2023年
No.8
PubMed
(tuberculosis[Title/Abstract]) OR (lung cancer[Title/Abstract])
Filters applied: from 2023/8/1 - 2023/8/31.
1. Lancet. 2023 Aug 19;402(10402):627-640. doi: 10.1016/S0140-6736(23)01231-X. Epub 2023 Aug 8.
Nutritional supplementation to prevent tuberculosis incidence in household
contacts of patients with pulmonary tuberculosis in India (RATIONS): a
field-based, open-label, cluster-randomised, controlled trial.
Bhargava A(1), Bhargava M(2), Meher A(3), Benedetti A(4), Velayutham B(3), Sai
Teja G(5), Watson B(3), Barik G(3), Pathak RR(6), Prasad R(7), Dayal R(8),
Madhukeshwar AK(9), Chadha V(10), Pai M(11), Joshi R(12), Menzies D(13),
Swaminathan S(14).
Author information:
(1)Department of Medicine, Yenepoya Medical College, Mangalore, India; Center
for Nutrition Studies, Yenepoya (Deemed to be University), Mangalore, India;
Department of Medicine, McGill University, Montreal, QC, Canada. Electronic
address: anuragb17@gmail.com.
(2)Department of Community Medicine, Yenepoya Medical College, Mangalore, India;
Center for Nutrition Studies, Yenepoya (Deemed to be University), Mangalore,
India.
(3)Indian Council of Medical Research-National Institute for Research in
Tuberculosis, Chennai, India.
…
Comment in
Lancet. 2023 Aug 19;402(10402):588-590.
BACKGROUND: In India, tuberculosis and undernutrition are syndemics with a high
burden of tuberculosis coexisting with a high burden of undernutrition in
patients and in the population. The aim of this study was to determine the
effect of nutritional supplementation on tuberculosis incidence in household
contacts of adults with microbiologically confirmed pulmonary tuberculosis.
METHODS: In this field-based, open-label, cluster-randomised controlled trial,
we enrolled household contacts of 2800 patients with microbiologically confirmed
pulmonary tuberculosis across 28 tuberculosis units of the National Tuberculosis
Elimination Programme in four districts of Jharkhand, India. The tuberculosis
units were randomly allocated 1:1 by block randomisation to the control group or
the intervention group, by a statistician using computer-generated random
numbers. Although microbiologically confirmed pulmonary tuberculosis patients in
both groups received food rations (1200 kcal, 52 grams of protein per day with
micronutrients) for 6 months, only household contacts in the intervention group
received monthly food rations and micronutrients (750 kcal, 23 grams of protein
per day with micronutrients). After screening all household contacts for
co-prevalent tuberculosis at baseline, all participants were followed up
actively until July 31, 2022, for the primary outcome of incident tuberculosis
(all forms). The ascertainment of the outcome was by independent medical staff
in health services. We used Cox proportional hazards model and Poisson
regression via the generalised estimating equation approach to estimate
unadjusted hazard ratios, adjusted hazard ratios (aHRs), and incidence rate
ratios (IRRs). This study is registered with CTRI-India, CTRI/2019/08/020490.
FINDINGS: Between Aug 16, 2019, and Jan 31, 2021, there were 10 345 household
contacts, of whom 5328 (94·8%) of 5621 household contacts in the intervention
group and 4283 (90·7%) of 4724 household contacts in the control group completed
the primary outcome assessment. Almost two-thirds of the population belonged to
Indigenous communities (eg, Santhals, Ho, Munda, Oraon, and Bhumij) and 34%
(3543 of 10 345) had undernutrition. We detected 31 (0·3%) of 10 345 household
contact patients with co-prevalent tuberculosis disease in both groups at
baseline and 218 (2·1%) people were diagnosed with incident tuberculosis (all
forms) over 21 869 person-years of follow-up, with 122 of 218 incident cases in
the control group (2·6% [122 of 4712 contacts at risk], 95% CI 2·2-3·1;
incidence rate 1·27 per 100 person-years) and 96 incident cases in the
intervention group (1·7% [96 of 5602], 1·4-2·1; 0·78 per 100 person-years),
of whom 152 (69·7%) of 218 were patients with microbiologically confirmed pulmonary
tuberculosis. Tuberculosis incidence (all forms) in the intervention group had an
adjusted IRR of 0·61 (95% CI 0·43-0·85; aHR 0·59 [0·42-0·83]), with an even
greater decline in incidence of microbiologically confirmed pulmonary
tuberculosis (0·52 [0·35-0·79]; 0·51 [0·34-0·78]). This translates into a
relative reduction of tuberculosis incidence of 39% (all forms) to 48%
(microbiologically confirmed pulmonary tuberculosis) in the intervention group.
An estimated 30 households (111 household contacts) would need to be provided
nutritional supplementation to prevent one incident tuberculosis.
INTERPRETATION: To our knowledge, this is the first randomised trial looking at
the effect of nutritional support on tuberculosis incidence in household
contacts, whereby the nutritional intervention was associated with substantial
(39-48%) reduction in tuberculosis incidence in the household during 2 years of
follow-up. This biosocial intervention can accelerate reduction in tuberculosis
incidence in countries or communities with a tuberculosis and undernutrition
syndemic.
FUNDING: Indian Council of Medical Research-India TB Research Consortium.
Copyright © 2023 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S0140-6736(23)01231-X
PMID: 37567200 [Indexed for MEDLINE]
2. Nat Genet. 2023 Aug;55(8):1301-1310. doi: 10.1038/s41588-023-01446-3. Epub 2023 Jul 27.
Single-molecule genome-wide mutation profiles of cell-free DNA for non-invasive
detection of cancer.
Bruhm DC(1), Mathios D(1), Foda ZH(1), Annapragada AV(1), Medina JE(1), Adleff
V(1), Chiao EJ(1), Ferreira L(1), Cristiano S(1), White JR(1), Mazzilli SA(2),
Billatos E(2)(3), Spira A(2)(3), Zaidi AH(4), Mueller J(4), Kim AK(1),
Anagnostou V(1), Phallen J(1), Scharpf RB(5), Velculescu VE(6).
Author information:
(1)The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University
School of Medicine, Baltimore, MD, USA.
(2)Division of Computational Biomedicine, Department of Medicine, Boston
University, Boston, MA, USA.
(3)Section of Pulmonary and Critical Care Medicine, Department of Medicine,
Boston University, Boston, MA, USA.
…
Comment in
Nat Genet. 2023 Aug;55(8):1261-1262.
Somatic mutations are a hallmark of tumorigenesis and may be useful for
non-invasive diagnosis of cancer. We analyzed whole-genome sequencing data from
2,511 individuals in the Pan-Cancer Analysis of Whole Genomes (PCAWG) study as
well as 489 individuals from four prospective cohorts and found distinct
regional mutation type-specific frequencies in tissue and cell-free DNA from
patients with cancer that were associated with replication timing and other
chromatin features. A machine-learning model using genome-wide mutational
profiles combined with other features and followed by CT imaging detected >90%
of patients with lung cancer, including those with stage I and II disease. The
fixed model was validated in an independent cohort, detected patients with
cancer earlier than standard approaches and could be used to monitor response to
therapy. This approach lays the groundwork for non-invasive cancer detection
using genome-wide mutation features that may facilitate cancer screening and
monitoring.
© 2023. The Author(s).
DOI: 10.1038/s41588-023-01446-3
PMCID: PMC10412448
PMID: 37500728 [Indexed for MEDLINE]
3. Nature. 2023 Aug;620(7973):445-452. doi: 10.1038/s41586-023-06366-0. Epub 2023
Jul 26.
Structure of an endogenous mycobacterial MCE lipid transporter.
Chen J(1), Fruhauf A(1), Fan C(1), Ponce J(2), Ueberheide B(2)(3)(4), Bhabha
G(5), Ekiert DC(6)(7).
Author information:
(1)Department of Cell Biology, New York University School of Medicine, New York,
NY, USA.
(2)Proteomics Laboratory, Division of Advanced Research Technologies, New York
University School of Medicine, New York, NY, USA.
(3)Department of Biochemistry and Molecular Pharmacology, New York University
School of Medicine, New York, NY, USA.
…
Update of
Res Sq. 2023 Jan 10;:
To replicate inside macrophages and cause tuberculosis, Mycobacterium
tuberculosis must scavenge a variety of nutrients from the host1,2. The
mammalian cell entry (MCE) proteins are important virulence factors in M.
tuberculosis1,3, where they are encoded by large gene clusters and have been
implicated in the transport of fatty acids4-7 and cholesterol1,4,8 across the
impermeable mycobacterial cell envelope. Very little is known about how cargos
are transported across this barrier, and it remains unclear how the
approximately ten proteins encoded by a mycobacterial mce gene cluster assemble
to transport cargo across the cell envelope. Here we report the cryo-electron
microscopy (cryo-EM) structure of the endogenous Mce1 lipid-import machine of
Mycobacterium smegmatis-a non-pathogenic relative of M. tuberculosis. The
structure reveals how the proteins of the Mce1 system assemble to form an
elongated ABC transporter complex that is long enough to span the cell envelope.
The Mce1 complex is dominated by a curved, needle-like domain that appears to be
unrelated to previously described protein structures, and creates a protected
hydrophobic pathway for lipid transport across the periplasm. Our structural
data revealed the presence of a subunit of the Mce1 complex, which we identified
using a combination of cryo-EM and AlphaFold2, and name LucB. Our data lead to a
structural model for Mce1-mediated lipid import across the mycobacterial cell
envelope.
© 2023. The Author(s), under exclusive licence to Springer Nature Limited.
DOI: 10.1038/s41586-023-06366-0
PMID: 37495693 [Indexed for MEDLINE]
4. Lancet. 2023 Aug 5;402(10400):451-463. doi: 10.1016/S0140-6736(23)00774-2. Epub 2023 Jul 6.
First-line atezolizumab monotherapy versus single-agent chemotherapy in patients
with non-small-cell lung cancer ineligible for treatment with a
platinum-containing regimen (IPSOS): a phase 3, global, multicentre, open-label,
randomised controlled study.
Lee SM(1), Schulz C(2), Prabhash K(3), Kowalski D(4), Szczesna A(5), Han B(6),
Rittmeyer A(7), Talbot T(8), Vicente D(9), Califano R(10), …
Author information:
(1)Department of Oncology, University College London Hospitals NHS Foundation
Trust, CRUK Lung Cancer Centre of Excellence and UCL Cancer Institute, London,
UK. Electronic address: sm.lee@nhs.net.
(2)Bereich Pneumologie Klinik und Poliklinik für Innere Medizin II, University
Hospital Regensburg, Regensburg, Germany.
(3)Department of Medical Oncology, Tata Memorial Hospital, Mumbai, India.
…
Erratum in
Lancet. 2023 Aug 5;402(10400):450.
Comment in
Lancet. 2023 Aug 5;402(10400):426-427.
BACKGROUND: Despite immunotherapy advancements for patients with advanced or
metastatic non-small-cell lung cancer (NSCLC), pivotal first-line trials were
limited to patients with an Eastern Cooperative Oncology Group performance
status (ECOG PS) 0-1 and a median age of 65 years or younger. We aimed to
compare the efficacy and safety of first-line atezolizumab monotherapy with
single-agent chemotherapy in patients ineligible for platinum-based
chemotherapy.
METHODS: This trial was a phase 3, open-label, randomised controlled study
conducted at 91 sites in 23 countries across Asia, Europe, North America, and
South America. Eligible patients had stage IIIB or IV NSCLC in whom
platinum-doublet chemotherapy was deemed unsuitable by the investigator due to
an ECOG PS 2 or 3, or alternatively, being 70 years or older with an ECOG PS 0-1
with substantial comorbidities or contraindications for platinum-doublet
chemotherapy. Patients were randomised 2:1 by permuted-block randomisation
(block size of six) to receive 1200 mg of atezolizumab given intravenously every
3 weeks or single-agent chemotherapy (vinorelbine [oral or intravenous] or
gemcitabine [intravenous]; dosing per local label) at 3-weekly or 4-weekly
cycles. The primary endpoint was overall survival assessed in the
intention-to-treat population. Safety analyses were conducted in the
safety-evaluable population, which included all randomised patients who received
any amount of atezolizumab or chemotherapy. This trial is registered with
ClinicalTrials.gov, NCT03191786.
FINDINGS: Between Sept 11, 2017, and Sept 23, 2019, 453 patients were enrolled
and randomised to receive atezolizumab (n=302) or chemotherapy (n=151).
Atezolizumab improved overall survival compared with chemotherapy (median
overall survival 10·3 months [95% CI 9·4-11·9] vs 9·2 months [5·9-11·2];
stratified hazard ratio 0·78 [0·63-0·97], p=0·028), with a 2-year survival
rate of 24% (95% CI 19·3-29·4) with atezolizumab compared with 12% (6·7-18·0)
with chemotherapy. Compared with chemotherapy, atezolizumab was associated with
stabilisation or improvement of patient-reported health-related quality-of-life
functioning scales and symptoms and fewer grade 3-4 treatment-related adverse
events (49 [16%] of 300 vs 49 [33%] of 147) and treatment-related deaths (three
[1%] vs four [3%]).
INTERPRETATION: First-line treatment with atezolizumab monotherapy was
associated with improved overall survival, a doubling of the 2-year survival
rate, maintenance of quality of life, and a favourable safety profile compared
with single-agent chemotherapy. These data support atezolizumab monotherapy as a
potential first-line treatment option for patients with advanced NSCLC who are
ineligible for platinum-based chemotherapy.
FUNDING: F Hoffmann-La Roche and Genentech Inc, a member of the Roche group.
Copyright © 2023 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S0140-6736(23)00774-2
PMID: 37423228 [Indexed for MEDLINE]
5. N Engl J Med. 2023 Aug 10;389(6):504-513. doi: 10.1056/NEJMoa2215530. Epub 2023 Jun 28.
Perioperative Nivolumab and Chemotherapy in Stage III Non-Small-Cell Lung
Cancer.
Provencio M(1), Nadal E(1), González-Larriba JL(1), Martínez-Martí A(1), Bernabé
R(1), Bosch-Barrera J(1), Casal-Rubio J(1), Calvo V(1), Insa A(1),…
Author information:
(1)From Hospital Universitario Puerta de Hierro-Majadahonda (M.P., V.C.,
R.S.-B., J.M.-L., A.C.-B., A.R.), Hospital Universitario Clínico San Carlos
(J.L.G.-L., C.A.R., F.H.-T.), Hospital Universitario 12 de Octubre (S.P.),
Hospital Universitario La Paz (J.C.), and the Genetic and Molecular Epidemiology
Group, Spanish National Cancer Research Center (R. Benítez), Madrid, Institut
Català d'Oncologia, L'Hospitalet de Llobregat (E.N., R.P.), Vall d'Hebron
Institute of Oncology, Hospital Universitari Vall d'Hebrón (A.M.-M.), …
BACKGROUND: Approximately 20% of patients with non-small-cell lung cancer
(NSCLC) receive a diagnosis of stage III disease. There is no current consensus
regarding the most appropriate treatment for these patients.
METHODS: In this open-label, phase 2 trial, we randomly assigned patients with
resectable stage IIIA or IIIB NSCLC to receive neoadjuvant nivolumab plus
platinum-based chemotherapy (experimental group) or chemotherapy alone (control
group), followed by surgery. Patients in the experimental group who had R0
resections received adjuvant treatment with nivolumab for 6 months. The primary
end point was a pathological complete response (0% viable tumor in resected lung
and lymph nodes). Secondary end points included progression-free survival and
overall survival at 24 months and safety.
RESULTS: A total of 86 patients underwent randomization; 57 were assigned to the
experimental group and 29 were assigned to the control group. A pathological
complete response occurred in 37% of the patients in the experimental group and
in 7% in the control group (relative risk, 5.34; 95% confidence interval [CI],
1.34 to 21.23; P = 0.02). Surgery was performed in 93% of the patients in the
experimental group and in 69% in the control group (relative risk, 1.35; 95% CI,
1.05 to 1.74). Kaplan-Meier estimates of progression-free survival at 24 months
were 67.2% in the experimental group and 40.9% in the control group (hazard
ratio for disease progression, disease recurrence, or death, 0.47; 95% CI, 0.25
to 0.88). Kaplan-Meier estimates of overall survival at 24 months were 85.0% in
the experimental group and 63.6% in the control group (hazard ratio for death,
0.43; 95% CI, 0.19 to 0.98). Grade 3 or 4 adverse events occurred in 11 patients
in the experimental group (19%; some patients had events of both grades) and 3
patients in the control group (10%).
CONCLUSIONS: In patients with resectable stage IIIA or IIIB NSCLC, perioperative
treatment with nivolumab plus chemotherapy resulted in a higher percentage of
patients with a pathological complete response and longer survival than
chemotherapy alone. (Funded by Bristol Myers Squibb and others; NADIM II
ClinicalTrials.gov number, NCT03838159; EudraCT number, 2018-004515-45.).
Copyright © 2023 Massachusetts Medical Society.
DOI: 10.1056/NEJMoa2215530
PMID: 37379158 [Indexed for MEDLINE]
6. N Engl J Med. 2023 Aug 10;389(6):491-503. doi: 10.1056/NEJMoa2302983. Epub 2023 Jun 3.
Perioperative Pembrolizumab for Early-Stage Non-Small-Cell Lung Cancer.
Wakelee H(1), Liberman M(1), Kato T(1), Tsuboi M(1), Lee SH(1), Gao S(1), Chen
KN(1), Dooms C(1), Majem M(1), Eigendorff E(1), Martinengo GL(1), Bylicki O(1),
Rodríguez-Abreu D(1), Chaft JE(1), Novello S(1), Yang J(1), Keller SM(1),
Samkari A(1), Spicer JD(1); KEYNOTE-671 Investigators.
Author information:
(1)From Stanford University School of Medicine, Stanford Cancer Institute,
Stanford, CA (H.W.); Centre Hospitalier de l'Université de Montréal (M.L.) and
McGill University Health Centre (J.D.S.) - both in Montreal; Kanagawa Cancer
Center, Yokohama (T.K.), …
BACKGROUND: Among patients with resectable early-stage non-small-cell lung
cancer (NSCLC), a perioperative approach that includes both neoadjuvant and
adjuvant immune checkpoint inhibition may provide benefit beyond either approach
alone.
METHODS: We conducted a randomized, double-blind, phase 3 trial to evaluate
perioperative pembrolizumab in patients with early-stage NSCLC. Participants
with resectable stage II, IIIA, or IIIB (N2 stage) NSCLC were assigned in a 1:1
ratio to receive neoadjuvant pembrolizumab (200 mg) or placebo once every 3
weeks, each of which was given with cisplatin-based chemotherapy for 4 cycles,
followed by surgery and adjuvant pembrolizumab (200 mg) or placebo once every 3
weeks for up to 13 cycles. The dual primary end points were event-free survival
(the time from randomization to the first occurrence of local progression that
precluded the planned surgery, unresectable tumor, progression or recurrence, or
death) and overall survival. Secondary end points included major pathological
response, pathological complete response, and safety.
RESULTS: A total of 397 participants were assigned to the pembrolizumab group,
and 400 to the placebo group. At the prespecified first interim analysis, the
median follow-up was 25.2 months. Event-free survival at 24 months was 62.4% in
the pembrolizumab group and 40.6% in the placebo group (hazard ratio for
progression, recurrence, or death, 0.58; 95% confidence interval [CI], 0.46 to
0.72; P<0.001). The estimated 24-month overall survival was 80.9% in the
pembrolizumab group and 77.6% in the placebo group (P = 0.02, which did not meet
the significance criterion). A major pathological response occurred in 30.2% of
the participants in the pembrolizumab group and in 11.0% of those in the placebo
group (difference, 19.2 percentage points; 95% CI, 13.9 to 24.7; P<0.0001;
threshold, P = 0.0001), and a pathological complete response occurred in 18.1%
and 4.0%, respectively (difference, 14.2 percentage points; 95% CI, 10.1 to
18.7; P<0.0001; threshold, P = 0.0001). Across all treatment phases, 44.9% of
the participants in the pembrolizumab group and 37.3% of those in the placebo
group had treatment-related adverse events of grade 3 or higher, including 1.0%
and 0.8%, respectively, who had grade 5 events.
CONCLUSIONS: Among patients with resectable, early-stage NSCLC, neoadjuvant
pembrolizumab plus chemotherapy followed by resection and adjuvant pembrolizumab
significantly improved event-free survival, major pathological response, and
pathological complete response as compared with neoadjuvant chemotherapy alone
followed by surgery. Overall survival did not differ significantly between the
groups in this analysis. (Funded by Merck Sharp and Dohme; KEYNOTE-671
ClinicalTrials.gov number, NCT03425643.).
Copyright © 2023 Massachusetts Medical Society.
DOI: 10.1056/NEJMoa2302983
PMID: 37272513 [Indexed for MEDLINE]
7. Cancer Cell. 2023 Aug 9:S1535-6108(23)00252-0. doi: 10.1016/j.ccell.2023.07.012. Online ahead of print.
CD44(+) lung cancer stem cell-derived pericyte-like cells cause brain metastases
through GPR124-enhanced trans-endothelial migration.
Huang Q(1), Liu L(2), Xiao D(2), Huang Z(1), Wang W(2), Zhai K(1), Fang X(1),
Kim J(3), Liu J(3), Liang W(2), He J(4), Bao S(5).
Author information:
(1)Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic,
Cleveland, OH 44195, USA.
(2)Department of Thoracic Surgery, the First Affiliated Hospital of Guangzhou
Medical University, the State Key Laboratory of Respiratory Disease, and the
National Clinical Research Centre for Respiratory Disease, Guangzhou 510120,
China.
(3)Department of Neuro-Oncology, H. Lee Moffitt Cancer Center and Research
Institute, Tampa, FL 33612, USA.
…
Brain metastasis of lung cancer causes high mortality, but the exact mechanisms
underlying the metastasis remain unclear. Here we report that vascular pericytes
derived from CD44+ lung cancer stem cells (CSCs) in lung adenocarcinoma (ADC)
potently cause brain metastases through the G-protein-coupled receptor 124
(GPR124)-enhanced trans-endothelial migration (TEM). CD44+ CSCs in perivascular
niches generate the majority of vascular pericytes in lung ADC. CSC-derived
pericyte-like cells (Cd-pericytes) exhibit remarkable TEM capacity to
effectively intravasate into the vessel lumina, survive in the circulation,
extravasate into the brain parenchyma, and then de-differentiate into
tumorigenic CSCs to form metastases. Cd-pericytes uniquely express GPR124 that
activates Wnt7-β-catenin signaling to enhance TEM capacity of Cd-pericytes for
intravasation and extravasation, two critical steps during tumor metastasis.
Furthermore, selective disruption of Cd-pericytes, GPR124, or the Wnt7-β-catenin
signaling markedly reduces brain and liver metastases of lung ADC. Our findings
uncover an unappreciated cellular and molecular paradigm driving tumor
metastasis.
Copyright © 2023 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ccell.2023.07.012
PMID: 37595587
8. Nat Cell Biol. 2023 Sep;25(9):1346-1358. doi: 10.1038/s41556-023-01210-z. Epub
2023 Aug 17.
KDM6A epigenetically regulates subtype plasticity in small cell lung cancer.
Duplaquet L(#)(1), Li Y(#)(1), Booker MA(2), Xie Y(1)(3), Olsen SN(4), Patel
RA(5), Hong D(1), Hatton C(4), Denize T(6), Walton E(6), Laimon YN(6), Li
R(1)(3), Jiang Y(1)(3), Bronson RT(7), Southard J(8), Li S(8), Signoretti
S(6)(9)(10), Qiu X(1)(3), Cejas P(1)(3), Armstrong SA(4), Long HW(1)(3),
Tolstorukov MY(2), Haffner MC(5)(11)(12), Oser MG(13)(14).
Author information:
(1)Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and
Women's Hospital, Harvard Medical School, Boston, MA, USA.
(2)Department of Informatics and Analytics, Dana-Farber Cancer Institute,
Boston, MA, USA.
(3)Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute,
Boston, MA, USA.
…
Small cell lung cancer (SCLC) exists broadly in four molecular subtypes: ASCL1,
NEUROD1, POU2F3 and Inflammatory. Initially, SCLC subtypes were thought to be
mutually exclusive, but recent evidence shows intra-tumoural subtype
heterogeneity and plasticity between subtypes. Here, using a CRISPR-based
autochthonous SCLC genetically engineered mouse model to study the consequences
of KDM6A/UTX inactivation, we show that KDM6A inactivation induced plasticity
from ASCL1 to NEUROD1 resulting in SCLC tumours that express both ASCL1 and
NEUROD1. Mechanistically, KDM6A normally maintains an active chromatin state
that favours the ASCL1 subtype with its loss decreasing H3K4me1 and increasing
H3K27me3 at enhancers of neuroendocrine genes leading to a cell state that is
primed for ASCL1-to-NEUROD1 subtype switching. This work identifies KDM6A as an
epigenetic regulator that controls ASCL1 to NEUROD1 subtype plasticity and
provides an autochthonous SCLC genetically engineered mouse model to model ASCL1
and NEUROD1 subtype heterogeneity and plasticity, which is found in 35-40% of
human SCLCs.
© 2023. The Author(s), under exclusive licence to Springer Nature Limited.
DOI: 10.1038/s41556-023-01210-z
PMID: 37591951
9. Lancet Oncol. 2023 Sep;24(9):989-1001. doi: 10.1016/S1470-2045(23)00329-7. Epub 2023 Aug 14.
First-line cemiplimab monotherapy and continued cemiplimab beyond progression
plus chemotherapy for advanced non-small-cell lung cancer with PD-L1 50% or more
(EMPOWER-Lung 1): 35-month follow-up from a mutlicentre, open-label, randomised,
phase 3 trial.
Özgüroğlu M(1), Kilickap S(2), Sezer A(3), Gümüş M(4), Bondarenko I(5),
Gogishvili M(6), Nechaeva M(7), Schenker M(8), Cicin I(9), Ho GF(10), Kulyaba
Y(11), Zyuhal K(12), Scheusan RI(13), Garassino MC(14), He X(15), Kaul M(15),
Okoye E(15), Li Y(15), Li S(15), Pouliot JF(15), Seebach F(15), Lowy I(15),
Gullo G(15), Rietschel P(15).
Author information:
(1)Cerrahpaşa Faculty of Medicine, Division of Medical Oncology, Istanbul
University Cerrahpaşa, Istanbul, Türkiye. Electronic address:
ozguroglu@gmail.com.
(2)Faculty of Medicine, Department of Internal Medicine and Medical Oncology,
Istinye University Istanbul, Türkiye.
(3)Department of Medical Oncology, Başkent University, Adana, Türkiye.
…
BACKGROUND: Cemiplimab provided significant survival benefit to patients with
advanced non-small-cell lung cancer with PD-L1 tumour expression of at least 50%
and no actionable biomarkers at 1-year follow-up. In this exploratory analysis,
we provide outcomes after 35 months' follow-up and the effect of adding
chemotherapy to cemiplimab at the time of disease progression.
METHODS: EMPOWER-Lung 1 was a multicentre, open-label, randomised, phase 3
trial. We enrolled patients (aged ≥18 years) with histologically confirmed
squamous or non-squamous advanced non-small-cell lung cancer with PD-L1 tumour
expression of 50% or more. We randomly assigned (1:1) patients to intravenous
cemiplimab 350 mg every 3 weeks for up to 108 weeks, or until disease
progression, or investigator's choice of chemotherapy. Central randomisation
scheme generated by an interactive web response system governed the
randomisation process that was stratified by histology and geographical region.
Primary endpoints were overall survival and progression free survival, as
assessed by a blinded independent central review (BICR) per Response Evaluation
Criteria in Solid Tumours version 1.1. Patients with disease progression on
cemiplimab could continue cemiplimab with the addition of up to four cycles of
chemotherapy. We assessed response in these patients by BICR against a new
baseline, defined as the last scan before chemotherapy initiation. The primary
endpoints were assessed in all randomly assigned participants (ie,
intention-to-treat population) and in those with a PD-L1 expression of at least
50%. We assessed adverse events in all patients who received at least one dose
of their assigned treatment. This trial is registered with ClinicalTrials.gov,
NCT03088540.
FINDINGS: Between May 29, 2017, and March 4, 2020, we recruited 712 patients
(607 [85%] were male and 105 [15%] were female). We randomly assigned 357 (50%)
to cemiplimab and 355 (50%) to chemotherapy. 284 (50%) patients assigned to
cemiplimab and 281 (50%) assigned to chemotherapy had verified PD-L1 expression
of at least 50%. At 35 months' follow-up, among those with a verified PD-L1
expression of at least 50% median overall survival in the cemiplimab group was
26·1 months (95% CI 22·1-31·8; 149 [52%] of 284 died) versus 13·3 months
(10·5-16·2; 188 [67%] of 281 died) in the chemotherapy group (hazard ratio [HR]
0·57, 95% CI 0·46-0·71; p<0·0001), median progression-free survival was 8·1
months (95% CI 6·2-8·8; 214 events occurred) in the cemiplimab group versus 5·3
months (4·3-6·1; 236 events occurred) in the chemotherapy group (HR 0·51, 95% CI
0·42-0·62; p<0·0001). Continued cemiplimab plus chemotherapy as second-line
therapy (n=64) resulted in a median progression-free survival of 6·6 months
(6·1-9·3) and overall survival of 15·1 months (11·3-18·7). The most common
grade 3-4 treatment-emergent adverse events were anaemia (15 [4%] of 356 patients
in the cemiplimab group vs 60 [17%] of 343 in the control group), neutropenia
(three [1%] vs 35 [10%]), and pneumonia (18 [5%] vs 13 [4%]). Treatment-related
deaths occurred in ten (3%) of 356 patients treated with cemiplimab (due to
autoimmune myocarditis, cardiac failure, cardio-respiratory arrest,
cardiopulmonary failure, septic shock, tumour hyperprogression, nephritis,
respiratory failure, [n=1 each] and general disorders or unknown [n=2]) and in
seven (2%) of 343 patients treated with chemotherapy (due to pneumonia and
pulmonary embolism [n=2 each], and cardiac arrest, lung abscess, and myocardial
infarction [n=1 each]). The safety profile of cemiplimab at 35 months, and of
continued cemiplimab plus chemotherapy, was generally consistent with that
previously observed for these treatments, with no new safety signals
INTERPRETATION: At 35 months' follow-up, the survival benefit of cemiplimab for
patients with advanced non-small-cell lung cancer was at least as pronounced as
at 1 year, affirming its use as first-line monotherapy for this population.
Adding chemotherapy to cemiplimab at progression might provide a new second-line
treatment for patients with advanced non-small-cell lung cancer.
FUNDING: Regeneron Pharmaceuticals and Sanofi.
Copyright © 2023 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1470-2045(23)00329-7
PMID: 37591293
10. Cancer Cell. 2023 Aug 14;41(8):1516-1534.e9. doi: 10.1016/j.ccell.2023.07.005.
Epub 2023 Aug 3.
Mammalian SWI/SNF chromatin remodeling complexes promote tyrosine kinase
inhibitor resistance in EGFR-mutant lung cancer.
de Miguel FJ(1), Gentile C(2), Feng WW(3), Silva SJ(4), Sankar A(2), Exposito
F(1), Cai WL(4), Melnick MA(1), Robles-Oteiza C(5), Hinkley MM(2), Tsai JA(3),
Hartley AV(3), Wei J(6), Wurtz A(1), Li F(7), Toki MI(8), Rimm DL(9), Homer
R(8), Wilen CB(6), Xiao AZ(10), Qi J(11), Yan Q(12), Nguyen DX(13), Jänne PA(3),
Kadoch C(14), Politi KA(15).
Author information:
(1)Yale Cancer Center, New Haven, CT 06520, USA.
(2)Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard
Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard,
Cambridge, MA 02142, USA.
(3)Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard
Medical School, Boston, MA, USA.
…
Acquired resistance to tyrosine kinase inhibitors (TKI), such as osimertinib
used to treat EGFR-mutant lung adenocarcinomas, limits long-term efficacy and is
frequently caused by non-genetic mechanisms. Here, we define the chromatin
accessibility and gene regulatory signatures of osimertinib sensitive and
resistant EGFR-mutant cell and patient-derived models and uncover a role for
mammalian SWI/SNF chromatin remodeling complexes in TKI resistance. By profiling
mSWI/SNF genome-wide localization, we identify both shared and cancer cell
line-specific gene targets underlying the resistant state. Importantly, genetic
and pharmacologic disruption of the SMARCA4/SMARCA2 mSWI/SNF ATPases
re-sensitizes a subset of resistant models to osimertinib via inhibition of
mSWI/SNF-mediated regulation of cellular programs governing cell proliferation,
epithelial-to-mesenchymal transition, epithelial cell differentiation, and NRF2
signaling. These data highlight the role of mSWI/SNF complexes in supporting TKI
resistance and suggest potential utility of mSWI/SNF inhibitors in TKI-resistant
lung cancers.
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ccell.2023.07.005
PMID: 37541244 [Indexed for MEDLINE]
11. Lancet Infect Dis. 2023 Aug 28:S1473-3099(23)00375-4. doi:
10.1016/S1473-3099(23)00375-4. Online ahead of print.
Improving measurement of tuberculosis care cascades to enhance people-centred
care.
Faust L(1), Naidoo P(2), Caceres-Cardenas G(3), Ugarte-Gil C(4), Muyoyeta M(5),
Kerkhoff AD(6), Nagarajan K(7), Satyanarayana S(8), Rakotosamimanana N(9),
Grandjean Lapierre S(10), Adejumo OA(11), Kuye J(12), Oga-Omenka C(13), Pai
M(1), Subbaraman R(14).
Author information:
(1)Department of Epidemiology, Biostatistics and Occupational Health, McGill
University, Montréal, QC, Canada; McGill International TB Centre, Montréal, QC,
Canada.
(2)Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty
of Medicine and Health Sciences, Stellenbosch University, Cape Town, South
Africa.
(3)Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana
Cayetano Heredia, Lima, Peru.
…
Care cascades represent the proportion of people reaching milestones in care for
a disease and are widely used to track progress towards global targets for HIV
and other diseases. Despite recent progress in estimating care cascades for
tuberculosis (TB) disease, they have not been routinely applied at national and
subnational levels, representing a lost opportunity for public health impact. As
researchers who have estimated TB care cascades in high-incidence countries
(India, Madagascar, Nigeria, Peru, South Africa, and Zambia), we describe the
utility of care cascades and identify measurement challenges, including the lack
of population-based disease burden data and electronic data capture, the
under-reporting of people with TB navigating fragmented and privatised health
systems, the heterogeneity of TB tests, and the lack of post-treatment
follow-up. We outline an agenda for rectifying these gaps and argue that
improving care cascade measurement is crucial to enhancing people-centred care
and achieving the End TB goals.
Copyright © 2023 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1473-3099(23)00375-4
PMID: 37652066
12. ACS Nano. 2023 Aug 29. doi: 10.1021/acsnano.3c04420. Online ahead of print.
Quantitation of Circulating Mycobacterium tuberculosis Antigens by Nanopore
Biosensing in Children Evaluated for Pulmonary Tuberculosis in South Africa.
Wang X(1), Wei X(1)(2), van der Zalm MM(3), Zhang Z(2), Subramanian N(2), Demers
AM(3)(4), Ghimenton Walters E(3)(5), Hesseling A(3), Liu C(1)(2).
Author information:
(1)Department of Chemical Engineering, University of South Carolina, Columbia,
South Carolina 29208, United States.
(2)Biomedical Engineering Program, University of South Carolina, Columbia, South
Carolina 29208, United States.
(3)Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty
of Medicine and Health Sciences, Stellenbosch University, Cape Town, 8000, South
Africa.
…
Nanopore sensing of proteomic biomarkers lacks accuracy due to the ultralow
abundance of targets, a wide variety of interferents in clinical samples, and
the mismatch between pore and analyte sizes. By converting antigens to DNA
probes via click chemistry and quantifying their characteristic signals, we show
a nanopore assay with several amplification mechanisms to achieve an attomolar
level limit of detection that enables quantitation of the circulating
Mycobacterium tuberculosis (Mtb) antigen ESAT-6/CFP-10 complex in human serum.
The assay's nonsputum-based feature and low-volume sample requirements make it
particularly well-suited for detecting pediatric tuberculosis (TB) disease,
where establishing an accurate diagnosis is greatly complicated by the
paucibacillary nature of respiratory secretions, nonspecific symptoms, and
challenges with sample collection. In the clinical assessment, the assay was
applied to analyze ESAT-6/CFP-10 levels in serum samples collected during
baseline investigation for TB in 75 children, aged 0-12 years, enrolled in a
diagnostic study conducted in Cape Town, South Africa. This nanopore assay
showed superior sensitivity in children with confirmed TB (94.4%) compared to
clinical "gold standard" diagnostic technologies (Xpert MTB/RIF 44.4% and Mtb
culture 72.2%) and filled the diagnostic gap for children with unconfirmed TB,
where these traditional technologies fell short. We envision that, in
combination with automated sample processing and portable nanopore devices, this
methodology will offer a powerful tool to support the diagnosis of pulmonary TB
in children.
DOI: 10.1021/acsnano.3c04420
PMID: 37643288
13. J Clin Oncol. 2023 Aug 21:JCO2202561. doi: 10.1200/JCO.22.02561. Online ahead of print.
Phase II Trial of Atezolizumab Combined With Carboplatin and Pemetrexed for
Patients With Advanced Nonsquamous Non-Small-Cell Lung Cancer With Untreated
Brain Metastases (Atezo-Brain, GECP17/05).
Nadal E(1)(2), Rodríguez-Abreu D(3), Simó M(4), Massutí B(5), Juan O(6),
Huidobro G(7), López R(8), De Castro J(9), Estival A(10), Mosquera J(11),
Sullivan I(12), Felip E(13), Blasco A(14), Guirado M(15), Pereira E(16),
Vilariño N(1)(2)(4), Navarro V(1), Bruna J(4).
Author information:
(1)Department of Medical Oncology, Institut Català d'Oncologia (ICO),
L'Hospitalet de Llobregat, Barcelona, Spain.
(2)Preclinical and Experimental Research in Thoracic Tumors (PReTT) Group,
Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL),
L'Hospitalet de Llobregat, Barcelona, Spain.
(3)Department of Medical Oncology, Complejo Hospitalario Universitario
Insular-Materno Infantil de Gran Canaria, Universidad de Las Palmas de Gran
Canaria, Las Palmas de Gran Canaria, Spain.
…
PURPOSE: The Atezo-Brain study evaluated atezolizumab combined with chemotherapy
in patients with advanced non-small-cell lung cancer (NSCLC) with untreated
brain metastases, a population traditionally excluded from trials.
METHODS: This single-arm phase II clinical trial enrolled patients with advanced
nonsquamous NSCLC with untreated brain metastases without neurologic symptoms or
asymptomatic with medical treatment. Dexamethasone was allowed up to 4 mg once
daily. Atezolizumab plus carboplatin and pemetrexed was given for four to six
cycles followed by atezolizumab plus pemetrexed until progression for a maximum
of 2 years. The primary end points were to determine the progression-free
survival (PFS) rate at 12 weeks and the incidence of grade ≥3 adverse events
during the first 9 weeks. Intracranial outcomes were assessed using response
assessment in neuro-oncology brain metastases criteria.
RESULTS: Forty patients were enrolled and 22 (55%) were receiving
corticosteroids at baseline. The overall 12-week PFS rate was 62.2% (95%
credibility interval [CrI], 47.1 to 76.2). The rate of grade 3/4 adverse events
during the first 9 weeks was 27.5%. Most neurologic events were grade 1 and 2
but five patients (12.5%) experienced grade 3-4 neurologic events. With a median
follow-up of 31 months, intracranial median PFS was 6.9 months and response rate
was 42.7% (95% CrI, 28.1 to 57.9). Systemic median PFS was 8.9 months and
response rate was 45% (95% CrI, 28.1 to 57.9). The median overall survival (OS)
was 11.8 months (95% CI, 7.6 to 16.9) and the 2-year OS rate was 27.5% (95% CI,
16.6 to 45.5).
CONCLUSION: Atezolizumab plus carboplatin and pemetrexed demonstrates activity
in patients with advanced nonsquamous NSCLC with untreated brain metastases with
an acceptable safety profile.
DOI: 10.1200/JCO.22.02561
PMID: 37603816
14. Nat Commun. 2023 Aug 17;14(1):4644. doi: 10.1038/s41467-023-40264-3.
MenT nucleotidyltransferase toxins extend tRNA acceptor stems and can be
inhibited by asymmetrical antitoxin binding.
Xu X(#)(1), Usher B(#)(2), Gutierrez C(3), Barriot R(1), Arrowsmith TJ(2), Han
X(1), Redder P(1), Neyrolles O(3), Blower TR(4), Genevaux P(5).
Author information:
(1)Laboratoire de Microbiologie et Génétique Moléculaires (LMGM), Centre de
Biologie Intégrative (CBI), Université de Toulouse, CNRS, Université Toulouse
III - Paul Sabatier (UT3), Toulouse, France.
(2)Department of Biosciences, Durham University, South Road, Durham, DH1 3LE,
UK.
(3)Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de
Toulouse, CNRS, Université Toulouse III - Paul Sabatier (UT3), Toulouse, France.
…
Mycobacterium tuberculosis, the bacterium responsible for human tuberculosis,
has a genome encoding a remarkably high number of toxin-antitoxin systems of
largely unknown function. We have recently shown that the M. tuberculosis genome
encodes four of a widespread, MenAT family of nucleotidyltransferase
toxin-antitoxin systems. In this study we characterize MenAT1, using tRNA
sequencing to demonstrate MenT1 tRNA modification activity. MenT1 activity is
blocked by MenA1, a short protein antitoxin unrelated to the MenA3 kinase. X-ray
crystallographic analysis shows blockage of the conserved MenT fold by
asymmetric binding of MenA1 across two MenT1 protomers, forming a heterotrimeric
toxin-antitoxin complex. Finally, we also demonstrate tRNA modification by toxin
MenT4, indicating conserved activity across the MenT family. Our study
highlights variation in tRNA target preferences by MenT toxins, selective use of
nucleotide substrates, and diverse modes of MenA antitoxin activity.
© 2023. The Author(s).
DOI: 10.1038/s41467-023-40264-3
PMCID: PMC10435456
PMID: 37591829 [Indexed for MEDLINE]
15. Lancet Infect Dis. 2023 Aug 14:S1473-3099(23)00371-7. doi:
10.1016/S1473-3099(23)00371-7. Online ahead of print.
Incidence and risk factors of tuberculosis among 420 854 household contacts of
patients with tuberculosis in the 100 Million Brazilian Cohort (2004-18): a
cohort study.
Pinto PFPS(1), Teixeira CSS(2), Ichihara MY(2), Rasella D(3), Nery JS(4), Sena
SOL(2), Brickley EB(5), Barreto ML(4), Sanchez MN(6), Pescarini JM(7).
Author information:
(1)Centro de Integração de Dados e Conhecimentos para Saúde (Cidacs), Fundação
Oswaldo Cruz, Salvador, Brazil. Electronic address: priferscaff@hotmail.com.
(2)Centro de Integração de Dados e Conhecimentos para Saúde (Cidacs), Fundação
Oswaldo Cruz, Salvador, Brazil.
(3)Centro de Integração de Dados e Conhecimentos para Saúde (Cidacs), Fundação
Oswaldo Cruz, Salvador, Brazil; Institute of Global Health (ISGlobal), Hospital
Clínic-Universitat de Barcelona, Barcelona, Spain.
…
BACKGROUND: Although household contacts of patients with tuberculosis are known
to be particularly vulnerable to tuberculosis, the published evidence focused on
this group at high risk within the low-income and middle-income country context
remains sparse. Using nationwide data from Brazil, we aimed to estimate the
incidence and investigate the socioeconomic and clinical determinants of
tuberculosis in a cohort of contacts of tuberculosis patients.
METHODS: In this cohort study, we linked individual socioeconomic and
demographic data from the 100 Million Brazilian Cohort to mortality data and
tuberculosis registries, identified contacts of tuberculosis index patients
diagnosed from Jan 1, 2004 to Dec 31, 2018, and followed up the contacts until
the contact's subsequent tuberculosis diagnosis, the contact's death, or Dec 31,
2018. We investigated factors associated with active tuberculosis using
multilevel Poisson regressions, allowing for municipality-level and
household-level random effects.
FINDINGS: We studied 420 854 household contacts of 137 131 tuberculosis index
patients. During the 15 years of follow-up (median 4·4 years [IQR 1·9-7·6]), we
detected 8953 contacts with tuberculosis. The tuberculosis incidence among
contacts was 427·8 per 100 000 person-years at risk (95% CI 419·1-436·8),
16-times higher than the incidence in the general population (26·2 [26·1-26·3])
and the risk was prolonged. Tuberculosis incidence was associated with the index
patient being preschool aged (<5 years; adjusted risk ratio 4·15 [95% CI
3·26-5·28]) or having pulmonary tuberculosis (2·84 [2·55-3·17]).
INTERPRETATION: The high and sustained risk of tuberculosis among contacts
reinforces the need to systematically expand and strengthen contact tracing and
preventive treatment policies in Brazil in order to achieve national and
international targets for tuberculosis elimination.
FUNDING: Wellcome Trust and Brazilian Ministry of Health.
Copyright © 2023 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)00371-7
PMID: 37591301
16. PLoS Biol. 2023 Aug 17;21(8):e3002231. doi: 10.1371/journal.pbio.3002231.
eCollection 2023 Aug.
NCoR1 controls Mycobacterium tuberculosis growth in myeloid cells by regulating
the AMPK-mTOR-TFEB axis.
Biswas VK(1)(2), Sen K(1)(3), Ahad A(1), Ghosh A(1)(2), Verma S(4), Pati R(1),
Prusty S(1)(3), Nayak SP(1), Podder S(1)(2), Kumar D(4), Gupta B(2), Raghav
SK(1)(2).
Author information:
(1)Immuno-genomics & Systems Biology Laboratory, Institute of Life Sciences
(ILS), Bhubaneswar, India.
(2)School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT),
Bhubaneswar, India.
(3)Regional Centre for Biotechnology, Faridabad, India.
(4)Molecular Medicine: Cellular Immunology, International Centre for Genetic
Engineering and Biotechnology (ICGEB), New Delhi, India.
Mycobacterium tuberculosis (Mtb) defends host-mediated killing by repressing the
autophagolysosome machinery. For the first time, we report NCoR1 co-repressor as
a crucial host factor, controlling Mtb growth in myeloid cells by regulating
both autophagosome maturation and lysosome biogenesis. We found that the dynamic
expression of NCoR1 is compromised in human peripheral blood mononuclear cells
(PBMCs) during active Mtb infection, which is rescued upon prolonged
anti-mycobacterial therapy. In addition, a loss of function in myeloid-specific
NCoR1 considerably exacerbates the growth of M. tuberculosis in vitro in THP1
differentiated macrophages, ex vivo in bone marrow-derived macrophages (BMDMs),
and in vivo in NCoR1MyeKO mice. We showed that NCoR1 depletion controls the
AMPK-mTOR-TFEB signalling axis by fine-tuning cellular adenosine triphosphate
(ATP) homeostasis, which in turn changes the expression of proteins involved in
autophagy and lysosomal biogenesis. Moreover, we also showed that the treatment
of NCoR1 depleted cells by Rapamycin, Antimycin-A, or Metformin rescued the TFEB
activity and LC3 levels, resulting in enhanced Mtb clearance. Similarly,
expressing NCoR1 exogenously rescued the AMPK-mTOR-TFEB signalling axis and Mtb
killing. Overall, our data revealed a central role of NCoR1 in Mtb pathogenesis
in myeloid cells.
Copyright: © 2023 Biswas et al. This is an open access article distributed under
the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the
original author and source are credited.
DOI: 10.1371/journal.pbio.3002231
PMCID: PMC10465006
PMID: 37590294 [Indexed for MEDLINE]
17. Nat Commun. 2023 Aug 3;14(1):4655. doi: 10.1038/s41467-023-40349-z.
Neoadjuvant Afatinib for stage III EGFR-mutant non-small cell lung cancer: a
phase II study.
Bian D(#)(1), Sun L(#)(1), Hu J(#)(1), Duan L(#)(1), Xia H(#)(1), Zhu X(1), Sun
F(1), Zhang L(2), Yu H(3), Xiong Y(1), Huang Z(1)(4), Zhao D(1), Song N(1), Yang
J(1), Bao X(5), Wu W(6), Huang J(7), He W(8), Zhu Y(9), Jiang G(10), Zhang
P(11)(12)(13).
Author information:
(1)Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji
University School of Medicine, Shanghai, 200433, China.
(2)Central Laboratory, Shanghai Pulmonary Hospital, School of Medicine, Tongji
University, Shanghai, 200433, China.
(3)Department of Animal Experimental Center, Shanghai Pulmonary Hospital, Tongji
University School of Medicine, Shanghai, 200433, China.
…
Afatinib, an irreversible ErbB-family blocker, could improve the survival of
advanced epidermal growth factor receptor (EGFR)-mutant non-small cell lung
cancer patients (NSCLCm+). This phase II trial (NCT04201756) aimed to assess the
feasibility of neoadjuvant Afatinib treatment for stage III NSCLCm+. Forty-seven
patients received neoadjuvant Afatinib treatment (40 mg daily). The primary
endpoint was objective response rate (ORR). Secondary endpoints included
pathological complete response (pCR) rate, pathological downstaging rate,
margin-free resection (R0) rate, event-free survival, disease-free survival,
progression-free survival, overall survival, treatment-related adverse events
(TRAEs). The ORR was 70.2% (95% CI: 56.5% to 84.0%), meeting the pre-specified
endpoint. The major pathological response (MPR), pCR, pathological downstaging,
and R0 rates were 9.1%, 3.0%, 57.6%, and 87.9%, respectively. The median
survivals were not reached. The most common TRAEs were diarrhea (78.7%) and rash
(78.7%). Only three patients experienced grade 3/4 TRAEs. Biomarker analysis and
tumor microenvironment dynamics by bulk RNA sequencing were included as
predefined exploratory endpoints. CISH expression was a promising marker for
Afatinib response (AUC = 0.918). In responders, compared to baseline samples,
increasing T-cell- and B-cell-related features were observed in post-treatment
tumor and lymph-node samples, respectively. Neoadjuvant Afatinib is feasible for
stage III NSCLC+ patients and leads to dynamic changes in the tumor
microenvironment.
© 2023. The Author(s).
DOI: 10.1038/s41467-023-40349-z
PMCID: PMC10400609
PMID: 37537219 [Indexed for MEDLINE]
18. J Clin Oncol. 2023 Aug 20;41(24):e63-e72. doi: 10.1200/JCO.23.01055. Epub 2023 Jul 11.
Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations: ASCO
Living Guideline, Version 2023.2.
Owen DH(1), Singh N(2), Ismaila N(3), Masters G(4), Riely GJ(5), Robinson AG(6),
Schneider BJ(7), Jaiyesimi IA(8).
Author information:
(1)Ohio State University, Columbus OH.
(2)Postgraduate Institute of Medical Education and Research, Chandigarh, India.
(3)American Society of Clinical Oncology, Alexandria, VA.
…
Update of
J Clin Oncol. 2022 Oct 1;40(28):3310-3322.
Living guidelines are developed for selected topic areas with rapidly evolving
evidence that drives frequent change in clinical practice. Living guidelines are
updated on a regular schedule by a standing expert panel that systematically
reviews the health literature on a continuous basis; as described in the ASCO
Guidelines Methodology Manual. ASCO Living Guidelines follow the ASCO Conflict
of Interest Policy Implementation for Clinical Practice Guidelines. Living
Guidelines and updates are not intended to substitute for independent
professional judgment of the treating provider and do not account for individual
variation among patients. See appendix for disclaimers and other important
information (Appendix 1 and Appendix 2). Updates are published regularly and can
be found at https://ascopubs.org/nsclc-da-living-guideline.
DOI: 10.1200/JCO.23.01055
PMID: 37433095 [Indexed for MEDLINE]
19. J Exp Med. 2023 Aug 7;220(8):e20222090. doi: 10.1084/jem.20222090. Epub 2023 Apr 25.
CD30 co-stimulation drives differentiation of protective T cells during
Mycobacterium tuberculosis infection.
Foreman TW(1), Nelson CE(1), Sallin MA(1), Kauffman KD(1), Sakai S(1),
Otaizo-Carrasquero F(2), Myers TG(2), Barber DL(1).
Author information:
(1)T Lymphocyte Biology Section, Laboratory of Parasitic Diseases, National
Institute of Allergy and Infectious Diseases, National Institutes of Health ,
Bethesda, MD, USA.
(2)Genomic Technologies Section, Research Technologies Branch, National
Institute of Allergy and Infectious Diseases, National Institutes of Health ,
Bethesda, MD, USA.
Comment in
J Exp Med. 2023 Aug 7;220(8):
Control of Mycobacterium tuberculosis (Mtb) infection requires generation of T
cells that migrate to granulomas, complex immune structures surrounding sites of
bacterial replication. Here we compared the gene expression profiles of T cells
in pulmonary granulomas, bronchoalveolar lavage, and blood of Mtb-infected
rhesus macaques to identify granuloma-enriched T cell genes. TNFRSF8/CD30 was
among the top genes upregulated in both CD4 and CD8 T cells from granulomas. In
mice, CD30 expression on CD4 T cells is required for survival of Mtb infection,
and there is no major role for CD30 in protection by other cell types.
Transcriptomic comparison of WT and CD30-/- CD4 T cells from the lungs of
Mtb-infected mixed bone marrow chimeric mice showed that CD30 directly promotes
CD4 T cell differentiation and the expression of multiple effector molecules.
These results demonstrate that the CD30 co-stimulatory axis is highly
upregulated on granuloma T cells and is critical for protective T cell responses
against Mtb infection.
This is a work of the U.S. Government and is not subject to copyright protection
in the United States. Foreign copyrights may apply.
DOI: 10.1084/jem.20222090
PMCID: PMC10130742
PMID: 37097292 [Indexed for MEDLINE]
