2022年
No.1
Filters applied: from 2021/11/1 - 2021/12/31 (PubMed)
1. Cell. 2022 Jan 6;185(1):169-183.e19. doi: 10.1016/j.cell.2021.12.005. Epub 2021 Dec 27.
EMSY inhibits homologous recombination repair and the interferon response,
promoting lung cancer immune evasion.
Marzio A(1), Kurz E(2), Sahni JM(3), Di Feo G(2), Puccini J(2), Jiang S(2),
Hirsch CA(2), Arbini AA(4), Wu WL(3), Pass HI(5), Bar-Sagi D(2),
Papagiannakopoulos T(6), Pagano M(7).
Author information:
(1)Department of Biochemistry and Molecular Pharmacology, New York University
Grossman School of Medicine, New York, NY 10016, USA; Laura and Isaac Perlmutter
NYU Cancer Center, New York University Grossman School of Medicine, New York, NY
10016, USA. Electronic address: antonio.marzio@nyulangone.org.
(2)Department of Biochemistry and Molecular Pharmacology, New York University
Grossman School of Medicine, New York, NY 10016, USA; Laura and Isaac Perlmutter
NYU Cancer Center, New York University Grossman School of Medicine, New York, NY
10016, USA.
(3)Laura and Isaac Perlmutter NYU Cancer Center, New York University Grossman
School of Medicine, New York, NY 10016, USA; Department of Pathology, New York
University Grossman School of Medicine, New York, NY 10016, USA.
…
Non-small cell lung cancers (NSCLCs) harboring KEAP1 mutations are often
resistant to immunotherapy. Here, we show that KEAP1 targets EMSY for
ubiquitin-mediated degradation to regulate homologous recombination repair (HRR)
and anti-tumor immunity. Loss of KEAP1 in NSCLC induces stabilization of EMSY,
producing a BRCAness phenotype, i.e., HRR defects and sensitivity to PARP
inhibitors. Defective HRR contributes to a high tumor mutational burden that, in
turn, is expected to prompt an innate immune response. Notably, EMSY
accumulation suppresses the type I interferon response and impairs innate immune
signaling, fostering cancer immune evasion. Activation of the type I interferon
response in the tumor microenvironment using a STING agonist results in the
engagement of innate and adaptive immune signaling and impairs the growth of
KEAP1-mutant tumors. Our results suggest that targeting PARP and STING pathways,
individually or in combination, represents a therapeutic strategy in NSCLC
patients harboring alterations in KEAP1.
Copyright © 2021 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.cell.2021.12.005
PMCID: PMC8751279
PMID: 34963055
2. N Engl J Med. 2021 Dec 23;385(26):2441-2450. doi: 10.1056/NEJMoa2105470.
Multicomponent Strategy with Decentralized Molecular Testing for Tuberculosis.
Cattamanchi A(1), Reza TF(1), Nalugwa T(1), Adams K(1), Nantale M(1), Oyuku
D(1), Nabwire S(1), Babirye D(1), Turyahabwe S(1), Tucker A(1), Sohn H(1),
Ferguson O(1), Thompson R(1), Shete PB(1), Handley MA(1), Ackerman S(1), Joloba
M(1), Moore DAJ(1), Davis JL(1), Dowdy DW(1), Fielding K(1), Katamba A(1).
Author information:
(1)From the Division of Pulmonary and Critical Care Medicine and the Center for
Tuberculosis, San Francisco General Hospital (A.C., T.F.R., P.B.S.), the
Partnerships for Research in Implementation Science for Equity Center (A.C.,
P.B.S., M.A.H.), and the Departments of Epidemiology and Biostatistics (M.A.H.)
and Social and Behavioral Sciences (S.A.), University of California,…
BACKGROUND: Effective strategies are needed to facilitate the prompt diagnosis
and treatment of tuberculosis in countries with a high burden of the disease.
METHODS: We conducted a cluster-randomized trial in which Ugandan community
health centers were assigned to a multicomponent diagnostic strategy (on-site
molecular testing for tuberculosis, guided restructuring of clinic workflows,
and monthly feedback of quality metrics) or routine care (on-site sputum-smear
microscopy and referral-based molecular testing). The primary outcome was the
number of adults treated for confirmed tuberculosis within 14 days after
presenting to the health center for evaluation during the 16-month intervention
period. Secondary outcomes included completion of tuberculosis testing, same-day
diagnosis, and same-day treatment. Outcomes were also assessed on the basis of
proportions.
RESULTS: A total of 20 health centers underwent randomization, with 10 assigned
to each group. Of 10,644 eligible adults (median age, 40 years) whose data were
evaluated, 60.1% were women and 43.8% had human immunodeficiency virus
infection. The intervention strategy led to a greater number of patients being
treated for confirmed tuberculosis within 14 days after presentation (342
patients across 10 intervention health centers vs. 220 across 10 control health
centers; adjusted rate ratio, 1.56; 95% confidence interval [CI], 1.21 to 2.01).
More patients at intervention centers than at control centers completed
tuberculosis testing (adjusted rate ratio, 1.85; 95% CI, 1.21 to 2.82), received
a same-day diagnosis (adjusted rate ratio, 1.89; 95% CI, 1.39 to 2.56), and
received same-day treatment for confirmed tuberculosis (adjusted rate ratio,
2.38; 95% CI, 1.57 to 3.61). Among 706 patients with confirmed tuberculosis, a
higher proportion in the intervention group than in the control group were
treated on the same day (adjusted rate ratio, 2.29; 95% CI, 1.23 to 4.25) or
within 14 days after presentation (adjusted rate ratio, 1.22; 95% CI, 1.06 to
1.40).
CONCLUSIONS: A multicomponent diagnostic strategy that included on-site
molecular testing plus implementation supports to address barriers to delivery
of high-quality tuberculosis evaluation services led to greater numbers of
patients being tested, receiving a diagnosis, and being treated for confirmed
tuberculosis. (Funded by the National Heart, Lung, and Blood Institute; XPEL-TB
ClinicalTrials.gov number, NCT03044158.).
Copyright © 2021 Massachusetts Medical Society.
DOI: 10.1056/NEJMoa2105470
PMID: 34936740 [Indexed for MEDLINE]
3. Nature. 2021 Dec;600(7888):319-323. doi: 10.1038/s41586-021-04135-5. Epub 2021
Nov 24.
The CLIP1-LTK fusion is an oncogenic driver in non-small-cell lung cancer.
Izumi H(#)(1), Matsumoto S(#)(1), Liu J(2), Tanaka K(2), Mori S(1), Hayashi
K(3), Kumagai S(4), Shibata Y(1), Hayashida T(2)(5), Watanabe K(6), Fukuhara
T(6), Ikeda T(1), Yoh K(1), Kato T(7), Nishino K(8), Nakamura A(9), Nakachi
I(10), Kuyama S(11), Furuya N(12), Sakakibara-Konishi J(13), Okamoto I(14),
Taima K(15), Ebi N(16), Daga H(17), Yamasaki A(18), Kodani M(18), Udagawa
H(1)(2), Kirita K(1), Zenke Y(1), Nosaki K(1), Sugiyama E(1), Sakai T(1), Nakai
T(19), Ishii G(19), Niho S(1), Ohtsu A(20), Kobayashi SS(21)(22)(23), Goto
K(24).
Author information:
(1)Department of Thoracic Oncology, National Cancer Center Hospital East,
Kashiwa, Japan.
(2)Division of Translational Genomics, Exploratory Oncology Research and
Clinical Trial Center, National Cancer Center, Kashiwa, Japan.
(3)LSI Medience Corporation Central Laboratory, Itabashi-ku, Japan.
…
Comment in
Cancer Cell. 2022 Jan 10;40(1):23-25.
Lung cancer is one of the most aggressive tumour types. Targeted therapies
stratified by oncogenic drivers have substantially improved therapeutic outcomes
in patients with non-small-cell lung cancer (NSCLC)1. However, such oncogenic
drivers are not found in 25-40% of cases of lung adenocarcinoma, the most common
histological subtype of NSCLC2. Here we identify a novel fusion transcript of
CLIP1 and LTK using whole-transcriptome sequencing in a multi-institutional
genome screening platform (LC-SCRUM-Asia, UMIN000036871). The CLIP1-LTK fusion
was present in 0.4% of NSCLCs and was mutually exclusive with other known
oncogenic drivers. We show that kinase activity of the CLIP1-LTK fusion protein
is constitutively activated and has transformation potential. Treatment of Ba/F3
cells expressing CLIP1-LTK with lorlatinib, an ALK inhibitor, inhibited
CLIP1-LTK kinase activity, suppressed proliferation and induced apoptosis. One
patient with NSCLC harbouring the CLIP1-LTK fusion showed a good clinical
response to lorlatinib treatment. To our knowledge, this is the first
description of LTK alterations with oncogenic activity in cancers. These results
identify the CLIP1-LTK fusion as a target in NSCLC that could be treated with
lorlatinib.
© 2021. The Author(s), under exclusive licence to Springer Nature Limited.
DOI: 10.1038/s41586-021-04135-5
PMCID: PMC8687755
PMID: 34819663
4. Lancet Oncol. 2022 Jan;23(1):104-114. doi: 10.1016/S1470-2045(21)00606-9. Epub
2021 Dec 15.
Postoperative radiotherapy versus no postoperative radiotherapy in patients with
completely resected non-small-cell lung cancer and proven mediastinal N2
involvement (Lung ART): an open-label, randomised, phase 3 trial.
Le Pechoux C(1), Pourel N(2), Barlesi F(3), Lerouge D(4), Antoni D(5), Lamezec
B(6), Nestle U(7), Boisselier P(8), Dansin E(9), Paumier A(10), Peignaux K(11),
Thillays F(12), Zalcman G(13), Madelaine J(14), Pichon E(15), Larrouy A(16),
Lavole A(17), Argo-Leignel D(18), Derollez M(19), Faivre-Finn C(20), Hatton
MQ(21), Riesterer O(22), Bouvier-Morel E(23), Dunant A(23), Edwards JG(24),
Thomas PA(25), Mercier O(26), Bardet A(27).
Author information:
(1)Department of Radiation Oncology, Gustave Roussy, Villejuif, France.
Electronic address: cecile.lepechoux@gustaveroussy.fr.
(2)Radiation Oncology, Institut Sainte Catherine, Avignon, France.
(3)Department of Medical Oncology, Gustave Roussy, Villejuif, France;
Aix-Marseille University, Centre National de la Recherche Scientifique, Institut
National des Sciences et de la Recherche Médicale, Centre de Recherche en
Cancérologie de Marseille, Assistance Publique - Hôpitaux de Marseille,
Marseille, France.
…
Comment in
Lancet Oncol. 2022 Jan;23(1):8-9.
BACKGROUND: In patients with non-small-cell lung cancer (NSCLC), the use of
postoperative radiotherapy (PORT) has been controversial since 1998, because of
one meta-analysis showing a deleterious effect on survival in patients with pN0
and pN1, but with an unclear effect in patients with pN2 NSCLC. Because many
changes have occurred in the management of patients with NSCLC, the role of
three-dimensional (3D) conformal PORT warrants further investigation in patients
with stage IIIAN2 NSCLC. The aim of this study was to establish whether PORT
should be part of their standard treatment.
METHODS: Lung ART is an open-label, randomised, phase 3, superiority trial
comparing mediastinal PORT to no PORT in patients with NSCLC with complete
resection, nodal exploration, and cytologically or histologically proven N2
involvement. Previous neoadjuvant or adjuvant chemotherapy was allowed. Patients
aged 18 years or older, with an WHO performance status of 0-2, were recruited
from 64 hospitals and cancer centres in five countries (France, UK, Germany,
Switzerland, and Belgium). Patients were randomly assigned (1:1) to either the
PORT or no PORT (control) groups via a web randomisation system, and
minimisation factors were the institution, administration of chemotherapy,
number of mediastinal lymph node stations involved, histology, and use of
pre-treatment PET scan. Patients received PORT at a dose of 54 Gy in 27 or 30
daily fractions, on five consecutive days a week. Three dimensional conformal
radiotherapy was mandatory, and intensity-modulated radiotherapy was permitted
in centres with expertise. The primary endpoint was disease-free survival,
analysed by intention to treat at 3 years; patients from the PORT group who did
not receive radiotherapy and patients from the control group with no follow-up
were excluded from the safety analyses. This trial is now closed. This trial is
registered with ClinicalTrials.gov number, NCT00410683.
FINDINGS: Between Aug 7, 2007, and July 17, 2018, 501 patients, predominantly
staged with 18F-fluorodeoxyglucose (18F-FDG) PET (456 [91%]; 232 (92%) in the
PORT group and 224 (90%) in the control group), were enrolled and randomly
assigned to receive PORT (252 patients) or no PORT (249 patients). At the cutoff
date of May 31, 2019, median follow-up was 4·8 years (IQR 2·9-7·0). 3-year
disease-free survival was 47% (95% CI 40-54) with PORT versus 44% (37-51)
without PORT, and the median disease-free survival was 30·5 months (95% CI
24-49) in the PORT group and 22·8 months (17-37) in the control group (hazard
ratio 0·86; 95% CI 0·68-1·08; p=0·18). The most common grade 3-4 adverse events were pneumonitis (13 [5%] of 241 patients in the PORT group vs one [<1%] of 246 in the control group), lymphopenia (nine [4%] vs 0), and fatigue (six [3%] vs one [<1%]). Late-grade 3-4 cardiopulmonary toxicity was reported in 26 patients
(11%) in the PORT group versus 12 (5%) in the control group. Two patients died
from pneumonitis, partly related to radiotherapy and infection, and one patient
died due to chemotherapy toxicity (sepsis) that was deemed to be
treatment-related, all of whom were in the PORT group.
INTERPRETATION: Lung ART evaluated 3D conformal PORT after complete resection in
patients who predominantly had been staged using (18F-FDG PET-CT and received
neoadjuvant or adjuvant chemotherapy. 3-year disease-free survival was higher
than expected in both groups, but PORT was not associated with an increased
disease-free survival compared with no PORT. Conformal PORT cannot be
recommended as the standard of care in patients with stage IIIAN2 NSCLC.
FUNDING: French National Cancer Institute, Programme Hospitalier de Recherche
Clinique from the French Health Ministry, Gustave Roussy, Cancer Research UK,
Swiss State Secretary for Education, Research, and Innovation, Swiss Cancer
Research Foundation, Swiss Cancer League.
Copyright © 2022 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1470-2045(21)00606-9
PMID: 34919827
5. Lancet Oncol. 2022 Jan;23(1):138-148. doi: 10.1016/S1470-2045(21)00590-8. Epub
2021 Dec 11.
USPSTF2013 versus PLCOm2012 lung cancer screening eligibility criteria
(International Lung Screening Trial): interim analysis of a prospective cohort
study.
Tammemägi MC(1), Ruparel M(2), Tremblay A(3), Myers R(4), Mayo J(5), Yee J(6),
Atkar-Khattra S(7), Yuan R(8), Cressman S(9), English J(10), Bedard E(11),
MacEachern P(12), Burrowes P(13), Quaife SL(14), Marshall H(15), Yang I(15),
Bowman R(15), Passmore L(15), McWilliams A(16), Brims F(17), Lim KP(18), Mo
L(19), Melsom S(20), Saffar B(20), Teh M(21), Sheehan R(21), Kuok Y(21), Manser
R(22), Irving L(22), Steinfort D(22), McCusker M(23), Pascoe D(23), Fogarty
P(24), Stone E(25), Lam DCL(26), Ng MY(27), Vardhanabhuti V(27), Berg CD(28),
Hung RJ(29), Janes SM(2), Fong K(15), Lam S(7).
Author information:
(1)Department of Health Sciences, Brock University, St Catharines, ON, Canada.
Electronic address: martin.tammemagi@brocku.ca.
(2)Lungs for Living, UCL Respiratory, Department of Medicine, University College
London, London, UK.
(3)Division of Respiratory Medicine & Arnie Charbonneau Cancer Institute,
Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
…
Comment in
Lancet Oncol. 2022 Jan;23(1):13-14.
BACKGROUND: Lung cancer is a major health problem. CT lung screening can reduce
lung cancer mortality through early diagnosis by at least 20%. Screening
high-risk individuals is most effective. Retrospective analyses suggest that
identifying individuals for screening by accurate prediction models is more
efficient than using categorical age-smoking criteria, such as the US Preventive
Services Task Force (USPSTF) criteria. This study prospectively compared the
effectiveness of the USPSTF2013 and PLCOm2012 model eligibility criteria.
METHODS: In this prospective cohort study, participants from the International
Lung Screening Trial (ILST), aged 55-80 years, who were current or former
smokers (ie, had ≥30 pack-years smoking history or ≤15 quit-years since last
permanently quitting), and who met USPSTF2013 criteria or a PLCOm2012 risk
threshold of at least 1·51% within 6 years of screening, were recruited from
nine screening sites in Canada, Australia, Hong Kong, and the UK. After
enrolment, patients were assessed with the USPSTF2013 criteria and the PLCOm2012
risk model with a threshold of at least 1·70% at 6 years. Data were collected
locally and centralised. Main outcomes were the comparison of lung cancer
detection rates and cumulative life expectancies in patients with lung cancer
between USPSTF2013 criteria and the PLCOm2012 model. In this Article, we present
data from an interim analysis. To estimate the incidence of lung cancers in
individuals who were USPSTF2013-negative and had PLCOm2012 of less than 1·51% at
6 years, ever-smokers in the Prostate Lung Colorectal and Ovarian Cancer
Screening Trial (PLCO) who met these criteria and their lung cancer incidence
were applied to the ILST sample size for the mean follow-up occurring in the
ILST. This trial is registered at ClinicalTrials.gov, NCT02871856. Study
enrolment is almost complete.
FINDINGS: Between June 17, 2015, and Dec 29, 2020, 5819 participants from the
International Lung Screening Trial (ILST) were enrolled on the basis of meeting
USPSTF2013 criteria or the PLCOm2012 risk threshold of at least 1·51% at 6
years. The same number of individuals was selected for the PLCOm2012 model as
for the USPSTF2013 criteria (4540 [78%] of 5819). After a mean follow-up of 2·3
years (SD 1·0), 135 lung cancers occurred in 4540 USPSTF2013-positive
participants and 162 in 4540 participants included in the PLCOm2012 of at least
1·70% at 6 years group (cancer sensitivity difference 15·8%, 95% CI 10·7-22·1%; absolute odds ratio 4·00, 95% CI 1·89-9·44; p<0·0001). Compared to
USPSTF2013-positive individuals, PLCOm2012-selected participants were older
(mean age 65·7 years [SD 5·9] vs 63·3 years [5·7]; p<0·0001), had more
comorbidities (median 2 [IQR 1-3] vs 1 [1-2]; p<0·0001), and shorter life
expectancy (13·9 years [95% CI 12·8-14·9] vs 14·8 [13·6-16·0] years).
Model-based difference in cumulative life expectancies for those diagnosed with
lung cancer were higher in those who had PLCOm2012 risk of at least 1·70% at 6
years than individuals who were USPSTF2013-positive (2248·6 years [95% CI
2089·6-2425·9] vs 2000·7 years [1841·2-2160·3]; difference 247·9 years,
p=0·015).
INTERPRETATION: PLCOm2012 appears to be more efficient than the USPSTF2013
criteria for selecting individuals to enrol into lung cancer screening
programmes and should be used for identifying high-risk individuals who benefit
from the inclusion in these programmes.
FUNDING: Terry Fox Research Institute, The UBC-VGH Hospital Foundation and the
BC Cancer Foundation, the Alberta Cancer Foundation, the Australian National
Health and Medical Research Council, Cancer Research UK and a consortium of
funders, and the Roy Castle Lung Cancer Foundation for the UK Lung Screen Uptake
Trial.
Copyright © 2022 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/S1470-2045(21)00590-8
PMCID: PMC8716337
PMID: 34902336
6. Nat Immunol. 2021 Dec;22(12):1515-1523. doi: 10.1038/s41590-021-01066-1. Epub
2021 Nov 22.
Robust IgM responses following intravenous vaccination with Bacille
Calmette-Guérin associate with prevention of Mycobacterium tuberculosis
infection in macaques.
Irvine EB(1)(2), O'Neil A(1), Darrah PA(3), Shin S(1), Choudhary A(4), Li W(5),
Honnen W(4), Mehra S(6), Kaushal D(7), Gideon HP(8), Flynn JL(8), Roederer M(3),
Seder RA(3), Pinter A(4), Fortune S(#)(9)(10), Alter G(#)(11).
Author information:
(1)Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.
(2)Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of
Public Health, Boston, MA, USA.
(3)Vaccine Research Center, National Institute of Allergy and Infectious
Diseases (NIAID), National Institutes of Health, Bethesda, MD, USA.
…
Comment in
Nat Immunol. 2021 Dec;22(12):1470-1471.
Development of an effective tuberculosis (TB) vaccine has suffered from an
incomplete understanding of the correlates of protection against Mycobacterium
tuberculosis (Mtb). Intravenous (i.v.) vaccination with Bacille Calmette-Guérin
(BCG) provides nearly complete protection against TB in rhesus macaques, but the
antibody response it elicits remains incompletely defined. Here we show that
i.v. BCG drives superior antibody responses in the plasma and the lungs of
rhesus macaques compared to traditional intradermal BCG administration. While
i.v. BCG broadly expands antibody titers and functions, IgM titers in the plasma
and lungs of immunized macaques are among the strongest markers of reduced
bacterial burden. IgM was also enriched in macaques that received protective
vaccination with an attenuated strain of Mtb. Finally, an Mtb-specific IgM
monoclonal antibody reduced Mtb survival in vitro. Collectively, these data
highlight the potential importance of IgM responses as a marker and mediator of
protection against TB.
© 2021. The Author(s).
DOI: 10.1038/s41590-021-01066-1
PMCID: PMC8642241
PMID: 34811542 [Indexed for MEDLINE]
7. Cancer Cell. 2021 Dec 13;39(12):1594-1609.e12. doi: 10.1016/ j.ccell.2021.10.009. Epub 2021 Nov 11.
Single-cell analysis of human non-small cell lung cancer lesions refines tumor
classification and patient stratification.
Leader AM(1), Grout JA(1), Maier BB(1), Nabet BY(2), Park MD(1), Tabachnikova
A(1), Chang C(3), Walker L(3), Lansky A(1), Le Berichel J(1), Troncoso L(1),
Malissen N(4), Davila M(3), Martin JC(5), Magri G(1), Tuballes K(3), Zhao Z(6),
Petralia F(7), Samstein R(8), D'Amore NR(9), Thurston G(10), Kamphorst AO(1),
Wolf A(11), Flores R(11), Wang P(7), Müller S(12), Mellman I(13), Beasley MB(6),
Salmon H(1), Rahman AH(14), Marron TU(15), Kenigsberg E(16), Merad M(17).
Author information:
(1)The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai,
New York, NY, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount
Sinai, New York, NY, USA; Department of Oncological Sciences, Icahn School of
Medicine at Mount Sinai, New York, NY, USA.
(2)Department of Oncology Biomarker Development, Genentech, South San Francisco,
CA, USA.
(3)The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai,
New York, NY, USA; Human Immune Monitoring Center, Icahn School of Medicine at
Mount Sinai, New York, NY, USA.
…
Immunotherapy is a mainstay of non-small cell lung cancer (NSCLC) management.
While tumor mutational burden (TMB) correlates with response to immunotherapy,
little is known about the relationship between the baseline immune response and
tumor genotype. Using single-cell RNA sequencing, we profiled 361,929 cells from
35 early-stage NSCLC lesions. We identified a cellular module consisting of
PDCD1+CXCL13+ activated T cells, IgG+ plasma cells, and SPP1+ macrophages,
referred to as the lung cancer activation module (LCAMhi). We confirmed LCAMhi
enrichment in multiple NSCLC cohorts, and paired CITE-seq established an
antibody panel to identify LCAMhi lesions. LCAM presence was found to be
independent of overall immune cell content and correlated with TMB, cancer
testis antigens, and TP53 mutations. High baseline LCAM scores correlated with
enhanced NSCLC response to immunotherapy even in patients with above median TMB,
suggesting that immune cell composition, while correlated with TMB, may be a
nonredundant biomarker of response to immunotherapy.
Copyright © 2021. Published by Elsevier Inc.
DOI: 10.1016/j.ccell.2021.10.009
PMCID: PMC8728963
PMID: 34767762 [Indexed for MEDLINE]
8. Am J Respir Crit Care Med. 2021 Dec 23. doi: 10.1164/rccm.202012-4541OC. Online ahead of print.
Efficacy of Long-Acting Bedaquiline Regimens in a Mouse Model of Tuberculosis
Preventive Therapy.
Kaushik A(1), Ammerman NC(1), Tasneen R(1), Lachau-Durand S(2), Andries K(2),
Nuermberger E(3).
Author information:
(1)Johns Hopkins School of Medicine, 1500, Medicine, Baltimore, Maryland, United
States.
(2)Janssen Pharmaceutica NV, 50148, Beerse, Belgium.
(3)Johns Hopkins School of Medicine, 1500, Medicine, Baltimore, Maryland, United
States; enuermb@jhmi.edu.
RATIONALE: Completion of preventive therapy is a major bottleneck in global
tuberculosis control. Long-acting injectable drug formulations would shorten
therapy administration and may thereby improve completion rates. Recently, a
long-acting formulation of bedaquiline demonstrated anti-tuberculosis activity
for up to 12 weeks post-injection in a validated mouse model of preventive
therapy.
OBJECTIVES: The objectives of this study were to (i) determine the total
duration of activity following an injection of long-acting bedaquiline, and (ii)
evaluate the activity of regimens comprised of long-acting bedaquiline plus
short (2-4 week) oral companion courses of bedaquiline, with or without
rifapentine, using the validated mouse model of tuberculosis preventive therapy.
METHODS: After establishment of a stable Mycobacterium tuberculosis lung
infection in BCG-immunized BALB/c mice, treatment was initiated with one of 12
randomly assigned regimens. In addition to positive and negative controls, six
regimens included 1 or 2 injections of long-acting bedaquiline (alone or with
oral bedaquiline +/- rifapentine), and 4 comparator regimens consisted of oral
agents only. Lung bacterial burden was measured monthly for up to 28 weeks.
MEASUREMENTS AND MAIN RESULTS: One injection of long-acting bedaquiline at 160
mg/kg exerted anti-tuberculosis activity for 12 weeks. Compared to the positive
control (daily isoniazid-rifapentine for 4 weeks), six regimens had equivalent
bactericidal activity (including two all-oral comparator regimens), and two
regimens has superior sterilizing activity: one injection with 2 weeks of oral
bedaquiline and high-dose rifapentine; and 2 injections with 4 weeks of oral
bedaquiline.
CONCLUSION: Long-acting injectable bedaquiline has significant potential for
shortening tuberculosis preventive therapy.
DOI: 10.1164/rccm.202012-4541OC
PMID: 34939891
9. J Clin Oncol. 2021 Dec 22:JCO2102528. doi: 10.1200/JCO.21.02528. Online ahead of print.
Management of Stage III Non-Small-Cell Lung Cancer: ASCO Guideline.
Daly ME(1), Singh N(2), Ismaila N(3), Antonoff MB(4), Arenberg DA(5), Bradley
J(6), David E(7), Detterbeck F(8), Früh M(9)(10), Gubens MA(11), Moore AC(12),
Padda SK(13), Patel JD(14), Phillips T(15), Qin A(5), Robinson C(16), Simone CB
2nd(17).
Author information:
(1)University of California, Davis, CA.
(2)Postgraduate Institute of Medical Education & Research, Chandigarh, India.
(3)American Society of Clinical Oncology (ASCO), Alexandria, VA.
…
PURPOSE: To provide evidence-based recommendations to practicing clinicians on
management of patients with stage III non-small-cell lung cancer (NSCLC).
METHODS: An Expert Panel of medical oncology, thoracic surgery, radiation
oncology, pulmonary oncology, community oncology, research methodology, and
advocacy experts was convened to conduct a literature search, which included
systematic reviews, meta-analyses, and randomized controlled trials published
from 1990 through 2021. Outcomes of interest included survival, disease-free or
recurrence-free survival, and quality of life. Expert Panel members used
available evidence and informal consensus to develop evidence-based guideline
recommendations.
RESULTS: The literature search identified 127 relevant studies to inform the
evidence base for this guideline.
RECOMMENDATIONS: Evidence-based recommendations were developed to address
evaluation and staging workup of patients with suspected stage III NSCLC,
surgical management, neoadjuvant and adjuvant approaches, and management of
patients with unresectable stage III NSCLC.Additional information is available
at www.asco.org/thoracic-cancer-guidelines.
DOI: 10.1200/JCO.21.02528
PMID: 34936470
10. PLoS Med. 2021 Dec 16;18(12):e1003875. doi: 10.1371/journal.pmed.1003875.
eCollection 2021 Dec.
Completion of isoniazid-rifapentine (3HP) for tuberculosis prevention among
people living with HIV: Interim analysis of a hybrid type 3 effectiveness-implementation randomized trial.
Semitala FC(1)(2)(3), Kadota JL(4), Musinguzi A(2), Nabunje J(2), Welishe F(2),
Nakitende A(2), Akello L(2), Bishop O(2), Patel D(5), Sammann A(5), Nahid P(4),
Belknap R(6), Kamya MR(1)(2), Handley MA(7)(8), Phillips PPJ(4), Katahoire A(9),
Berger CA(4), Kiwanuka N(10), Katamba A(10)(11), Dowdy DW(11)(12), Cattamanchi
A(4)(11).
Author information:
(1)Makerere University, Department of Medicine, College of Health Sciences,
Kampala, Uganda.
(2)Infectious Diseases Research Collaboration, Kampala, Uganda.
(3)Makerere University Joint AIDS Program, Kampala, Uganda.
…
BACKGROUND: Scaling up shorter regimens for tuberculosis (TB) prevention such as
once weekly isoniazid-rifapentine (3HP) taken for 3 months is a key priority for
achieving targets set forth in the World Health Organization's (WHO) END TB
Strategy. However, there are few data on 3HP patient acceptance and completion
in the context of routine HIV care in sub-Saharan Africa.
METHODS AND FINDINGS: The 3HP Options Trial is a pragmatic, parallel type 3
effectiveness-implementation randomized trial comparing 3 optimized strategies
for delivering 3HP-facilitated directly observed therapy (DOT), facilitated
self-administered therapy (SAT), or informed choice between DOT and SAT using a
shared decision-making aid-to people receiving care at a large urban HIV clinic
in Kampala, Uganda. Participants and healthcare providers were not blinded to
arm assignment due to the nature of the 3HP delivery strategies. We conducted an
interim analysis of participants who were enrolled and exited the 3HP treatment
period between July 13, 2020 and April 30, 2021. The primary outcome, which was
aggregated across trial arms for this interim analysis, was the proportion who
accepted and completed 3HP (≥11 of 12 doses within 16 weeks of randomization).
We used Bayesian inference analysis to estimate the posterior probability that
this proportion would exceed 80% under at least 1 of the 3HP delivery
strategies, a coprimary hypothesis of the trial. Through April 2021, 684
participants have been enrolled, and 479 (70%) have exited the treatment period.
Of these 479 participants, 309 (65%) were women, mean age was 41.9 years
(standard deviation (SD): 9.2), and mean time on antiretroviral therapy (ART)
was 7.8 years (SD: 4.3). In total, 445 of them (92.9%, 95% confidence interval
(CI): [90.2 to 94.9]) accepted and completed 3HP treatment. There were no
differences in treatment acceptance and completion by sex, age, or time on ART.
Treatment was discontinued due to a documented adverse event (AE) in 8 (1.7%)
patients. The probability that treatment acceptance and completion exceeds 80%
under at least 1 of the three 3HP delivery strategies was greater than 99%. The
main limitations are that the trial was conducted at a single site, and the
interim analysis focused on aggregate outcome data to maintain blinding of
investigators to arm-specific outcomes.
CONCLUSIONS: 3HP was widely accepted by people living with HIV (PLHIV) in
Uganda, and very high levels of treatment completion were achieved in a
programmatic setting. These findings show that 3HP can enable effective scale-up
of tuberculosis preventive therapy (TPT) in high-burden countries, particularly
when delivery strategies are tailored to target known barriers to treatment
completion.
TRIAL REGISTRATION: ClinicalTrials.gov NCT03934931.
DOI: 10.1371/journal.pmed.1003875
PMCID: PMC8726462
PMID: 34914696 [Indexed for MEDLINE]
11. Nat Commun. 2021 Dec 15;12(1):7312. doi: 10.1038/s41467-021-27616-7.
Genomic signatures of pre-resistance in Mycobacterium tuberculosis.
Torres Ortiz A(1), Coronel J(2), Vidal JR(3), Bonilla C(3)(4), Moore DAJ(5),
Gilman RH(6), Balloux F(7), Kon OM(8), Didelot X(9), Grandjean L(10)(11).
Author information:
(1)Imperial College London, Department of Infectious Diseases, London, UK.
(2)Universidad Peruana Cayetano Heredia, Lima, Perú.
(3)Unidad Técnica de Tuberculosis MDR, Ministerio de Salud, Lima, Perú.
…
Recent advances in bacterial whole-genome sequencing have resulted in a
comprehensive catalog of antibiotic resistance genomic signatures in
Mycobacterium tuberculosis. With a view to pre-empt the emergence of resistance,
we hypothesized that pre-existing polymorphisms in susceptible genotypes
(pre-resistance mutations) could increase the risk of becoming resistant in the
future. We sequenced whole genomes from 3135 isolates sampled over a 17-year
period. After reconstructing ancestral genomes on time-calibrated phylogenetic
trees, we developed and applied a genome-wide survival analysis to determine the
hazard of resistance acquisition. We demonstrate that M. tuberculosis lineage 2
has a higher risk of acquiring resistance than lineage 4, and estimate a higher
hazard of rifampicin resistance evolution following isoniazid mono-resistance.
Furthermore, we describe loci and genomic polymorphisms associated with a higher
risk of resistance acquisition. Identifying markers of future antibiotic
resistance could enable targeted therapy to prevent resistance emergence in M.
tuberculosis and other pathogens.
© 2021. The Author(s).
DOI: 10.1038/s41467-021-27616-7
PMCID: PMC8674244
PMID: 34911948 [Indexed for MEDLINE]
12. Nat Commun. 2021 Nov 22;12(1):6774. doi: 10.1038/s41467-021-27029-6.
A Phase I/II randomized trial of H56:IC31 vaccination and adjunctive
cyclooxygenase-2-inhibitor treatment in tuberculosis patients.
Jenum S(#)(1), Tonby K(#)(1)(2), Rueegg CS(3), Rühwald M(4)(5), Kristiansen
MP(6), Bang P(6), Olsen IC(7), Sellæg K(1), Røstad K(1), Mustafa T(8)(9), Taskén
K(2)(10), Kvale D(1)(2), Mortensen R(4), Dyrhol-Riise AM(11)(12).
Author information:
(1)Department of Infectious diseases, Oslo University Hospital, P.O box 4952,
Nydalen, N-0424, Oslo, Norway.
(2)Institute of Clinical Medicine, University of Oslo, P.O box 1171, Blindern,
N-0318, Oslo, Norway.
(3)Oslo Centre for Biostatistics and Epidemiology, Oslo University Hospital, P.O
box 4950, Nydalen, N-0424, Oslo, Norway.
…
Host-directed-therapy strategies are warranted to fight tuberculosis. Here we
assess the safety and immunogenicity of adjunctive vaccination with the H56:IC31
candidate and cyclooxygenase-2-inhibitor treatment (etoricoxib) in pulmonary and
extra-pulmonary tuberculosis patients in a randomized open-label phase I/II
clinical trial (TBCOX2, NCT02503839). A total of 222 patients were screened, 51
enrolled and randomized; 13 in the etoricoxib-group, 14 in the H56:IC31-group,
12 in the etoricoxib+H56:IC31-group and 12 controls. Three Serious Adverse
Events were reported in the etoricoxib-groups; two urticarial rash and one
possible disease progression, no Serious Adverse Events were vaccine related.
H56:IC31 induces robust expansion of antigen-specific T-cells analyzed by
fluorospot and flow cytometry, and higher proportion of seroconversions.
Etoricoxib reduced H56:IC31-induced T-cell responses. Here, we show the first
clinical data that H56:IC31 vaccination is safe and immunogenic in tuberculosis
patients, supporting further studies of H56:IC31 as a host-directed-therapy
strategy. Although etoricoxib appears safe, our data do not support therapy
with adjunctive cyclooxygenase-2-inhibitors.
© 2021. The Author(s).
DOI: 10.1038/s41467-021-27029-6
PMCID: PMC8608791
PMID: 34811370 [Indexed for MEDLINE]
13. Nat Commun. 2021 Nov 15;12(1):6593. doi: 10.1038/s41467-021-26941-1.
Multiple acyl-CoA dehydrogenase deficiency kills Mycobacterium tuberculosis in
vitro and during infection.
Beites T(1), Jansen RS(2)(3), Wang R(1)(4), Jinich A(2), Rhee KY(1)(2),
Schnappinger D(1), Ehrt S(5).
Author information:
(1)Department of Microbiology and Immunology, Weill Cornell Medical College, New
York, NY, 10065, USA.
(2)Division of Infectious Diseases, Department of Medicine, Weill Cornell
Medical College, New York, NY, 10065, USA.
(3)Department of Microbiology, Radboud University, 6525 AJ, Nijmegen, The
Netherlands.
…
The human pathogen Mycobacterium tuberculosis depends on host fatty acids as a
carbon source. However, fatty acid β-oxidation is mediated by redundant enzymes,
which hampers the development of antitubercular drugs targeting this pathway.
Here, we show that rv0338c, which we refer to as etfD, encodes a membrane
oxidoreductase essential for β-oxidation in M. tuberculosis. An etfD deletion
mutant is incapable of growing on fatty acids or cholesterol, with long-chain
fatty acids being bactericidal, and fails to grow and survive in mice. Analysis
of the mutant's metabolome reveals a block in β-oxidation at the step catalyzed
by acyl-CoA dehydrogenases (ACADs), which in other organisms are functionally
dependent on an electron transfer flavoprotein (ETF) and its cognate
oxidoreductase. We use immunoprecipitation to show that M. tuberculosis EtfD
interacts with FixA (EtfB), a protein that is homologous to the human ETF
subunit β and is encoded in an operon with fixB, encoding a homologue of human
ETF subunit α. We thus refer to FixA and FixB as EtfB and EtfA, respectively.
Our results indicate that EtfBA and EtfD (which is not homologous to human EtfD)
function as the ETF and oxidoreductase for β-oxidation in M. tuberculosis and
support this pathway as a potential target for tuberculosis drug development.
© 2021. The Author(s).
DOI: 10.1038/s41467-021-26941-1
PMCID: PMC8593149
PMID: 34782606 [Indexed for MEDLINE]
14. Lancet Infect Dis. 2021 Nov 12:S1473-3099(21)00470-9. doi:
10.1016/S1473-3099(21)00470-9. Online ahead of print.
Assessment of epidemiological and genetic characteristics and clinical outcomes
of resistance to bedaquiline in patients treated for rifampicin-resistant
tuberculosis: a cross-sectional and longitudinal study.
Ismail NA(1), Omar SV(2), Moultrie H(3), Bhyat Z(3), Conradie F(4), Enwerem
M(5), Ferreira H(6), Hughes J(7), Joseph L(3), Kock Y(8), Letsaolo V(3),
Maartens G(9), Meintjes G(9), Ngcamu D(3), Okozi N(3), Padanilam X(10), Reuter
A(11), Romero R(12), Schaaf S(7), Te Riele J(13), Variava E(14), van der Meulen
M(3), Ismail F(15), Ndjeka N(8).
Author information:
(1)Centre for Tuberculosis, National Institute for Communicable Diseases,
Johannesburg, South Africa; Department of Medical Microbiology, University of
Pretoria, Pretoria, South Africa; Faculty of Health Sciences, University of
Witwatersrand, Johannesburg, South Africa.
(2)Centre for Tuberculosis, National Institute for Communicable Diseases,
Johannesburg, South Africa. Electronic address: shaheedvo@nicd.ac.za.
(3)Centre for Tuberculosis, National Institute for Communicable Diseases,
Johannesburg, South Africa.
…
BACKGROUND: Bedaquiline improves outcomes of patients with rifampicin-resistant
and multidrug-resistant (MDR) tuberculosis; however, emerging resistance
threatens this success. We did a cross-sectional and longitudinal analysis
evaluating the epidemiology, genetic basis, and treatment outcomes associated
with bedaquiline resistance, using data from South Africa (2015-19).
METHODS: Patients with drug-resistant tuberculosis starting bedaquiline-based
treatment had surveillance samples submitted at baseline, month 2, and month 6,
along with demographic information. Culture-positive baseline and post-baseline
isolates had phenotypic resistance determined. Eligible patients were aged 12
years or older with a positive culture sample at baseline or, if the sample was
invalid or negative, a sample within 30 days of the baseline sample submitted
for bedaquiline drug susceptibility testing. For the longitudinal study, the
first surveillance sample had to be phenotypically susceptible to bedaquiline
for inclusion. Whole-genome sequencing was done on bedaquiline-resistant
isolates and a subset of bedaquiline-susceptible isolates. The National
Institute for Communicable Diseases tuberculosis reference laboratory, and
national tuberculosis surveillance databases were matched to the Electronic
Drug-Resistant Tuberculosis Register. We assessed baseline resistance
prevalence, mutations, transmission, cumulative resistance incidence, and odds
ratios (ORs) associating risk factors for resistance with patient outcomes.
FINDINGS: Between Jan 1, 2015, and July 31, 2019, 8041 patients had surveillance
samples submitted, of whom 2023 were included in the cross-sectional analysis
and 695 in the longitudinal analysis. Baseline bedaquiline resistance prevalence
was 3·8% (76 of 2023 patients; 95% CI 2·9-4·6), and it was associated with
previous exposure to bedaquiline or clofazimine (OR 7·1, 95% CI 2·3-21·9) and
with rifampicin-resistant or MDR tuberculosis with additional resistance to
either fluoroquinolones or injectable drugs (pre-extensively-drug resistant
[XDR] tuberculosis: 4·2, 1·7-10·5) or to both (XDR tuberculosis: 4·8, 2·0-11·7). Rv0678 mutations were the sole genetic basis of phenotypic resistance. Baseline resistance could be attributed to previous bedaquiline or clofazimine exposure in four (5·3%) of 76 patients and to primary transmission in six (7·9%). Odds of successful treatment outcomes were lower in patients with baseline bedaquiline resistance (0·5, 0·3-1). Resistance during treatment developed in 16 (2·3%) of 695 patients, at a median of 90 days (IQR 62-195), with 12 of these 16 having pre-XDR or XDR.
INTERPRETATION: Bedaquiline resistance was associated with poorer treatment
outcomes. Rapid assessment of bedaquiline resistance, especially when patients
were previously exposed to bedaquiline or clofazimine, should be prioritised at
baseline or if patients remain culture-positive after 2 months of treatment.
Preventing resistance by use of novel combination therapies, current treatment
optimisation, and patient support is essential.
FUNDING: National Institute for Communicable Diseases of South Africa.
Copyright © 2021 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1473-3099(21)00470-9
PMID: 34780706
15. J Clin Oncol. 2022 Jan 20;40(3):231-241. doi: 10.1200/JCO.21.01729. Epub 2021
Nov 2.
Randomized Phase III Study of Gefitinib Versus Cisplatin Plus Vinorelbine for
Patients With Resected Stage II-IIIA Non-Small-Cell Lung Cancer With EGFR
Mutation (IMPACT).
Tada H(1), Mitsudomi T(2), Misumi T(3), Sugio K(4), Tsuboi M(5), Okamoto I(6),
Iwamoto Y(7), Sakakura N(8), Sugawara S(9), Atagi S(10), Takahashi T(11),
Hayashi H(12), Okada M(13), Inokawa H(14), Yoshioka H(15), Takahashi K(16),
Higashiyama M(17), Yoshino I(18), Nakagawa K(12); West Japan Oncology Group.
Author information:
(1)Department of Thoracic Surgery, Suita Tokushukai Hospital, Suita, Japan.
(2)Division of Thoracic Surgery, Department of Surgery, Kindai University
Faculty of Medicine, Osaka-Sayama, Japan.
(3)Department of Biostatistics, Yokohama City University School of Medicine,
Yokohama, Japan.
…
Comment in
J Clin Oncol. 2022 Jan 20;40(3):217-220.
PURPOSE: To investigate the efficacy of gefitinib as an adjuvant therapy for
non-small-cell lung cancer patients with EGFR mutation.
PATIENTS AND METHODS: IMPACT (WJOG6410L; University Hospital Medical Information
Network Clinical Trials Registry: UMIN000006252), a randomized, open-label,
phase III study, included patients with completely resected pathologic stage
II-III non-small-cell lung cancer harboring EGFR mutations (exon 19 deletion or
L858R) during September 2011 to December 2015. Patients were randomly assigned
to receive gefitinib (250 mg once daily) for 24 months or cisplatin (80 mg/m2 on
day 1) plus vinorelbine (25 mg/m2 on days 1 and 8; cis/vin) once every 3 weeks
for four cycles. The primary end point was disease-free survival (DFS).
RESULTS: Overall, 234 patients were randomly assigned. Among 232 eligible
patients (116 each; excluding two who withdrew consent), the median DFS was 35.9
and 25.1 months in the gefitinib and cis/vin groups, respectively. However,
Kaplan-Meier curves crossed around 4 years after surgery with no statistically
significant difference (stratified log-rank P = .63; hazard ratio by stratified
Cox proportional hazards model = 0.92; 95% CI, 0.67 to 1.28). Overall survival
(OS) was also not different (stratified log-rank P = .89; hazard ratio = 1.03;
95% CI, 0.65 to 1.65), with the 5-year OS rates being 78.0% and 74.6% in the
gefitinib and cis/vin groups, respectively. Treatment-related deaths occurred in
0 and three patients in the gefitinib and cis/vin groups, respectively.
CONCLUSION: Although adjuvant gefitinib appeared to prevent early relapse, it
did not prolong DFS or OS. However, similar DFS and OS may justify adjuvant
gefitinib in the selected patient subsets, especially those deemed ineligible
for platinum-doublet adjuvant therapy; however, this was not a noninferiority
trial.
DOI: 10.1200/JCO.21.01729
PMID: 34726958
16. Am J Respir Crit Care Med. 2021 Dec 15;204(12):1463-1472. doi:
10.1164/rccm.202103-0548OC.
Longitudinal Dynamics of a Blood Transcriptomic Signature of Tuberculosis.
Mulenga H(1), Musvosvi M(1), Mendelsohn SC(1), Penn-Nicholson A(1), Kimbung
Mbandi S(1), Fiore-Gartland A(2), Tameris M(1), Mabwe S(1), Africa H(1), Bilek
N(1), Kafaar F(1), Khader SA(3), Carstens B(1), Hadley K(1), Hikuam C(1),
Erasmus M(1), Jaxa L(1), Raphela R(1), Nombida O(1), Kaskar M(1), Nicol
MP(4)(5), Mbhele S(4), Van Heerden J(4), Innes C(6), Brumskine W(6), Hiemstra
A(7), Malherbe ST(7), Hassan-Moosa R(8)(9), Walzl G(7), Naidoo K(8)(9),
Churchyard G(6)(10), Hatherill M(1), Scriba TJ(1); CORTIS Study Team.
Author information:
(1)South African Tuberculosis Vaccine Initiative, Institute of Infectious
Disease and Molecular Medicine and Division of Immunology, and.
(2)Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research
Center, Seattle, Washington.
(3)Department of Molecular Microbiology, Washington University in St. Louis, St.
Louis, Missouri.
…
Comment in
Am J Respir Crit Care Med. 2021 Dec 15;204(12):1363-1365.
Rationale: Performance of blood transcriptomic tuberculosis (TB) signatures in
longitudinal studies and effects of TB-preventive therapy and coinfection with
HIV or respiratory organisms on transcriptomic signatures has not been
systematically studied. Objectives: We evaluated longitudinal kinetics of an
11-gene blood transcriptomic TB signature, RISK11, and effects of TB-preventive
therapy (TPT) and respiratory organisms on RISK11 signature score, in
HIV-uninfected and HIV-infected individuals. Methods: RISK11 was measured in a
longitudinal study of RISK11-guided TPT in HIV-uninfected adults, a
cross-sectional respiratory organisms cohort, or a longitudinal study in people
living with HIV (PLHIV). HIV-uninfected RISK11+ participants were randomized to
TPT or no TPT; RISK11- participants received no TPT. PLHIV received
standard-of-care antiretroviral therapy and TPT. In the cross-sectional
respiratory organisms cohort, viruses and bacteria in nasopharyngeal and
oropharyngeal swabs were quantified by real-time quantitative PCR. Measurements
and Main Results: RISK11+ status was transient in most of the 128 HIV-negative
participants with longitudinal samples; more than 70% of RISK11+ participants
reverted to RISK11- by 3 months, irrespective of TPT. By comparison, reversion
from a RISK11+ state was less common in 645 PLHIV (42.1%). Non-HIV viral and
nontuberculous bacterial organisms were detected in 7.2% and 38.9% of the 1,000
respiratory organisms cohort participants, respectively, and among those
investigated for TB, 3.8% had prevalent disease. Median RISK11 scores (%) were
higher in participants with viral organisms alone (46.7%), viral and bacterial
organisms (42.8%), or prevalent TB (85.7%) than those with bacterial organisms
other than TB (13.4%) or no organisms (14.2%). RISK11 could not discriminate
between prevalent TB and viral organisms. Conclusions: Positive RISK11 signature
status is often transient, possibly due to intercurrent viral infection,
highlighting potentially important challenges for implementation of these
biomarkers as new tools for TB control.
DOI: 10.1164/rccm.202103-0548OC
PMID: 34520313 [Indexed for MEDLINE]
17. J Clin Oncol. 2021 Nov 10;39(32):3633-3644. doi: 10.1200/JCO.20.03318. Epub 2021 Aug 26.
Veliparib in Combination With Platinum-Based Chemotherapy for First-Line
Treatment of Advanced Squamous Cell Lung Cancer: A Randomized, Multicenter Phase
III Study.
Ramalingam SS(1), Novello S(2), Guclu SZ(3)(4), Bentsion D(5), Zvirbule Z(6),
Szilasi M(7), Bernabe R(8), Syrigos K(9), Byers LA(10), Clingan P(11), Bar
J(12), Vokes EE(13), Govindan R(14), Dunbar M(15), Ansell P(15), He L(15), Huang
X(15), Sehgal V(15), Glasgow J(15), Bach BA(15), Mazieres J(16).
Author information:
(1)Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA.
(2)Department of Oncology, University of Turin, AOU San Luigi Gonzaga,
Orbassano, Torino, Italy.
(3)Chest Diseases Clinic, Izmir Chest Diseases Research Hospital, Izmir, Turkey.
…
PURPOSE: Squamous non-small-cell lung cancer (sqNSCLC) is genetically complex
with evidence of DNA damage. This phase III study investigated the efficacy and
safety of poly (ADP-ribose) polymerase inhibitor veliparib in combination with
conventional chemotherapy for advanced sqNSCLC (NCT02106546).
PATIENTS AND METHODS: Patients age ≥ 18 years with untreated, advanced sqNSCLC
were randomly assigned 1:1 to carboplatin and paclitaxel with veliparib 120 mg
twice daily (twice a day) or placebo twice a day for up to six cycles. The
primary end point was overall survival (OS) in the veliparib arm versus the
control arm in current smokers, based on phase II findings. Archival tumor
samples were provided for biomarker analysis using a 52-gene expression
histology classifier (LP52).
RESULTS: Overall, 970 patients were randomly assigned to carboplatin and
paclitaxel plus either veliparib (n = 486) or placebo (n = 484); 57% were
current smokers. There was no significant OS benefit with veliparib in current
smokers, with median OS 11.9 versus 11.1 months (hazard ratio [HR], 0.905; 95%
CI, 0.744 to 1.101; P = .266). In the overall population, OS favored veliparib;
median OS was 12.2 versus 11.2 months (HR, 0.853; 95% CI, 0.747 to 0.974), with
no difference in progression-free survival (median 5.6 months per arm). In
patients with biomarker-evaluable tumor samples (n = 360), OS favored veliparib
in the LP52-positive population (median 14.0 v 9.6 months; HR, 0.66; 95% CI,
0.49 to 0.89), but favored placebo in the LP52-negative population (median 11.0
v 14.4 months; HR, 1.33; 95% CI, 0.95 to 1.86). No new safety signals were
observed in the experimental arm.
CONCLUSION: In current smokers with advanced sqNSCLC, there was no therapeutic
benefit of adding veliparib to first-line chemotherapy. The LP52 signature may
identify a subgroup of patients likely to derive benefit from veliparib with
chemotherapy.
DOI: 10.1200/JCO.20.03318
PMCID: PMC8577684
PMID: 34436928 [Indexed for MEDLINE]
18. Am J Respir Crit Care Med. 2021 Dec 1;204(11):1327-1335. doi:
10.1164/rccm.202103-0534OC.
A Semimechanistic Model of the Bactericidal Activity of High-Dose Isoniazid
against Multidrug-Resistant Tuberculosis: Results from a Randomized Clinical
Trial.
Gausi K(1), Ignatius EH(2), Sun X(3), Kim S(4), Moran L(5), Wiesner L(1), von
Groote-Bidlingmaier F(6), Hafner R(7), Donahue K(8), Vanker N(6), Rosenkranz
SL(3), Swindells S(9), Diacon AH(6), Nuermberger EL(2), Dooley KE(2), Denti
P(1).
Author information:
(1)Division of Clinical Pharmacology, Department of Medicine, University of Cape
Town, Cape Town, South Africa.
(2)Department of Medicine, Johns Hopkins University School of Medicine,
Baltimore, Maryland.
(3)Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
(4)Frontier Science Foundation, Brookline Massachusetts.
(5)Social and Scientific Systems, a DLH Company, Silver Spring, Maryland.
(6)TASK Applied Science and Stellenbosch University, Cape Town, South Africa.
(7)Division of AIDS, National Institute of Allergy and Infectious Diseases,
Bethesda, Maryland.
(8)Frontier Science Foundation, Amherst, New York; and.
(9)Department of Internal Medicine, University of Nebraska Medical Center,
Omaha, Nebraska.
Comment in
Am J Respir Crit Care Med. 2021 Dec 1;204(11):1248-1250.
Rationale: There is accumulating evidence that higher-than-standard doses of
isoniazid are effective against low-to-intermediate-level isoniazid-resistant
strains of Mycobacterium tuberculosis, but the optimal dose remains unknown.
Objectives: To characterize the association between isoniazid pharmacokinetics
(standard or high dose) and early bactericidal activity against M. tuberculosis
(drug sensitive and inhA mutated) and N-acetyltransferase 2 status. Methods:
ACTG (AIDS Clinical Trial Group) A5312/INHindsight is a 7-day early bactericidal
activity study with isoniazid at a normal dose (5 mg/kg) for patients with
drug-sensitive bacteria and 5, 10, and 15 mg/kg doses for patients with inhA
mutants. Participants with pulmonary tuberculosis received daily isoniazid
monotherapy and collected sputum daily. Colony-forming units (cfu) on solid
culture and time to positivity in liquid culture were jointly analyzed using
nonlinear mixed-effects modeling. Measurements and Main Results: Fifty-nine
adults were included in this analysis. A decline in sputum cfu was described by
a one-compartment model, whereas an exponential bacterial growth model was used
to interpret time-to-positivity data. The model found that bacterial kill is
modulated by isoniazid concentration using an effect compartment and a sigmoidal
Emax relationship (a model linking the drug concentration to the observed
effect). The model predicted lower potency but similar maximum kill of isoniazid
against inhA-mutated compared with drug-sensitive isolates. Based on simulations
from the pharmacokinetics-pharmacodynamics model, to achieve a drop in bacterial
load comparable to 5 mg/kg against drug-sensitive tuberculosis, 10- and 15-mg/kg
doses are necessary against inhA-mutated isolates in slow and intermediate
N-acetyltransferase 2 acetylators, respectively. Fast acetylators underperformed
even at 15 mg/kg. Conclusions: Dosing of isoniazid based on N-acetyltransferase
2 acetylator status may help patients attain effective exposures against
inhA-mutated isolates. Clinical trial registered with www.clinicaltrials.gov
(NCT01936831).
DOI: 10.1164/rccm.202103-0534OC
PMCID: PMC8786077
PMID: 34403326 [Indexed for MEDLINE]
19. Am J Respir Crit Care Med. 2021 Nov 1;204(9):1086-1096. doi:
10.1164/rccm.202101-0117OC.
Precision-Enhancing Risk Stratification Tools for Selecting Optimal Treatment
Durations in Tuberculosis Clinical Trials.
Imperial MZ(1)(2), Phillips PPJ(2)(3), Nahid P(2)(3), Savic RM(1)(2)(3).
Author information:
(1)Department of Bioengineering and Therapeutic Sciences.
(2)University of California, San Francisco, Center for Tuberculosis, and.
(3)Division of Pulmonary and Critical Care Medicine, San Francisco General
Hospital, University of California, San Francisco, San Francisco, California.
Comment in
Am J Respir Crit Care Med. 2021 Nov 1;204(9):1013-1014.
Rationale: No evidence-based tools exist to enhance precision in the selection
of patient-specific optimal treatment durations to study in tuberculosis
clinical trials. Objectives: To develop risk stratification tools that assign
patients with tuberculosis into risk groups of unfavorable outcome and inform
selection of optimal treatment duration for each patient strata to study in
clinical trials. Methods: Publicly available data from four phase 3 trials, each
evaluating treatment duration shortening from 6 to 4 months, were used to
develop parametric time-to-event models that describe unfavorable outcomes.
Regimen, baseline, and on-treatment characteristics were evaluated as predictors
of outcomes. Exact regression coefficients of predictors were used to assign
risk groups and predict optimal treatment durations. Measurements and Main
Results: The parametric model had an area under the receiver operating
characteristic curve of 0.72. A six-item risk score (HIV status, smear grade,
sex, cavitary disease status, body mass index, and Month 2 culture status)
successfully grouped participants into low (1,060/3,791; 28%), moderate
(1,740/3,791; 46%), and high (991/3,791; 26%) risk, requiring treatment
durations of 4, 6, and greater than 6 months, respectively, to reach a target
cure rate of 93% when receiving standard-dose rifamycin-containing regimens.
With current one-duration-fits-all approaches, high-risk groups have a 3.7-fold
(95% confidence interval, 2.7-5.1) and 2.4-fold (1.9-2.9) higher hazard risk of
unfavorable outcomes compared with low- and moderate-risk groups, respectively.
Four-month regimens were noninferior to the standard 6-month regimen in the
low-risk group. Conclusions: Our model discrimination was modest but consistent
with current models of unfavorable outcomes. Our results showed that stratified
medicine approaches are feasible and may achieve high cure rates in all patients
with tuberculosis. An interactive risk stratification tool is provided to
facilitate decision-making in the regimen development pathway.
DOI: 10.1164/rccm.202101-0117OC
PMCID: PMC8663006
PMID: 34346856 [Indexed for MEDLINE]
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