2024年
No.2
PubMed
(tuberculosis[Title/Abstract]) OR (lung cancer[Title/Abstract])
Filters applied: from 2024/2/1 - 2024/2/29.
1. J Thorac Oncol. 2024 Feb;19(2):216-226. doi: 10.1016/j.jtho.2023.10.006. Epub
2023 Oct 12.
Rheumatoid Arthritis and Risk of Lung Cancer: A Nationwide Cohort Study.
Cho MH(1), Cho JH(2), Eun Y(3), Han K(4), Jung J(5), Cho IY(6), Yoo JE(7), Lee
H(8), Kim H(9), Park SY(2), Shin DW(10).
Author information:
(1)Samsung C&T Medical Clinic, Kangbuk Samsung Hospital, Sungkyunkwan University
School of Medicine, Seoul, Republic of Korea.
(2)Department of Thoracic Surgery, Samsung Medical Center, Sungkyunkwan
University School of Medicine, Seoul, Republic of Korea.
(3)Division of Rheumatology, Department of Internal Medicine, Kangbuk Samsung
Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
INTRODUCTION: There has been an increasing interest in the risk of lung cancer
related to rheumatoid arthritis (RA). We investigated the association between RA
and the risk of lung cancer with consideration of key confounding factors,
including RA serostatus and smoking status.
METHODS: Using a nationwide database, we identified 51,899 patients with newly
diagnosed RA between 2010 and 2017, which were matched by sex and age at a 1:5
ratio with 259,495 non-RA population. The association of lung cancer and RA was
investigated using Cox regression analyses. Stratified analyses by smoking
status, sex, age, and comorbidity of interstitial lung disease were conducted
using the same Cox modeling.
RESULTS: During 4.5 years of follow-up, the adjusted hazard ratio of lung cancer
in the patients with RA was 1.49 (95% confidence interval: 1.34-1.66). Compared
with the patients with seronegative RA, an increased risk of lung cancer was not
considerable in the patients with seropositive RA. In the stratified analyses,
the increased risk of lung cancer was more prominent in current or previous
heavy smokers with RA (interaction p value of 0.046) and male patients
(interaction p < 0.001), whereas there was no substantial effect associated with
age or interstitial lung disease status.
CONCLUSIONS: Patients with RA had an increased risk of lung cancer compared with
the non-RA group, and the risk did not differ by RA serostatus. There is a need
for increased awareness of smoking cessation and potentially for regular lung
cancer screening with proper risk stratification in patients with RA.
Copyright © 2023 International Association for the Study of Lung Cancer.
Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.jtho.2023.10.006
PMID: 37838085 [Indexed for MEDLINE]
2. Am J Respir Crit Care Med. 2024 Feb 1;209(3):307-315. doi:
10.1164/rccm.202305-0902OC.
Outdoor Ultrafine Particulate Matter and Risk of Lung Cancer in Southern
California.
Jones RR(1), Fisher JA(1), Hasheminassab S(2), Kaufman JD(3), Freedman ND(4),
Ward MH(1), Sioutas C(2), Vermeulen R(5)(6), Hoek G(5), Silverman DT(1).
Author information:
(1)Occupational and Environmental Epidemiology Branch and.
(2)Department of Civil and Environmental Engineering, University of Southern
California, Los Angeles, California.
(3)Department of Environmental and Occupational Health Sciences, School of
Public Health, University of Washington, Seattle, Washington.
(4)Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics,
National Cancer Institute, National Institutes of Health, Rockville, Maryland.
(5)Institute for Risk Assessment Sciences, Division of Environmental
Epidemiology, Utrecht University, Utrecht, the Netherlands; and.
(6)University Medical Center Utrecht, Utrecht, the Netherlands.
Comment in
Am J Respir Crit Care Med. 2024 Feb 1;209(3):241-242.
Rationale: Particulate matter ⩽2.5 μm in aerodynamic diameter (PM2.5) is an
established cause of lung cancer, but the association with ultrafine particulate
matter (UFP; aerodynamic diameter < 0.1 μm) is unclear. Objectives: To
investigate the association between UFP and lung cancer overall and by
histologic subtype. Methods: The Los Angeles Ultrafines Study includes 45,012
participants aged ⩾50 years in southern California at enrollment (1995-1996)
followed through 2017 for incident lung cancer (n = 1,770). We estimated
historical residential ambient UFP number concentrations via land use regression
and back extrapolation using PM2.5. In Cox proportional hazards models adjusted
for smoking and other confounders, we estimated associations between 10-year
lagged UFP (per 10,000 particles/cm3 and quartiles) and lung cancer overall and
by major histologic subtype (adenocarcinoma, squamous cell carcinoma, and small
cell carcinoma). We also evaluated relationships by smoking status, birth
cohort, and historical duration at the residence. Measurements and Main Results:
UFP was modestly associated with lung cancer risk overall (hazard ratio [HR],
1.03 [95% confidence interval (CI), 0.99-1.08]). For adenocarcinoma, we observed
a positive trend among men; risk was increased in the highest exposure quartile
versus the lowest (HR, 1.39 [95% CI, 1.05-1.85]; P for trend = 0.01) and was
also increased in continuous models (HR per 10,000 particles/cm3, 1.09 [95% CI,
1.00-1.18]), but no increased risk was apparent among women (P for
interaction = 0.03). Adenocarcinoma risk was elevated among men born between
1925 and 1930 (HR, 1.13 [95% CI, 1.02-1.26] per 10,000) but not for other birth
cohorts, and was suggestive for men with ⩾10 years of residential duration (HR,
1.11 [95% CI, 0.98-1.26]). We found no consistent associations for women or
other histologic subtypes. Conclusions: UFP exposure was modestly associated
with lung cancer overall, with stronger associations observed for adenocarcinoma
of the lung.
DOI: 10.1164/rccm.202305-0902OC
PMCID: PMC10840777
PMID: 37856832 [Indexed for MEDLINE]
3. J Thorac Oncol. 2024 Feb 2:S1556-0864(24)00034-0. doi:
10.1016/j.jtho.2024.01.014. Online ahead of print.
Global Burden of Lung Cancer Attributable to Household Fine Particulate Matter
Pollution in 204 Countries and Territories, 1990 to 2019.
Zhou RX(1), Liao HJ(2), Hu JJ(1), Xiong H(1), Cai XY(3), Ye DW(4).
Author information:
(1)Cancer Center, Tongji Hospital, Tongji Medical College, Huazhong University
of Science and Technology, Wuhan, People's Republic of China.
(2)The Second Affiliated Hospital of Nanchang University, Nanchang, People's
Republic of China.
(3)Department of VIP Inpatient, Sun Yat-Sen University Cancer Center, State Key
Laboratory of Oncology in South China, Guangdong Key Laboratory of
Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, People's Republic of
China.
(4)Cancer Center, Tongji Hospital, Tongji Medical College, Huazhong University
of Science and Technology, Wuhan, People's Republic of China. Electronic
address: dy0711@gmail.com.
INTRODUCTION: Household particulate matter (PM) air pollution is substantially
associated with lung cancer. Nevertheless, the global burden of lung cancer
attributable to household PM2.5 is still uncertain.
METHODS: In this study, data from the Global Burden and Disease Study 2019 are
used to thoroughly assess the burden of lung cancer associated with household
PM2.5.
RESULTS: The number of deaths and disability-adjusted life-years (DALYs)
attributable to household PM2.5 was found to be 0.08 million and 1.94 million,
respectively in 2019. Nevertheless, the burden of lung cancer attributable to
household PM2.5 decreased from 1990 to 2019. At the sociodemographic index (SDI)
district level, the middle SDI region had the most number of lung cancer deaths
and DALYs attributable to household PM2.5. Moreover, the burden of lung cancer
was mainly distributed in low-SDI regions, such as Sub-Saharan Africa.
Conversely, in high-SDI regions, the age-standardized mortality rate and
age-standardized DALY rate of lung cancer attributable to household PM2.5
exhibit the most rapid declines. The burden of lung cancer attributable to
household PM2.5 is heavier for men than for women. The sex difference is more
obvious in the elderly.
CONCLUSIONS: The prevalence of lung cancer attributable to household PM2.5 has
exhibited a declining trend from 1990 to 2019 owing to a concurrent decline in
household PM2.5 exposure.
Copyright © 2024 International Association for the Study of Lung Cancer.
Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.jtho.2024.01.014
PMID: 38311022
4. J Thorac Oncol. 2024 Feb 4:S1556-0864(24)00060-1. doi:
10.1016/j.jtho.2024.01.019. Online ahead of print.
The IASLC Lung Cancer Staging Project: Proposals for the Revision of the M
Descriptors in the Forthcoming 9th edition of the TNM Classification of Lung
Cancer.
Fong KM(1), Rosenthal A(2), Giroux DJ(2), Nishimura KK(2), Erasmus J(3), Lievens
Y(4), Marino M(5), Marom EM(6), Putora PM(7), Singh N(8), Suárez F(9),
Rami-Porta R(10), Detterbeck F(11), Eberhardt WE(12), Asamura H(13); Members of
the International Association for the Study of Lung Cancer Staging and
Prognostic Factors Committee, Members of the Advisory Boards, and Participating
Institutions of the Lung Cancer Domain..
Author information:
(1)Department of Thoracic Medicine, The Prince Charles Hospital, University of
Queensland Thoracic Research Centre, Brisbane, Australia. Electronic address:
kwun.fong@health.qld.gov.au.
(2)Cancer Research And Biostatistics (CRAB), Seattle, Washington.
(3)Department of Thoracic Imaging, The University of Texas MD Anderson Cancer
Center, Houston, Texas, USA.
(4)Department of Radiation Oncology, Ghent University Hospital and Ghent
University, Gent, Belgium.
(5)Department of Pathology, IRCCS Regina Elena National Cancer Institute, Rome,
Italy.
INTRODUCTION: This study analyzed all metastatic categories of the current
tumor, node, and metastasis (TNM) classification of non-small cell lung cancer
to propose modifications of the M component in the next edition (9th) of the
classification.
METHODS: A database of 124,581 patients diagnosed between 2011 and 2019 was
established; of these, 14,937 with NSCLC in stage IVA-IVB were available for
this analysis. Overall survival was calculated using the Kaplan-Meier method,
and prognosis assessed using multivariable-adjusted Cox proportional hazards
regression.
RESULTS: The 8th edition M categories demonstrated good discrimination in the
9th edition dataset. Assessments demonstrated that an increasing number of
metastatic lesions was associated with decreasing prognosis; because this
appears to be a continuum and adjustment for confounders was not possible, no
specific lesion number was deemed appropriate for stage classification. Among
tumors involving multiple metastases, decreasing prognosis was seen with an
increasing number of organ systems involved. Multiple assessments, including
after adjustment for potential confounders, demonstrated that patients with M1c
patients who had metastases to a single extrathoracic organ system were
prognostically distinct from M1c patients who had involvement of multiple
extrathoracic organ systems.
CONCLUSIONS: These data validate the 8th edition M1a and M1b categories, that
are recommended to be maintained. We propose the M1c category be divided into
M1c1 (involvement of a single extrathoracic organ system) and M1c2 (involvement
of multiple extrathoracic organ systems).
Copyright © 2024 International Association for the Study of Lung Cancer.
Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.jtho.2024.01.019
PMID: 38320664
5. Lancet Respir Med. 2024 Feb;12(2):141-152. doi: 10.1016/S2213-2600(23)00338-7.
Epub 2023 Nov 29.
Low-dose CT screening among never-smokers with or without a family history of
lung cancer in Taiwan: a prospective cohort study.
Chang GC(1), Chiu CH(2), Yu CJ(3), Chang YC(4), Chang YH(5), Hsu KH(6), Wu
YC(7), Chen CY(8), Hsu HH(9), Wu MT(10), Yang CT(11), Chong IW(12), Lin YC(13),
Hsia TC(14), Lin MC(15), Su WC(16), Lin CB(17), Lee KY(18), Wei YF(19), Lan
GY(20), Chan WP(21), Wang KL(22), Wu MH(23), Tsai HH(24), Chian CF(25), Lai
RS(26), Shih JY(27), Wang CL(28), Hsu JS(29), Chen KC(30), Chen CK(31), Hsia
JY(32), Peng CK(33), Tang EK(34), Hsu CL(27), Chou TY(35), Shen WC(36), Tsai
YH(37), Tsai CM(38), Chen YM(39), Lee YC(40), Chen HY(41), Yu SL(42), Chen
CJ(43), Wan YL(44), Hsiung CA(45), Yang PC(46); TALENT Investigators.
Collaborators: Chan CC, Chan SW, Chang IS, Chang JH, Chao KS, Chen CJ, Chen HW,
Chiang CJ, Chiou HY, Chou MC, Chung CL, Chung TJ, Guo YL, Hsiao CF, Huang CS, Ko
SF, Lee MH, Li YJ, Liao YS, Lu YH, Ou HY, Wu PA, Yang HI, Yang SY, Yang SC.
Author information:
(1)Department of Internal Medicine, Division of Pulmonary Medicine, Chung Shan
Medical University Hospital, Taichung, Taiwan; School of Medicine, Chung Shan
Medical University, Taichung, Taiwan; Institute of Medicine, Chung Shan Medical
University, Taichung, Taiwan; Institute of Biomedical Sciences, National Chung
Hsing University, Taichung, Taiwan; School of Medicine, National Yang Ming Chiao
Tung University, Taipei, Taiwan; Department of Internal Medicine, Division of
Chest Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
(2)School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan;
Taipei Cancer Center, Taipei Medical University Hospital, Taipei Medical
University, Taipei, Taiwan; Department of Chest Medicine, Taipei Veterans
General Hospital, Taipei, Taiwan.
(3)Department of Internal Medicine, College of Medicine, National Taiwan
University, Taipei, Taiwan; National Taiwan University Hospital, Hsinchu,
Taiwan.
(4)Department of Radiology, College of Medicine, National Taiwan University,
Taipei, Taiwan; Department of Medical Imaging, National Taiwan University
Hospital, Taipei, Taiwan.
(5)Institute of Statistical Science, Academia Sinica, Taipei, Taiwan; Institute
of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli,
Taiwan.
BACKGROUND: In Taiwan, lung cancers occur predominantly in never-smokers, of
whom nearly 60% have stage IV disease at diagnosis. We aimed to assess the
efficacy of low-dose CT (LDCT) screening among never-smokers, who had other risk
factors for lung cancer.
METHODS: The Taiwan Lung Cancer Screening in Never-Smoker Trial (TALENT) was a nationwide, multicentre, prospective cohort study done at 17 tertiary medical
centres in Taiwan. Eligible individuals had negative chest radiography, were
aged 55-75 years, had never smoked or had smoked fewer than 10 pack-years and
stopped smoking for more than 15 years (self-report), and had one of the
following risk factors: a family history of lung cancer; passive smoke exposure;
a history of pulmonary tuberculosis or chronic obstructive pulmonary disorders;
a cooking index of 110 or higher; or cooking without using ventilation. Eligible
participants underwent LDCT at baseline, then annually for 2 years, and then
every 2 years up to 6 years thereafter, with follow-up assessments at each LDCT
scan (ie, total follow-up of 8 years). A positive scan was defined as a solid or
part-solid nodule larger than 6 mm in mean diameter or a pure ground-glass
nodule larger than 5 mm in mean diameter. Lung cancer was diagnosed through
invasive procedures, such as image-guided aspiration or biopsy or surgery. Here,
we report the results of 1-year follow-up after LDCT screening at baseline. The
primary outcome was lung cancer detection rate. The p value for detection rates
was estimated by the χ2 test. Univariate and multivariable logistic regression
analyses were used to assess the association between lung cancer incidence and
each risk factor. The sensitivity, specificity, positive predictive value (PPV),
and negative predictive value (NPV) of LDCT screening were also assessed. This
study is registered with ClinicalTrials.gov, NCT02611570, and is ongoing.
FINDINGS: Between Dec 1, 2015, and July 31, 2019, 12 011 participants (8868
females) were enrolled, of whom 6009 had a family history of lung cancer. Among
12 011 LDCT scans done at baseline, 2094 (17·4%) were positive. Lung cancer was
diagnosed in 318 (2·6%) of 12 011 participants (257 [2·1%] participants had
invasive lung cancer and 61 [0·5%] had adenocarcinomas in situ). 317 of 318
participants had adenocarcinoma and 246 (77·4%) of 318 had stage I disease. The
prevalence of invasive lung cancer was higher among participants with a family
history of lung cancer (161 [2·7%] of 6009 participants) than in those without
(96 [1·6%] of 6002 participants). In participants with a family history of lung
cancer, the detection rate of invasive lung cancer increased significantly with
age, whereas the detection rate of adenocarcinoma in situ remained stable. In
multivariable analysis, female sex, a family history of lung cancer, and age
older than 60 years were associated with an increased risk of lung cancer and
invasive lung cancer; passive smoke exposure, cumulative exposure to cooking,
cooking without ventilation, and a previous history of chronic lung diseases
were not associated with lung cancer, even after stratification by family
history of lung cancer. In participants with a family history of lung cancer,
the higher the number of first-degree relatives affected, the higher the risk of
lung cancer; participants whose mother or sibling had lung cancer were also at
an increased risk. A positive LDCT scan had 92·1% sensitivity, 84·6%
specificity, a PPV of 14·0%, and a NPV of 99·7% for lung cancer diagnosis.
INTERPRETATION: TALENT had a high invasive lung cancer detection rate at 1 year
after baseline LDCT scan. Overdiagnosis could have occurred, especially in
participants diagnosed with adenocarcinoma in situ. In individuals who do not
smoke, our findings suggest that a family history of lung cancer among
first-degree relatives significantly increases the risk of lung cancer as well
as the rate of invasive lung cancer with increasing age. Further research on
risk factors for lung cancer in this population is needed, particularly for
those without a family history of lung cancer.
FUNDING: Ministry of Health and Welfare of Taiwan.
Copyright © 2024 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S2213-2600(23)00338-7
PMID: 38042167 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of interests We declare no competing
interests.
6. Science. 2024 Feb 23;383(6685):eadi3808. doi: 10.1126/science.adi3808. Epub 2024
Feb 23.
An immunogenetic basis for lung cancer risk.
Krishna C(#)(1), Tervi A(#)(2), Saffern M(#)(3)(4), Wilson EA(#)(3)(4)(5), Yoo
SK(3)(4)(5), Mars N(2), Roudko V(3)(4), Cho BA(3)(4)(5), Jones SE(2), Vaninov
N(3)(4), Selvan ME(6), Gümüş ZH(6)(7); FinnGen§; Lenz TL(8), Merad
M(3)(4)(9)(10)(11), Boffetta P(12)(13), Martínez-Jiménez F(14)(15), Ollila
HM(#)(1)(2)(16)(17), Samstein RM(#)(3)(4)(7)(18), Chowell D(#)(3)(4)(5)(9).
Author information:
(1)Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
(2)Institute for Molecular Medicine, Finland (FIMM), HiLIFE, University of
Helsinki, Helsinki 00290, Finland.
(3)The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School
of Medicine at Mount Sinai, New York, NY 10029, USA.
(4)Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount
Sinai, New York, NY 10029, USA.
(5)Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York,
NY 10029, USA.
(#)Contributed equally
Cancer risk is influenced by inherited mutations, DNA replication errors, and
environmental factors. However, the influence of genetic variation in
immunosurveillance on cancer risk is not well understood. Leveraging
population-level data from the UK Biobank and FinnGen, we show that
heterozygosity at the human leukocyte antigen (HLA)-II loci is associated with
reduced lung cancer risk in smokers. Fine-mapping implicated amino acid
heterozygosity in the HLA-II peptide binding groove in reduced lung cancer risk,
and single-cell analyses showed that smoking drives enrichment of
proinflammatory lung macrophages and HLA-II+ epithelial cells. In lung cancer,
widespread loss of HLA-II heterozygosity (LOH) favored loss of alleles with
larger neopeptide repertoires. Thus, our findings nominate genetic variation in
immunosurveillance as a critical risk factor for lung cancer.
DOI: 10.1126/science.adi3808
PMID: 38386728 [Indexed for MEDLINE]
7. Lancet Infect Dis. 2024 Feb;24(2):140-149. doi: 10.1016/S1473-3099(23)00491-7.
Epub 2023 Oct 30.
Diagnostic accuracy of a three-gene Mycobacterium tuberculosis host response
cartridge using fingerstick blood for childhood tuberculosis: a multicentre
prospective study in low-income and middle-income countries.
Olbrich L(1), Verghese VP(2), Franckling-Smith Z(3), Sabi I(4), Ntinginya NE(4),
Mfinanga A(4), Banze D(5), Viegas S(5), Khosa C(5), Semphere R(6), Nliwasa M(6),
McHugh TD(7), Larsson L(8), Razid A(8), Song R(9), Corbett EL(10), Nabeta P(11),
Trollip A(11), Graham SM(12), Hoelscher M(13), Geldmacher C(14), Zar HJ(3),
Michael JS(15), Heinrich N(16); RaPaed-TB consortium.
Author information:
(1)Division of Infectious Diseases and Tropical Medicine, LMU University
Hospital, LMU Munich, Munich, Germany; German Centre for Infection Research
(DZIF), Partner Site Munich, Munich, Germany; Fraunhofer Institute ITMP,
Immunology, Infection and Pandemic Research, Munich, Germany; Oxford Vaccine
Group, Department of Paediatrics and the NIHR Oxford Biomedical Research Centre,
University of Oxford, Oxford, UK.
(2)Pediatric Infectious Diseases, Department of Pediatrics, Christian Medical
College, Vellore, India.
(3)Department of Paediatrics and Child Health, SA-MRC Unit on Child and
Adolescent Health, University of Cape Town, Cape Town, South Africa.
(4)Mbeya Medical Research Centre, National Institute for Medical Research,
Mbeya, Tanzania.
(5)Instituto Nacional de Saúde, Marracuene, Mozambique.
BACKGROUND: Childhood tuberculosis remains a major cause of morbidity and
mortality in part due to missed diagnosis. Diagnostic methods with enhanced
sensitivity using easy-to-obtain specimens are needed. We aimed to assess the
diagnostic accuracy of the Cepheid Mycobacterium tuberculosis Host Response
prototype cartridge (MTB-HR), a candidate test measuring a three-gene
transcriptomic signature from fingerstick blood, in children with presumptive
tuberculosis disease.
METHODS: RaPaed-TB was a prospective diagnostic accuracy study conducted at four
sites in African countries (Malawi, Mozambique, South Africa, and Tanzania) and
one site in India. Children younger than 15 years with presumptive pulmonary or
extrapulmonary tuberculosis were enrolled between Jan 21, 2019, and June 30,
2021. MTB-HR was performed at baseline and at 1 month in all children and was
repeated at 3 months and 6 months in children on tuberculosis treatment.
Accuracy was compared with tuberculosis status based on standardised
microbiological, radiological, and clinical data.
FINDINGS: 5313 potentially eligible children were screened, of whom 975 were
eligible. 784 children had MTB-HR test results, of whom 639 had a diagnostic
classification and were included in the analysis. MTB-HR differentiated children
with culture-confirmed tuberculosis from those with unlikely tuberculosis with a
sensitivity of 59·8% (95% CI 50·8-68·4). Using any microbiological confirmation
(culture, Xpert MTB/RIF Ultra, or both), sensitivity was 41·6% (34·7-48·7), and
using a composite clinical reference standard, sensitivity was 29·6%
(25·4-34·2). Specificity for all three reference standards was 90·3% (95% CI
85·5-94·0). Performance was similar in different age groups and by malnutrition
status. Among children living with HIV, accuracy against the strict reference
standard tended to be lower (sensitivity 50·0%, 15·7-84·3) compared with those
without HIV (61·0%, 51·6-69·9), although the difference did not reach
statistical significance. Combining baseline MTB-HR result with one Ultra result
identified 71·2% of children with microbiologically confirmed tuberculosis.
INTERPRETATION: MTB-HR showed promising diagnostic accuracy for
culture-confirmed tuberculosis in this large, geographically diverse, paediatric
cohort and hard-to-diagnose subgroups.
FUNDING: European and Developing Countries Clinical Trials Partnership, UK
Medical Research Council, Swedish International Development Cooperation Agency,
Bundesministerium für Bildung und Forschung; German Center for Infection
Research (DZIF).
Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open
Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All
rights reserved.
DOI: 10.1016/S1473-3099(23)00491-7
PMCID: PMC10808504
PMID: 37918414 [Indexed for MEDLINE]
8. Am J Respir Crit Care Med. 2024 Feb 28. doi: 10.1164/rccm.202307-1217OC. Online
ahead of print.
Who Transmits Tuberculosis to Whom: A Cross-Sectional Analysis of a Cohort Study
in Lima, Peru.
Trevisi L(1), Brooks MB(2), Becerra MC(3)(4), Calderón RI(5), Contreras
CC(5)(6), Galea JT(7), Jimenez J(5), Lecca LW(5), Yataco RM(5), Tovar X(1),
Zhang Z(4), Murray M(1), Huang CC(1)(8).
Author information:
(1)Harvard Medical School, 1811, Global Health and Social Medicine, Boston,
Massachusetts, United States.
(2)Boston University School of Public Health, 27118, Department of Global
Health, Boston, Massachusetts, United States.
(3)Harvard Medical School, 1811, Department of Global Health and Social
Medicine, Boston, Massachusetts, United States.
(4)Brigham and Women's Hospital, 1861, Division of Global Health Equity, Boston,
Massachusetts, United States.
(5)Socios En Salud Sucursal Perú, 558883, Lima, Peru.
RATIONALE: The persistent burden of TB disease emphasizes the need to identify
individuals with TB for treatment and those at a high risk of incident TB for
prevention. Targeting interventions towards those at high risk of developing and
transmitting tuberculosis is a public health priority.
OBJECTIVES: We aimed to identify characteristics of individuals involved in
tuberculosis transmission in a community setting, which may guide the
prioritization of targeted interventions.
METHODS: We collected clinical and socio-demographic data from a cohort of
tuberculosis patients in Lima, Peru. We used whole-genome sequencing data to
assess the genetic distance between all possible pairs of patients; we
considered pairs to be the result of a direct transmission event if they
differed by three or fewer SNPs and we assumed that the first diagnosed patient
in a pair was the transmitter and the second to be the recipient. We used
logistic regression to examine the association between host factors and the
likelihood of direct tuberculosis transmission.
MAIN RESULTS: Analyzing data from 2,518 tuberculosis index patients, we
identified 1,447 direct transmission pairs. Regardless of recipient attributes,
individuals less than 34 years old, males, and those with a history of
incarceration had a higher likelihood of being transmitters in direct
transmission pairs. Direct transmission was more likely when both patients were
drinkers or smokers.
CONCLUSIONS: This study identifies men, young adults, former prisoners, alcohol
consumers, and smokers as priority groups for targeted interventions. Innovative
strategies are needed to extend tuberculosis screening to social groups like
young adults and prisoners with limited access to routine preventive care. 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.202307-1217OC
PMID: 38416532
9. Clin Infect Dis. 2024 Feb 26:ciae101. doi: 10.1093/cid/ciae101. Online ahead of
print.
Long-term protective effect of tuberculosis preventive therapy in a medium/high
TB incidence setting.
Teixeira LAA(1), Santos B(1), Correia MG(1), Valiquette C(2), Bastos ML(2)(3),
Menzies D(2), Trajman A(4).
Author information:
(1)Instituto Nacional de Cardiologia (INC), Núcleo de Avaliação de Tecnologias
em Saúde, Rio de Janeiro, Brasil.
(2)McGill International Tuberculosis Centre, Research Institute of the McGill
University Health Centre, and McGill University, Montreal, Quebec, Canada.
(3)University of Manitoba, Family Medicine Department, Winnipeg, Canada.
(4)Universidade Federal do Rio de Janeiro Departamento de Clínica Médica, Rio de
Janeiro, Brasil and McGill International Tuberculosis Centre, McGill University,
Montreal, Quebec, Canada.
BACKGROUND: The duration of the protective effect of TB preventive therapy (TPT)
is controversial. Some studies have found that the protective effect of TPT is
lost after cessation of therapy among people living with HIV in settings with
very high tuberculosis incidence, but others have found long-term protection in
low incidence settings.
METHODS: We estimated the incidence rate (IR) of new tuberculosis disease (TB)
for up to 12 years after randomization to four months of rifampin or nine months
of isoniazid, among 991 Brazilian participants in a TPT trial in the state of
Rio de Janeiro, with incidence 68.6/100,000 population in 2022. Adjusted hazard
ratios (aHR) of independent variables for incident TB were calculated.
RESULTS: Overall TB incidence rate (IR) was 1.7 (1.01; 2.7)/1,000 person years
(PY). The TB IR among those who did not complete TPT was higher than in those
who completed [2.9/1000 PY (95% CI: 1.3; 5.6) versus 1.1/1000 PY (95% CI: 0.4;
2.3), IR ratio (IRR)= 2.7 (95% CI: 1.0; 7.2)]. TB IR was higher within 28 months
after randomization [IR: 3.5/1000 PY (1.6; 6.6) PY, compared to 1.1/1000 PY (95%
CI: 0.5; 2.1) between 28 and 143 months, IRR= 3.1, 95% CI: 1.2-8.2]. Treatment
non-completion was the only variable associated with incident TB [aHR= 3.2 (1.1;
9.7)].
CONCLUSION: In a mostly HIV non-infected population, a complete course of TPT
conferred long-term protection against tuberculosis.
© The Author(s) 2024. Published by Oxford University Press on behalf of
Infectious Diseases Society of America. All rights reserved. For permissions,
please e-mail: journals.permissions@oup.com.
DOI: 10.1093/cid/ciae101
PMID: 38407417
10. Nat Nanotechnol. 2024 Feb 21. doi: 10.1038/s41565-024-01618-0. Online ahead of
print.
Photothermal therapy of tuberculosis using targeting pre-activated macrophage
membrane-coated nanoparticles.
Li B(#)(1)(2)(3), Wang W(#)(1), Zhao L(#)(3), Wu Y(#)(3), Li X(1), Yan D(4), Gao
Q(3), Yan Y(5), Zhang J(6), Feng Y(1), Zheng J(1), Shu B(1), Wang J(1), Wang
H(1), He L(1), Zhang Y(5), Pan M(5), Wang D(7), Tang BZ(8)(9), Liao Y(10)(11).
Author information:
(1)Molecular Diagnosis and Treatment Center for Infectious Diseases, Dermatology
Hospital of Southern Medical University, Guangzhou, China.
(2)School of Inspection, Ningxia Medical University, Yinchuan, China.
(3)Institute of Translational Medicine, Department of Clinical Laboratory &
Department of Burn Surgery, The First People's Hospital of Foshan, Foshan,
China.
(4)Center for AIE Research, Shenzhen Key Laboratory of Polymer Science and
Technology, Guangdong Research Center for Interfacial Engineering of Functional
Materials, College of Materials Science and Engineering, Shenzhen University,
Shenzhen, China.
(5)Department of Critical Care Medicine, Department of Emergency, Renmin
Hospital of Wuhan University, Wuhan, China.
(#)Contributed equally
Conventional antibiotics used for treating tuberculosis (TB) suffer from drug
resistance and multiple complications. Here we propose a lesion-pathogen
dual-targeting strategy for the management of TB by coating
Mycobacterium-stimulated macrophage membranes onto polymeric cores encapsulated
with an aggregation-induced emission photothermal agent that is excitable with a
1,064 nm laser. The coated nanoparticles carry specific receptors for
Mycobacterium tuberculosis, which enables them to target tuberculous granulomas
and internal M. tuberculosis simultaneously. In a mouse model of TB,
intravenously injected nanoparticles image individual granulomas in situ in the
lungs via signal emission in the near-infrared region IIb, with an imaging
resolution much higher than that of clinical computed tomography. With 1,064 nm
laser irradiation from outside the thoracic cavity, the photothermal effect
generated by these nanoparticles eradicates the targeted M. tuberculosis and
alleviates pathological damage and excessive inflammation in the lungs,
resulting in a better therapeutic efficacy compared with a combination of
first-line antibiotics. This precise photothermal modality that uses
dual-targeted imaging in the near-infrared region IIb demonstrates a theranostic
strategy for TB management.
© 2024. The Author(s), under exclusive licence to Springer Nature Limited.
DOI: 10.1038/s41565-024-01618-0
PMID: 38383890
11. Nat Med. 2024 Feb 16. doi: 10.1038/s41591-024-02829-7. Online ahead of print.
A first-in-class leucyl-tRNA synthetase inhibitor, ganfeborole, for
rifampicin-susceptible tuberculosis: a phase 2a open-label, randomized trial.
Diacon AH(1), Barry CE 3rd(2)(3), Carlton A(4), Chen RY(2), Davies M(4), de
Jager V(1), Fletcher K(4), Koh GCKW(4)(5), Kontsevaya I(6)(7)(8)(9)(10),
Heyckendorf J(11), Lange C(6)(7)(8)(12), Reimann M(6)(7)(8), Penman SL(4), Scott
R(4), Maher-Edwards G(4), Tiberi S(4)(13), Vlasakakis G(14), Upton CM(1),
Aguirre DB(15).
Author information:
(1)TASK, Cape Town, South Africa.
(2)National Institutes of Health, Bethesda, MD, USA.
(3)Institute of Infectious Disease and Molecular Medicine, University of Cape
Town, Cape Town, South Africa.
(4)GSK, London, UK.
(5)Generate:Biomedicines, Boston, MA, USA.
New tuberculosis treatments are needed to address drug resistance, lengthy
treatment duration and adverse reactions of available agents. GSK3036656
(ganfeborole) is a first-in-class benzoxaborole inhibiting the Mycobacterium
tuberculosis leucyl-tRNA synthetase. Here, in this phase 2a, single-center,
open-label, randomized trial, we assessed early bactericidal activity (primary
objective) and safety and pharmacokinetics (secondary objectives) of ganfeborole
in participants with untreated, rifampicin-susceptible pulmonary tuberculosis.
Overall, 75 males were treated with ganfeborole (1/5/15/30 mg) or standard of
care (Rifafour e-275 or generic alternative) once daily for 14 days. We observed
numerical reductions in daily sputum-derived colony-forming units from baseline
in participants receiving 5, 15 and 30 mg once daily but not those receiving
1 mg ganfeborole. Adverse event rates were comparable across groups; all events
were grade 1 or 2. In a participant subset, post hoc exploratory computational
analysis of 18F-fluorodeoxyglucose positron emission tomography/computed
tomography findings showed measurable treatment responses across several lesion
types in those receiving ganfeborole 30 mg at day 14. Analysis of whole-blood
transcriptional treatment response to ganfeborole 30 mg at day 14 revealed a
strong association with neutrophil-dominated transcriptional modules. The
demonstrated bactericidal activity and acceptable safety profile suggest that
ganfeborole is a potential candidate for combination treatment of pulmonary
tuberculosis.ClinicalTrials.gov identifier: NCT03557281 .
© 2024. The Author(s).
DOI: 10.1038/s41591-024-02829-7
PMID: 38365949
12. MMWR Morb Mortal Wkly Rep. 2024 Feb 22;73(7):145-148. doi:
10.15585/mmwr.mm7307a2.
Outbreak of Mycobacterium orygis in a Shipment of Cynomolgus Macaques Imported
from Southeast Asia - United States, February-May 2023.
Swisher SD, Taetzsch SJ, Laughlin ME, Walker WL, Langer AJ, Thacker TC, Rinsky
JL, Lehman KA, Taffe A, Burton N, Bravo DM, McDonald E, Brown CM, Pieracci EG.
Nonhuman primates (NHP) can become infected with the same species of
Mycobacteria that cause human tuberculosis. All NHP imported into the United
States are quarantined and screened for tuberculosis; no confirmed cases of
tuberculosis were diagnosed among NHP during CDC-mandated quarantine during
2013-2020. In February 2023, an outbreak of tuberculosis caused by Mycobacterium
orygis was detected in a group of 540 cynomolgus macaques (Macaca fascicularis)
imported to the United States from Southeast Asia for research purposes.
Although the initial exposure to M. orygis is believed to have occurred before
the macaques arrived in the United States, infected macaques were first detected
during CDC-mandated quarantine. CDC collaborated with the importer and U.S.
Department of Agriculture's National Veterinary Services Laboratories in the
investigation and public health response. A total of 26 macaques received
positive test results for M. orygis by culture, but rigorous occupational safety
protocols implemented during transport and at the quarantine facility prevented
cases among caretakers in the United States. Although the zoonotic disease risk
to the general population remains low, this outbreak underscores the importance
of CDC's regulatory oversight of NHP importation and adherence to established
biosafety protocols to protect the health of the United States research animal
population and the persons who interact with them.
DOI: 10.15585/mmwr.mm7307a2
PMCID: PMC10899076
PMID: 38386802 [Indexed for MEDLINE]
13. Nat Microbiol. 2024 Mar;9(3):684-697. doi: 10.1038/s41564-024-01608-x. Epub 2024 Feb 27.
Autophagy promotes efficient T cell responses to restrict high-dose
Mycobacterium tuberculosis infection in mice.
Feng S(#)(1), McNehlan ME(#)(2), Kinsella RL(2), Sur Chowdhury C(2), Chavez
SM(2), Naik SK(2), McKee SR(2), Van Winkle JA(2), Dubey N(2), Samuels A(2),
Swain A(3), Cui X(1), Hendrix SV(2), Woodson R(2), Kreamalmeyer D(2), Smirnov
A(2), Artyomov MN(3), Virgin HW(3)(4), Wang YT(5)(6)(7), Stallings CL(8).
Author information:
(1)Center for Infectious Disease Research, Department of Basic Medical Sciences,
School of Medicine, Tsinghua University, Beijing, China.
(2)Department of Molecular Microbiology, Center for Women's Infectious Disease
Research, Washington University School of Medicine, St. Louis, MO, USA.
(3)Department of Pathology and Immunology, Washington University School of
Medicine, St Louis, MO, USA.
(4)Department of Internal Medicine, University of Texas Southwestern Medical
Center, Dallas, TX, USA.
(5)Center for Infectious Disease Research, Department of Basic Medical Sciences,
School of Medicine, Tsinghua University, Beijing, China.
yatingwang@tsinghua.edu.cn.
(#)Contributed equally
Although autophagy sequesters Mycobacterium tuberculosis (Mtb) in in vitro
cultured macrophages, loss of autophagy in macrophages in vivo does not result
in susceptibility to a standard low-dose Mtb infection until late during
infection, leaving open questions regarding the protective role of autophagy
during Mtb infection. Here we report that loss of autophagy in lung macrophages
and dendritic cells results in acute susceptibility of mice to high-dose Mtb
infection, a model mimicking active tuberculosis. Rather than observing a role
for autophagy in controlling Mtb replication in macrophages, we find that
autophagy suppresses macrophage responses to Mtb that otherwise result in
accumulation of myeloid-derived suppressor cells and subsequent defects in T
cell responses. Our finding that the pathogen-plus-susceptibility gene
interaction is dependent on dose has important implications both for
understanding how Mtb infections in humans lead to a spectrum of outcomes and
for the potential use of autophagy modulators in clinical medicine.
© 2024. The Author(s), under exclusive licence to Springer Nature Limited.
DOI: 10.1038/s41564-024-01608-x
PMID: 38413834 [Indexed for MEDLINE]
14. Cancer Cell. 2024 Feb 12;42(2):225-237.e5. doi: 10.1016/j.ccell.2024.01.001.
Epub 2024 Jan 25.
Tumor- and circulating-free DNA methylation identifies clinically relevant small
cell lung cancer subtypes.
Heeke S(1), Gay CM(1), Estecio MR(2), Tran H(1), Morris BB(1), Zhang B(1), Tang
X(3), Raso MG(3), Rocha P(4), Lai S(5), Arriola E(4), Hofman P(6), Hofman V(6),
Kopparapu P(7), Lovly CM(7), Concannon K(1), De Sousa LG(1), Lewis WE(1), Kondo
K(2), Hu X(8), Tanimoto A(1), Vokes NI(1), Nilsson MB(1), Stewart A(1), Jansen
M(9), Horváth I(10), Gaga M(11), Panagoulias V(12), Raviv Y(13), Frumkin D(14),
Wasserstrom A(14), Shuali A(14), Schnabel CA(15), Xi Y(16), Diao L(16), Wang
Q(16), Zhang J(17), Van Loo P(18), Wang J(16), Wistuba II(3), Byers LA(19),
Heymach JV(20).
Author information:
(1)Department of Thoracic/Head & Neck Medical Oncology, The University of Texas
MD Anderson Cancer Center, Houston, TX, USA.
(2)Epigenetic and Molecular Carcinogenesis, The University of Texas MD Anderson
Cancer Center, Houston, TX, USA.
(3)Department of Translational Molecular Pathology, the University of Texas MD
Anderson Cancer Center, Houston, TX, USA.
(4)Medical Oncology Department, Hospital del Mar, Barcelona, Spain.
(5)Department of Genetics, The University of Texas MD Anderson Cancer Center,
Houston, TX, USA; Graduate School of Biomedical Sciences, The University of
Texas MD Anderson Cancer Center UTHealth Houston, Houston, TX, USA.
Small cell lung cancer (SCLC) is an aggressive malignancy composed of distinct
transcriptional subtypes, but implementing subtyping in the clinic has remained
challenging, particularly due to limited tissue availability. Given the known
epigenetic regulation of critical SCLC transcriptional programs, we hypothesized
that subtype-specific patterns of DNA methylation could be detected in tumor or
blood from SCLC patients. Using genomic-wide reduced-representation bisulfite
sequencing (RRBS) in two cohorts totaling 179 SCLC patients and using machine
learning approaches, we report a highly accurate DNA methylation-based
classifier (SCLC-DMC) that can distinguish SCLC subtypes. We further adjust the
classifier for circulating-free DNA (cfDNA) to subtype SCLC from plasma. Using
the cfDNA classifier (cfDMC), we demonstrate that SCLC phenotypes can evolve
during disease progression, highlighting the need for longitudinal tracking of
SCLC during clinical treatment. These data establish that tumor and cfDNA
methylation can be used to identify SCLC subtypes and might guide precision SCLC
therapy.
Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ccell.2024.01.001
PMID: 38278149 [Indexed for MEDLINE]
15. Cancer Cell. 2024 Feb 20:S1535-6108(24)00036-9. doi:
10.1016/j.ccell.2024.01.012. Online ahead of print.
Adeno-to-squamous transition drives resistance to KRAS inhibition in LKB1 mutant
lung cancer.
Tong X(1), Patel AS(2), Kim E(3), Li H(4), Chen Y(5), Li S(2), Liu S(3), Dilly
J(6), Kapner KS(7), Zhang N(8), Xue Y(9), Hover L(10), Mukhopadhyay S(2),
Sherman F(2), Myndzar K(2), Sahu P(2), Gao Y(11), Li F(12), Li F(13), Fang
Z(14), Jin Y(1), Gao J(15), Shi M(16), Sinha S(17), Chen L(18), Chen Y(19),
Kheoh T(20), Yang W(20), Yanai I(21), Moreira AL(2), Velcheti V(2), Neel BG(2),
Hu L(1), Christensen JG(20), Olson P(20), Gao D(1), Zhang MQ(22), Aguirre
AJ(23), Wong KK(24), Ji H(25).
Author information:
(1)State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and
Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy
of Sciences, Shanghai 200031, China.
(2)Laura and Isaac Perlmutter Cancer Center, New York University Langone Health,
New York, NY 10016, USA.
(3)Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA;
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School,
Boston, MA 02115, USA.
(4)MOE Key Laboratory of Bioinformatics, Bioinformatics Division and Center for
Synthetic and Systems Biology, BNRist, Department of Automation, Tsinghua
University, Beijing 100084, China.
(5)State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and
Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy
of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences,
Beijing 100049, China.
KRASG12C inhibitors (adagrasib and sotorasib) have shown clinical promise in
targeting KRASG12C-mutated lung cancers; however, most patients eventually
develop resistance. In lung patients with adenocarcinoma with KRASG12C and
STK11/LKB1 co-mutations, we find an enrichment of the squamous cell carcinoma
gene signature in pre-treatment biopsies correlates with a poor response to
adagrasib. Studies of Lkb1-deficient KRASG12C and KrasG12D lung cancer mouse
models and organoids treated with KRAS inhibitors reveal tumors invoke a lineage
plasticity program, adeno-to-squamous transition (AST), that enables resistance
to KRAS inhibition. Transcriptomic and epigenomic analyses reveal ΔNp63 drives
AST and modulates response to KRAS inhibition. We identify an intermediate
high-plastic cell state marked by expression of an AST plasticity signature and
Krt6a. Notably, expression of the AST plasticity signature and KRT6A at baseline
correlates with poor adagrasib responses. These data indicate the role of AST in
KRAS inhibitor resistance and provide predictive biomarkers for KRAS-targeted
therapies in lung cancer.
Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ccell.2024.01.012
PMID: 38402609
16. Mol Cancer. 2024 Feb 24;23(1):41. doi: 10.1186/s12943-024-01953-9.
Small cells - big issues: biological implications and preclinical advancements
in small cell lung cancer.
Solta A(#)(1), Ernhofer B(#)(1), Boettiger K(1), Megyesfalvi Z(1)(2)(3), Heeke
S(4), Hoda MA(1), Lang C(1)(5), Aigner C(1), Hirsch FR(6)(7), Schelch
K(#)(1)(8), Döme B(#)(9)(10)(11)(12).
Author information:
(1)Department of Thoracic Surgery, Comprehensive Cancer Center, Medical
University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.
(2)Department of Thoracic Surgery, Semmelweis University and National Institute
of Oncology, Budapest, Hungary.
(3)National Koranyi Institute of Pulmonology, Budapest, Hungary.
(4)Department of Thoracic Head and Neck Medical Oncology, The University of
Texas MD Anderson Cancer Center, Houston, TX, USA.
(5)Division of Pulmonology, Department of Medicine II, Medical University of
Vienna, Vienna, Austria.
Current treatment guidelines refer to small cell lung cancer (SCLC), one of the
deadliest human malignancies, as a homogeneous disease. Accordingly, SCLC
therapy comprises chemoradiation with or without immunotherapy. Meanwhile,
recent studies have made significant advances in subclassifying SCLC based on
the elevated expression of the transcription factors ASCL1, NEUROD1, and POU2F3,
as well as on certain inflammatory characteristics. The role of the
transcription regulator YAP1 in defining a unique SCLC subset remains to be
established. Although preclinical analyses have described numerous
subtype-specific characteristics and vulnerabilities, the so far non-existing
clinical subtype distinction may be a contributor to negative clinical trial
outcomes. This comprehensive review aims to provide a framework for the
development of novel personalized therapeutic approaches by compiling the most
recent discoveries achieved by preclinical SCLC research. We highlight the
challenges faced due to limited access to patient material as well as the
advances accomplished by implementing state-of-the-art models and methodologies.
© 2024. The Author(s).
DOI: 10.1186/s12943-024-01953-9
PMCID: PMC10893629
PMID: 38395864 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no competing interests.
17. Nat Rev Clin Oncol. 2024 Feb;21(2):121-146. doi: 10.1038/s41571-023-00844-0.
Epub 2024 Jan 9.
Lung cancer in patients who have never smoked - an emerging disease.
LoPiccolo J(1)(2), Gusev A(3)(4), Christiani DC(5)(6), Jänne PA(3)(7).
Author information:
(1)Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA,
USA. jaclyn_lopiccolo@dfci.harvard.edu.
(2)The Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston,
MA, USA. jaclyn_lopiccolo@dfci.harvard.edu.
(3)Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA,
USA.
(4)The Eli and Edythe L. Broad Institute, Cambridge, MA, USA.
(5)Department of Environmental Health, Harvard T. H. Chan School of Public
Health, Boston, MA, USA.
(6)Massachusetts General Hospital, Boston, MA, USA.
(7)The Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston,
MA, USA.
Lung cancer is the most common cause of cancer-related deaths globally. Although
smoking-related lung cancers continue to account for the majority of diagnoses,
smoking rates have been decreasing for several decades. Lung cancer in
individuals who have never smoked (LCINS) is estimated to be the fifth most
common cause of cancer-related deaths worldwide in 2023, preferentially
occurring in women and Asian populations. As smoking rates continue to decline,
understanding the aetiology and features of this disease, which necessitate
unique diagnostic and treatment paradigms, will be imperative. New data have
provided important insights into the molecular and genomic characteristics of
LCINS, which are distinct from those of smoking-associated lung cancers and
directly affect treatment decisions and outcomes. Herein, we review the emerging
data regarding the aetiology and features of LCINS, particularly the genetic and
environmental underpinnings of this disease as well as their implications for
treatment. In addition, we outline the unique diagnostic and therapeutic
paradigms of LCINS and discuss future directions in identifying individuals at
high risk of this disease for potential screening efforts.
© 2024. Springer Nature Limited.
DOI: 10.1038/s41571-023-00844-0
PMID: 38195910 [Indexed for MEDLINE]
18. Cancer Cell. 2024 Feb 9:S1535-6108(24)00015-1. doi: 10.1016/j.ccell.2024.01.010.
Online ahead of print.
Immune heterogeneity in small-cell lung cancer and vulnerability to immune
checkpoint blockade.
Nabet BY(1), Hamidi H(2), Lee MC(2), Banchereau R(2), Morris S(3), Adler L(3),
Gayevskiy V(4), Elhossiny AM(2), Srivastava MK(2), Patil NS(2), Smith KA(2),
Jesudason R(2), Chan C(2), Chang PS(2), Fernandez M(2), Rost S(2), McGinnis
LM(2), Koeppen H(2), Gay CM(5), Minna JD(6), Heymach JV(5), Chan JM(7), Rudin
CM(8), Byers LA(5), Liu SV(9), Reck M(10), Shames DS(11).
Author information:
(1)Genentech Inc., South San Francisco CA, USA. Electronic address:
nabet.barzin@gene.com.
(2)Genentech Inc., South San Francisco CA, USA.
(3)F. Hoffmann-La Roche Ltd, Basel, Switzerland.
(4)Genentech Inc., South San Francisco CA, USA; Rancho Biosciences, San Diego,
CA, US.
(5)Department of Thoracic/Head & Neck Medical Oncology, The University of Texas
MD Anderson Cancer Center, Houston, TX, USA.
Atezolizumab (anti-PD-L1), combined with carboplatin and etoposide (CE), is now
a standard of care for extensive-stage small-cell lung cancer (ES-SCLC). A
clearer understanding of therapeutically relevant SCLC subsets could identify
rational combination strategies and improve outcomes. We conduct transcriptomic
analyses and non-negative matrix factorization on 271 pre-treatment patient
tumor samples from IMpower133 and identify four subsets with general concordance
to previously reported SCLC subtypes (SCLC-A, -N, -P, and -I). Deeper
investigation into the immune heterogeneity uncovers two subsets with differing
neuroendocrine (NE) versus non-neuroendocrine (non-NE) phenotypes, demonstrating
immune cell infiltration hallmarks. The NE tumors with low tumor-associated
macrophage (TAM) but high T-effector signals demonstrate longer overall survival
with PD-L1 blockade and CE versus CE alone than non-NE tumors with high TAM and
high T-effector signal. Our study offers a clinically relevant approach to
discriminate SCLC patients likely benefitting most from immunotherapies and
highlights the complex mechanisms underlying immunotherapy responses.
Copyright © 2024 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ccell.2024.01.010
PMID: 38366589
19. Nature. 2024 Feb 28. doi: 10.1038/s41586-024-07105-9. Online ahead of print.
Incomplete transcripts dominate the Mycobacterium tuberculosis transcriptome.
Ju X(1), Li S(2), Froom R(2)(3), Wang L(1), Lilic M(3), Delbeau M(3), Campbell
EA(3), Rock JM(4), Liu S(5).
Author information:
(1)Laboratory of Nanoscale Biophysics and Biochemistry, The Rockefeller
University, New York, NY, USA.
(2)Laboratory of Host-Pathogen Biology, The Rockefeller University, New York,
NY, USA.
(3)Laboratory of Molecular Biophysics, The Rockefeller University, New York, NY,
USA.
(4)Laboratory of Host-Pathogen Biology, The Rockefeller University, New York,
NY, USA. rock@rockefeller.edu.
(5)Laboratory of Nanoscale Biophysics and Biochemistry, The Rockefeller
University, New York, NY, USA. shixinliu@rockefeller.edu.
Mycobacterium tuberculosis (Mtb) is a bacterial pathogen that causes
tuberculosis (TB), an infectious disease that is responsible for major health
and economic costs worldwide1. Mtb encounters diverse environments during its
life cycle and responds to these changes largely by reprogramming its
transcriptional output2. However, the mechanisms of Mtb transcription and how
they are regulated remain poorly understood. Here we use a sequencing method
that simultaneously determines both termini of individual RNA molecules in
bacterial cells3 to profile the Mtb transcriptome at high resolution.
Unexpectedly, we find that most Mtb transcripts are incomplete, with their
5' ends aligned at transcription start sites and 3' ends located 200-500
nucleotides downstream. We show that these short RNAs are mainly associated with
paused RNA polymerases (RNAPs) rather than being products of premature
termination. We further show that the high propensity of Mtb RNAP to pause early
in transcription relies on the binding of the σ-factor. Finally, we show that a
translating ribosome promotes transcription elongation, revealing a
potential role for transcription-translation coupling in controlling Mtb gene
expression. In sum, our findings depict a mycobacterial transcriptome that
prominently features incomplete transcripts resulting from RNAP pausing. We
propose that the pausing phase constitutes an important transcriptional
checkpoint in Mtb that allows the bacterium to adapt to environmental changes
and could be exploited for TB therapeutics.
© 2024. The Author(s).
DOI: 10.1038/s41586-024-07105-9
PMID: 38418874
20. Lancet Glob Health. 2024 Feb;12(2):e226-e234. doi:
10.1016/S2214-109X(23)00541-7.
Evaluation of the Xpert MTB Host Response assay for the triage of patients with
presumed pulmonary tuberculosis: a prospective diagnostic accuracy study in Viet
Nam, India, the Philippines, Uganda, and South Africa.
Gupta-Wright A(1), Ha H(2), Abdulgadar S(3), Crowder R(4), Emmanuel J(5),
Mukwatamundu J(6), Marcelo D(7), Phillips PPJ(8), Christopher DJ(5), Nhung
NV(9), Theron G(3), Yu C(7), Nahid P(8), Cattamanchi A(10), Worodria W(11),
Denkinger CM(12); R2D2 TB Network.
Author information:
(1)Division of Infectious Disease and Tropical Medicine and German Centre for
Infection Research, Heidelberg University Hospital, Heidelberg, Germany;
Institute for Global Health, University College London, London, UK. Electronic
address: agupta@uni-heidelberg.de.
(2)Hanoi Lung Hospital, Hanoi, Viet Nam.
(3)DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research, South
African Medical Research Council Centre for Tuberculosis Research, Division of
Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences,
Stellenbosch University, Cape Town, South Africa.
(4)UCSF Center for Tuberculosis, San Francisco General Hospital, University of
California San Francisco, San Francisco, CA, USA.
(5)Department of Pulmonary Medicine, Christian Medical College, Vellore, India.
BACKGROUND: Non-sputum-based triage tests for tuberculosis are a priority for
ending tuberculosis. We aimed to evaluate the diagnostic accuracy of the
late-prototype Xpert MTB Host Response (Xpert HR) blood-based assay.
METHODS: We conducted a prospective diagnostic accuracy study among outpatients
with presumed tuberculosis in outpatient clinics in Viet Nam, India, the
Philippines, Uganda, and South Africa. Eligible participants were aged 18 years
or older and reported cough lasting at least 2 weeks. We excluded those
receiving tuberculosis treatment in the preceding 12 months and those who were
unwilling to consent. Xpert HR was performed on capillary or venous blood.
Reference standard testing included sputum Xpert MTB/RIF Ultra and mycobacterial
culture. We performed receiver operating characteristic (ROC) analysis to
identify the optimal cutoff value for the Xpert HR to achieve the target
sensitivity of 90% or more while maximising specificity, then calculated
diagnostic accuracy using this cutoff value. This study was prospectively
registered with ClinicalTrials.gov, NCT04923958.
FINDINGS: Between July 13, 2021, and Aug 15, 2022, 2046 adults with at least 2
weeks of cough were identified, of whom 1499 adults (686 [45·8%] females and 813
[54·2%] males) had valid Xpert HR and reference standard results. 329 (21·9%)
had microbiologically confirmed tuberculosis. Xpert HR had an area under the ROC
curve of 0·89 (95% CI 0·86-0·91). The optimal cutoff value was less than or
equal to -1·25, giving a sensitivity of 90·3% (95% CI 86·5-93·3; 297 of 329) and
a specificity of 62·6% (95% CI 59·7-65·3; 732 of 1170). Sensitivity was similar
across countries, by sex, and by subgroups, although specificity was lower in
people living with HIV (45·1%, 95% CI 37·8-52·6) than in those not living with
HIV (65·9%, 62·8-68·8; difference of 20·8%, 95% CI 13·0-28·6; p<0·0001). Xpert
HR had high negative predictive value (95·8%, 95% CI 94·1-97·1), but positive
predictive value was only 40·1% (95% CI 36·8-44·1). Using the Xpert HR as a
triage test would have reduced confirmatory sputum testing by 57·3% (95% CI
54·2-60·4).
INTERPRETATION: Xpert HR did not meet WHO minimum specificity targets for a
non-sputum-based triage test for pulmonary tuberculosis. Despite promise as a
rule-out test that could reduce confirmatory sputum testing, further
cost-effectiveness modelling and data on acceptability and usability are needed
to inform policy recommendations.
FUNDING: National Institute of Allergy and Infectious Diseases of the US
National Institutes of Health.
TRANSLATIONS: For the Vietnamese and Tagalog translations of the abstract see
Supplementary Materials section.
Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open
Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All
rights reserved.
DOI: 10.1016/S2214-109X(23)00541-7
PMID: 38245113 [Indexed for MEDLINE]
21. Cancer Cell. 2024 Feb 12;42(2):209-224.e9. doi: 10.1016/j.ccell.2023.12.013.
Epub 2024 Jan 11.
Clinical and molecular features of acquired resistance to immunotherapy in
non-small cell lung cancer.
Memon D(1), Schoenfeld AJ(2), Ye D(3), Fromm G(4), Rizvi H(5), Zhang X(6),
Keddar MR(7), Mathew D(8), Yoo KJ(4), Qiu J(3), Lihm J(9), Miriyala J(4), Sauter
JL(10), Luo J(11), Chow A(2), Bhanot UK(12), McCarthy C(13), Vanderbilt CM(10),
Liu C(14), Abu-Akeel M(14), Plodkowski AJ(15), McGranahan N(16), Łuksza M(17),
Greenbaum BD(9), Merghoub T(18), Achour I(19), Barrett JC(19), Stewart R(19),
Beltrao P(20), Schreiber TH(4), Minn AJ(21), Miller ML(22), Hellmann MD(23).
Author information:
(1)European Molecular Biology Laboratory (EMBL), European Bioinformatics
Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK; Cancer Research UK
Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way,
Cambridge, UK; M:M Bio Limited, 99 Park Drive, Milton, Abingdon, UK.
(2)Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY,
USA; Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
(3)Department of Radiation Oncology, Perelman School of Medicine, University of
Pennsylvania, Philadelphia, PA, USA; Abramson Family Cancer Research Institute,
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA;
Parker Institute for Cancer Immunotherapy, Perelman School of Medicine,
University of Pennsylvania, Philadelphia, PA, USA; Mark Foundation Center for
Immunotherapy, Immune Signaling, and Radiation, University of Pennsylvania,
Philadelphia, PA, USA.
(4)Shattuck Labs, Durham, NC, USA.
(5)Druckenmiller Center for Lung Cancer Research, Memorial Sloan Kettering
Cancer Center, New York, NY, USA; Early Clinical Development, Oncology R&D,
AstraZeneca, New York, NY, USA.
Although immunotherapy with PD-(L)1 blockade is routine for lung cancer, little
is known about acquired resistance. Among 1,201 patients with non-small cell
lung cancer (NSCLC) treated with PD-(L)1 blockade, acquired resistance is
common, occurring in >60% of initial responders. Acquired resistance shows
differential expression of inflammation and interferon (IFN) signaling. Relapsed
tumors can be separated by upregulated or stable expression of IFNγ response
genes. Upregulation of IFNγ response genes is associated with putative routes of
resistance characterized by signatures of persistent IFN signaling, immune
dysfunction, and mutations in antigen presentation genes which can be
recapitulated in multiple murine models of acquired resistance to PD-(L)1
blockade after in vitro IFNγ treatment. Acquired resistance to PD-(L)1 blockade
in NSCLC is associated with an ongoing, but altered IFN response. The
persistently inflamed, rather than excluded or deserted, tumor microenvironment
of acquired resistance may inform therapeutic strategies to effectively
reprogram and reverse acquired resistance.
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ccell.2023.12.013
PMID: 38215748 [Indexed for MEDLINE]
