberculosis Infection.
Ravesloot-Chávez MM(1), Van Dis E(2), Stanley SA(2)(3).
Author information:
(1)Department of Plant and Microbial Biology, University of California,
Berkeley, California 94720, USA; email: mchavez@berkeley.edu.
(2)Division of Immunology and Pathogenesis, Department of Molecular and Cell
Biology, University of California, Berkeley, California 94720, USA; email:
sastanley@berkeley.edu, vandise@berkeley.edu.
(3)Division of Infectious Diseases and Vaccinology, School of Public Health,
University of California, Berkeley, California 94720, USA.
Infection with Mycobacterium tuberculosis causes >1.5 million deaths worldwide
annually. Innate immune cells are the first to encounter M. tuberculosis, and
their response dictates the course of infection. Dendritic cells (DCs) activate
the adaptive response and determine its characteristics. Macrophages are
responsible both for exerting cell-intrinsic antimicrobial control and for
initiating and maintaining inflammation. The inflammatory response to M.
tuberculosis infection is a double-edged sword. While cytokines such as TNF-α
and IL-1 are important for protection, either excessive or insufficient cytokine
production results in progressive disease. Furthermore, neutrophils-cells
normally associated with control of bacterial infection-are emerging as key
drivers of a hyperinflammatory response that results in host mortality. The
roles of other innate cells, including natural killer cells and innate-like T
cells, remain enigmatic. Understanding the nuances of both cell-intrinsic
control of infection and regulation of inflammation will be crucial for the
successful development of host-targeted therapeutics and vaccines.
DOI: 10.1146/annurev-immunol-093019-010426
PMID: 33637017
5. Nat Rev Cancer. 2021 Apr;21(4):217-238. doi: 10.1038/s41568-020-00329-7. Epub
2021 Feb 15.
The matrix in cancer.
Cox TR(1)(2).
Author information:
(1)The Kinghorn Cancer Centre, The Garvan Institute of Medical Research, Sydney,
New South Wales, Australia. t.cox@garvan.org.au.
(2)St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, New
South Wales, Australia. t.cox@garvan.org.au.
The extracellular matrix is a fundamental, core component of all tissues and
organs, and is essential for the existence of multicellular organisms. From the
earliest stages of organism development until death, it regulates and fine-tunes
every cellular process in the body. In cancer, the extracellular matrix is
altered at the biochemical, biomechanical, architectural and topographical
levels, and recent years have seen an exponential increase in the study and
recognition of the importance of the matrix in solid tumours. Coupled with the
advancement of new technologies to study various elements of the matrix and
cell-matrix interactions, we are also beginning to see the deployment of
matrix-centric, stromal targeting cancer therapies. This Review touches on many
of the facets of matrix biology in solid cancers, including breast, pancreatic
and lung cancer, with the aim of highlighting some of the emerging interactions
of the matrix and influences that the matrix has on tumour onset, progression
and metastatic dissemination, before summarizing the ongoing work in the field
aimed at developing therapies to co-target the matrix in cancer and cancer
metastasis.
DOI: 10.1038/s41568-020-00329-7
PMID: 33589810 [Indexed for MEDLINE]
6. Acc Chem Res. 2021 May 18;54(10):2361-2376. doi: 10.1021/acs.accounts.0c00878.
Epub 2021 Apr 22.
Strategies to Combat Multi-Drug Resistance in Tuberculosis.
Singh V(1)(2), Chibale K(1)(2).
Author information:
(1)Drug Discovery and Development Centre (H3D), University of Cape Town,
Rondebosch 7701, South Africa.
(2)South African Medical Research Council Drug Discovery and Development
Research Unit, Department of Chemistry and Institute of Infectious Disease and
Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa.
"Drug resistance is an unavoidable consequence of the use of drugs; however, the
emergence of multi-drug resistance can be managed by accurate diagnosis and
tailor-made regimens."Antimicrobial resistance (AMR), is one of the most
paramount health perils that has emerged in the 21st century. The global
increase in drug-resistant strains of various bacterial pathogens prompted the
World Health Organization (WHO) to develop a priority list of AMR pathogens.
Mycobacterium tuberculosis (Mtb), an acid-fast bacillus that causes tuberculosis
(TB), merits being one of the highest priority pathogens on this list since
drug-resistant TB (DR-TB) accounts for ∼29% of deaths attributable to AMR. In
recent years, funded collaborative efforts of researchers from academia,
not-for-profit virtual R&D organizations and industry have resulted in the
continuous growth of the TB drug discovery and development pipeline. This has so
far led to the accelerated regulatory approval of bedaquiline and delamanid for
the treatment of DR-TB. However, despite the availability of drug regimes, the
current cure rate for multi-drug-resistant TB (MDR-TB) and extensively
drug-resistant TB (XDR-TB) treatment regimens is 50% and 30%, respectively. It
is to be noted that these regimens are administered over a long duration and
have a serious side effect profile. Coupled with poor patient adherence, this
has led to further acquisition of drug resistance and treatment failure. There
is therefore an urgent need to develop new TB drugs with novel mechanism of
actions (MoAs) and associated regimens.This Account recapitulates drug
resistance in TB, existing challenges in addressing DR-TB, new drugs and
regimens in development, and potential ways to treat DR-TB. We highlight our
research aimed at identifying novel small molecule leads and associated targets
against TB toward contributing to the global TB drug discovery and development
pipeline. Our work mainly involves screening of various small molecule chemical
libraries in phenotypic whole-cell based assays to identify hits for medicinal
chemistry optimization, with attendant deconvolution of the MoA. We discuss the
identification of small molecule chemotypes active against Mtb and subsequent
structure-activity relationships (SAR) and MoA deconvolution studies. This is
followed by a discussion on a chemical series identified by whole-cell
cross-screening against Mtb, for which MoA deconvolution studies revealed a
pathway that explained the lack of in vivo efficacy in a mouse model of TB and
reiterated the importance of selecting an appropriate growth medium during
phenotypic screening. We also discuss our efforts on drug repositioning toward
addressing DR-TB. In the concluding section, we preview some promising future
directions and the challenges inherent in advancing the drug pipeline to address
DR-TB.
DOI: 10.1021/acs.accounts.0c00878
PMCID: PMC8154215
PMID: 33886255
7. Acc Chem Res. 2021 May 4;54(9):2065-2075. doi: 10.1021/acs.accounts.1c00048.
Epub 2021 Apr 20.
The Enzymes of the Rifamycin Antibiotic Resistome.
Surette MD(1), Spanogiannopoulos P(1), Wright GD(1).
Author information:
(1)M.G. DeGroote Institute for Infectious Disease Research, David Braley Center
for Antibiotic Discovery, Department of Biochemistry and Biomedical Sciences,
McMaster University, Hamilton, Ontario L8S 3Z5, Canada.
Rifamycin antibiotics include the WHO essential medicines rifampin, rifabutin,
and rifapentine. These are semisynthetic derivatives of the natural product
rifamycins, originally isolated from the soil bacterium Amycolatopsis
rifamycinica. These antibiotics are primarily used to treat mycobacterial
infections, including tuberculosis. Rifamycins act by binding to the β-subunit
of bacterial RNA polymerase, inhibiting transcription, which results in cell
death. These antibiotics consist of a naphthalene core spanned by a polyketide
ansa bridge. This structure presents a unique 3D configuration that engages RNA
polymerase through a series of hydrogen bonds between hydroxyl groups linked to
the naphthalene core and C21 and C23 of the ansa bridge. This binding occurs not
in the enzyme active site where template-directed RNA synthesis occurs but
instead in the RNA exit tunnel, thereby blocking productive formation of
full-length RNA. In their clinical use to treat tuberculosis, resistance to
rifamycin antibiotics arises principally from point mutations in RNA polymerase
that decrease the antibiotic's affinity for the binding site in the RNA exit
tunnel. In contrast, the rifamycin resistome of environmental mycobacteria and
actinomycetes is much richer and diverse. In these organisms, rifamycin
resistance includes many different enzymatic mechanisms that modify and alter
the antibiotic directly, thereby inactivating it. These enzymes include ADP
ribosyltransferases, glycosyltransferases, phosphotransferases, and
monooxygenases.ADP ribosyltransferases catalyze group transfer of ADP ribose
from the cofactor NAD+, which is more commonly deployed for metabolic redox
reactions. ADP ribose is transferred to the hydroxyl linked to C23 of the
antibiotic, thereby sterically blocking productive interaction with RNA
polymerase. Like ADP ribosyltransferases, rifamycin glycosyl transferases also
modify the hydroxyl of position C23 of rifamycins, transferring a glucose moiety
from the donor molecule UDP-glucose. Unlike other antibiotic resistance kinases
that transfer the γ-phosphate of ATP to inactivate antibiotics such as
aminoglycosides or macrolides, rifamycin phosphotransferases are ATP-dependent
dikinases. These enzymes transfer the β-phosphate of ATP to the C21 hydroxyl of
the rifamycin ansa bridge. The result is modification of a critical RNA
polymerase binding group that blocks productive complex formation. On the other
hand, rifamycin monooxygenases are FAD-dependent enzymes that hydroxylate the
naphthoquinone core. The result of this modification is untethering of the ansa
chain from the naphthyl moiety, disrupting the essential 3D shape necessary for
productive RNA polymerase binding and inhibition that leads to cell death.All of
these enzymes have homologues in bacterial metabolism that either are their
direct precursors or share common ancestors to the resistance enzyme. The
diversity of these resistance mechanisms, often redundant in individual
bacterial isolates, speaks to the importance of protecting RNA polymerase from
these compounds and validates this enzyme as a critical antibiotic target.
DOI: 10.1021/acs.accounts.1c00048
PMID: 33877820
8. Cancer Cell. 2021 Apr 12;39(4):566-579.e7. doi: 10.1016/j.ccell.2021.02.014.
Therapeutic targeting of ATR yields durable regressions in small cell lung
cancers with high replication stress.
Thomas A(1), Takahashi N(2), Rajapakse VN(2), Zhang X(3), Sun Y(2), Ceribelli
M(3), Wilson KM(3), Zhang Y(2), Beck E(3), Sciuto L(2), Nichols S(2), Elenbaas
B(4), Puc J(4), Dahmen H(5), Zimmermann A(5), Varonin J(6), Schultz CW(2), Kim
S(2), Shimellis H(2), Desai P(2), Klumpp-Thomas C(3), Chen L(3), Travers J(3),
McKnight C(3), Michael S(3), Itkin Z(3), Lee S(2), Yuno A(2), Lee MJ(2), Redon
CE(2), Kindrick JD(7), Peer CJ(7), Wei JS(8), Aladjem MI(2), Figg WD(7),
Steinberg SM(9), Trepel JB(2), Zenke FT(5), Pommier Y(2), Khan J(8), Thomas
CJ(10).
Author information:
(1)Developmental Therapeutics Branch, Center for Cancer Research, National
Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Electronic address: anish.thomas@nih.gov.
(2)Developmental Therapeutics Branch, Center for Cancer Research, National
Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
(3)Division of Preclinical Innovation, National Center for Advancing
Translational Sciences, National Institute of Health, Rockville, MD 20850, USA.
…
Small cell neuroendocrine cancers (SCNCs) are recalcitrant cancers arising from
diverse primary sites that lack effective treatments. Using chemical genetic
screens, we identified inhibition of ataxia telangiectasia and rad3 related
(ATR), the primary activator of the replication stress response, and
topoisomerase I (TOP1), nuclear enzyme that suppresses genomic instability, as
synergistically cytotoxic in small cell lung cancer (SCLC). In a
proof-of-concept study, we combined M6620 (berzosertib), first-in-class ATR
inhibitor, and TOP1 inhibitor topotecan in patients with relapsed SCNCs.
Objective response rate among patients with SCLC was 36% (9/25), achieving the
primary efficacy endpoint. Durable tumor regressions were observed in patients
with platinum-resistant SCNCs, typically fatal within weeks of recurrence. SCNCs
with high neuroendocrine differentiation, characterized by enhanced replication
stress, were more likely to respond. These findings highlight replication stress
as a potentially transformative vulnerability of SCNCs, paving the way for
rational patient selection in these cancers, now treated as a single disease.
Published by Elsevier Inc.
DOI: 10.1016/j.ccell.2021.02.014
PMCID: PMC8048383
PMID: 33848478
9. Nat Rev Clin Oncol. 2021 Apr 28. doi: 10.1038/s41571-021-00501-4. Online ahead
of print.
Evolution of systemic therapy for stages I-III non-metastatic non-small-cell
lung cancer.
Chaft JE(#)(1), Rimner A(#)(2), Weder W(3), Azzoli CG(4), Kris MG(5), Cascone
T(6).
Author information:
(1)Thoracic Oncology Service, Department of Medicine, Memorial Sloan Kettering
Cancer Center, New York, NY and Weill Cornell Medical College, New York, NY,
USA. chaftj@mskcc.org.
(2)Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New
York, NY, USA.
(3)Thoracic Surgery, Klinik Bethanien Zurich, Zurich, Switzerland.
…
The treatment goal for patients with early-stage lung cancer is cure.
Multidisciplinary discussions of surgical resectability and medical operability
determine the modality of definitive local treatment (surgery or radiotherapy)
and the associated systemic therapies to further improve the likelihood of cure.
Trial evidence supports cisplatin-based adjuvant therapy either after surgical
resection or concurrently with radiotherapy. Consensus guidelines support
neoadjuvant chemotherapy in lieu of adjuvant chemotherapy and carboplatin-based
regimens for patients who are ineligible for cisplatin. The incorporation of
newer agents, now standard for patients with stage IV lung cancer, into the
curative therapy paradigm has lagged owing to inefficient trial designs, the
lengthy follow-up needed to assess survival end points and a developmental focus
on the advanced-stage disease setting. Surrogate end points, such as
pathological response, are being studied and might shorten trial durations. In
2018, the anti-PD-L1 antibody durvalumab was approved for patients with stage
III lung cancer after concurrent chemoradiotherapy. Since then, the study of
targeted therapies and immunotherapies in patients with early-stage lung cancer
has rapidly expanded. In this Review, we present the current considerations in
the treatment of patients with early-stage lung cancer and explore the current
and future state of clinical research to develop systemic therapies for
non-metastatic lung cancer.
DOI: 10.1038/s41571-021-00501-4
PMID: 33911215
10. PLoS Med. 2021 Apr 26;18(4):e1003566. doi: 10.1371/journal.pmed.1003566.
eCollection 2021 Apr.
Dynamics of sputum conversion during effective tuberculosis treatment: A
systematic review and meta-analysis.
Calderwood CJ(1), Wilson JP(1), Fielding KL(1), Harris RC(1), Karat AS(1),
Mansukhani R(1), Falconer J(2), Bergstrom M(1), Johnson SM(1), McCreesh N(1),
Monk EJM(1), Odayar J(3), Scott PJ(1), Stokes SA(1), Theodorou H(1), Moore
DAJ(1).
Author information:
(1)TB Centre, London School of Hygiene & Tropical Medicine, London, United
Kingdom.
(2)Library & Archives Service, London School of Hygiene & Tropical Medicine,
London, United Kingdom.
(3)Division of Epidemiology and Biostatistics, School of Public Health & Family
Medicine, University of Cape Town, Cape Town, South Africa.
BACKGROUND: Two weeks' isolation is widely recommended for people commencing
treatment for pulmonary tuberculosis (TB). The evidence that this corresponds to
clearance of potentially infectious tuberculous mycobacteria in sputum is not
well established. This World Health Organization-commissioned review
investigated sputum sterilisation dynamics during TB treatment.
METHODS AND FINDINGS: For the main analysis, 2 systematic literature searches of
OvidSP MEDLINE, Embase, and Global Health, and EBSCO CINAHL Plus were conducted
to identify studies with data on TB infectiousness (all studies to search date,
1 December 2017) and all randomised controlled trials (RCTs) for
drug-susceptible TB (from 1 January 1990 to search date, 20 February 2018).
Included articles reported on patients receiving effective treatment for
culture-confirmed drug-susceptible pulmonary TB. The outcome of interest was
sputum bacteriological conversion: the proportion of patients having converted
by a defined time point or a summary measure of time to conversion, assessed by
smear or culture. Any study design with 10 or more particpants was considered.
Record sifting and data extraction were performed in duplicate. Random effects
meta-analyses were performed. A narrative summary additionally describes the
results of a systematic search for data evaluating infectiousness from humans to
experimental animals (PubMed, all studies to 27 March 2018). Other evidence on
duration of infectiousness-including studies reporting on cough dynamics, human
tuberculin skin test conversion, or early bactericidal activity of TB
treatments-was outside the scope of this review. The literature search was
repeated on 22 November 2020, at the request of the editors, to identify studies
published after the previous censor date. Four small studies reporting 3
different outcome measures were identified, which included no data that would
alter the findings of the review; they are not included in the meta-analyses. Of
5,290 identified records, 44 were included. Twenty-seven (61%) were RCTs and 17
(39%) were cohort studies. Thirteen studies (30%) reported data from Africa, 12
(27%) from Asia, 6 (14%) from South America, 5 (11%) from North America, and 4
(9%) from Europe. Four studies reported data from multiple continents. Summary
estimates suggested smear conversion in 9% of patients at 2 weeks (95% CI
3%-24%, 1 single study [N = 1]), and 82% of patients at 2 months of treatment
(95% CI 78%-86%, N = 10). Among baseline smear-positive patients, solid culture
conversion occurred by 2 weeks in 5% (95% CI 0%-14%, N = 2), increasing to 88%
at 2 months (95% CI 84%-92%, N = 20). At equivalent time points, liquid culture
conversion was achieved in 3% (95% CI 1%-16%, N = 1) and 59% (95% CI 47%-70%, N
= 8). Significant heterogeneity was observed. Further interrogation of the data
to explain this heterogeneity was limited by the lack of disaggregation of
results, including by factors such as HIV status, baseline smear status, and the
presence or absence of lung cavitation.
CONCLUSIONS: This systematic review found that most patients remained culture
positive at 2 weeks of TB treatment, challenging the view that individuals are
not infectious after this interval. Culture positivity is, however, only 1
component of infectiousness, with reduced cough frequency and aerosol generation
after TB treatment initiation likely to also be important. Studies that
integrate our findings with data on cough dynamics could provide a more complete
perspective on potential transmission of Mycobacterium tuberculosis by
individuals on treatment.
TRIAL REGISTRATION: Systematic review registration: PROSPERO 85226.
DOI: 10.1371/journal.pmed.1003566
PMCID: PMC8109831
PMID: 33901173
11. Lancet Infect Dis. 2021 Apr 20:S1473-3099(20)30728-3. doi:
10.1016/S1473-3099(20)30728-3. Online ahead of print.
Quantifying the rates of late reactivation tuberculosis: a systematic review.
Dale KD(1), Karmakar M(2), Snow KJ(3), Menzies D(4), Trauer JM(5), Denholm
JT(6).
Author information:
(1)Victorian Tuberculosis Program, Royal Melbourne Hospital, Peter Doherty
Institute for Infection and Immunity, The University of Melbourne, Melbourne,
VIC, Australia; Department of Microbiology and Immunology, Peter Doherty
Institute for Infection and Immunity, The University of Melbourne, Melbourne,
VIC, Australia. Electronic address: katie.dale@mh.org.au.
(2)Department of Microbiology and Immunology, Peter Doherty Institute for
Infection and Immunity, The University of Melbourne, Melbourne, VIC, Australia;
Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.
(3)Centre for International Child Health, Department of Paediatrics, Royal
Children's Hospital, University of Melbourne, Parkville, VIC, Australia;
Australia Department of Paediatrics, University of Melbourne, Parkville, VIC,
Australia.
…
The risk of tuberculosis is greatest soon after infection, but Mycobacterium
tuberculosis can remain in the body latently, and individuals can develop
disease in the future, sometimes years later. However, there is uncertainty
about how often reactivation of latent tuberculosis infection (LTBI) occurs. We
searched eight databases (inception to June 25, 2019) to identify studies that
quantified tuberculosis reactivation rates occurring more than 2 years after
infection (late reactivation), with a focus on identifying untreated study
cohorts with defined timing of LTBI acquisition (PROSPERO registered:
CRD42017070594). We included 110 studies, divided into four methodological
groups. Group 1 included studies that documented late reactivation rates from
conversion (n=14) and group 2 documented late reactivation rates in LTBI cohorts
from exposure (n=11). Group 3 included 86 studies in LTBI cohorts with an
unknown exposure history, and group 4 included seven ecological studies. Since
antibiotics have been used to treat tuberculosis, only 11 studies have
documented late reactivation rates in infected, untreated cohorts from either
conversion (group 1) or exposure (group 2); six of these studies lasted at least
4 years and none lasted longer than 10 years. These studies found that
tuberculosis rates declined over time, reaching approximately 200 cases per
100 000 person-years or less by the fifth year, and possibly declining further
after 5 years but interpretation was limited by decreasing or unspecified cohort
sizes. In cohorts with latent tuberculosis and an unknown exposure history
(group 3), tuberculosis rates were generally lower than those seen in groups 1
and 2, and beyond 10 years after screening, rates had declined to less than 100
per 100 000 person-years. Reinfection risks limit interpretation in all studies
and the effect of age is unclear. Late reactivation rates are commonly estimated
or modelled to prioritise tuberculosis control strategies towards tubuculosis
elimination, but significant gaps remain in our understanding that must be
acknowledged; the relative importance of late reactivation versus early
progression to the global burden of tuberculosis remains unknown.
Copyright © 2021 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1473-3099(20)30728-3
PMID: 33891908
12. 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
13. Nat Commun. 2021 Apr 15;12(1):2259. doi: 10.1038/s41467-021-22480-x.
SOD1 regulates ribosome biogenesis in KRAS mutant non-small cell lung cancer.
Wang X(#)(1)(2)(3), Zhang H(#)(1)(2), Sapio R(4), Yang J(5), Wong J(1), Zhang
X(1)(2), Guo JY(1)(6), Pine S(1)(2), Van Remmen H(7), Li H(1)(8), White E(1)(9),
Liu C(1)(10), Kiledjian M(1)(5), Pestov DG(11), Steven Zheng XF(12)(13)(14).
Author information:
(1)Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New
Jersey, New Brunswick, NJ, USA.
(2)Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers, The
State University of New Jersey, Piscataway, NJ, USA.
(3)Graduate Program in Cellular and Molecular Pharmacology, Rutgers, The State
University of New Jersey, Piscataway, NJ, USA.
SOD1 is known as the major cytoplasmic superoxide dismutase and an anticancer
target. However, the role of SOD1 in cancer is not fully understood. Herein we
describe the generation of an inducible Sod1 knockout in KRAS-driven NSCLC mouse
model. Sod1 knockout markedly reduces tumor burden in vivo and blocks growth of
KRAS mutant NSCLC cells in vitro. Intriguingly, SOD1 is enriched in the nucleus
and notably in the nucleolus of NSCLC cells. The nuclear and nucleolar, not
cytoplasmic, form of SOD1 is essential for lung cancer cell proliferation.
Moreover, SOD1 interacts with PeBoW complex and controls its assembly necessary
for pre-60S ribosomal subunit maturation. Mechanistically, SOD1 regulates
co-localization of PeBoW with and processing of pre-rRNA, and maturation of
cytoplasmic 60S ribosomal subunits in KRAS mutant lung cancer cells.
Collectively, our study unravels a nuclear SOD1 function essential for ribosome
biogenesis and proliferation in KRAS-driven lung cancer.
DOI: 10.1038/s41467-021-22480-x
PMCID: PMC8050259
PMID: 33859191 [Indexed for MEDLINE]
14. Nat Commun. 2021 Apr 12;12(1):2163. doi: 10.1038/s41467-021-22433-4.
Epigenetic modulation of immune synaptic-cytoskeletal networks potentiates γδ T
cell-mediated cytotoxicity in lung cancer.
Weng RR(1), Lu HH(1), Lin CT(2)(3), Fan CC(4), Lin RS(2)(3), Huang TC(1), Lin
SY(1), Huang YJ(4), Juan YH(1), Wu YC(4), Hung ZC(1), Liu C(5), Lin XH(2)(3),
Hsieh WC(6)(7), Chiu TY(8), Liao JC(8), Chiu YL(9)(10)(11), Chen SY(6), Yu
CJ(1)(12), Tsai HC(13)(14)(15).
Author information:
(1)Department of Internal Medicine, National Taiwan University Hospital, Taipei,
Taiwan.
(2)Tai Cheng Stem Cell Therapy Center, National Taiwan University, Taipei,
Taiwan.
(3)Pell Biomedical Technology Ltd, Taipei, Taiwan.
…
γδ T cells are a distinct subgroup of T cells that bridge the innate and
adaptive immune system and can attack cancer cells in an MHC-unrestricted
manner. Trials of adoptive γδ T cell transfer in solid tumors have had limited
success. Here, we show that DNA methyltransferase inhibitors (DNMTis) upregulate
surface molecules on cancer cells related to γδ T cell activation using
quantitative surface proteomics. DNMTi treatment of human lung cancer
potentiates tumor lysis by ex vivo-expanded Vδ1-enriched γδ T cells.
Mechanistically, DNMTi enhances immune synapse formation and mediates
cytoskeletal reorganization via coordinated alterations of DNA methylation and
chromatin accessibility. Genetic depletion of adhesion molecules or
pharmacological inhibition of actin polymerization abolishes the potentiating
effect of DNMTi. Clinically, the DNMTi-associated cytoskeleton signature
stratifies lung cancer patients prognostically. These results support a
combinatorial strategy of DNMTis and γδ T cell-based immunotherapy in lung
cancer management.
DOI: 10.1038/s41467-021-22433-4
PMCID: PMC8042060
PMID: 33846331 [Indexed for MEDLINE]
15. Nat Commun. 2021 Apr 6;12(1):2048. doi: 10.1038/s41467-021-22336-4.
Ferroptosis response segregates small cell lung cancer (SCLC) neuroendocrine
subtypes.
Bebber CM(1)(2)(3), Thomas ES(1)(2)(4), Stroh J(1)(2), Chen Z(1)(2),
Androulidaki A(1)(2), Schmitt A(2)(3), Höhne MN(2)(5), Stüker L(1)(2), de Pádua
Alves C(1), Khonsari A(1)(6)(7), Dammert MA(1)(6)(7), Parmaksiz F(1)(6)(7),
Tumbrink HL(1)(6)(7), Beleggia F(3), Sos ML(1)(6)(7), Riemer J(2)(5), George
J(1), Brodesser S(2), Thomas RK(1)(6)(8), Reinhardt HC(9), von Karstedt
S(10)(11)(12).
Author information:
(1)Department of Translational Genomics, Medical Faculty, University of Cologne,
Cologne, Germany.
(2)CECAD Cluster of Excellence, University of Cologne, Cologne, Germany.
(3)Clinic I for Internal Medicine, Medical Faculty, University Hospital of
Cologne, Cologne, Germany.
Loss of TP53 and RB1 in treatment-naïve small cell lung cancer (SCLC) suggests
selective pressure to inactivate cell death pathways prior to therapy. Yet,
which of these pathways remain available in treatment-naïve SCLC is unknown.
Here, through systemic analysis of cell death pathway availability in
treatment-naïve SCLC, we identify non-neuroendocrine (NE) SCLC to be vulnerable
to ferroptosis through subtype-specific lipidome remodeling. While NE SCLC is
ferroptosis resistant, it acquires selective addiction to the TRX anti-oxidant
pathway. In experimental settings of non-NE/NE intratumoral heterogeneity,
non-NE or NE populations are selectively depleted by ferroptosis or TRX pathway
inhibition, respectively. Preventing subtype plasticity observed under single
pathway targeting, combined treatment kills established non-NE and NE tumors in
xenografts, genetically engineered mouse models of SCLC and patient-derived
cells, and identifies a patient subset with drastically improved overall
survival. These findings reveal cell death pathway mining as a means to identify
rational combination therapies for SCLC.
DOI: 10.1038/s41467-021-22336-4
PMCID: PMC8024350
PMID: 33824345 [Indexed for MEDLINE]
16. Am J Respir Crit Care Med. 2021 Apr 6. doi: 10.1164/rccm.202007-2791OC. Online
ahead of print.
Machine Learning for Early Lung Cancer Identification Using Routine Clinical and
Laboratory Data.
Gould MK(1), Huang BZ(2), Tammemagi MC(3), Kinar Y(4), Shiff R(4).
Author information:
(1)Kaiser Permanente Bernard J Tyson School of Medicine, 547934, Health Systems
Science, Pasadena, California, United States; michael.k.gould@kp.org.
(2)Kaiser Permanente, Research and Evaluation, Pasadena, California, United
States.
(3)Brock University, 7497, Medical Sciences, Saint Catharines, Ontario, Canada.
(4)Medial EarlySign, Newton, Massachusetts, United States.
RATIONALE: Most lung cancers are diagnosed at an advanced stage. Pre-symptomatic
identification of high-risk individuals can prompt earlier intervention and
improve long-term outcomes.
OBJECTIVE: To develop a model to predict a future diagnosis of lung cancer based
on routine clinical and laboratory data, using machine-learning.
METHODS: We assembled 6,505 non-small cell lung cancer (NSCLC) cases and 189,597
contemporaneous controls and compared the accuracy of a novel machine-learning
model to a modified version of the well-validated PLCOm2012 risk model, using
the area under the receiver operating characteristic curve (AUC), sensitivity
and diagnostic odds ratio (OR) as measures of model performance.
RESULTS: Among ever-smokers in the test set, the a machine-learning model was
more accurate than the modified PLCOm2012 for identifying NSCLC 9-12 months
before clinical diagnosis (P<0.00001), with an AUC of 0.86, a diagnostic OR of
12.8 3 and a sensitivity of 40.31% at a pre-defined specificity of 95%. In
comparison, the modified PLCOm2012 had an AUC of 0.79, an OR of 7.4 and a
sensitivity of 27.9% at the same specificity. The machine-learning model was
more accurate than standard eligibility criteria for lung cancer screening and
more accurate than the modified PLCOm2012 model when applied to a
screening-eligible population. Influential model variables included known risk
factors and novel predictors such as white blood cell and platelet counts.
CONCLUSIONS: A machine-learning model was more accurate for early diagnosis of
NSCLC than either standard eligibility criteria for screening or the modified
PLCOm2012, demonstrating the potential to help prevent lung cancer deaths
through early detection.
DOI: 10.1164/rccm.202007-2791OC
PMID: 33823116
17. Cell Host Microbe. 2021 Apr 14;29(4):594-606.e6. doi:
10.1016/j.chom.2021.02.005. Epub 2021 Mar 11.
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. IFNɣ 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 IFNɣ, and IFNɣ plays a lesser
protective role within the lung than at sites of Mtb dissemination. In a murine
infection model, we observed that IFNɣ 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 IFNɣ
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
18. J Clin Oncol. 2021 Apr 20;39(12):1349-1359. doi: 10.1200/JCO.20.02212. Epub 2021
Mar 8.
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
PMCID: PMC8078251
PMID: 33683919
19. 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
PMCID: PMC8078299
PMID: 33646820
20. J Clin Oncol. 2021 Apr 20;39(12):1389-1411. doi: 10.1200/JCO.20.03465. Epub 2021
Feb 22.
Management of Dyspnea in Advanced Cancer: ASCO Guideline.
Hui D(1), Bohlke K(2), Bao T(3), Campbell TC(4), Coyne PJ(5), Currow DC(6),
Gupta A(7), Leiser AL(8), Mori M(9), Nava S(10), Reinke LF(11), Roeland EJ(12),
Seigel C(13), Walsh D(14), Campbell ML(15).
Author information:
(1)MD Anderson Cancer Center, Houston, TX.
(2)American Society of Clinical Oncology, Alexandria, VA.
(3)Memorial Sloan Kettering Cancer Center, New York, NY.
…
PURPOSE: To provide guidance on the clinical management of dyspnea in adult
patients with advanced cancer.
METHODS: ASCO convened an Expert Panel to review the evidence and formulate
recommendations. An Agency for Healthcare Research and Quality (AHRQ) systematic
review provided the evidence base for nonpharmacologic and pharmacologic
interventions to alleviate dyspnea. The review included randomized controlled
trials (RCTs) and observational studies with a concurrent comparison group
published through early May 2020. The ASCO Expert Panel also wished to address
dyspnea assessment, management of underlying conditions, and palliative care
referrals, and for these questions, an additional systematic review identified
RCTs, systematic reviews, and guidelines published through July 2020.
RESULTS: The AHRQ systematic review included 48 RCTs and two retrospective
cohort studies. Lung cancer and mesothelioma were the most commonly addressed
types of cancer. Nonpharmacologic interventions such as fans provided some
relief from breathlessness. Support for pharmacologic interventions was limited.
A meta-analysis of specialty breathlessness services reported improvements in
distress because of dyspnea.
RECOMMENDATIONS: A hierarchical approach to dyspnea management is recommended,
beginning with dyspnea assessment, ascertainment and management of potentially
reversible causes, and referral to an interdisciplinary palliative care team.
Nonpharmacologic interventions that may be offered to relieve dyspnea include
airflow interventions (eg, a fan directed at the cheek), standard supplemental
oxygen for patients with hypoxemia, and other psychoeducational,
self-management, or complementary approaches. For patients who derive inadequate
relief from nonpharmacologic interventions, systemic opioids should be offered.
Other pharmacologic interventions, such as corticosteroids and benzodiazepines,
are also discussed.Additional information is available at
www.asco.org/supportive-care-guidelines.
DOI: 10.1200/JCO.20.03465
PMID: 33617290
