2022年
No.5
Filters applied: from 2022/5/1 - 2022/5/31.
1. Genes Dev. 2022 May 1;36(9-10):582-600. doi: 10.1101/gad.349321.121. Epub 2022
Jun 2.
The microRNA-183/96/182 cluster inhibits lung cancer progression and metastasis
by inducing an interleukin-2-mediated antitumor CD8(+) cytotoxic T-cell
response.
Kundu ST(#)(1), Rodriguez BL(#)(1), Gibson LA(1), Warner AN(1), Perez MG(1),
Bajaj R(1), Fradette JJ(1), Class CA(2), Solis LM(3), Rojas Alvarez FR(3),
Wistuba II(3), Diao L(4), Chen F(5), Sachdeva M(6), Wang J(4), Kirsch DG(6)(7),
Creighton CJ(4)(5)(8), Gibbons DL(1)(9).
Author information:
(1)Department of Thoracic/Head and Neck Medical Oncology, The University of
Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
(2)Department of Biostatistics, The University of Texas MD Anderson Cancer
Center, Houston, Texas 77030, USA.
(3)Department of Translational Molecular Pathology, The University of Texas MD
Anderson Cancer Center, Houston, Texas 77030, USA.
…
One of the mechanisms by which cancer cells acquire hyperinvasive and migratory
properties with progressive loss of epithelial markers is the
epithelial-to-mesenchymal transition (EMT). We have previously reported that in
different cancer types, including nonsmall cell lung cancer (NSCLC), the
microRNA-183/96/182 cluster (m96cl) is highly repressed in cells that have
undergone EMT. In the present study, we used a novel conditional m96cl mouse to
establish that loss of m96cl accelerated the growth of Kras mutant autochthonous
lung adenocarcinomas. In contrast, ectopic expression of the m96cl in NSCLC
cells results in a robust suppression of migration and invasion in vitro, and
tumor growth and metastasis in vivo. Detailed immune profiling of the tumors
revealed a significant enrichment of activated CD8+ cytotoxic T lymphocytes
(CD8+ CTLs) in m96cl-expressing tumors, and m96cl-mediated suppression of tumor
growth and metastasis was CD8+ CTL-dependent. Using coculture assays with naïve
immune cells, we show that m96cl expression drives paracrine stimulation of CD8+
CTL proliferation and function. Using tumor microenvironment-associated gene
expression profiling, we identified that m96cl elevates the interleukin-2 (IL2)
signaling pathway and results in increased IL2-mediated paracrine stimulation of
CD8+ CTLs. Furthermore, we identified that the m96cl modulates the expression of
IL2 in cancer cells by regulating the expression of transcriptional repressors
Foxf2 and Zeb1, and thereby alters the levels of secreted IL2 in the tumor
microenvironment. Last, we show that in vivo depletion of IL2 abrogates
m96cl-mediated activation of CD8+ CTLs and results in loss of metastatic
suppression. Therefore, we have identified a novel mechanistic role of the m96cl
in the suppression of lung cancer growth and metastasis by inducing an
IL2-mediated systemic CD8+ CTL immune response.
© 2022 Kundu et al.; Published by Cold Spring Harbor Laboratory Press.
DOI: 10.1101/gad.349321.121
PMCID: PMC9186390
PMID: 35654454 [Indexed for MEDLINE]
2. PLoS Biol. 2022 May 31;20(5):e3001648. doi: 10.1371/journal.pbio.3001648.
eCollection 2022 May.
A novel class of antimicrobial drugs selectively targets a Mycobacterium
tuberculosis PE-PGRS protein.
Seo H(1)(2), Kim S(1)(2), Mahmud HA(1), Islam MI(1), Yoon Y(1), Cho HD(3), Nam
KW(4), Choi J(5), Gil YS(6), Lee BE(2), Song HY(1)(2).
Author information:
(1)Department of Microbiology and Immunology, School of Medicine, Soonchunhyang
University, Dongnam-gu, Cheonan-si, Chungnam, Republic of Korea.
(2)Probiotics Microbiome Convergence Center, Soonchunhyang University,
Sinchang-myeon, Asan-si, Chungnam, Republic of Korea.
(3)Department of Pathology, School of Medicine, Soonchunhyang University,
Dongnam-gu, Cheonan-si, Chungnam, Republic of Korea.
(4)Department of Life Science and Biotechnology, School of Life Sciences,
Soonchunhyang University, Sinchang-myeon, Asan-si, Chungnam, Republic of Korea.
(5)College of Pharmacy, Dongduk Women's University, Seongbuk-gu, Seoul, Republic
of Korea.
(6)R&D Center, Kolmarpharma Co., Ltd., Jecheon-si, Chungbuk, Republic of Korea.
The continued spread of drug-resistant tuberculosis is one of the most pressing
and complex challenges facing tuberculosis management worldwide. Therefore,
developing a new class of drugs is necessary and urgently needed to cope with
the increasing threat of drug-resistant tuberculosis. This study aims to
discover a potential new class of tuberculosis drug candidates different from
existing tuberculosis drugs. By screening a library of compounds, methyl
(S)-1-((3-alkoxy-6,7-dimethoxyphenanthren-9-yl)methyl)-5-oxopyrrolidine-2-carboxylate (PP) derivatives with antitubercular activity were discovered. MIC ranges for
PP1S, PP2S, and PP3S against clinically isolated drug-resistant Mycobacterium
tuberculosis strains were 0.78 to 3.13, 0.19 to 1.56, and 0.78 to 6.25 μg/ml,
respectively. PPs demonstrated antitubercular activities in macrophage and
tuberculosis mouse models, showing no detectable toxicity in all assays tested.
PPs specifically inhibited M. tuberculosis without significantly changing the
intestinal microbiome in mice. Mutants selected in vitro suggest that the drug
targets the PE-PGRS57, which has been found only in the genomes of the M.
tuberculosis complex, highlighting the specificity and safety potency of this
compound. As PPs show an excellent safety profile and highly selective toxicity
specific to M. tuberculosis, PPs are considered a promising new candidate for
the treatment of drug-resistant tuberculosis while maintaining microbiome
homeostasis.
DOI: 10.1371/journal.pbio.3001648
PMCID: PMC9154192
PMID: 35639773 [Indexed for MEDLINE]
3. Lancet Infect Dis. 2022 May 27:S1473-3099(22)00227-4. doi:
10.1016/S1473-3099(22)00227-4. Online ahead of print.
Mycobacterial infections in adults with haematological malignancies and
haematopoietic stem cell transplants: guidelines from the 8th European
Conference on Infections in Leukaemia.
Bergeron A(1), Mikulska M(2), De Greef J(3), Bondeelle L(4), Franquet T(5),
Herrmann JL(6), Lange C(7), Spriet I(8), Akova M(9), Donnelly JP(10), Maertens
J(11), Maschmeyer G(12), Rovira M(13), Goletti D(14), de la Camara R(15);
European Conference on Infections in Leukaemia group.
Author information:
(1)Division of Pulmonology, Geneva University Hospitals, Geneva, Switzerland;
University of Paris, ECSTRRA Team, Inserm, Paris, France. Electronic address:
anne.bergeron@hcuge.ch.
(2)Division of Infectious Diseases, Department of Health Sciences, University of
Genoa, Genoa, Italy; San Martino Polyclinic Hospital, Genoa, Italy.
(3)Division of Internal Medicine and Infectious Diseases, Saint-Luc University
Clinics, Catholic University of Louvain, Brussels, Belgium.
…
Mycobacterial infections, both tuberculosis and nontuberculous, are more common
in patients with haematological malignancies and haematopoietic stem cell
transplant recipients than in the general population-although these infections
remain rare. Mycobacterial infections pose both diagnostic and therapeutic
challenges. The management of mycobacterial infections is particularly
complicated for patients in haematology because of the many drug-drug
interactions between antimycobacterial drugs and haematological and
immunosuppressive treatments. The management of mycobacterial infections must
also consider the effect of delaying haematological management. We surveyed the
management practices for latent tuberculosis infection (LTBI) in haematology
centres in Europe. We then conducted a meticulous review of the literature on
the epidemiology, diagnosis, and management of LTBI, tuberculosis, and
nontuberculous mycobacterial infections among patients in haematology, and we
formulated clinical guidelines according to standardised European Conference on
Infections in Leukaemia (ECIL) methods. In this Review, we summarise the
available literature and the recommendations of ECIL 8 for managing
mycobacterial infections in patients with haematological malignancies.
Copyright © 2022 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1473-3099(22)00227-4
PMID: 35636446
4. Am J Respir Crit Care Med. 2022 May 26. doi: 10.1164/rccm.202201-0114OC. Online
ahead of print.
Solid Fuel, Second-Hand Smoke, and Lung Cancer Mortality: A Prospective Cohort
of 323,794 Chinese Never-Smokers.
Cheng ES(1)(2), Chan KH(3)(4), Weber M(5), Steinberg J(5), Young J(1)(5),
Canfell K(5), Yu XQ(5).
Author information:
(1)The University of Sydney, 4334, Sydney School of Public Health, Sydney, New
South Wales, Australia.
(2)The Daffodil Centre, 608295, The University of Sydney, a joint venture with
Cancer Council NSW, Sydney, New South Wales, Australia;
elvin.cheng@sydney.edu.au.
(3)University of Oxford, 6396, Oxford British Heart Foundation Centre of
Research Excellence, Oxford, United Kingdom of Great Britain and Northern
Ireland.
(4)University of Oxford, 6396, Clinical Trial Service Unit and Epidemiological
Studies Unit (CTSU), Nuffield Department of Population Health, Oxford, United
Kingdom of Great Britain and Northern Ireland.
(5)The Daffodil Centre, 608295, The University of Sydney, a joint venture with
Cancer Council NSW, Sydney, New South Wales, Australia.
Rationale Household air pollution and secondhand tobacco smoke are known
carcinogens for lung cancer but large-scale estimates of the relationship with
lung cancer mortality are lacking. Objectives Using the large-scale cohort China
Kadoorie Biobank, we prospectively investigated associations between these two
risk factors and lung cancer death among never-smokers. Methods The Biobank
recruited 512,715 adults aged 30-79 years from ten regions in China during
2004-2008. Self-reported never-smoking participants were followed up to
31/12/2016 with linkage to mortality data. Total duration of exposure to
household air pollution was calculated from self-reported domestic solid fuel
use. Exposure to secondhand tobacco smoke was ascertained using exposure at home
and/or other places. Hazard ratios and 95% confidence intervals for associations
between these two exposures and lung cancer death were estimated using Cox
regression, adjusting for key confounders. Measurements and Main Results There
were 979 lung cancer deaths among 323,794 never-smoking participants without a
previous cancer during 10.2 years of follow-up. There was a log-linear positive
association between exposure to household air pollution and lung cancer death,
with a 4% increased risk per 5-year increment of exposure (hazard ratio=1.04;
95% confidence interval=1.01-1.06, p-trend=0.0034); and participants with
40.1-50.0 years of exposure had the highest risk compared to the never-exposed
(hazard ratio=1.53; 95% confidence interval=1.13-2.07). The association was
largely consistent across various subgroups. No significant association was
found between secondhand smoke and lung cancer death. Conclusions This cohort
study provides new prospective evidence suggesting that domestic solid fuel use
is associated with lung cancer death among never-smokers. This article is open
access and distributed under the terms of the Creative Commons Attribution
Non-Commercial No Derivatives License 4.0
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
DOI: 10.1164/rccm.202201-0114OC
PMID: 35616543
5. Am J Respir Crit Care Med. 2022 May 24. doi: 10.1164/rccm.202202-0259OC. Online
ahead of print.
The Contribution of Chest Radiography to the Clinical Management of Children
Exposed to Tuberculosis.
Huang CC(1)(2), Tan Q(3), Becerra MC(4)(5), Calderon R(6), Chiang SS(7)(8),
Contreras C(6), Lecca L(6), Jimenez J(9), Perez-Velez CM(10)(11), Roya-Pabon
CL(10), Yataco R(6), Xu H(12), Zhang Z(1), Murray M(13).
Author information:
(1)Brigham and Women's Hospital, 1861, Division of Global Health Equity, Boston,
Massachusetts, United States.
(2)Harvard Medical School, 1811, Department of Global Health and Social
Medicine, Boston, Massachusetts, United States.
(3)nanjing medical university, Nanjing, China.
…
RATIONALE: Although World Health Organization guidelines emphasize contact
investigation for tuberculosis-exposed children, data that support chest
radiography as a useful tool are lacking.
OBJECTIVES: We evaluated the diagnostic and prognostic information of chest
radiography in children exposed to TB and measured the efficacy of isoniazid
preventive therapy in those with relevant radiographic abnormalities.
METHODS: Between September 2009 and August 2012, we enrolled 4,468 TB-exposed
children who were screened by tuberculin skin testing, symptom assessment and
chest radiography. Those negative for TB disease were followed for one year for
the occurrence of new TB diagnoses. We assessed the protective efficacy of
isoniazid preventive therapy in children with and without abnormal chest
radiographs.
MEASUREMENTS AND MAIN RESULTS: Compared to asymptomatic children with normal
chest films, asymptomatic children with abnormal radiographs were 25.1-fold more
likely to have co-prevalent TB (95%CIs=1.02-613.76) and 26.7-fold more likely to
be diagnosed with incident tuberculosis disease during follow-up
(95%CIs=10.44-68.30). Among the 29 symptom-negative/CXR-abnormal child contacts,
20% (3/15) of the isoniazid recipients developed incident TB, compared to 57%
(8/14) of those who did not receive isoniazid preventive therapy (82% IPT
efficacy).
CONCLUSIONS: Our results strongly support the use of chest radiography as a
routine screening tool for the evaluation of child TB contacts, where this is
readily available. Radiographic abnormalities not usually considered suggestive
of TB may indicate incipient or subclinical disease, although TB preventive
treatment is adequate in most cases.
DOI: 10.1164/rccm.202202-0259OC
PMID: 35608549
6. J Clin Oncol. 2022 May 23:JCO2102278. doi: 10.1200/JCO.21.02278. Online ahead of print.
Post Hoc Analysis of Lorlatinib Intracranial Efficacy and Safety in Patients
With ALK-Positive Advanced Non-Small-Cell Lung Cancer From the Phase III CROWN
Study.
Solomon BJ(1), Bauer TM(2), Ou SI(#)(3), Liu G(4), Hayashi H(5), Bearz A(6),
Penkov K(7), Wu YL(8), Arrieta O(9), Jassem J(10), Calella AM(11), Peltz G(12),
Polli A(11), Thurm H(13), Mok T(14).
Author information:
(1)Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
(2)Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN.
(3)University of California Irvine School of Medicine, Orange, CA.
…
PURPOSE: Lorlatinib significantly improved progression-free survival (PFS)
versus crizotinib and showed robust intracranial activity in patients with
previously untreated advanced ALK-positive non-small-cell lung cancer (NSCLC) in
the phase III CROWN trial. Here, we report post hoc efficacy outcomes in
patients with and without brain metastases at baseline, and present data on the
incidence and management of CNS adverse events (AEs) in CROWN.
METHODS: Eligible patients were randomly assigned 1:1 to first-line lorlatinib
(100 mg once daily) or crizotinib (250 mg twice a day); no crossover between
treatment arms was permitted. Tumor assessments, including CNS magnetic
resonance imaging, were performed at screening and then at 8-week intervals.
Regular assessments of patient-reported outcomes were conducted.
RESULTS: PFS by blinded independent central review was improved with lorlatinib
versus crizotinib in patients with and without brain metastases at baseline
(12-month PFS rates: 78% v 22% and 78% v 45%, respectively). Lorlatinib was
associated with lower 12-month cumulative incidence of CNS progression versus
crizotinib in patients with (7% v 72%) and without (1% v 18%) brain metastases
at baseline. In total, 35% of patients had CNS AEs with lorlatinib, most of
grade 1 severity. Occurrence of CNS AEs did not result in a clinically
meaningful difference in patient-reported quality of life. At analysis, 56% of
CNS AEs had resolved (33% without intervention; 17% with lorlatinib dose
modification), and 38% were unresolved; most required no intervention.
Lorlatinib dose modification did not notably influence PFS.
CONCLUSION: First-line lorlatinib improved PFS outcomes and reduced CNS
progression versus crizotinib in patients with advanced ALK-positive
non-small-cell lung cancer with or without brain metastases at baseline. Half of
all CNS AEs resolved without intervention or with lorlatinib dose modification.
DOI: 10.1200/JCO.21.02278
PMID: 35605188
7. Lancet Infect Dis. 2022 May 17:S1473-3099(22)00149-9. doi:
10.1016/S1473-3099(22)00149-9. Online ahead of print.
Prevalence of bacteriologically confirmed pulmonary tuberculosis in South
Africa, 2017-19: a multistage, cluster-based, cross-sectional survey.
Moyo S(1), Ismail F(2), Van der Walt M(3), Ismail N(4), Mkhondo N(5), Dlamini
S(6), Mthiyane T(3), Chikovore J(7), Oladimeji O(7), Mametja D(8), Maribe P(3),
Seocharan I(3), Ximiya P(6), Law I(4), Tadolini M(9), Zuma K(7), Manda S(3),
Sismanidis C(4), Pillay Y(10), Mvusi L(6).
Author information:
(1)Human Sciences Research Council, Cape Town, South Africa; School of Public
Health and Family Medicine, University of Cape Town, Cape Town, South Africa.
Electronic address: smoyo@hsrc.ac.za.
(2)Centre for Tuberculosis, National Institute for Communicable Diseases,
Johannesburg, South Africa; Department of Medical Microbiology, University of
Pretoria, Pretoria, South Africa.
(3)South African Medical Research Council, Cape Town, South Africa.
…
Erratum in
Lancet Infect Dis. 2022 Jul;22(7):e177.
BACKGROUND: Tuberculosis remains an important clinical and public health issue
in South Africa, which has one of the highest tuberculosis burdens in the world.
We aimed to estimate the burden of bacteriologically confirmed pulmonary
tuberculosis among people aged 15 years or older in South Africa.
METHODS: This multistage, cluster-based, cross-sectional survey included
eligible residents (age ≥15 years, who had slept in a house for ≥10 nights in
the preceding 2 weeks) in 110 clusters nationally (cluster size of 500 people;
selected by probability proportional-to-population size sampling). Participants
completed face-to-face symptom questionnaires (for cough, weight loss, fever,
and night sweats) and manually read digital chest X-ray screening. Screening was
recorded as positive if participants had at least one symptom or an abnormal
chest X-ray suggestive of tuberculosis, or a combination thereof. Sputum samples
from participants who were screen-positive were tested by the Xpert MTB/RIF
Ultra assay (first sample) and Mycobacteria Growth Indicator Tube culture
(second sample), with optional HIV testing. Participants with a positive
Mycobacterium tuberculosis complex culture were considered positive for
bacteriologically confirmed pulmonary tuberculosis; when culture was not
positive, participants with a positive Xpert MTB/RIF Ultra result with an
abnormal chest X-ray suggestive of active tuberculosis and without current or
previous tuberculosis were considered positive for bacteriologically confirmed
pulmonary tuberculosis.
FINDINGS: Between Aug 15, 2017, and July 28, 2019, 68 771 people were enumerated
from 110 clusters, with 53 250 eligible to participate in the survey, of whom
35 191 (66·1%) participated. 9066 (25·8%) of 35 191 participants were
screen-positive and 234 (0·7%) were identified as having bacteriologically
confirmed pulmonary tuberculosis. Overall, the estimated prevalence of
bacteriologically confirmed pulmonary tuberculosis was 852 cases (95% CI
679-1026) per 100 000 population; the prevalence was highest in people aged
35-44 years (1107 cases [95% CI 703-1511] per 100 000 population) and those aged
65 years or older (1104 cases [680-1528] per 100 000 population). The estimated
prevalence was approximately 1·6 times higher in men than in women (1094 cases
[95% CI 835-1352] per 100 000 population vs 675 cases [494-855] per 100 000
population). 135 (57·7%) of 234 participants with tuberculosis screened positive
by chest X-ray only, 16 (6·8%) by symptoms only, and 82 (35·9%) by both. 55
(28·8%) of 191 participants with tuberculosis with known HIV status were
HIV-positive.
INTERPRETATION: Pulmonary tuberculosis prevalence in this survey was high,
especially in men. Despite the ongoing burden of HIV, many participants with
tuberculosis in this survey did not have HIV. As more than half of the
participants with tuberculosis had an abnormal chest X-ray without symptoms,
prioritising chest X-ray screening could substantially increase case finding.
FUNDING: Global Fund, Bill & Melinda Gates Foundation, USAID.
DOI: 10.1016/S1473-3099(22)00149-9
PMID: 35594897
8. Am J Respir Crit Care Med. 2022 May 18. doi: 10.1164/rccm.202110-2378OC. Online
ahead of print.
Aerosolization of Mycobacterium tuberculosis by Tidal Breathing.
Dinkele R(1)(2), Gessner S(3)(2), McKerry A(4), Leonard B(4), Leukes J(4),
Seldon R(4), Warner DF(1)(5), Wood R(2)(4).
Author information:
(1)University of Cape Town MRC/NHLS/UCT Molecular Mycobacteriology Research
Unit, 574002, Cape Town, South Africa.
(2)University of Cape Town Institute of Infectious Disease and Molecular
Medicine, 71985, Cape Town, South Africa.
(3)University of Cape Town MRC/NHLS/UCT Molecular Mycobacteriology Research
Unit, 574002, Rondebosch, South Africa.
(4)Desmond Tutu HIV Foundation, 108181, Cape Town, South Africa.
(5)University of Cape Town Institute of Infectious Disease and Molecular
Medicine, 71985, Cape Town, South Africa; Digby.Warner@uct.ac.za.
RATIONALE: Interrupting tuberculosis (TB) transmission requires an improved
understanding of how - and when - the causative organism, Mycobacterium
tuberculosis (Mtb), is aerosolized. Although cough is commonly assumed to be the
dominant source of Mtb aerosols, recent evidence of cough-independent Mtb
release implies the contribution of alternative mechanisms.
OBJECTIVE: To compare the aerosolization of Mtb bacilli and total particulate
matter from TB patients during three separate respiratory manoeuvres: Tidal
Breathing (TiBr), Forced Vital Capacity (FVC), and cough.
METHODOLOGY: Bioaerosol sampling and Mtb enumeration by live-cell, fluorescence
microscopy were combined with real-time measurement of CO2 concentration and
total particle counts from 38 GeneXpert-positive TB patients prior to treatment
initiation.
MEASUREMENTS AND MAIN RESULTS: For all manoeuvres, the proportions of particles
detected across five size categories were similar with most particles falling
between 0.5-5 μm. Although total particle counts were 4.8-fold greater in cough
samples than either TiBr or FVC, all three manoeuvres returned similar rates of
positivity for Mtb. No correlation was observed between total particle
production and Mtb count. Instead, for total Mtb counts, the variability between
individuals was greater than the variability between sampling manoeuvres.
Finally, when modelled utilizing 24-hour breath and cough frequencies, our data
indicate that TiBr might contribute >90% of the daily aerosolised Mtb among
symptomatic TB patients.
CONCLUSIONS: Assuming the number of viable Mtb organisms released offers a
reliable proxy of patient infectiousness, our observations imply that TiBr and
inter-individual variability in Mtb release might be significant contributors to
TB transmission among active cases. This article is open access and distributed
under the terms of the Creative Commons Attribution 4.0 International License
(https://creativecommons.org/licenses/by/4.0/).
DOI: 10.1164/rccm.202110-2378OC
PMID: 35584342
9. J Clin Oncol. 2022 May 17:JCO2102641. doi: 10.1200/JCO.21.02641. Online ahead of print.
AENEAS: A Randomized Phase III Trial of Aumolertinib Versus Gefitinib as
First-Line Therapy for Locally Advanced or Metastatic Non-Small-Cell Lung Cancer
With EGFR Exon 19 Deletion or L858R Mutations.
Lu S(1), Dong X(2), Jian H(1), Chen J(3), Chen G(4), Sun Y(5), Ji Y(6),…
Author information:
(1)Department of Medical Oncology, Shanghai Chest Hospital, Shanghai JiaoTong
University, Shanghai, China.
(2)Cancer Center, Union Hospital Tongji Medical College Huazhong University of
Science and Technology, Wuhan, China.
(3)Department of Medical Oncology-Chest, Hunan Cancer Hospital & The Affiliated
Cancer Hospital of Xiangya School of Medicine, Central South University,
Changsha, China.
…
PURPOSE: Aumolertinib (formerly almonertinib; HS-10296) is a novel
third-generation epidermal growth factor receptor tyrosine kinase inhibitor
approved in China. This double-blind phase III trial evaluated the efficacy and
safety of aumolertinib compared with gefitinib as a first-line treatment for
locally advanced or metastatic EGFR-mutated non-small-cell lung cancer (NSCLC;
ClinicalTrials.gov identifier: NCT03849768).
METHODS: Patients at 53 sites in China were randomly assigned 1:1 to receive
either aumolertinib (110 mg) or gefitinib (250 mg) once daily. The primary end
point was progression-free survival (PFS) per investigator assessment.
RESULTS: A total of 429 patients who were naïve to treatment for locally
advanced or metastatic NSCLC were enrolled. PFS was significantly longer with
aumolertinib compared with gefitinib (hazard ratio, 0.46; 95% CI, 0.36 to 0.60;
P < .0001). The median PFS with aumolertinib was 19.3 months (95% CI, 17.8 to
20.8) versus 9.9 months with gefitinib (95% CI, 8.3 to 12.6). Objective response
rate and disease control rate were similar in the aumolertinib and gefitinib
groups (objective response rate, 73.8% and 72.1%, respectively; disease control
rate, 93.0% and 96.7%, respectively). The median duration of response was 18.1
months (95% CI, 15.2 to not applicable) with aumolertinib versus 8.3 months (95%
CI, 6.9 to 11.1) with gefitinib. Adverse events of grade ≥ 3 severity (any
cause) were observed in 36.4% and 35.8% of patients in the aumolertinib and
gefitinib groups, respectively. Rash and diarrhea (any grade) were observed in
23.4% and 16.4% of patients who received aumolertinib compared with 41.4% and
35.8% of those who received gefitinib, respectively.
CONCLUSION: Aumolertinib is a well-tolerated third-generation epidermal growth
factor receptor tyrosine kinase inhibitor that could serve as a treatment option
for EGFR-mutant NSCLC in the first-line setting.
DOI: 10.1200/JCO.21.02641
PMID: 35580297
10. J Clin Oncol. 2022 May 16:JCO2102660. doi: 10.1200/JCO.21.02660. Online ahead of print.
Overall Survival and Biomarker Analysis of Neoadjuvant Nivolumab Plus
Chemotherapy in Operable Stage IIIA Non-Small-Cell Lung Cancer (NADIM phase II
trial).
Provencio M(1), Serna-Blasco R(1), Nadal E(2), Insa A(3), García-Campelo MR(4),
Casal Rubio J(5), Dómine M(6), Majem M(7), Rodríguez-Abreu D(8), Martínez-Martí
A(9), De Castro Carpeño J(10), Cobo M(11), López Vivanco G(12), Del Barco E(13),
Bernabé Caro R(14), Viñolas N(15), Barneto Aranda I(16), Viteri S(17), Pereira
E(18), Royuela A(1), Calvo V(1), Martín-López J(1), García-García F(19),
Casarrubios M(1), Franco F(1), Sánchez-Herrero E(1)(20), Massuti B(21),
Cruz-Bermúdez A(1), Romero A(1).
Author information:
(1)Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain.
(2)Institut Català d'Oncologia, L'Hospitalet De Llobregat, Barcelona, Spain.
(3)Fundación INCLIVA, Hospital Clínico Universitario de Valencia, Valencia,
Spain.
…
PURPOSE: Neoadjuvant chemotherapy plus nivolumab has been shown to be effective
in resectable non-small-cell lung cancer (NSCLC) in the NADIM trial
(ClinicalTrials.gov identifier: NCT03081689). The 3-year overall survival (OS)
and circulating tumor DNA (ctDNA) analysis have not been reported.
METHODS: This was an open-label, multicenter, single-arm, phase II trial in
which patients with stage IIIA NSCLC, who were deemed to be surgically
resectable, were treated with neoadjuvant paclitaxel (200 mg/m2 once a day) and
carboplatin (area under curve 6) plus nivolumab (360 mg) once on day 1 of each
21-day cycle, for three cycles, followed by adjuvant nivolumab monotherapy for 1
year (240 mg once every 2 weeks for 4 months, followed by 480 mg once every 4
weeks for 8 months). The 3-year OS and ctDNA analysis were secondary objectives
of the trial.
RESULTS: OS at 36 months was 81.9% (95% CI, 66.8 to 90.6) in the
intention-to-treat population, rising to 91.0% (95% CI, 74.2 to 97.0) in the
per-protocol population. Neither tumor mutation burden nor programmed cell death
ligand-1 staining was predictive of survival. Conversely, low pretreatment
levels of ctDNA were significantly associated with improved progression-free
survival and OS (hazard ratio [HR]: 0.20; 95% CI, 0.06 to 0.63, and HR: 0.07;
95% CI, 0.01 to 0.39, respectively). Clinical responses according to RECIST v1.1
criteria did not predict survival outcomes. However, undetectable ctDNA levels
after neoadjuvant treatment were significantly associated with progression-free
survival and OS (HR: 0.26; 95% CI, 0.07 to 0.93, and HR: 0.04; 95% CI, 0.00 to
0.55, respectively). The C-index to predict OS for ctDNA levels after
neoadjuvant treatment (0.82) was superior to that of RECIST criteria (0.72).
CONCLUSION: The efficacy of neoadjuvant chemotherapy plus nivolumab in
resectable NSCLC is supported by 3-year OS. ctDNA levels were significantly
associated with OS and outperformed radiologic assessments in the prediction of
survival.
DOI: 10.1200/JCO.21.02660
PMID: 35576508
11. J Clin Oncol. 2022 May 16:JCO2200687. doi: 10.1200/JCO.22.00687. Online ahead of print.
Exercise, Diet, and Weight Management During Cancer Treatment: ASCO Guideline.
Ligibel JA(1), Bohlke K(2), May AM(3), Clinton SK(4), Demark-Wahnefried W(5),
Gilchrist SC(6), Irwin ML(7), Late M(8), Mansfield S(9), Marshall TF(10),
Meyerhardt JA(1), Thomson CA(11), Wood WA(12), Alfano CM(13).
Author information:
(1)Dana-Farber Cancer Institute, Boston, MA.
(2)American Society of Clinical Oncology, Alexandria, VA.
(3)University Medical Center Utrecht, Utrecht University, Utrecht, the
Netherlands.
…
PURPOSE: To provide guidance on exercise, diet, and weight management during
active cancer treatment in adults.
METHODS: A systematic review of the literature identified systematic reviews and
randomized controlled trials evaluating the impact of aerobic and resistance
exercise, specific diets and foods, and intentional weight loss and avoidance of
weight gain in adults during cancer treatment, on quality of life, treatment
toxicity, and cancer control. PubMed and the Cochrane Library were searched from
January 2000 to May 2021. ASCO convened an Expert Panel to review the evidence
and formulate recommendations.
RESULTS: The evidence base consisted of 52 systematic reviews (42 for exercise,
nine for diet, and one for weight management), and an additional 23 randomized
controlled trials. The most commonly studied types of cancer were breast,
prostate, lung, and colorectal. Exercise during cancer treatment led to
improvements in cardiorespiratory fitness, strength, fatigue, and other
patient-reported outcomes. Preoperative exercise in patients with lung cancer
led to a reduction in postoperative length of hospital stay and complications.
Neutropenic diets did not decrease risk of infection during cancer treatment.
RECOMMENDATIONS: Oncology providers should recommend regular aerobic and
resistance exercise during active treatment with curative intent and may
recommend preoperative exercise for patients undergoing surgery for lung cancer.
Neutropenic diets are not recommended to prevent infection in patients with
cancer during active treatment. Evidence for other dietary and weight loss
interventions during cancer treatment was very limited. The guideline discusses
special considerations, such as exercise in individuals with advanced cancer,
and highlights the critical need for more research in this area, particularly
regarding diet and weight loss interventions during cancer treatment.Additional
information is available at www.asco.org/supportive-care-guidelines.
DOI: 10.1200/JCO.22.00687
PMID: 35576506
12. Nat Commun. 2022 May 12;13(1):2641. doi: 10.1038/s41467-022-30373-w.
Substrate recognition and cryo-EM structure of the ribosome-bound TAC toxin of
Mycobacterium tuberculosis.
Mansour M(#)(1), Giudice E(#)(2), Xu X(1), Akarsu H(3)(4), Bordes P(1), Guillet
V(5), Bigot DJ(1)(5), Slama N(1), D'urso G(2), Chat S(2), Redder P(1), Falquet
L(3), Mourey L(5), Gillet R(6), Genevaux P(7).
Author information:
(1)Laboratoire de Microbiologie et de Génétique Moléculaires, Centre de Biologie
Intégrative (CBI), Université de Toulouse, CNRS, UPS, Toulouse, France.
(2)Institut de Génétique et Développement de Rennes (IGDR), UMR6290, Université
de Rennes, CNRS, Rennes, France.
(3)Department of Biology, University of Fribourg & Swiss Institute of
Bioinformatics, Fribourg, Switzerland.
…
Toxins of toxin-antitoxin systems use diverse mechanisms to control bacterial
growth. Here, we focus on the deleterious toxin of the atypical tripartite
toxin-antitoxin-chaperone (TAC) system of Mycobacterium tuberculosis, whose
inhibition requires the concerted action of the antitoxin and its dedicated
SecB-like chaperone. We show that the TAC toxin is a bona fide ribonuclease and
identify exact cleavage sites in mRNA targets on a transcriptome-wide scale in
vivo. mRNA cleavage by the toxin occurs after the second nucleotide of the
ribosomal A-site codon during translation, with a strong preference for CCA
codons in vivo. Finally, we report the cryo-EM structure of the ribosome-bound
TAC toxin in the presence of native M. tuberculosis cspA mRNA, revealing the
specific mechanism by which the TAC toxin interacts with the ribosome and the
tRNA in the P-site to cleave its mRNA target.
© 2022. The Author(s).
DOI: 10.1038/s41467-022-30373-w
PMCID: PMC9098466
PMID: 35552387 [Indexed for MEDLINE]
13. J Exp Med. 2022 Jun 6;219(6):e20220445. doi: 10.1084/jem.20220445. Epub 2022 May 11.
Drug development challenges in nontuberculous mycobacterial lung disease: TB to
the rescue.
Dartois V(1)(2), Dick T(1)(2)(3).
Author information:
(1)Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ.
(2)Department of Medical Sciences, Hackensack Meridian School of Medicine,
Nutley, NJ.
(3)Department of Microbiology and Immunology, Georgetown University, Washington,
DC.
Nontuberculous mycobacterial pulmonary disease (NTM-PD) is treated with multiple
repurposed drugs. Chemotherapy is long and often toxic, includes parenteral
drugs, and suffers from poor cure rates. There is an urgent need for more
efficacious, tolerated, and oral antibiotics optimized towards the treatment of
NTM-PD, adapted to the spectrum of disease. In contrast to the empty NTM
pipeline, drug development for the related tuberculosis lung disease has
experienced a renaissance. Here, we argue that applying lessons learned from
tuberculosis will facilitate the discovery of curative oral regimens for NTM-PD.
© 2022 Dartois and Dick.
DOI: 10.1084/jem.20220445
PMCID: PMC9098649
PMID: 35543723 [Indexed for MEDLINE]
14. Lancet Infect Dis. 2022 May 5:S1473-3099(22)00153-0. doi:
10.1016/S1473-3099(22)00153-0. Online ahead of print.
Are we underestimating the annual risk of infection with Mycobacterium
tuberculosis in high-burden settings?
Dowdy DW(1), Behr MA(2).
Author information:
(1)Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health,
Baltimore, MD, USA. Electronic address: ddowdy1@jhmi.edu.
(2)McGill International Tuberculosis Centre and Department of Medicine, McGill
University, Montreal, QC, Canada.
The annual risk of infection with Mycobacterium tuberculosis determines a
population's exposure level and thus the fraction of incident tuberculosis
resulting from recent infection (often considered as having occurred within the
past 2 years). Contemporary annual risk of infection estimates centre around 1%
in most high-burden countries. We present three arguments why these
estimates-primarily derived from cross-sectional tuberculin surveys in young
school children (aged 5-12 years)-might underrepresent the true annual risk of
infection. First, young children are expected to have lower risk of infection
than older adolescents and adults (ie, those aged 15 years and older). Second,
exposure might not lead to a positive test result in some individuals. Third,
cross-sectional surveys might overlook transient immune responses. Accounting
for these biases, the true annual risk of infection among adults in high-burden
settings is probably closer to 5-10%. Consequently, most tuberculosis in those
settings should reflect infection within the past 2 years rather than remote
infection occurring many years ago. Under this reframing, major reductions in
tuberculosis incidence could be achievable by focusing on the minority of people
who have been recently infected.
Copyright © 2022 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1473-3099(22)00153-0
PMID: 35526558
15. Lancet Infect Dis. 2022 Jul;22(7):1042-1051. doi: 10.1016/S1473-3099(21)00811-2. Epub 2022 May 2.
Treatment outcomes 24 months after initiating short, all-oral
bedaquiline-containing or injectable-containing rifampicin-resistant
tuberculosis treatment regimens in South Africa: a retrospective cohort study.
Ndjeka N(1), Campbell JR(2), Meintjes G(3), Maartens G(3), Schaaf HS(4), Hughes
J(4), Padanilam X(5), Reuter A(6), Romero R(7), Ismail F(8), Enwerem M(9),
Ferreira H(10), Conradie F(11), Naidoo K(12), Menzies D(2).
Author information:
(1)National Department of Health, Tuberculosis Control and Management Cluster,
Pretoria, South Africa; Nelson R Mandela School of Medicine, University of
KwaZulu Natal, Durban, South Africa. Electronic address:
norbert.ndjeka@health.gov.za.
(2)Department of Epidemiology, Biostatistics, and Occupational Health and the
McGill International TB Centre, McGill University, and The Montreal Chest
Institute, McGill University Health Centre, Montreal, QC, Canada.
(3)Department of Medicine and Wellcome Centre for Infectious Diseases Research
in Africa, Institute of Infectious Disease and Molecular Medicine, University of
Cape Town, South Africa.
…
BACKGROUND: There is a need for short and safe all-oral treatment of
rifampicin-resistant tuberculosis. We compared outcomes up to 24 months after
treatment initiation for patients with rifampicin-resistant tuberculosis in
South Africa treated with a short, all-oral bedaquiline-containing regimen
(bedaquiline group), or a short, injectable-containing regimen (injectable
group).
METHODS: Patients with rifampicin-resistant tuberculosis, aged 18 years or
older, eligible for a short regimen starting treatment between Jan 1 and Dec 31,
2017, with a bedaquiline-containing or WHO recommended injectable-containing
treatment regimen of 9-12 months, registered in the drug-resistant tuberculosis
database (EDRWeb), and with known age, sex, HIV status, and national
identification number were eligible for study inclusion; patients receiving
linezolid, carbapenems, terizidone or cycloserine, delamanid, or
para-aminosalicylic acid were excluded. Bedaquiline was given at a dose of 400
mg once daily for two weeks followed by 200 mg three times a week for 22 weeks.
To compare regimens, patients were exactly matched on HIV and ART status,
previous tuberculosis treatment history, and baseline acid-fast bacilli smear
and culture result, while propensity score matched on age, sex, province of
treatment, and isoniazid-susceptibility status. We did binomial linear
regression to estimate adjusted risk differences (aRD) and 95% CIs for 24-month
outcomes, which included: treatment success (ie, cure or treatment completion
without evidence of recurrence) versus all other outcomes, survival versus
death, disease free survival versus survival with treatment failure or
recurrence, and loss to follow-up versus all other outcomes.
FINDINGS: Overall, 1387 (14%) of 10152 patients with rifampicin-resistant
tuberculosis treated during 2017 met inclusion criteria; 688 in the bedaquiline
group and 699 in the injectable group. Four patients (1%) had treatment failure
or recurrence, 44 (6%) were lost to follow-up, and 162 (24%) died in the
bedaquiline group, compared with 17 (2%), 87 (12%), and 199 (28%), respectively,
in the injectable group. In adjusted analyses, treatment success was 14% (95% CI
8-20) higher in the bedaquiline group than in the injectable group (70% vs 57%);
loss to follow-up was 4% (1-8) lower in the bedaquiline group (6% vs 12%); and
disease-free survival was 2% (0-5) higher in the bedaquiline group (99% vs 97%).
The bedaquiline group had 8% (4-11) lower risk of mortality during treatment
(17·0% vs 22·4%), but there was no difference in mortality post-treatment.
INTERPRETATION: Patients in the bedaquiline group experienced significantly
higher rates of treatment success at 24 months. This finding supports the use of
short bedaquiline-containing regimens in eligible patients.
FUNDING: WHO Global TB Programme.
TRANSLATION: For the French translation of the abstract see Supplementary
Materials section.
DOI: 10.1016/S1473-3099(21)00811-2
PMCID: PMC9217754
PMID: 35512718 [Indexed for MEDLINE]
16. Sci Transl Med. 2022 May 4;14(643):eaaz6280. doi: 10.1126/scitranslmed.aaz6280.
Epub 2022 May 4.
The small-molecule SMARt751 reverses Mycobacterium tuberculosis resistance to
ethionamide in acute and chronic mouse models of tuberculosis.
Flipo M(1), Frita R(2), Bourotte M(1)(3), Martínez-Martínez MS(4), Boesche M(5),
Boyle GW(6), Derimanov G(7), Drewes G(5), Gamallo P(4), Ghidelli-Disse S(5),
Gresham S(6), Jiménez E(4), de Mercado J(4), Pérez-Herrán E(4), Porras-De
Francisco E(4), Rullas J(4), Casado P(4), Leroux F(1)(8), Piveteau C(1), Kiass
M(9), Mathys V(9), Soetaert K(9), Megalizzi V(10), Tanina A(10), Wintjens R(10),
Antoine R(2), Brodin P(2)(8), Delorme V(2), Moune M(2), Djaout K(2), Slupek
S(2), Kemmer C(11), Gitzinger M(11), Ballell L(4), Mendoza-Losana A(4), Lociuro
S(11), Deprez B(1)(8), Barros-Aguirre D(4), Remuiñán MJ(4), Willand N(1),
Baulard AR(2)(8).
Author information:
(1)Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules
for living Systems, F-59000 Lille, France.
(2)Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 -
UMR9017 - CIIL - Center for Infection and Immunity of Lille, F-59000 Lille,
France.
(3)BioVersys SAS, Lille, France.
…
The sensitivity of Mycobacterium tuberculosis, the pathogen that causes
tuberculosis (TB), to antibiotic prodrugs is dependent on the efficacy of the
activation process that transforms the prodrugs into their active antibacterial
moieties. Various oxidases of M. tuberculosis have the potential to activate the
prodrug ethionamide. Here, we used medicinal chemistry coupled with a phenotypic
assay to select the N-acylated 4-phenylpiperidine compound series. The lead
compound, SMARt751, interacted with the transcriptional regulator VirS of M.
tuberculosis, which regulates the mymA operon encoding a monooxygenase that
activates ethionamide. SMARt751 boosted the efficacy of ethionamide in vitro and
in mouse models of acute and chronic TB. SMARt751 also restored full efficacy of
ethionamide in mice infected with M. tuberculosis strains carrying mutations in
the ethA gene, which cause ethionamide resistance in the clinic. SMARt751 was
shown to be safe in tests conducted in vitro and in vivo. A model extrapolating
animal pharmacokinetic and pharmacodynamic parameters to humans predicted that
as little as 25 mg of SMARt751 daily would allow a fourfold reduction in the
dose of ethionamide administered while retaining the same efficacy and reducing
side effects.
DOI: 10.1126/scitranslmed.aaz6280
PMID: 35507672 [Indexed for MEDLINE]
17. Cell Metab. 2022 Jun 7;34(6):874-887.e6. doi: 10.1016/j.cmet.2022.04.003. Epub
2022 May 2.
Glutaminase inhibition impairs CD8 T cell activation in STK11-/Lkb1-deficient
lung cancer.
Best SA(1), Gubser PM(2), Sethumadhavan S(3), Kersbergen A(4), Negrón Abril
YL(3), Goldford J(3), Sellers K(3), Abeysekera W(5), Garnham AL(5), McDonald
JA(6), Weeden CE(7), Anderson D(8), Pirman D(3), Roddy TP(3), Creek DJ(8),
Kallies A(2), Kingsbury G(3), Sutherland KD(9).
Author information:
(1)ACRF Cancer Biology and Stem Cells Division, The Walter and Eliza Hall
Institute of Medical Research, Parkville, VIC, Australia; Department of Medical
Biology, University of Melbourne, Parkville, VIC, Australia. Electronic address:
best@wehi.edu.au.
(2)Department of Microbiology and Immunology, The Peter Doherty Institute for
Infection and Immunity, University of Melbourne, Melbourne, Australia.
(3)Agios Pharmaceuticals, Cambridge, MA, USA.
…
The tumor microenvironment (TME) contains a rich source of nutrients that
sustains cell growth and facilitate tumor development. Glucose and glutamine in
the TME are essential for the development and activation of effector T cells
that exert antitumor function. Immunotherapy unleashes T cell antitumor
function, and although many solid tumors respond well, a significant proportion
of patients do not benefit. In patients with KRAS-mutant lung adenocarcinoma,
KEAP1 and STK11/Lkb1 co-mutations are associated with impaired response to
immunotherapy. To investigate the metabolic and immune microenvironment of
KRAS-mutant lung adenocarcinoma, we generated murine models that reflect the
KEAP1 and STK11/Lkb1 mutational landscape in these patients. Here, we show
increased glutamate abundance in the Lkb1-deficient TME associated with CD8
T cell activation in response to anti-PD1. Combination treatment with the
glutaminase inhibitor CB-839 inhibited clonal expansion and activation of CD8
T cells. Thus, glutaminase inhibition negatively impacts CD8 T cells activated
by anti-PD1 immunotherapy.
Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.cmet.2022.04.003
PMID: 35504291 [Indexed for MEDLINE]
18. Immunity. 2022 May 10;55(5):827-846.e10. doi: 10.1016/j.immuni.2022.04.004. Epub 2022 Apr 27.
Multimodal profiling of lung granulomas in macaques reveals cellular correlates
of tuberculosis control.
Gideon HP(1), Hughes TK(2), Tzouanas CN(2), Wadsworth MH 2nd(3), Tu AA(4),
Gierahn TM(4), Peters JM(5), Hopkins FF(6), Wei JR(6), Kummerlowe C(7), Grant
NL(8), Nargan K(9), Phuah JY(8), Borish HJ(8), Maiello P(8), White AG(8),
Winchell CG(10), Nyquist SK(11), Ganchua SKC(8), Myers A(8), Patel KV(8), Ameel
CL(8), Cochran CT(8), Ibrahim S(2), Tomko JA(8), Frye LJ(8), Rosenberg JM(12),
Shih A(13), Chao M(6), Klein E(14), Scanga CA(1), Ordovas-Montanes J(15), Berger
B(16), Mattila JT(17), Madansein R(18), Love JC(19), Lin PL(20), Leslie A(21),
Behar SM(22), Bryson B(5), Flynn JL(23), Fortune SM(24), Shalek AK(25).
Author information:
(1)Department of Microbiology and Molecular Genetics, University of Pittsburgh
School of Medicine, Pittsburgh, PA, USA; Center for Vaccine Research, University
of Pittsburgh, Pittsburgh, PA, USA.
(2)Institute for Medical Engineering & Science, Massachusetts Institute of
Technology, Cambridge, MA, USA; Ragon Institute of MGH, MIT, and Harvard,
Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
(3)Institute for Medical Engineering & Science, Massachusetts Institute of
Technology, Cambridge, MA, USA; Ragon Institute of MGH, MIT, and Harvard,
Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA;
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA,
USA.
…
Comment in
Immunity. 2022 May 10;55(5):819-821.
Mycobacterium tuberculosis lung infection results in a complex multicellular
structure: the granuloma. In some granulomas, immune activity promotes bacterial
clearance, but in others, bacteria persist and grow. We identified correlates of
bacterial control in cynomolgus macaque lung granulomas by co-registering
longitudinal positron emission tomography and computed tomography imaging,
single-cell RNA sequencing, and measures of bacterial clearance. Bacterial
persistence occurred in granulomas enriched for mast, endothelial, fibroblast,
and plasma cells, signaling amongst themselves via type 2 immunity and
wound-healing pathways. Granulomas that drove bacterial control were
characterized by cellular ecosystems enriched for type 1-type 17, stem-like, and
cytotoxic T cells engaged in pro-inflammatory signaling networks involving
diverse cell populations. Granulomas that arose later in infection displayed
functional characteristics of restrictive granulomas and were more capable of
killing Mtb. Our results define the complex multicellular ecosystems underlying
(lack of) granuloma resolution and highlight host immune targets that can be
leveraged to develop new vaccine and therapeutic strategies for TB.
Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.immuni.2022.04.004
PMCID: PMC9122264
PMID: 35483355 [Indexed for MEDLINE]
19. Am J Respir Crit Care Med. 2022 May 15;205(10):1228-1235. doi:
10.1164/rccm.202108-1976OC.
Early Bactericidal Activity of Meropenem plus Clavulanate (with or without
Rifampin) for Tuberculosis: The COMRADE Randomized, Phase 2A Clinical Trial.
De Jager V(1), Gupte N(2)(3), Nunes S(1), Barnes GL(2), van Wijk RC(4), Mostert
J(1), Dorman SE(5), Abulfathi AA(6)(7), Upton CM(1), Faraj A(4), Nuermberger
EL(2), Lamichhane G(2), Svensson EM(8)(9), Simonsson USH(4), Diacon AH(1),
Dooley KE(2).
Author information:
(1)TASK Applied Science, Cape Town, South Africa.
(2)Department of Medicine, Johns Hopkins University School of Medicine,
Baltimore, Maryland.
(3)Johns Hopkins India, Pune, India.
…
Comment in
Am J Respir Crit Care Med. 2022 May 15;205(10):1142-1144.
Rationale: Carbapenems are recommended for treatment of drug-resistant
tuberculosis. Optimal dosing remains uncertain. Objectives: To evaluate the
14-day bactericidal activity of meropenem, at different doses, with or without
rifampin. Methods: Individuals with drug-sensitive pulmonary tuberculosis were
randomized to one of four intravenous meropenem-based arms: 2 g every 8 hours
(TID) (arm C), 2 g TID plus rifampin at 20 mg/kg once daily (arm D), 1 g TID
(arm E), or 3 g once daily (arm F). All participants received
amoxicillin/clavulanate with each meropenem dose. Serial overnight sputum
samples were collected from baseline and throughout treatment. Median daily fall
in colony-forming unit (CFU) counts per milliliter of sputum (solid culture)
(EBACFU0-14) and increase in time to positive culture (TTP) in liquid media were
estimated with mixed-effects modeling. Serial blood samples were collected for
pharmacokinetic analysis on Day 13. Measurements and Main Results: Sixty
participants enrolled. Median EBACFU0-14 counts (2.5th-97.5th percentiles) were
0.22 (0.12-0.33), 0.12 (0.057-0.21), 0.059 (0.033-0.097), and 0.053
(0.035-0.081); TTP increased by 0.34 (0.21-0.75), 0.11 (0.052-0.37), 0.094
(0.034-0.23), and 0.12 (0.04-0.41) (log10 h), for arms C-F, respectively.
Meropenem pharmacokinetics were not affected by rifampin coadministration.
Twelve participants withdrew early, many of whom cited gastrointestinal adverse
events. Conclusions: Bactericidal activity was greater with the World Health
Organization-recommended total daily dose of 6 g daily than with a lower dose of
3 g daily. This difference was only detectable with solid culture. Tolerability
of intravenous meropenem, with amoxicillin/clavulanate, though, was poor at all
doses, calling into question the utility of this drug in second-line regimens.
Clinical trial registered with www.clinicaltrials.gov (NCT03174184).
DOI: 10.1164/rccm.202108-1976OC
PMID: 35258443 [Indexed for MEDLINE]
20. Am J Respir Crit Care Med. 2022 May 15;205(10):1214-1227. doi:
10.1164/rccm.202107-1779OC.
An All-Oral 6-Month Regimen for Multidrug-Resistant Tuberculosis: A Multicenter,
Randomized Controlled Clinical Trial (the NExT Study).
Esmail A(1)(2), Oelofse S(1)(2), Lombard C(3)(4), Perumal R(1)(2), Mbuthini
L(1), Goolam Mahomed A(5), Variava E(6)(7)(8), Black J(9), Oluboyo P(10),
Gwentshu N(11), Ngam E(11), Ackerman T(12), Marais L(12), Mottay L(1)(2), Meier
S(1)(2), Pooran A(1)(2), Tomasicchio M(1)(2), Te Riele J(13), Derendinger B(14),
Ndjeka N(15), Maartens G(16), Warren R(14), Martinson N(17)(18), Dheda
K(1)(2)(19).
Author information:
(1)Division of Pulmonology, Department of Medicine, Centre for Lung Infection
and Immunity, University of Cape Town Lung Institute, Cape Town, South Africa.
(2)Centre for the Study of Antimicrobial Resistance, South African Medical
Research Council, and.
(3)Biostatistics Unit, South African Medical Research Council, Cape Town, South
Africa.
…
Comment in
Am J Respir Crit Care Med. 2022 May 15;205(10):1142-1144.
Rationale: Improving treatment outcomes while reducing drug toxicity and
shortening the treatment duration to ∼6 months remains an aspirational goal for
the treatment of multidrug-resistant/rifampicin-resistant tuberculosis
(MDR/RR-TB). Objectives: To conduct a multicenter randomized controlled trial in
adults with MDR/RR-TB (i.e., without resistance to fluoroquinolones or
aminoglycosides). Methods: Participants were randomly assigned (1:1 ratio) to a
∼6-month all-oral regimen that included levofloxacin, bedaquiline, and
linezolid, or the standard-of-care (SOC) ⩾9-month World Health Organization
(WHO)-approved injectable-based regimen. The primary endpoint was a favorable
WHO-defined treatment outcome (which mandates that prespecified drug
substitution is counted as an unfavorable outcome) 24 months after treatment
initiation. The trial was stopped prematurely when bedaquiline-based therapy
became the standard of care in South Africa. Measurements and Main Results: In
total, 93 of 111 randomized participants (44 in the comparator arm and 49 in the
interventional arm) were included in the modified intention-to-treat analysis;
51 (55%) were HIV coinfected (median CD4 count, 158 cells/ml). Participants in
the intervention arm were 2.2 times more likely to experience a favorable
24-month outcome than participants in the SOC arm (51% [25 of 49] vs. 22.7% [10
of 44]; risk ratio, 2.2 [1.2-4.1]; P = 0.006). Toxicity-related drug
substitution occurred more frequently in the SOC arm (65.9% [29 of 44] vs. 34.7%
[17 of 49]; P = 0.001)], 82.8% (24 of 29) owing to kanamycin (mainly hearing
loss; replaced by bedaquiline) in the SOC arm, and 64.7% (11 of 17) owing to
linezolid (mainly anemia) in the interventional arm. Adverse event-related
treatment discontinuation in the safety population was more common in the SOC
arm (56.4% [31 of 55] vs. 32.1% [17 of 56]; P = 0.007). However, grade 3 adverse
events were more common in the interventional arm (55.4% [31 of 56] vs. 32.7 [18
of 55]; P = 0.022). Culture conversion was significantly better in the
intervention arm (hazard ratio, 2.6 [1.4-4.9]; P = 0.003) after censoring those
with bedaquiline replacement in the SOC arm (and this pattern remained
consistent after censoring for drug replacement in both arms; P = 0.01).
Conclusions: Compared with traditional injectable-containing regimens, an
all-oral 6-month levofloxacin, bedaquiline, and linezolid-containing MDR/RR-TB
regimen was associated with a significantly improved 24-month WHO-defined
treatment outcome (predominantly owing to toxicity-related drug substitution).
However, drug toxicity occurred frequently in both arms. These findings inform
strategies to develop future regimens for MDR/RR-TB.Clinical trial registered
with www.clinicaltrials.gov (NCT02454205).
DOI: 10.1164/rccm.202107-1779OC
PMID: 35175905 [Indexed for MEDLINE]
21. Lancet Oncol. 2022 Jul;23(7):931-939. doi: 10.1016/S1470-2045(22)00271-6. Epub
2022 May 26.
Stereotactic radiosurgery versus whole brain radiotherapy in patients with
intracranial metastatic disease and small-cell lung cancer: a systematic review
and meta-analysis.
Gaebe K(1), Li AY(1), Park A(1), Parmar A(2), Lok BH(3), Sahgal A(4), Chan
KKW(5), Erickson AW(6), Das S(7).
Author information:
(1)Institute of Medical Science, Faculty of Medicine, University of Toronto,
Toronto, ON, Canada.
(2)Department of Medical Oncology, Odette Cancer Centre, Sunnybrook Health
Sciences Centre, Toronto, ON, Canada.
(3)Institute of Medical Science, Faculty of Medicine, University of Toronto,
Toronto, ON, Canada; Department of Radiation Oncology, Princess Margaret Cancer
Centre, Toronto, ON, Canada.
…
BACKGROUND: Patients with small-cell lung cancer (SCLC) are at high risk for
intracranial metastatic disease (IMD). Although stereotactic radiosurgery (SRS)
has supplanted whole brain radiotherapy (WBRT) as first-line treatment for IMD
in most solid cancers, WBRT remains first-line treatment for IMD in patients
with SCLC. We aimed to evaluate the efficacy of SRS in comparison with WBRT and
assess treatment outcomes following SRS.
METHODS: In this systematic review and meta-analysis, we searched MEDLINE,
Embase, CENTRAL, and grey literature sources for controlled trials and cohort
studies published in English reporting on SRS for IMD treatment in patients with
SCLC from inception to March 23, 2022. Studies were excluded that did not report
on SRS for IMD secondary to SCLC. Summary data were extracted. The primary
outcome was overall survival, presented as pooled hazard ratios (HR) through
random-effects meta-analysis for studies comparing SRS with WBRT with or without
SRS boost, and as medians for single-arm SRS studies. This study is registered
with the Open Science Framework, DOI 10.17605/OSF.IO/8M4HC, and PROSPERO,
CRD42021258197.
FINDINGS: Of 3823 identified records, 31 were eligible for inclusion; seven were
included in the meta-analysis. Overall survival following SRS was longer than
following WBRT with or without SRS boost (HR 0·85; 95% CI 0·75-0·97; n=7
studies; n=18 130 patients), or WBRT alone (0·77; 0·72-0·83; n=7 studies;
n=16 961 patients), but not WBRT plus SRS boost (1·17, 0·78-1·75; n=4 studies;
n=1167 patients). Using single-arm studies, pooled median overall survival from
SRS was 8·99 months (95% CI 7·86-10·16; n=14 studies; n=1682 patients).
Between-study heterogeneity was considerable when pooled among all comparative
studies (I2=71·9%).
INTERPRETATION: These results suggest survival outcomes are equitable following
treatment with SRS compared with WBRT in patients with SCLC and IMD. Future
prospective studies should focus on tumour burden and differences in local and
distant intracranial progression between WBRT-treated and SRS-treated patients
with SCLC.
FUNDING: None.
Copyright © 2022 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1470-2045(22)00271-6
PMID: 35644163 [Indexed for MEDLINE]
22. Lancet Oncol. 2022 Jun;23(6):781-792. doi: 10.1016/S1470-2045(22)00226-1. Epub
2022 May 13.
Tiragolumab plus atezolizumab versus placebo plus atezolizumab as a first-line
treatment for PD-L1-selected non-small-cell lung cancer (CITYSCAPE): primary and
follow-up analyses of a randomised, double-blind, phase 2 study.
Cho BC(1), Abreu DR(2), Hussein M(3), Cobo M(4), Patel AJ(5), Secen N(6), Lee
KH(7), Massuti B(8), Hiret S(9), Yang JCH(10), Barlesi F(11), Lee DH(12), Ares
LP(13), Hsieh RW(14), Patil NS(14), Twomey P(14), Yang X(14), Meng R(14),
Johnson ML(15).
Author information:
(1)Yonsei Cancer Centre, Yonsei University College of Medicine, Seoul, South
Korea. Electronic address: cbc1971@yuhs.ac.
(2)Hospital Universitario Insular de Gran Canaria, Las Palmas, Spain.
(3)SCRI Florida Cancer Specialists, Leesburg, FL, USA.
…
Comment in
Lancet Oncol. 2022 Jun;23(6):695-697.
BACKGROUND: Targeted inhibition of the PD-L1-PD-1 pathway might be further
amplified through combination of PD-1 or PD-L1 inhibitors with novel anti-TIGIT
inhibitory immune checkpoint agents, such as tiragolumab. In the CITYSCAPE
trial, we aimed to assess the preliminary efficacy and safety of tiragolumab
plus atezolizumab (anti-PD-L1) therapy as first-line treatment for
non-small-cell lung cancer (NSCLC).
METHODS: CITYSCAPE is a phase 2, randomised, double-blind, placebo-controlled
trial. Patients with chemotherapy-naive, PD-L1-positive (defined as a tumour
proportion score of ≥1% by 22C3 immunohistochemistry pharmDx assay; Dako,
Agilent Technologies, Santa Clara, CA, USA) recurrent or metastatic NSCLC with
measurable disease, Eastern Cooperative Oncology Group performance status of 0
or 1, and no EGFR or ALK alterations were enrolled from 41 clinics in Europe,
Asia, and the USA. Patients were randomly assigned (1:1), via an interactive
voice or web-based response system, to receive tiragolumab (600 mg) plus
atezolizumab (1200 mg) or placebo plus atezolizumab intravenously once every 3
weeks. Investigators and patients were masked to treatment assignment. The
co-primary endpoints were investigator-assessed objective response rate and
progression-free survival as per Response Evaluation Criteria in Solid Tumors
version 1.1 in the intention-to-treat population, analysed after approximately
80 progression-free survival events had been observed in the primary population.
Safety was assessed in all patients who received at least one dose of study
drug. This trial is registered with ClinicalTrials.gov, NCT03563716, and is
ongoing.
FINDINGS: Patients were enrolled between Aug 10, 2018, and March 20, 2019. At
data cutoff for the primary analysis (June 30, 2019), 135 of 275 patients
assessed for eligibility were randomly assigned to receive tiragolumab plus
atezolizumab (67 [50%]) or placebo plus atezolizumab (68 [50%]). In this primary
analysis, after a median follow-up of 5·9 months (4·6-7·6, in the
intention-to-treat population, 21 patients (31·3% [95% CI 19·5-43·2]) in the
tiragolumab plus atezolizumab group versus 11 patients (16·2% [6·7-25·7]) in the
placebo plus atezolizumab group had an objective response (p=0·031). Median
progression-free survival was 5·4 months (95% CI 4·2-not estimable) in the
tiragolumab plus atezolizumab group versus 3·6 months (2·7-4·4) in the placebo
plus atezolizumab group (stratified hazard ratio 0·57 [95% CI 0·37-0·90],
p=0·015). 14 (21%) patients receiving tiragolumab plus atezolizumab and 12 (18%)
patients receiving placebo plus atezolizumab had serious treatment-related
adverse events. The most frequently reported grade 3 or worse treatment-related
adverse event was lipase increase (in six [9%] patients in the tiragolumab plus
atezolizumab group vs two [3%] in the placebo plus atezolizumab group). Two
treatment-related deaths (of pyrexia and infection) occurred in the tiragolumab
plus atezolizumab group.
INTERPRETATION: Tiragolumab plus atezolizumab showed a clinically meaningful
improvement in objective response rate and progression-free survival compared
with placebo plus atezolizumab in patients with chemotherapy-naive,
PD-L1-positive, recurrent or metastatic NSCLC. Tiragolumab plus atezolizumab was
well tolerated, with a safety profile generally similar to that of atezolizumab
alone. These findings demonstrate that tiragolumab plus atezolizumab is a
promising immunotherapy combination for the treatment of previously untreated,
locally advanced unresectable or metastatic NSCLC.
FUNDING: F Hoffmann-La Roche and Genentech.
Copyright © 2022 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1470-2045(22)00226-1
PMID: 35576957 [Indexed for MEDLINE]
23. Lancet Oncol. 2022 Jun;23(6):739-747. doi: 10.1016/S1470-2045(22)00224-8. Epub
2022 May 13.
Adebrelimab or placebo plus carboplatin and etoposide as first-line treatment
for extensive-stage small-cell lung cancer (CAPSTONE-1): a multicentre,
randomised, double-blind, placebo-controlled, phase 3 trial.
Wang J(1), Zhou C(2), Yao W(3), Wang Q(4), Min X(5), Chen G(6), Xu X(7), Li
X(8), Xu F(9), Fang Y(10), Yang R(11), Yu G(12), Gong Y(13), Zhao J(14), Fan
Y(15), Liu Q(16), Cao L(17), Yao Y(18), Liu Y(19), Li X(20), Wu J(21), He Z(22),
Lu K(23), Jiang L(24), Hu C(25), Zhao W(26), Zhang B(27), Shi W(27), Zhang
X(27), Cheng Y(28); CAPSTONE-1 Study Group.
Author information:
(1)Department of Medical Oncology, National Cancer Center, National Clinical
Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences
& Peking Union Medical College, Beijing, China.
(2)Department of Medical Oncology, Shanghai Pulmonary Hospital, Shanghai, China.
(3)Department of Thoracic Oncology, Sichuan Cancer Hospital & Institute,
Chengdu, China.
…
Comment in
Lancet Oncol. 2022 Jun;23(6):692-693.
BACKGROUND: Extensive-stage small-cell lung cancer (ES-SCLC) is associated with
poor prognosis and treatment options are scarce. Immunotherapy has shown robust
clinical activity in ES-SCLC in previous phase 3 trials. We aimed to assess the
efficacy and safety of adebrelimab (SHR-1316), a novel anti-PD-L1 antibody, with
standard chemotherapy as a first-line treatment for ES-SCLC.
METHODS: The CAPSTONE-1 study was a randomised, double-blind,
placebo-controlled, phase 3 trial, done in 47 tertiary hospitals in China. Key
inclusion criteria were patients aged 18-75 years, with previously untreated
histologically or cytologically confirmed ES-SCLC and an Eastern Cooperative
Oncology Group (ECOG) performance status of 0-1. Eligible patients were randomly
assigned (1:1) to receive four to six cycles of carboplatin (area under the
curve of 5 mg/mL per min, day 1 of each cycle) and etoposide (100 mg/m2 of
body-surface area, on days 1-3 of each cycle) with either adebrelimab (20 mg/kg,
day 1 of each cycle) or matching placebo, followed by maintenance therapy with
adebrelimab or placebo. All treatments were given intravenously in 21-day
cycles. Randomisation was done using a centralised interactive web response
system with a block size of four, stratified by liver metastases, brain
metastases, and lactate dehydrogenase concentration. The primary endpoint was
overall survival in patients who received at least one dose of study medication.
Safety was analysed in the as-treated population. This study is complete and
registered with ClinicalTrials.gov, NCT03711305.
FINDINGS: Between Dec 26, 2018, and Sept 4, 2020, 462 eligible patients were
enrolled and randomly assigned: 230 (50%) patients received adebrelimab plus
chemotherapy (adebrelimab group) and 232 (50%) patients received placebo plus
chemotherapy (placebo group). At data cutoff (Oct 8, 2021), median follow-up was
13·5 months (IQR 8·9-20·1). Median overall survival was significantly improved
in the adebrelimab group (median 15·3 months [95% CI 13·2-17·5]) compared with
the placebo group (12·8 months [11·3-13·7]; hazard ratio 0·72 [95% CI
0·58-0·90]; one-sided p=0·0017). The most common treatment-related grade 3 or 4
adverse events were decreased neutrophil count (174 [76%] patients in the
adebrelimab group and 175 [75%] patients in the placebo group), decreased white
blood cell count (106 [46%] and 88 [38%]), decreased platelet count (88 [38%]
and 78 [34%]), and anaemia (64 [28%] and 66 [28%]). Treatment-related serious
adverse events occurred in 89 (39%) patients in the adebrelimab group and 66
(28%) patients in the placebo group. Four treatment-related deaths were
reported: two each in the adebrelimab group (respiratory failure and
interstitial lung disease and pneumonia) and placebo group (multiple organ
dysfunction and unknown cause of death).
INTERPRETATION: Adding adebrelimab to chemotherapy significantly improved
overall survival with an acceptable safety profile in patients with ES-SCLC,
supporting this combination as a new first-line treatment option for this
population.
FUNDING: Jiangsu Hengrui Pharmaceuticals.
Copyright © 2022 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1470-2045(22)00224-8
PMID: 35576956 [Indexed for MEDLINE]
24. Cancer Cell. 2022 May 9;40(5):479-493.e6. doi: 10.1016/j.ccell.2022.03.012. Epub
2022 Apr 21.
A phenotypic signature that identifies neoantigen-reactive T cells in fresh
human lung cancers.
Hanada KI(1), Zhao C(2), Gil-Hoyos R(2), Gartner JJ(2), Chow-Parmer C(2), Lowery
FJ(2), Krishna S(2), Prickett TD(2), Kivitz S(2), Parkhurst MR(2), Wong N(3),
Rae Z(4), Kelly MC(4), Goff SL(2), Robbins PF(2), Rosenberg SA(2), Yang JC(5).
Author information:
(1)Surgery Branch, Center for Cancer Research, National Cancer Institute,
National Institutes of Health, Bethesda, MD 20892, USA. Electronic address:
hanada@nih.gov.
(2)Surgery Branch, Center for Cancer Research, National Cancer Institute,
National Institutes of Health, Bethesda, MD 20892, USA.
(3)CCR Collaborative Bioinformatics Resource, Center for Cancer Research,
National Cancer Institute, National Institutes of Health, Bethesda, MD 20892,
USA; Advanced Biomedical Computational Science, Frederick National Laboratory
for Cancer Research, Leidos Biomedical Research, Frederick, MD 21701, USA.
…
A common theme across multiple successful immunotherapies for cancer is the
recognition of tumor-specific mutations (neoantigens) by T cells. The rapid
discovery of such antigen responses could lead to improved therapies through the
adoptive transfer of T cells engineered to express neoantigen-reactive T cell
receptors (TCRs). Here, through CITE-seq (cellular indexing of transcriptomes
and epitopes by sequencing) and TCR-seq of non-small cell lung cancer (NSCLC)
tumor-infiltrating lymphocytes (TILs), we develop a neoantigen-reactive T cell
signature based on clonotype frequency and CD39 protein and CXCL13 mRNA
expression. Screening of TCRs selected by the signature allows us to identify
neoantigen-reactive TCRs with a success rate of 45% for CD8+ and 66% for CD4+
T cells. Because of the small number of samples analyzed (4 patients),
generalizability remains to be tested. However, this approach can enable the
quick identification of neoantigen-reactive TCRs and expedite the engineering of
personalized neoantigen-reactive T cells for therapy.
Published by Elsevier Inc.
DOI: 10.1016/j.ccell.2022.03.012
PMCID: PMC9196205
PMID: 35452604 [Indexed for MEDLINE]
25. Lancet Neurol. 2022 May;21(5):450-464. doi: 10.1016/S1474-4422(21)00435-X.
Tuberculous meningitis: progress and remaining questions.
Huynh J(1), Donovan J(1), Phu NH(2), Nghia HDT(3), Thuong NTT(1), Thwaites
GE(4).
Author information:
(1)Centre for Tropical Medicine and Global Health, Nuffield Department of
Medicine, Oxford University, Oxford, UK; Oxford University Clinical Research
Unit, Centre for Tropical Medicine, Ho Chi Minh City, Vietnam.
(2)Centre for Tropical Medicine and Global Health, Nuffield Department of
Medicine, Oxford University, Oxford, UK; Vietnam National University School of
Medicine, Ho Chi Minh City, Vietnam.
(3)Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam; Pham Ngoc Thach
University of Medicine, Ho Chi Minh City, Vietnam.
(4)Centre for Tropical Medicine and Global Health, Nuffield Department of
Medicine, Oxford University, Oxford, UK; Oxford University Clinical Research
Unit, Centre for Tropical Medicine, Ho Chi Minh City, Vietnam. Electronic
address: gthwaites@oucru.org.
Tuberculous meningitis is a devastating brain infection that is caused by
Mycobacterium tuberculosis and is notoriously difficult to diagnose and treat.
New technologies characterising the transcriptome, proteome, and metabolome have
identified new molecules and pathways associated with tuberculous meningitis
severity and poor outcomes that could offer novel diagnostic and therapeutic
targets. The next-generation GeneXpert MTB/RIF Ultra assay, when used on CSF,
offers diagnostic sensitivity for tuberculous meningitis of approximately 70%,
although it is not widely available and a negative result cannot rule out
tuberculous meningitis. Small trials indicate that clinical outcomes might be
improved with increased doses of rifampicin, the addition of linezolid or
fluoroquinolones to standard antituberculosis therapy, or treatment with
adjunctive aspirin combined with corticosteroids. Large phase 3 clinical trials
are underway worldwide to address these and other questions concerning the
optimal management of tuberculous meningitis; these studies also form a platform
for studying pathogenesis and identifying novel diagnostic and treatment
strategies, by allowing the implementation of new genomic, transcriptomic,
proteomic, and metabolomic technologies in nested substudies.
Copyright © 2022 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1474-4422(21)00435-X
PMID: 35429482 [Indexed for MEDLINE]
26. Nat Med. 2022 May;28(5):939-945. doi: 10.1038/s41591-022-01754-x. Epub 2022 Apr
14.
Blood-based tumor mutational burden as a biomarker for atezolizumab in non-small
cell lung cancer: the phase 2 B-F1RST trial.
Kim ES(#)(1), Velcheti V(#)(2)(3), Mekhail T(4), Yun C(5), Shagan SM(5), Hu
S(5), Chae YK(6), Leal TA(7), Dowell JE(8), Tsai ML(9), Dakhil CSR(10), Stella
P(11), Jin Y(12), Shames DS(5), Schleifman E(5), Fabrizio DA(13), Phan S(5),
Socinski MA(4).
Author information:
(1)City of Hope National Medical Center, Los Angeles, CA, USA.
(2)Cleveland Clinic, Cleveland, OH, USA. vamsidhar.velcheti@nyulangone.org.
(3)New York University School of Medicine, New York, NY, USA.
vamsidhar.velcheti@nyulangone.org.
…
Comment in
Nat Rev Clin Oncol. 2022 Jun;19(6):360.
Tumor mutational burden (TMB) in circulating tumor DNA (ctDNA) has shown promise
in predicting benefit from PD-L1/PD-1 inhibitors in retrospective studies.
Aiming to assess blood TMB (bTMB) prospectively, we conducted B-F1RST (
NCT02848651 ), an open-label, phase 2 trial that evaluated bTMB as a predictive
biomarker for first-line atezolizumab monotherapy in locally advanced or
metastatic stage IIIB-IVB non-small cell lung cancer (n = 152). The co-primary
endpoints were investigator-assessed objective response rate (ORR) per RECIST
version 1.1 and investigator-assessed progression-free survival (PFS) between
high and low bTMB subgroups at the pre-defined bTMB ≥ 16 (14.5 mutations per
megabase) cutoff. Secondary endpoints included investigator-assessed PFS,
overall survival (OS) and duration of response at various bTMB cutoffs, as well
as safety. Investigator-assessed PFS in the bTMB ≥ 16 versus bTMB < 16 groups
was not statistically significant. However, bTMB ≥ 16 was associated with higher
ORR, and ORR improved as bTMB cutoffs increased. No new safety signals were
seen. In exploratory analyses, patients with maximum somatic allele frequency
(MSAF) < 1% had higher ORR than patients with MSAF ≥ 1%. However, further
analysis showed that this effect was driven by better baseline prognostics
rather than by MSAF itself. At 36.5-month follow-up, an exploratory analysis of
OS found that bTMB ≥ 16 was associated with longer OS than bTMB < 16. Further
study and assay optimization will be required to develop bTMB as a predictive,
standalone biomarker of immunotherapy or for use in conjunction with other
biomarkers.
© 2022. The Author(s).
DOI: 10.1038/s41591-022-01754-x
PMCID: PMC9117143
PMID: 35422531 [Indexed for MEDLINE]
27. N Engl J Med. 2022 May 26;386(21):1973-1985. doi: 10.1056/NEJMoa2202170. Epub
2022 Apr 11.
Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer.
Forde PM(1), Spicer J(1), Lu S(1), Provencio M(1), Mitsudomi T(1), Awad MM(1),
Felip E(1), Broderick SR(1), Brahmer JR(1), Swanson SJ(1), Kerr K(1), Wang C(1),
Ciuleanu TE(1), Saylors GB(1), Tanaka F(1), Ito H(1), Chen KN(1), Liberman M(1),
Vokes EE(1), Taube JM(1), Dorange C(1), Cai J(1), Fiore J(1), Jarkowski A(1),
Balli D(1), Sausen M(1), Pandya D(1), Calvet CY(1), Girard N(1); CheckMate 816
Investigators.
Author information:
(1)From the Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins
Kimmel Cancer Center, Baltimore (P.M.F., S.R.B., J.R.B., J.M.T.); McGill
University Health Center (J.S.), and Centre Hospitalier de l'Université de
Montréal (M.L.) - both in Montreal; Shanghai Chest Hospital, School of Medicine,
Shanghai Jiao Tong University, Shanghai (S.L.), Tianjin Lung Cancer Center,
Tianjin Medical University Cancer Institute and Hospital, Tianjin (C.W.), and
Peking University School of Oncology, Beijing Cancer Hospital, Beijing (K.-N.C.)
- all in China; Hospital Universitario Puerta de Hierro, Madrid (M.P.); Kindai
University Faculty of Medicine, Ohno-Higashi, Osaka-Sayama (T.M.),…
Comment in
N Engl J Med. 2022 May 26;386(21):2050-2051.
BACKGROUND: Neoadjuvant or adjuvant chemotherapy confers a modest benefit over
surgery alone for resectable non-small-cell lung cancer (NSCLC). In early-phase
trials, nivolumab-based neoadjuvant regimens have shown promising clinical
activity; however, data from phase 3 trials are needed to confirm these
findings.
METHODS: In this open-label, phase 3 trial, we randomly assigned patients with
stage IB to IIIA resectable NSCLC to receive nivolumab plus platinum-based
chemotherapy or platinum-based chemotherapy alone, followed by resection. The
primary end points were event-free survival and pathological complete response
(0% viable tumor in resected lung and lymph nodes), both evaluated by blinded
independent review. Overall survival was a key secondary end point. Safety was
assessed in all treated patients.
RESULTS: The median event-free survival was 31.6 months (95% confidence interval
[CI], 30.2 to not reached) with nivolumab plus chemotherapy and 20.8 months (95%
CI, 14.0 to 26.7) with chemotherapy alone (hazard ratio for disease progression,
disease recurrence, or death, 0.63; 97.38% CI, 0.43 to 0.91; P = 0.005). The
percentage of patients with a pathological complete response was 24.0% (95% CI,
18.0 to 31.0) and 2.2% (95% CI, 0.6 to 5.6), respectively (odds ratio, 13.94;
99% CI, 3.49 to 55.75; P<0.001). Results for event-free survival and
pathological complete response across most subgroups favored nivolumab plus
chemotherapy over chemotherapy alone. At the first prespecified interim
analysis, the hazard ratio for death was 0.57 (99.67% CI, 0.30 to 1.07) and did
not meet the criterion for significance. Of the patients who underwent
randomization, 83.2% of those in the nivolumab-plus-chemotherapy group and 75.4%
of those in the chemotherapy-alone group underwent surgery. Grade 3 or 4
treatment-related adverse events occurred in 33.5% of the patients in the
nivolumab-plus-chemotherapy group and in 36.9% of those in the
chemotherapy-alone group.
CONCLUSIONS: In patients with resectable NSCLC, neoadjuvant nivolumab plus
chemotherapy resulted in significantly longer event-free survival and a higher
percentage of patients with a pathological complete response than chemotherapy
alone. The addition of nivolumab to neoadjuvant chemotherapy did not increase
the incidence of adverse events or impede the feasibility of surgery. (Funded by
Bristol Myers Squibb; CheckMate 816 ClinicalTrials.gov number, NCT02998528.).
Copyright © 2022 Massachusetts Medical Society.
DOI: 10.1056/NEJMoa2202170
PMID: 35403841 [Indexed for MEDLINE]
