2023年
No.4
PubMed
(tuberculosis[Title/Abstract]) OR (lung cancer[Title/Abstract])
Filters applied: from 2023/4/1 - 2023/4/30.
1. Nature. 2023 Apr;616(7957):553-562. doi: 10.1038/s41586-023-05776-4. Epub 2023
Apr 13.
Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA.
Abbosh C(#)(1), Frankell AM(#)(2)(3), Harrison T(#)(4), Kisistok J(#)(5)(6)(7),
Garnett A(#)(4), …
Author information:
(1)Cancer Research UK Lung Cancer Centre of Excellence, University College
London Cancer Institute, London, UK. c.abbosh@ucl.ac.uk.
(2)Cancer Research UK Lung Cancer Centre of Excellence, University College
London Cancer Institute, London, UK.
(3)Cancer Evolution and Genome Instability Laboratory, The Francis Crick
Institute, London, UK.
…
Circulating tumour DNA (ctDNA) can be used to detect and profile residual tumour
cells persisting after curative intent therapy1. The study of large patient
cohorts incorporating longitudinal plasma sampling and extended follow-up is
required to determine the role of ctDNA as a phylogenetic biomarker of relapse
in early-stage non-small-cell lung cancer (NSCLC). Here we developed ctDNA
methods tracking a median of 200 mutations identified in resected NSCLC tissue
across 1,069 plasma samples collected from 197 patients enrolled in the TRACERx
study2. A lack of preoperative ctDNA detection distinguished biologically
indolent lung adenocarcinoma with good clinical outcome. Postoperative plasma
analyses were interpreted within the context of standard-of-care radiological
surveillance and administration of cytotoxic adjuvant therapy. Landmark analyses
of plasma samples collected within 120 days after surgery revealed ctDNA
detection in 25% of patients, including 49% of all patients who experienced
clinical relapse; 3 to 6 monthly ctDNA surveillance identified impending disease
relapse in an additional 20% of landmark-negative patients. We developed a
bioinformatic tool (ECLIPSE) for non-invasive tracking of subclonal architecture
at low ctDNA levels. ECLIPSE identified patients with polyclonal metastatic
dissemination, which was associated with a poor clinical outcome. By measuring
subclone cancer cell fractions in preoperative plasma, we found that subclones
seeding future metastases were significantly more expanded compared with
non-metastatic subclones. Our findings will support (neo)adjuvant trial advances
and provide insights into the process of metastatic dissemination using
low-ctDNA-level liquid biopsy.
© 2023. The Author(s).
DOI: 10.1038/s41586-023-05776-4
PMID: 37055640 [Indexed for MEDLINE]
2. Nature. 2023 Apr;616(7957):525-533. doi: 10.1038/s41586-023-05783-5. Epub 2023
Apr 12.
The evolution of lung cancer and impact of subclonal selection in TRACERx.
Frankell AM(#)(1)(2), Dietzen M(#)(1)(2)(3), Al Bakir M(#)(1)(2), Lim
EL(#)(1)(2),…
Author information:
(1)Cancer Evolution and Genome Instability Laboratory, The Francis Crick
Institute, London, UK.
(2)Cancer Research UK Lung Cancer Centre of Excellence, University College
London Cancer Institute, London, UK.
(3)Cancer Genome Evolution Research Group, Cancer Research UK Lung Cancer Centre
of Excellence, University College London Cancer Institute, London, UK.
…
Lung cancer is the leading cause of cancer-associated mortality worldwide1. Here
we analysed 1,644 tumour regions sampled at surgery or during follow-up from the
first 421 patients with non-small cell lung cancer prospectively enrolled into
the TRACERx study. This project aims to decipher lung cancer evolution and
address the primary study endpoint: determining the relationship between
intratumour heterogeneity and clinical outcome. In lung adenocarcinoma,
mutations in 22 out of 40 common cancer genes were under significant subclonal
selection, including classical tumour initiators such as TP53 and KRAS. We
defined evolutionary dependencies between drivers, mutational processes and
whole genome doubling (WGD) events. Despite patients having a history of
smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced
mutagenesis. These tumours also had similar detection rates for EGFR mutations
and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours
in never-smokers, which suggests that they have a similar aetiology and
pathogenesis. Large subclonal expansions were associated with positive subclonal
selection. Patients with tumours harbouring recent subclonal expansions, on the
terminus of a phylogenetic branch, had significantly shorter disease-free
survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours
harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD
was associated with shorter disease-free survival. Copy number heterogeneity was
associated with extrathoracic relapse within 1 year after surgery. These data
demonstrate the importance of clonal expansion, WGD and copy number instability
in determining the timing and patterns of relapse in non-small cell lung cancer
and provide a comprehensive clinical cancer evolutionary data resource.
© 2023. The Author(s).
DOI: 10.1038/s41586-023-05783-5
PMCID: PMC10115649
PMID: 37046096 [Indexed for MEDLINE]
3. Nature. 2023 Apr;616(7957):534-542. doi: 10.1038/s41586-023-05729-x. Epub 2023
Apr 12.
The evolution of non-small cell lung cancer metastases in TRACERx.
Al Bakir M(#)(1)(2), Huebner A(#)(1)(2)(3), Martínez-Ruiz C(#)(1)(3),
Grigoriadis K(#)(1)(2)(3), Watkins TBK(#)(2), Pich O(#)(2),…
Author information:
(1)Cancer Research UK Lung Cancer Centre of Excellence, University College
London Cancer Institute, London, UK.
(2)Cancer Evolution and Genome Instability Laboratory, The Francis Crick
Institute, London, UK.
(3)Cancer Genome Evolution Research Group, Cancer Research UK Lung Cancer Centre
of Excellence, University College London Cancer Institute, London, UK.
…
Metastatic disease is responsible for the majority of cancer-related deaths1. We
report the longitudinal evolutionary analysis of 126 non-small cell lung cancer
(NSCLC) tumours from 421 prospectively recruited patients in TRACERx who
developed metastatic disease, compared with a control cohort of 144
non-metastatic tumours. In 25% of cases, metastases diverged early, before the
last clonal sweep in the primary tumour, and early divergence was enriched for
patients who were smokers at the time of initial diagnosis. Simulations
suggested that early metastatic divergence more frequently occurred at smaller
tumour diameters (less than 8 mm). Single-region primary tumour sampling
resulted in 83% of late divergence cases being misclassified as early,
highlighting the importance of extensive primary tumour sampling. Polyclonal
dissemination, which was associated with extrathoracic disease recurrence, was
found in 32% of cases. Primary lymph node disease contributed to metastatic
relapse in less than 20% of cases, representing a hallmark of metastatic
potential rather than a route to subsequent recurrences/disease progression.
Metastasis-seeding subclones exhibited subclonal expansions within primary
tumours, probably reflecting positive selection. Our findings highlight the
importance of selection in metastatic clone evolution within untreated primary
tumours, the distinction between monoclonal versus polyclonal seeding in
dictating site of recurrence, the limitations of current radiological screening
approaches for early diverging tumours and the need to develop strategies to
target metastasis-seeding subclones before relapse.
© 2023. The Author(s).
DOI: 10.1038/s41586-023-05729-x
PMCID: PMC10115651
PMID: 37046095 [Indexed for MEDLINE]
4. Nature. 2023 Apr;616(7957):563-573. doi: 10.1038/s41586-023-05771-9. Epub 2023
Apr 12.
Antibodies against endogenous retroviruses promote lung cancer immunotherapy.
Ng KW(#)(1), Boumelha J(#)(2), Enfield KSS(#)(3), Almagro J(4), Cha H(5)(6),
Pich O(3),...
Author information:
(1)Retroviral Immunology Laboratory, The Francis Crick Institute, London, UK.
(2)Oncogene Biology Laboratory, The Francis Crick Institute, London, UK.
(3)Cancer Evolution and Genome Instability Laboratory, The Francis Crick
Institute, London, UK.
…
B cells are frequently found in the margins of solid tumours as organized
follicles in ectopic lymphoid organs called tertiary lymphoid structures
(TLS)1,2. Although TLS have been found to correlate with improved patient
survival and response to immune checkpoint blockade (ICB), the underlying
mechanisms of this association remain elusive1,2. Here we investigate
lung-resident B cell responses in patients from the TRACERx 421 (Tracking
Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer
cohorts, and in a recently established immunogenic mouse model for lung
adenocarcinoma3. We find that both human and mouse lung adenocarcinomas elicit
local germinal centre responses and tumour-binding antibodies, and further
identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant
anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB
in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse
model. ERV-reactive antibodies exert anti-tumour activity that extends survival
in the mouse model, and ERV expression predicts the outcome of ICB in human lung
adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model
requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13
treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings
provide a possible mechanistic basis for the association of TLS with
immunotherapy response.
© 2023. The Author(s).
DOI: 10.1038/s41586-023-05771-9
PMCID: PMC10115647
PMID: 37046094 [Indexed for MEDLINE]
5. Nature. 2023 Apr;616(7957):543-552. doi: 10.1038/s41586-023-05706-4. Epub 2023
Apr 12.
Genomic-transcriptomic evolution in lung cancer and metastasis.
Martínez-Ruiz C(#)(1)(2), Black JRM(#)(1)(2), Puttick C(#)(1)(2)(3), Hill
MS(#)(3), …
Author information:
(1)Cancer Research UK Lung Cancer Centre of Excellence, University College
London Cancer Institute, London, UK.
(2)Cancer Genome Evolution Research Group, Cancer Research UK Lung Cancer Centre
of Excellence, University College London Cancer Institute, London, UK.
(3)Cancer Evolution and Genome Instability Laboratory, The Francis Crick
Institute and University College London Cancer Institute, London, UK.
…
Intratumour heterogeneity (ITH) fuels lung cancer evolution, which leads to
immune evasion and resistance to therapy1. Here, using paired whole-exome and
RNA sequencing data, we investigate intratumour transcriptomic diversity in 354
non-small cell lung cancer tumours from 347 out of the first 421 patients
prospectively recruited into the TRACERx study2,3. Analyses of 947 tumour
regions, representing both primary and metastatic disease, alongside 96
tumour-adjacent normal tissue samples implicate the transcriptome as a major
source of phenotypic variation. Gene expression levels and ITH relate to
patterns of positive and negative selection during tumour evolution. We observe
frequent copy number-independent allele-specific expression that is linked to
epigenomic dysfunction. Allele-specific expression can also result in
genomic-transcriptomic parallel evolution, which converges on cancer gene
disruption. We extract signatures of RNA single-base substitutions and link
their aetiology to the activity of the RNA-editing enzymes ADAR and APOBEC3A,
thereby revealing otherwise undetected ongoing APOBEC activity in tumours.
Characterizing the transcriptomes of primary-metastatic tumour pairs, we combine
multiple machine-learning approaches that leverage genomic and transcriptomic
variables to link metastasis-seeding potential to the evolutionary context of
mutations and increased proliferation within primary tumour regions. These
results highlight the interplay between the genome and transcriptome in
influencing ITH, lung cancer evolution and metastasis.
© 2023. The Author(s).
DOI: 10.1038/s41586-023-05706-4
PMCID: PMC10115639
PMID: 37046093 [Indexed for MEDLINE]
6. Nat Genet. 2023 Apr 6. doi: 10.1038/s41588-023-01355-5. Online ahead of print.
Genomic and transcriptomic analysis of checkpoint blockade response in advanced
non-small cell lung cancer.
Ravi A(#)(1)(2), Hellmann MD(#)(3), Arniella MB(#)(1), Holton M(1), Freeman
SS(1), …
Author information:
(1)Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard,
Cambridge, MA, USA.
(2)Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston,
MA, USA.
(3)AstraZeneca, Oncology R&D, New York, NY, USA.
…
Anti-PD-1/PD-L1 agents have transformed the treatment landscape of advanced
non-small cell lung cancer (NSCLC). To expand our understanding of the molecular
features underlying response to checkpoint inhibitors in NSCLC, we describe here
the first joint analysis of the Stand Up To Cancer-Mark Foundation cohort, a
resource of whole exome and/or RNA sequencing from 393 patients with NSCLC
treated with anti-PD-(L)1 therapy, along with matched clinical response
annotation. We identify a number of associations between molecular features and
outcome, including (1) favorable (for example, ATM altered) and unfavorable (for
example, TERT amplified) genomic subgroups, (2) a prominent association between
expression of inducible components of the immunoproteasome and response and (3)
a dedifferentiated tumor-intrinsic subtype with enhanced response to checkpoint
blockade. Taken together, results from this cohort demonstrate the complexity of
biological determinants underlying immunotherapy outcomes and reinforce the
discovery potential of integrative analysis within large, well-curated,
cancer-specific cohorts.
© 2023. The Author(s).
DOI: 10.1038/s41588-023-01355-5
PMID: 37024582
7. Mol Cell. 2023 May 4;83(9):1474-1488.e8. doi: 10.1016/j.molcel.2023.04.007. Epub 2023 Apr 27.
Structural and functional basis of the universal transcription factor NusG
pro-pausing activity in Mycobacterium tuberculosis.
Delbeau M(1), Omollo EO(2), Froom R(3), Koh S(1), Mooney RA(2), Lilic M(1),
Brewer JJ(1), Rock J(4), Darst SA(5), Campbell EA(6), Landick R(7).
Author information:
(1)Laboratory of Molecular Biophysics, The Rockefeller University, New York, NY
10065, USA.
(2)Department of Biochemistry, University of Wisconsin-Madison, Madison, WI
53706, USA.
(3)Laboratory of Molecular Biophysics, The Rockefeller University, New York, NY
10065, USA; Laboratory of Host-Pathogen Biology, The Rockefeller University, New
York, NY 10065, USA.
(4)Laboratory of Host-Pathogen Biology, The Rockefeller University, New York, NY
10065, USA.
(5)Laboratory of Molecular Biophysics, The Rockefeller University, New York, NY
10065, USA. Electronic address: darst@rockefeller.edu.
(6)Laboratory of Molecular Biophysics, The Rockefeller University, New York, NY
10065, USA. Electronic address: campbee@rockefeller.edu.
(7)Department of Biochemistry, University of Wisconsin-Madison, Madison, WI
53706, USA; Department of Bacteriology, University of Wisconsin-Madison,
Madison, WI 53706, USA. Electronic address: rlandick@wisc.edu.
Transcriptional pauses mediate regulation of RNA biogenesis. DNA-encoded pause
signals trigger pausing by stabilizing RNA polymerase (RNAP) swiveling and
inhibiting DNA translocation. The N-terminal domain (NGN) of the only universal
transcription factor, NusG/Spt5, modulates pausing through contacts to RNAP and
DNA. Pro-pausing NusGs enhance pauses, whereas anti-pausing NusGs suppress
pauses. Little is known about pausing and NusG in the human pathogen
Mycobacterium tuberculosis (Mtb). We report that MtbNusG is pro-pausing. MtbNusG
captures paused, swiveled RNAP by contacts to the RNAP protrusion and
nontemplate-DNA wedged between the NGN and RNAP gate loop. In contrast,
anti-pausing Escherichia coli (Eco) NGN contacts the MtbRNAP gate loop,
inhibiting swiveling and pausing. Using CRISPR-mediated genetics, we show that
pro-pausing NGN is required for mycobacterial fitness. Our results define an
essential function of mycobacterial NusG and the structural basis of pro- versus
anti-pausing NusG activity, with broad implications for the function of all NusG
orthologs.
Copyright © 2023 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.molcel.2023.04.007
PMID: 37116494 [Indexed for MEDLINE]
8. J Clin Oncol. 2023 Apr 25:JCO2202524. doi: 10.1200/JCO.22.02524. Online ahead of print.
Long-Term Outcomes and Molecular Correlates of Sotorasib Efficacy in Patients
With Pretreated KRAS G12C-Mutated Non-Small-Cell Lung Cancer: 2-Year Analysis of
CodeBreaK 100.
Dy GK(1), Govindan R(2), Velcheti V(3), Falchook GS(4), Italiano A(5), Wolf
J(6), Sacher AG(7), Takahashi T(8), Ramalingam SS(9), Dooms C(10), Kim DW(11),
Addeo A(12), Desai J(13), Schuler M(14), Tomasini P(15), Hong DS(16), Lito
P(17), Tran Q(18), Jones S(18), Anderson A(18), Hindoyan A(18), Snyder W(18),
Skoulidis F(16), Li BT(17).
Author information:
(1)Roswell Park Comprehensive Cancer Center, Buffalo, NY.
(2)Siteman Cancer Center, Washington University School of Medicine, St Louis,
MO.
(3)Perlmutter Cancer Center, New York University Langone, New York, NY.
…
Clinical trials frequently include multiple end points that mature at different
times. The initial report, typically based on the primary end point, may be
published when key planned co-primary or secondary analyses are not yet
available. Clinical Trial Updates provide an opportunity to disseminate
additional results from studies, published in JCO or elsewhere, for which the
primary end point has already been reported.In the longest follow-up, to our
knowledge, for a KRASG12C inhibitor, we assessed the long-term efficacy, safety,
and biomarkers of sotorasib in patients with KRAS G12C-mutated advanced
non-small-cell lung cancer (NSCLC) from the CodeBreaK 100 clinical trial
(ClinicalTrials.gov identifier: NCT03600883). This multicenter, single-group,
open-label phase I/phase II trial enrolled 174 patients with KRAS G12C-mutated,
locally advanced or metastatic NSCLC after progression on prior therapies.
Patients (N = 174) received sotorasib 960 mg once daily with the primary end
points for phase I of safety and tolerability and for phase II of objective
response rate (ORR). Sotorasib produced an ORR of 41%, median duration of
response of 12.3 months, progression-free survival (PFS) of 6.3 months, overall
survival (OS) of 12.5 months, and 2-year OS rate of 33%. Long-term clinical
benefit (PFS ≥ 12 months) was observed in 40 (23%) patients across PD-L1
expression levels, in a proportion of patients with somatic STK11 and/or KEAP1
alterations, and was associated with lower baseline circulating tumor DNA
levels. Sotorasib was well tolerated, with few late-onset treatment-related
toxicities, none of which led to treatment discontinuation. These results
demonstrate the long-term benefit of sotorasib, including in subgroups with poor
prognosis.
DOI: 10.1200/JCO.22.02524
PMID: 37098232
9. 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.
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]
10. Nat Commun. 2023 Apr 20;14(1):2280. doi: 10.1038/s41467-023-38045-z.
Structural insights into RNase J that plays an essential role in Mycobacterium
tuberculosis RNA metabolism.
Bao L(#)(1), Hu J(#)(1), Zhan B(#)(1), Chi M(1), Li Z(1), Wang S(1), Shan C(2),
Zhao Z(2), Guo Y(1), Ding X(2), Ji C(1), Tao S(3), Ni T(2), Zhang X(4), Zhao
G(5)(6), Li J(7)(8).
Author information:
(1)State Key Laboratory of Genetic Engineering, School of Life Sciences and
Huashan Hospital, Shanghai Engineering Research Center of Industrial
Microorganisms, Engineering Research Center of Gene Technology of MOE, Fudan
University, 200438, Shanghai, China.
(2)State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan
University, 200438, Shanghai, China.
(3)Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai
Center for Systems Biomedicine, Shanghai Jiao Tong University, 200240, Shanghai,
China.
…
Ribonucleases (RNases) are responsible for RNA metabolism. RNase J, the core
enzyme of the RNA degradosome, plays an essential role in global mRNA decay.
Emerging evidence showed that the RNase J of Mycobacterium tuberculosis
(Mtb-RNase J) could be an excellent target for treating Mtb infection. Here,
crystal structures of Mtb-RNase J in apo-state and complex with the
single-strand RNA reveal the conformational change upon RNA binding and
hydrolysis. Mtb-RNase J forms an active homodimer through the interactions
between the β-CASP and the β-lactamase domain. Knockout of RNase J slows the
growth rate and changes the colony morphologies and cell length in Mycobacterium
smegmatis, which is restored by RNase J complementation. Finally, RNA-seq
analysis shows that the knockout strain significantly changes the expression
levels of 49 genes in metabolic pathways. Thus, our current study explores the
structural basis of Mtb-RNase J and might provide a promising candidate in
pharmacological treatment for tuberculosis.
© 2023. The Author(s).
DOI: 10.1038/s41467-023-38045-z
PMCID: PMC10119312
PMID: 37080992 [Indexed for MEDLINE]
11. J Clin Invest. 2023 Apr 17;133(8):e159941. doi: 10.1172/JCI159941.
Mycobacterium tuberculosis hijacks host TRIM21- and NCOA4-dependent
ferritinophagy to enhance intracellular growth.
Dai Y(1)(2), Zhu C(3), Xiao W(1)(4), Huang K(5), Wang X(6), Shi C(1), Lin D(1),
Zhang H(1)(2), Liu X(7)(8), Peng B(9), Gao Y(10), Liu CH(11), Ge B(12), Kaufmann
SH(13)(14)(15), Feng CG(16), Chen X(1)(4), Cai Y(1).
Author information:
(1)Guangdong Provincial Key Laboratory of Regional Immunity and Diseases,
Department of Pathogen Biology, Shenzhen University Medical School, Shenzhen,
China.
(2)Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou,
China.
(3)Laboratory of Molecular Biology, Beijing Key Laboratory for Drug Resistance
Tuberculosis Research, Beijing Chest Hospital, Capital Medical University,
Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China.
…
Ferritin, a key regulator of iron homeostasis in macrophages, has been reported
to confer host defenses against Mycobacterium tuberculosis (Mtb) infection.
Nuclear receptor coactivator 4 (NCOA4) was recently identified as a cargo
receptor in ferritin degradation. Here, we show that Mtb infection enhanced
NCOA4-mediated ferritin degradation in macrophages, which in turn increased the
bioavailability of iron to intracellular Mtb and therefore promoted bacterial
growth. Of clinical relevance, the upregulation of FTH1 in macrophages was
associated with tuberculosis (TB) disease progression in humans.
Mechanistically, Mtb infection enhanced NCOA4-mediated ferritin degradation
through p38/AKT1- and TRIM21-mediated proteasomal degradation of HERC2, an E3
ligase of NCOA4. Finally, we confirmed that NCOA4 deficiency in myeloid cells
expedites the clearance of Mtb infection in a murine model. Together, our
findings revealed a strategy by which Mtb hijacks host ferritin metabolism for
its own intracellular survival. Therefore, this represents a potential target
for host-directed therapy against tuberculosis.
DOI: 10.1172/JCI159941
PMCID: PMC10104892
PMID: 37066876 [Indexed for MEDLINE]
12. Cancer Discov. 2023 Apr 16:CD-22-0620. doi: 10.1158/2159-8290.CD-22-0620. Online ahead of print.
Integrative analysis of a large real-world cohort of small cell lung cancer
identifies distinct genetic subtypes and insights into histological
transformation.
Sivakumar S(1), Moore JA(2), Montesion M(3), Sharaf R(3), Lin DI(1), Colon
CI(4), Fleischmann Z(1), Ebot EM(1), Newberg JY(5), Mills JM(6), Hegde PS(3),
Pan Q(7), Dowlati A(8), Frampton GM(2), Sage J(9), Lovly CM(10).
Author information:
(1)Foundation Medicine, Cambridge, MA, United States.
(2)Foundation Medicine Inc., Cambridge, MA, United States.
(3)Foundation Medicine, Inc., Cambridge, MA, United States.
…
Small cell lung cancer (SCLC) is a recalcitrant neuroendocrine carcinoma with
dismal survival outcomes. A major barrier in the field has been the relative
paucity of human tumors studied. Here we provide an integrated analysis of 3,600
"real-world" SCLC cases. This large cohort allowed us to identify new recurrent
alterations and genetic subtypes, including STK11-mutant tumors (1.7%) and
TP53/RB1 wild-type tumors (5.5%), as well as rare cases that were human
papillomavirus-positive. In our cohort, gene amplifications on 4q12 are
associated with increased overall survival while CCNE1 amplification is
associated with decreased overall survival. We also identify more frequent
alterations in the PTEN pathway in brain metastases. Finally, profiling cases of
SCLC containing oncogenic drivers typically associated with NSCLC demonstrates
that SCLC transformation may occur across multiple distinct molecular cohorts of
NSCLC. These novel and unsuspected genetic features of SCLC may help personalize
treatment approaches for this fatal form of cancer.
DOI: 10.1158/2159-8290.CD-22-0620
PMID: 37062002
13. Nat Commun. 2023 Apr 8;14(1):1988. doi: 10.1038/s41467-023-37719-y.
The relative transmission fitness of multidrug-resistant Mycobacterium
tuberculosis in a drug resistance hotspot.
Loiseau C(#)(1)(2), Windels EM(#)(3)(4), Gygli SM(1)(2), Jugheli L(1)(2)(5),
Maghradze N(1)(2)(5), Brites D(1)(2), Ross A(1)(2), Goig G(1)(2), Reinhard
M(1)(2), Borrell S(1)(2), Trauner A(1)(2), Dötsch A(1)(2), Aspindzelashvili
R(5), Denes R(6), Reither K(1)(2), Beisel C(6), Tukvadze N(1)(2)(5), Avaliani
Z(5), Stadler T(6)(7), Gagneux S(8)(9).
Author information:
(1)Swiss Tropical and Public Health Institute, Allschwil, Switzerland.
(2)University of Basel, Basel, Switzerland.
(3)Department of Biosystems Science and Engineering, ETH Zürich, Basel,
Switzerland. etthel.windels@bsse.ethz.ch.
…
Multidrug-resistant tuberculosis (MDR-TB) is among the most frequent causes of
death due to antimicrobial resistance. Although only 3% of global TB cases are
MDR, geographical hotspots with up to 40% of MDR-TB have been observed in
countries of the former Soviet Union. While the quality of TB control and
patient-related factors are known contributors to such hotspots, the role of the
pathogen remains unclear. Here we show that in the country of Georgia, a known
hotspot of MDR-TB, MDR Mycobacterium tuberculosis strains of lineage 4 (L4)
transmit less than their drug-susceptible counterparts, whereas most MDR strains
of L2 suffer no such defect. Our findings further indicate that the high
transmission fitness of these L2 strains results from epistatic interactions
between the rifampicin resistance-conferring mutation RpoB S450L, compensatory
mutations in the RNA polymerase, and other pre-existing genetic features of
L2/Beijing clones that circulate in Georgia. We conclude that the transmission
fitness of MDR M. tuberculosis strains is heterogeneous, but can be as high as
drug-susceptible forms, and that such highly drug-resistant and transmissible
strains contribute to the emergence and maintenance of hotspots of MDR-TB. As
these strains successfully overcome the metabolic burden of drug resistance, and
given the ongoing rollout of new treatment regimens against MDR-TB, proper
surveillance should be implemented to prevent these strains from acquiring
resistance to the additional drugs.
© 2023. The Author(s).
DOI: 10.1038/s41467-023-37719-y
PMCID: PMC10082831
PMID: 37031225 [Indexed for MEDLINE]
14. J Clin Oncol. 2023 Apr 6:JCO2300282. doi: 10.1200/JCO.23.00282. Online ahead of print.
Therapy for Stage IV Non-Small-Cell Lung Cancer Without Driver Alterations: ASCO
Living Guideline, Version 2023.1.
Singh N(1), Jaiyesimi IA(2), Ismaila N(3), Leighl NB(4), Mamdani H(5), Phillips
T(6), Owen DH(7).
Author information:
(1)Postgraduate Institute of Medical Education and Research, Chandigarh, India.
(2)Corewell Health William Beaumont University Hospital Royal Oak and Oakland
University William Beaumont School of Medicine, Rochester, MI.
(3)American Society of Clinical Oncology, Alexandria, VA.
(4)Princess Margaret Cancer Center, University Health Network, Toronto, Ontario,
Canada.
(5)Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State
University, Detroit, MI.
(6)City of Hope, Duarte, CA.
(7)Ohio State University, Columbus, OH.
Update of
J Clin Oncol. 2022 Oct 1;40(28):3323-3343.
Living guidelines are developed for selected topic areas with rapidly evolving
evidence that drives frequent change in recommended 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-non-da-living-guideline.
DOI: 10.1200/JCO.23.00282
PMID: 37023387
15. J Clin Oncol. 2023 Apr 6:JCO2300281. doi: 10.1200/JCO.23.00281. Online ahead of print.
Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations: ASCO
Living Guideline, Version 2023.1.
Singh N(1), Jaiyesimi IA(2), Ismaila N(3), Leighl NB(4), Mamdani H(5), Phillips
T(6), Owen DH(7).
Author information:
(1)Postgraduate Institute of Medical Education and Research, Chandigarh, India.
(2)Corewell Health William Beaumont University Hospital Royal Oak and Oakland
University William Beaumont School of Medicine, Rochester, MI.
(3)American Society of Clinical Oncology, Alexandria, VA.
(4)Princess Margaret Cancer Center, University Health Network, Toronto, Ontario,
Canada.
(5)Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State
University, Detroit, MI.
(6)City of Hope, Duarte, CA.
(7)Ohio State University, Columbus, OH.
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 recommended 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, online only). Updates are
published regularly and can be found at
https://ascopubs.org/nsclc-da-living-guideline.
DOI: 10.1200/JCO.23.00281
PMID: 37023367
16. J Clin Oncol. 2023 Apr 5:JCO2201728. doi: 10.1200/JCO.22.01728. Online ahead of print.
Endosonography With or Without Confirmatory Mediastinoscopy for Resectable Lung
Cancer: A Randomized Clinical Trial.
Bousema JE(1), Dijkgraaf MGW(2), van der Heijden EHFM(3), Verhagen AFTM(4),
Annema JT(5), van den Broek FJC(1); MEDIASTrial study group.
Author information:
(1)Department of Surgery, Máxima MC, Veldhoven, the Netherlands.
(2)Amsterdam UMC Location University of Amsterdam, Epidemiology and Data
Science, Amsterdam Public Health, Methodology, Amsterdam, the Netherlands.
(3)Department of Pulmonary Medicine, Radboud University Medical Center,
Nijmegen, the Netherlands.
…
PURPOSE: Resectable non-small-cell lung cancer (NSCLC) with a high probability
of mediastinal nodal involvement requires mediastinal staging by endosonography
and, in the absence of nodal metastases, confirmatory mediastinoscopy according
to current guidelines. However, randomized data regarding immediate lung tumor
resection after systematic endosonography versus additional confirmatory
mediastinoscopy before resection are lacking.
METHODS: Patients with (suspected) resectable NSCLC and an indication for
mediastinal staging after negative systematic endosonography were randomly
assigned to immediate lung tumor resection or confirmatory mediastinoscopy
followed by tumor resection. The primary outcome in this noninferiority trial
(noninferiority margin of 8% that previously showed to not compromise survival,
Pnoninferior < .0250) was the presence of unforeseen N2 disease after tumor
resection with lymph node dissection. Secondary outcomes were 30-day major
morbidity and mortality.
RESULTS: Between July 17, 2017, and October 5, 2020, 360 patients were randomly
assigned, 178 to immediate lung tumor resection (seven dropouts) and 182 to
confirmatory mediastinoscopy first (seven dropouts before and six after
mediastinoscopy). Mediastinoscopy detected metastases in 8.0% (14/175; 95% CI,
4.8 to 13.0) of patients. Unforeseen N2 rate after immediate resection (8.8%)
was noninferior compared with mediastinoscopy first (7.7%) in both
intention-to-treat (Δ, 1.03%; UL 95% CIΔ, 7.2%; Pnoninferior = .0144) and
per-protocol analyses (Δ, 0.83%; UL 95% CIΔ, 7.3%; Pnoninferior = .0157). Major
morbidity and 30-day mortality was 12.9% after immediate resection versus 15.4%
after mediastinoscopy first (P = .4940).
CONCLUSION: On the basis of our chosen noninferiority margin in the rate of
unforeseen N2, confirmatory mediastinoscopy after negative systematic
endosonography can be omitted in patients with resectable NSCLC and an
indication for mediastinal staging.
DOI: 10.1200/JCO.22.01728
PMID: 37018653
17. ACS Nano. 2023 Apr 11;17(7):6998-7006. doi: 10.1021/acsnano.3c01374. Epub 2023 Apr 3.
Sensitive Urine Immunoassay for Visualization of Lipoarabinomannan for
Noninvasive Tuberculosis Diagnosis.
Chen P(1), Meng Y(1), Liu T(1), Peng W(1), Gao Y(1), He Y(1), Qu R(1), Zhang
C(1), Hu W(1), Ying B(1).
Author information:
(1)Department of Laboratory Medicine, Med+X Center for Manufacturing, Department
of Radiology, National Clinical Research Center for Geriatrics, West China
Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
Lipoarabinomannan (LAM) is a prospective noninvasive biomarker for tuberculosis
(TB) diagnosis. Here, we report a visual immunoassay of high sensitivity for
detecting LAM in urine samples toward TB diagnosis. This method uses a
DNA-linked immunosorbent of LAM, followed by a transduction cascade into
amplified visual signals using quantum dots (QDs) and calcein reaction with Cu2+
and copper nanoparticles (Cu NPs). The limit of detection (LOD) for LAM in the
urine reaches 2.5 fg/mL and 25 fg/mL using a fluorometer and length readouts on
strips, respectively, demonstrating an ultrahigh sensitivity. The clinical
validation of the proposed assay was performed with 147 HIV-negative clinical
urine specimens. The results show the sensitivity of test is 94.1% (16/17) for
confirmed TB (culture-positive) and 85% (51/60) for unconfirmed TB (clinical
diagnosis without positive culture results), respectively, when the test cutoff
value is 40 fg/mL for TB. Its specificity is 89.2% (25/28) in non-TB and
nontuberculous mycobacterial patients. The area under the curve (AUC) was 0.86
when controls were non-TB and LTBI patients, while the AUC was 0.92 when
controls were only non-TB patients. This highly sensitive visual immunoassay of
LAM has shown potential for noninvasive diagnosis of TB using urine samples.
DOI: 10.1021/acsnano.3c01374
PMID: 37010068 [Indexed for MEDLINE]
18. Lancet Infect Dis. 2023 Apr;23(4):e138-e150. doi: 10.1016/S1473-3099(23)00004-X.
Post-tuberculosis sequelae in children and adolescents: a systematic review.
Igbokwe V(1), Ruby LC(2), Sultanli A(3), Bélard S(4).
Author information:
(1)Department of Pediatric Respiratory Medicine, Immunology and Critical Care
Medicine, Humboldt-Universität zu Berlin, Berlin, Germany.
(2)Department of Infectious Diseases, and Respiratory Medicine,
Charité-Universitätsmedizin Berlin, Freie Universität Berlin and
Humboldt-Universität zu Berlin, Berlin, Germany.
(3)Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany;
German Center for Infection Research, Tübingen, Germany.
(4)Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany;
German Center for Infection Research, Tübingen, Germany. Electronic address:
sabine.belard@med.uni-tuebingen.de.
In 2020, an estimated total of 155 million people had survived tuberculosis.
Among this number, a sizable proportion have considerable post-tuberculosis
morbidity, as shown for the adult population. This systematic review aims to
identify the spectrum and prevalence of post-tuberculosis sequelae in children
and adolescents. Four databases were systematically searched from database
inception to Feb 7, 2022, for literature on post-treatment outcomes of
tuberculosis acquired during childhood. Of the 4613 identified publications, 71
studies were included in this systematic review. Studies on cohorts with
comparably rare (most of which were extrapulmonary) tuberculosis presentations,
such as spinal tuberculosis and tuberculous meningitis were over-represented;
however, no study assessed long-term sequelae in a cohort with an average
childhood tuberculosis spectrum. The descriptive analysis includes long-term
outcomes of 3529 paediatric patients 1 month to 36 years after confirmed (47%)
or clinical (53%) tuberculosis. In a considerable proportion of children, a
broad spectrum of post-tuberculosis sequelae were identified, ranging from
radiological residua after pulmonary tuberculosis, to disabling deformities
after musculoskeletal and cutaneous tuberculosis, to somatic and psychosocial
impairment after tuberculous meningitis. A better understanding and
comprehensive assessment of post-tuberculosis sequelae in children are needed to
improve tuberculosis care beyond antituberculous treatment.
Copyright © 2023 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1473-3099(23)00004-X
PMID: 36963920 [Indexed for MEDLINE]
19. Nano Lett. 2023 Apr 12;23(7):2964-2973. doi: 10.1021/acs.nanolett.3c00354. Epub 2023 Mar 22.
Alveolar Macrophages-Mediated Translocation of Intratracheally Delivered
Perfluorocarbon Nanoparticles to Achieve Lung Cancer (19)F-MR Imaging.
Wang H(1)(2), Li X(1)(2), Wang J(1)(2), Wang J(1)(2), Zou H(1)(2), Hu X(1)(2),
Yang L(1)(2), Shen P(1)(2), A R(1)(2), Wang K(1)(2), Li Y(1)(2), Yang J(1)(2),
Wang K(1)(2), Yang L(1)(2), Wu L(1)(2), Sun X(1)(2).
Author information:
(1)Department of Nuclear Medicine, The Fourth Hospital of Harbin Medical
University, Harbin 150028, China.
(2)NHC Key Laboratory of Molecular Probe and Targeted Diagnosis and Therapy,
Molecular Imaging Research Center (MIRC), Harbin Medical University, Harbin
150028, China.
Recent advances in intratracheal delivery strategies have sparked considerable
biomedical interest in developing this promising approach for lung cancer
diagnosis and treatment. However, there are very few relevant studies on the
behavior and mechanism of imaging nanoparticles (NPs) after intratracheal
delivery. Here, we found that nanosized perfluoro-15-crown-5-ether (PFCE NPs,
∼200 nm) exhibite significant 19F-MRI signal-to-noise ratio (SNR) enhancement
than perfluorooctyl bromide (PFOB NPs) up to day 7 after intratracheal delivery.
Alveolar macrophages (AMs) engulf PFCE NPs, become PFCE NPs-laden AMs, and then
migrate into the tumor margin, resulting in increased tumor PFCE concentration
and 19F-MRI signals. AMs-mediated translocation of PFCE NPs to lung draning
lymph nodes (dLNs) decreases the background PFCE concentration. Our results shed
light on the dynamic AMs-mediated translocation of intratracheally delivered PFC
NPs for effective lung tumor visualization and reveal a pathway to develop and
promote the clinical translation of an intratracheal delivery-based imaging
strategy.
DOI: 10.1021/acs.nanolett.3c00354
PMID: 36947431 [Indexed for MEDLINE]
20. J Clin Invest. 2023 Apr 3;133(7):e164413. doi: 10.1172/JCI164413.
Kras oncogene ablation prevents resistance in advanced lung adenocarcinomas.
Salmón M(1), Álvarez-Díaz R(1), Fustero-Torre C(2), Brehey O(1), Lechuga CG(1),
Sanclemente M(1), Fernández-García F(1), López-García A(1), Martín-Guijarro
MC(3), Rodríguez-Perales S(3), Bousquet-Mur E(1), Morales-Cacho L(1), Mulero
F(4), Al-Shahrour F(2), Martínez L(5), Domínguez O(6), Caleiras E(7), Ortega
S(8), Guerra C(1)(9), Musteanu M(1)(9)(10), Drosten M(1)(9)(11), Barbacid
M(1)(9).
Author information:
(1)Experimental Oncology Group, Molecular Oncology Program.
(2)Bioinformatics Unit.
(3)Molecular Cytogenetics and Genome Editing Unit, Human Cancer Genetics
Program.
…
KRASG12C inhibitors have revolutionized the clinical management of patients with
KRASG12C-mutant lung adenocarcinoma. However, patient exposure to these
inhibitors leads to the rapid onset of resistance. In this study, we have used
genetically engineered mice to compare the therapeutic efficacy and the
emergence of tumor resistance between genetic ablation of mutant Kras expression
and pharmacological inhibition of oncogenic KRAS activity. Whereas Kras ablation
induces massive tumor regression and prevents the appearance of resistant cells
in vivo, treatment of KrasG12C/Trp53-driven lung adenocarcinomas with sotorasib,
a selective KRASG12C inhibitor, caused a limited antitumor response similar to
that observed in the clinic, including the rapid onset of resistance. Unlike in
human tumors, we did not observe mutations in components of the RAS-signaling
pathways. Instead, sotorasib-resistant tumors displayed amplification of the
mutant Kras allele and activation of xenobiotic metabolism pathways, suggesting
that reduction of the on-target activity of KRASG12C inhibitors is the main
mechanism responsible for the onset of resistance. In sum, our results suggest
that resistance to KRAS inhibitors could be prevented by achieving a more robust
inhibition of KRAS signaling mimicking the results obtained upon Kras ablation.
DOI: 10.1172/JCI164413
PMCID: PMC10065067
PMID: 36928090 [Indexed for MEDLINE]
21. Lancet Infect Dis. 2023 Apr;23(4):e122-e137. doi: 10.1016/S1473-3099(22)00875-1. Epub 2023 Feb 28.
Clinical implications of molecular drug resistance testing for Mycobacterium
tuberculosis: a 2023 TBnet/RESIST-TB consensus statement.
Domínguez J(1), Boeree MJ(2), Cambau E(3), Chesov D(4), Conradie F(5), Cox V(6),
Dheda K(7), Dudnyk A(8), Farhat MR(9), Gagneux S(10), Grobusch MP(11), Gröschel
MI(12), Guglielmetti L(13), Kontsevaya I(14), Lange B(15), van Leth F(16),
Lienhardt C(17), Mandalakas AM(18), Maurer FP(19), Merker M(20), Miotto P(21),
Molina-Moya B(22), Morel F(13), Niemann S(23), Veziris N(13), Whitelaw A(24),
Horsburgh CR Jr(25), Lange C(18); TBnet and RESIST-TB networks.
Author information:
(1)Institut d'Investigació Germans Trias i Pujol, Universitat Autònoma de
Barcelona, CIBER Enfermedades Respiratorias, INNOVA4TB Consortium, Barcelona,
Spain. Electronic address: jadominguez@igtp.cat.
(2)Department of Lung Diseases, Radboud Institute for Health Sciences, Radboud
University Medical Center, Nijmegen, Netherlands.
(3)Centre National de Référence des Mycobactéries et de la Résistance des
Mycobactéries aux Antituberculeux, Paris, France, APHP-Hôpital Bichat,
Mycobacteriology Laboratory, INSERM, University Paris Cite, IAME UMR1137, Paris,
France.
Erratum in
Lancet Infect Dis. 2023 Mar 28;:
Drug-resistant tuberculosis is a substantial health-care concern worldwide.
Despite culture-based methods being considered the gold standard for drug
susceptibility testing, molecular methods provide rapid information about the
Mycobacterium tuberculosis mutations associated with resistance to
anti-tuberculosis drugs. This consensus document was developed on the basis of a
comprehensive literature search, by the TBnet and RESIST-TB networks, about
reporting standards for the clinical use of molecular drug susceptibility
testing. Review and the search for evidence included hand-searching journals and
searching electronic databases. The panel identified studies that linked
mutations in genomic regions of M tuberculosis with treatment outcome data.
Implementation of molecular testing for the prediction of drug resistance in M
tuberculosis is key. Detection of mutations in clinical isolates has
implications for the clinical management of patients with multidrug-resistant or
rifampicin-resistant tuberculosis, especially in situations when phenotypic drug
susceptibility testing is not available. A multidisciplinary team including
clinicians, microbiologists, and laboratory scientists reached a consensus on
key questions relevant to molecular prediction of drug susceptibility or
resistance to M tuberculosis, and their implications for clinical practice. This
consensus document should help clinicians in the management of patients with
tuberculosis, providing guidance for the design of treatment regimens and
optimising outcomes.
Copyright © 2023 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1473-3099(22)00875-1
PMID: 36868253 [Indexed for MEDLINE]
22. J Clin Oncol. 2023 Apr 10;41(11):1992-1998. doi: 10.1200/JCO.22.01989. Epub 2023 Feb 21.
Pembrolizumab Plus Pemetrexed and Platinum in Nonsquamous Non-Small-Cell Lung
Cancer: 5-Year Outcomes From the Phase 3 KEYNOTE-189 Study.
Garassino MC(1)(2), Gadgeel S(3), Speranza G(4), Felip E(5), Esteban E(6),
Dómine M(7), Hochmair MJ(8), Powell SF(9), Bischoff HG(10), Peled N(11), Grossi
F(12), Jennens RR(13), Reck M(14), Hui R(15), Garon EB(16), Kurata T(17), Gray
JE(18), Schwarzenberger P(19), Jensen E(19), Pietanza MC(19), Rodríguez-Abreu
D(20).
Author information:
(1)Knapp Center for Biomedical Discovery, University of Chicago Medicine &
Biological Sciences, Chicago, IL.
(2)Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
(3)Henry Ford Cancer Institute/Henry Ford Health, Detroit, MI.
…
Clinical trials frequently include multiple end points that mature at different
times. The initial report, typically on the based on the primary end point, may
be published when key planned co-primary or secondary analyses are not yet
available. Clinical Trial Updates provide an opportunity to disseminate
additional results from studies, published in JCO or elsewhere, for which the
primary end point has already been reported.We present 5-year outcomes from the
phase 3 KEYNOTE-189 study (ClinicalTrials.gov identifier: NCT02578680). Eligible
patients with previously untreated metastatic nonsquamous non-small-cell lung
cancer without EGFR/ALK alterations were randomly assigned 2:1 to pembrolizumab
200 mg or placebo once every 3 weeks for up to 35 cycles with pemetrexed and
investigator's choice of carboplatin/cisplatin for four cycles, followed by
maintenance pemetrexed until disease progression or unacceptable toxicity.
Primary end points were overall survival (OS) and progression-free survival
(PFS). Among 616 randomly assigned patients (n = 410, pembrolizumab plus
pemetrexed-platinum; n = 206, placebo plus pemetrexed-platinum), median time
from random assignment to data cutoff (March 8, 2022) was 64.6 (range,
60.1-72.4) months. Hazard ratio (95% CI) for OS was 0.60 (0.50 to 0.72) and PFS
was 0.50 (0.42 to 0.60) for pembrolizumab plus platinum-pemetrexed versus
placebo plus platinum-pemetrexed. 5-year OS rates were 19.4% versus 11.3%.
Toxicity was manageable. Among 57 patients who completed 35 cycles of
pembrolizumab, objective response rate was 86.0% and 3-year OS rate after
completing 35 cycles (approximately 5 years after random assignment) was 71.9%.
Pembrolizumab plus pemetrexed-platinum maintained OS and PFS benefits versus
placebo plus pemetrexed-platinum, regardless of programmed cell death ligand-1
expression. These data continue to support pembrolizumab plus
pemetrexed-platinum as a standard of care in previously untreated metastatic
non-small-cell lung cancer without EGFR/ALK alterations.
DOI: 10.1200/JCO.22.01989
PMCID: PMC10082311
PMID: 36809080 [Indexed for MEDLINE]
23. J Clin Oncol. 2023 Apr 10;41(11):e21-e30. doi: 10.1200/JCO.22.02783. Epub 2023 Feb 21.
Therapy for Stage IV Non-Small-Cell Lung Cancer Without Driver Alterations: ASCO
Living Guideline, Version 2022.3.
Jaiyesimi IA(1)(2), Owen DH(3), Ismaila N(4), Blanchard E(5), Celano P(6),
Florez N(7), Jain D(8), Singh N(9).
Author information:
(1)Corewell Health William Beaumont University Hospital Royal Oak, MI.
(2)Oakland University William Beaumont School of Medicine, Rochester, MI.
(3)Ohio State University, Columbus, OH.
(4)American Society of Clinical Oncology, Alexandria, VA.
(5)Southcoast Centers for Cancer Care, New Bedford, MA.
(6)The Cancer Center at GBMC, Towson, MD.
(7)Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
(8)Houston Methodist Cancer Center, Houston, TX.
(9)Postgraduate Institute of Medical Education and Research, Chandigarh, India.
Update of
J Clin Oncol. 2022 Oct 1;40(28):3323-3343.
Living guidelines are developed for selected topic areas with rapidly evolving
evidence that drives frequent change in recommended 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-non-da-living-guideline.
DOI: 10.1200/JCO.22.02783
PMID: 36809066 [Indexed for MEDLINE]
24. J Clin Oncol. 2023 Apr 10;41(11):e31-e41. doi: 10.1200/JCO.22.02782. Epub 2023 Feb 21.
Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations: ASCO
Living Guideline, Version 2022.3.
Jaiyesimi IA(1)(2), Owen DH(3), Ismaila N(4), Blanchard E(5), Celano P(6),
Florez N(7), Jain D(8), Singh N(9).
Author information:
(1)Corewell Health William Beaumont University Hospital, Royal Oak, MI.
(2)Oakland University William Beaumont School of Medicine, Rochester, MI.
(3)Ohio State University, Columbus, OH.
…
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.22.02782
PMID: 36802359 [Indexed for MEDLINE]
25. Angew Chem Int Ed Engl. 2023 Apr 17;62(17):e202300221. doi:
10.1002/anie.202300221. Epub 2023 Mar 13.
Chemical Validation of Mycobacterium tuberculosis Phosphopantetheine
Adenylyltransferase Using Fragment Linking and CRISPR Interference.
El Bakali J(1)(2), Blaszczyk M(3)(4), Evans JC(5)(6), Boland JA(1), McCarthy
WJ(1)(7), Fathoni I(8), Dias MVB(3)(9), Johnson EO(6), Coyne AG(1), Mizrahi
V(5), Blundell TL(3), Abell C(1), Spry C(1)(8).
Author information:
(1)Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield
Road, Cambridge, CB2 1EW, UK.
(2)Present address: Univ. Lille, Inserm, CHU Lille, UMR-S 1172-LiNC-Lille
Neuroscience & Cognition, 59000, Lille, France.
(3)Department of Biochemistry, University of Cambridge, 80 Tennis Court Road,
Cambridge, CB2 1GA, UK.
…
The coenzyme A (CoA) biosynthesis pathway has attracted attention as a potential
target for much-needed novel antimicrobial drugs, including for the treatment of
tuberculosis (TB), the lethal disease caused by Mycobacterium tuberculosis
(Mtb). Seeking to identify inhibitors of Mtb phosphopantetheine
adenylyltransferase (MtbPPAT), the enzyme that catalyses the penultimate step in
CoA biosynthesis, we performed a fragment screen. In doing so, we discovered
three series of fragments that occupy distinct regions of the MtbPPAT active
site, presenting a unique opportunity for fragment linking. Here we show how,
guided by X-ray crystal structures, we could link weakly-binding fragments to
produce an active site binder with a KD<20 μM and on-target anti-Mtb activity,
as demonstrated using CRISPR interference. This study represents a big step
toward validating MtbPPAT as a potential drug target and designing a
MtbPPAT-targeting anti-TB drug.
© 2023 The Authors. Angewandte Chemie International Edition published by
Wiley-VCH GmbH.
DOI: 10.1002/anie.202300221
PMID: 36757665 [Indexed for MEDLINE]
26. Am J Respir Crit Care Med. 2023 Apr 15;207(8):1080-1088. doi:
10.1164/rccm.202208-1543OC.
The Long-Term Impact of Early-Life Tuberculosis Disease on Child Health: A
Prospective Birth Cohort Study.
Martinez L(1), Gray DM(2)(3), Botha M(2)(3), Nel M(2)(3), Chaya S(2)(3), Jacobs
C(2)(3), Workman L(2)(3), Nicol MP(3)(4)(5), Zar HJ(2)(3).
Author information:
(1)Department of Epidemiology, School of Public Health, Boston University,
Boston, Massachusetts.
(2)Department of Paediatrics and Child Health, Red Cross War Memorial Children's
Hospital.
(3)SA-Medical Research Council Unit on Child and Adolescent Health, and.
(4)Division of Medical Microbiology, University of Cape Town, Cape Town, South
Africa; and.
(5)Marshall Centre for Infection and Immunity, School of Biomedical Sciences,
University of Western Australia, Perth, Western Australia, Australia.
Comment in
Am J Respir Crit Care Med. 2023 Apr 15;207(8):975-977.
Rationale: There is growing concern that post-tuberculosis disease (TB) sequelae
and morbidity are substantial, but no studies have controlled for preexisting
factors before disease. Whether children have post-TB morbidity is not well
characterized. Objectives: To assess the effect of a TB diagnosis on wheezing
episodes, lung function, and anthropometric measurements among children enrolled
in a prospective birth cohort study in South Africa. Methods: We prospectively
followed children from birth through 5 years for TB using diagnostic tests
including chest radiography and repeated induced sputum sample testing with
Xpert MTB/RIF and liquid culture. We longitudinally measured health outcomes
including growth, wheezing, and lung function up to 5 years. Mixed-effects
linear regression models were used to assess growth and lung function after TB.
Poisson regression was used to assess risk of subsequent wheezing. Measurements
and Main Results: Among 1,068 participants, 96 TB cases occurred (1,228 cases
per 100,000 person-years [95% confidence interval (CI), 1,006-1,500]) occurred
over 7,815 child-years of follow-up. TB was associated with lower length-for-age
(-0.40 [95% CI, -0.68 to -0.11]), weight-for-age (-0.30 [95% CI, -0.59 to
-0.01]), and body mass index (-0.54 [95% CI, -0.83 to -0.25]) z-scores at 5
years. Children developing TB were consistently more likely to wheeze regardless
of the timing of TB. Children with diagnoses of TB between 0 and 1 year of age
had reduced time to peak tidal expiratory flow over total expiratory time
(-2.35% [95% CI, -4.86% to -0.17%]) and higher fractional exhaled nitric oxide
(2.88 ppb [95% CI, 0.57-5.19 ppb]) at 5 years. Children with diagnoses of TB
between 1 and 4 years of age had impaired Vt (-9.32 ml [95% CI, -14.89 to -3.75
ml]) and time to peak tidal expiratory flow over total expiratory time (-2.73%
[95% CI, -5.45% to -0.01%]) at 5 years. Conclusions: Prevention of TB disease in
the first few years of life may have substantial long-term benefits through
childhood.
DOI: 10.1164/rccm.202208-1543OC
PMCID: PMC10112440
PMID: 36746196 [Indexed for MEDLINE]
27. J Clin Oncol. 2023 Apr 10;41(11):1999-2006. doi: 10.1200/JCO.22.01990. Epub 2023 Feb 3.
Pembrolizumab Plus Chemotherapy in Squamous Non-Small-Cell Lung Cancer: 5-Year
Update of the Phase III KEYNOTE-407 Study.
Novello S(1), Kowalski DM(2), Luft A(3), Gümüş M(4), Vicente D(5), Mazières
J(6), Rodríguez-Cid J(7), Tafreshi A(8), Cheng Y(9), Lee KH(10), Golf A(11),
Sugawara S(12), Robinson AG(13), Halmos B(14), Jensen E(15), Schwarzenberger
P(16), Pietanza MC(16), Paz-Ares L(17).
Author information:
(1)Department of Oncology, University of Turin, Azienda Ospedaliero
Universitaria San Luigi, Turin, Italy.
(2)Department of Lung Cancer and Thoracic Tumours, Maria Sklodowska-Curie
National Research Institute of Oncology, Warsaw, Poland.
(3)Department of Oncology No. 1 (Thoracic Surgery), Leningrad Regional Clinical
Hospital, Saint Petersburg, Russia.
…
Clinical trials frequently include multiple end points that mature at different
times. The initial report, typically based on the primary end point, may be
published when key planned co-primary or secondary analyses are not yet
available. Clinical Trial Updates provide an opportunity to disseminate
additional results from studies, published in JCO or elsewhere, for which the
primary end point has already been reported.We report 5-year efficacy and safety
outcomes from the phase III KEYNOTE-407 study (ClinicalTrials.gov identifier:
NCT02775435). Eligible patients with previously untreated, metastatic squamous
non-small-cell lung cancer (NSCLC) were randomly assigned 1:1 to pembrolizumab
200 mg or placebo plus carboplatin and paclitaxel/nab-paclitaxel once every 3
weeks for four cycles, followed by pembrolizumab or placebo for up to 35 cycles.
Primary end points were overall survival (OS) and progression-free survival
(PFS) per RECIST version 1.1 by blinded independent central review (BICR). Five
hundred fifty-nine patients were randomly assigned in the intention-to-treat
population (pembrolizumab plus chemotherapy, n = 278; placebo plus chemotherapy,
n = 281). The median time from random assignment to data cutoff was 56.9 (range,
49.9-66.2) months. OS and PFS were improved with pembrolizumab plus chemotherapy
versus placebo plus chemotherapy (hazard ratio [95% CI], 0.71 [0.59 to 0.85] and
0.62 [0.52 to 0.74]), with 5-year OS rates of 18.4% versus 9.7%, respectively.
Toxicity was manageable. Among 55 patients who completed 35 cycles of
pembrolizumab, the objective response rate was 90.9% and the 3-year OS rate
after completion of 35 cycles (approximately 5 years after random assignment)
was 69.5%. Pembrolizumab plus chemotherapy maintained an OS and PFS benefit
versus placebo plus chemotherapy in previously untreated, metastatic squamous
NSCLC and is a standard-of-care first-line treatment option for metastatic
squamous NSCLC regardless of programmed death ligand 1 expression.
DOI: 10.1200/JCO.22.01990
PMCID: PMC10082300
PMID: 36735893 [Indexed for MEDLINE]
28. J Clin Oncol. 2023 Apr 1;41(10):1830-1840. doi: 10.1200/JCO.22.02186. Epub 2023 Jan 31.
Adjuvant Osimertinib for Resected EGFR-Mutated Stage IB-IIIA Non-Small-Cell Lung
Cancer: Updated Results From the Phase III Randomized ADAURA Trial.
Herbst RS(1), Wu YL(2), John T(3), Grohe C(4), Majem M(5), Wang J(6), Kato T(7),
Goldman JW(8), Laktionov K(9), Kim SW(10), Yu CJ(11)(12), Vu HV(13), Lu S(14),
Lee KY(15), Mukhametshina G(16), Akewanlop C(17), de Marinis F(18), Bonanno
L(19), Domine M(20), Shepherd FA(21), Urban D(22)(23), Huang X(24), Bolanos
A(25), Stachowiak M(26), Tsuboi M(27).
Author information:
(1)Medical Oncology, Yale School of Medicine and Yale Cancer Center, New Haven,
CT.
(2)Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital and
Guangdong Academy of Medical Sciences, Guangzhou, China.
(3)Department of Medical Oncology, Austin Health, Melbourne, Australia.
Erratum in
J Clin Oncol. 2023 Apr 27;:JCO2300658.
PURPOSE: The phase III ADAURA (ClinicalTrials.gov identifier: NCT02511106)
primary analysis demonstrated a clinically significant disease-free survival
(DFS) benefit with adjuvant osimertinib versus placebo in EGFR-mutated stage
IB-IIIA non-small-cell lung cancer (NSCLC) after complete tumor resection (DFS
hazard ratio [HR], 0.20 [99.12% CI, 0.14 to 0.30]; P < .001). We report an
updated exploratory analysis of final DFS data.
METHODS: Overall, 682 patients with stage IB-IIIA (American Joint Committee on
Cancer/Union for International Cancer Control, seventh edition) EGFR-mutated
(exon 19 deletion/L858R) NSCLC were randomly assigned 1:1 (stratified by stage,
mutational status, and race) to receive osimertinib 80 mg once-daily or placebo
for 3 years. The primary end point was DFS by investigator assessment in stage
II-IIIA disease analyzed by stratified log-rank test; following early reporting
of statistical significance in DFS, no further formal statistical testing was
planned. Secondary end points included DFS in stage IB-IIIA, overall survival,
and safety. Patterns of recurrence and CNS DFS were prespecified exploratory end
points.
RESULTS: At data cutoff (April 11, 2022), in stage II-IIIA disease, median
follow-up was 44.2 months (osimertinib) and 19.6 months (placebo); the DFS HR
was 0.23 (95% CI, 0.18 to 0.30); 4-year DFS rate was 70% (osimertinib) and 29%
(placebo). In the overall population, DFS HR was 0.27 (95% CI, 0.21 to 0.34);
4-year DFS rate was 73% (osimertinib) and 38% (placebo). Fewer patients treated
with osimertinib had local/regional and distant recurrence versus placebo. CNS
DFS HR in stage II-IIIA was 0.24 (95% CI, 0.14 to 0.42). The long-term safety
profile of osimertinib was consistent with the primary analysis.
CONCLUSION: These updated data demonstrate prolonged DFS benefit over placebo,
reduced risk of local and distant recurrence, improved CNS DFS, and a consistent
safety profile, supporting the efficacy of adjuvant osimertinib in resected
EGFR-mutated NSCLC.
DOI: 10.1200/JCO.22.02186
PMCID: PMC10082285
PMID: 36720083 [Indexed for MEDLINE]
29. Am J Respir Crit Care Med. 2023 Apr 1;207(7):929-935. doi:
10.1164/rccm.202208-1475OC.
Assessing Pretomanid for Tuberculosis (APT), a Randomized Phase 2 Trial of
Pretomanid-Containing Regimens for Drug-Sensitive Tuberculosis: 12-Week Results.
Dooley KE(1), Hendricks B(2), Gupte N(3), Barnes G(4), Narunsky K(2), Whitelaw
C(2), Smit T(2), Ignatius EH(4), Friedman A(2), Dorman SE(5), Dawson R(2);
Assessing Pretomanid for Tuberculosis (APT) Study Team.
Author information:
(1)Vanderbilt University Medical Center, Nashville, Tennessee.
(2)Division of Pulmonology, Department of Medicine and University of Cape Town
Lung Institute, University of Cape Town, Cape Town, South Africa.
(3)Johns Hopkins India Private Limited, Pune, India.
(4)School of Medicine, Johns Hopkins University, Baltimore, Maryland; and.
(5)Medical University of South Carolina, Charleston, South Carolina.
Comment in
Am J Respir Crit Care Med. 2023 Apr 1;207(7):816-818.
Rationale: Pretomanid is a new nitroimidazole with proven treatment-shortening
efficacy in drug-resistant tuberculosis. Pretomanid-rifamycin-pyrazinamide
combinations are potent in mice but have not been tested clinically. Rifampicin,
but not rifabutin, reduces pretomanid exposures. Objectives: To evaluate the
safety and efficacy of regimens containing pretomanid-rifamycin-pyrazinamide
among participants with drug-sensitive pulmonary tuberculosis. Methods: A phase
2, 12-week, open-label randomized trial was conducted of isoniazid and
pyrazinamide plus 1) pretomanid and rifampicin (arm 1), 2) pretomanid and
rifabutin (arm 2), or 3) rifampicin and ethambutol (standard of care; arm 3).
Laboratory values of safety and sputum cultures were collected at Weeks 1, 2, 3,
4, 6, 8, 10, and 12. Time to culture conversion on liquid medium was the primary
outcome. Measurements and Main Results: Among 157 participants, 125 (80%) had
cavitary disease. Median time to liquid culture negativity in the modified
intention-to-treat population (n = 150) was 42 (arm 1), 28 (arm 2), and 56 (arm
3) days (P = 0.01) (adjusted hazard ratio for arm 1 vs. arm 3, 1.41 [95%
confidence interval (CI), 0.93-2.12; P = 0.10]; adjusted hazard ratio for arm 2
vs. arm 3, 1.89 [95% CI, 1.24-2.87; P = 0.003]). Eight-week liquid culture
conversion was 79%, 89%, and 69%, respectively. Grade ≥3 adverse events occurred
in 3 of 56 (5%), 5 of 53 (9%), and 2 of 56 (4%) participants. Six participants
were withdrawn because of elevated transaminase concentrations (five in arm 2,
one in arm 1). There were three serious adverse events (arm 2) and no deaths.
Conclusions: Pretomanid enhanced the microbiologic activity of regimens
containing a rifamycin and pyrazinamide. Efficacy and hepatic adverse events
appeared highest with the pretomanid and rifabutin-containing regimen. Whether
this is due to higher pretomanid concentrations merits exploration. Clinical
trial registered with www.clinicaltrials.gov (NCT02256696).
DOI: 10.1164/rccm.202208-1475OC
PMID: 36455068 [Indexed for MEDLINE]
30. J Clin Oncol. 2023 Apr 10;41(11):1986-1991. doi: 10.1200/JCO.21.02885. Epub 2022 Oct 28.
Five-Year Outcomes With Pembrolizumab Versus Chemotherapy as First-Line Therapy
in Patients With Non-Small-Cell Lung Cancer and Programmed Death Ligand-1 Tumor
Proportion Score ≥ 1% in the KEYNOTE-042 Study.
de Castro G Jr(1), Kudaba I(2), Wu YL(3), Lopes G(4), Kowalski DM(5), Turna
HZ(6), Caglevic C(7), Zhang L(8), Karaszewska B(9), Laktionov KK(10),
Srimuninnimit V(11), Bondarenko I(12), Kubota K(13), Mukherjee R(14), Lin J(14),
Souza F(14), Mok TSK(15), Cho BC(16).
Author information:
(1)Instituto do Câncer do Estado de São Paulo, São Paulo, Brazil.
(2)Latvian Oncology Center, Riga East Clinical University, Riga, Latvia.
(3)Guangdong Lung Cancer Institute, Guangdong Provinicial People's Hospital and
Guangdong Academy of Medical Sciences, Guandong, China.
…
Clinical trials frequently include multiple end points that mature at different
times. The initial report, typically based on the primary end point, may be
published when key planned co-primary or secondary analyses are not yet
available. Clinical Trial Updates provide an opportunity to disseminate
additional results from studies, published in JCO or elsewhere, for which the
primary end point has already been reported.We report 5-year results from the
phase III KEYNOTE-042 study (ClinicalTrials.gov identifier: NCT02220894).
Eligible patients with locally advanced/metastatic non-small-cell lung cancer
(NSCLC) without EGFR/ALK alterations and with programmed death ligand-1 (PD-L1)
tumor proportion score (TPS) ≥ 1% received pembrolizumab 200 mg once every 3
weeks for 35 cycles or chemotherapy (carboplatin + paclitaxel or pemetrexed) for
4-6 cycles with optional maintenance pemetrexed. Primary end points were overall
survival (OS) in PD-L1 TPS ≥ 50%, ≥ 20%, and ≥ 1% groups. Patients who completed
35 cycles of pembrolizumab with ≥ stable disease could begin second-course
pembrolizumab upon progression. One thousand two hundred seventy-four patients
were randomly assigned (pembrolizumab, n = 637; chemotherapy, n = 637). Median
follow-up time was 61.1 (range, 50.0-76.3) months. OS outcomes favored
pembrolizumab (v chemotherapy) regardless of PD-L1 TPS (hazard ratio [95% CI]
for TPS ≥ 50%, 0.68 [0.57 to 0.81]; TPS ≥ 20%, 0.75 [0.64 to 0.87]; TPS ≥ 1%,
0.79 [0.70 to 0.89]), with estimated 5-year OS rates with pembrolizumab of
21.9%, 19.4%, and 16.6%, respectively. No new toxicities were identified.
Objective response rate was 84.3% among 102 patients who completed 35 cycles of
pembrolizumab and 15.2% among 33 patients who received second-course
pembrolizumab. First-line pembrolizumab monotherapy continued to show durable
clinical benefit versus chemotherapy after 5 years of follow-up in
PD-L1-positive, locally advanced/metastatic NSCLC without EGFR/ALK alterations
and remains a standard of care.
DOI: 10.1200/JCO.21.02885
PMCID: PMC10082298
PMID: 36306479 [Indexed for MEDLINE]
31. Cancer Cell. 2023 May 8;41(5):837-852.e6. doi: 10.1016/j.ccell.2023.03.019. Epub 2023 Apr 21.
Early immune pressure initiated by tissue-resident memory T cells sculpts tumor
evolution in non-small cell lung cancer.
Weeden CE(1), Gayevskiy V(1), Marceaux C(1), Batey D(2), Tan T(3), Yokote K(2),
Ribera NT(4), Clatch A(5), Christo S(5), Teh CE(6), Mitchell AJ(7), Trussart
M(8), Rankin L(6), Obers A(5), McDonald JA(9), Sutherland KD(9), Sharma VJ(10),
Starkey G(11), D'Costa R(12), Antippa P(13), Leong T(14), Steinfort D(15),
Irving L(15), Swanton C(16), Gordon CL(17), Mackay LK(5), Speed TP(18), Gray
DHD(19), Asselin-Labat ML(20).
Author information:
(1)Personalised Oncology Division, Walter and Eliza Hall Institute of Medical
Research, Parkville, VIC, Australia; Department of Medical Biology, the
University of Melbourne, Parkville, VIC, Australia.
(2)Personalised Oncology Division, Walter and Eliza Hall Institute of Medical
Research, Parkville, VIC, Australia.
(3)Immunology Division, Walter and Eliza Hall Institute of Medical Research,
Parkville, VIC, Australia.
…
Tissue-resident memory T (TRM) cells provide immune defense against local
infection and can inhibit cancer progression. However, it is unclear to what
extent chronic inflammation impacts TRM activation and whether TRM cells
existing in tissues before tumor onset influence cancer evolution in humans. We
performed deep profiling of healthy lungs and lung cancers in never-smokers
(NSs) and ever-smokers (ESs), finding evidence of enhanced immunosurveillance by
cells with a TRM-like phenotype in ES lungs. In preclinical models,
tumor-specific or bystander TRM-like cells present prior to tumor onset boosted
immune cell recruitment, causing tumor immune evasion through loss of MHC class
I protein expression and resistance to immune checkpoint inhibitors. In humans,
only tumors arising in ES patients underwent clonal immune evasion, unrelated to
tobacco-associated mutagenic signatures or oncogenic drivers. These data
demonstrate that enhanced TRM-like activity prior to tumor development shapes
the evolution of tumor immunogenicity and can impact immunotherapy outcomes.
Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ccell.2023.03.019
PMID: 37086716
32. Lancet Oncol. 2023 May;24(5):483-495. doi: 10.1016/S1470-2045(23)00108-0. Epub 2023 Apr 17.
Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line
treatment for advanced or metastatic oesophageal squamous cell carcinoma
(RATIONALE-306): a global, randomised, placebo-controlled, phase 3 study.
Xu J(1), Kato K(2), Raymond E(3), Hubner RA(4), Shu Y(5), Pan Y(6), Park SR(7),
Ping L(8), Jiang Y(9), Zhang J(10), Wu X(11), Yao Y(12), Shen L(13), Kojima
T(14), Gotovkin E(15), Ishihara R(16), Wyrwicz L(17), Van Cutsem E(18),
Jimenez-Fonseca P(19), Lin CY(20), Wang L(21), Shi J(22), Li L(21), Yoon HH(23).
Author information:
(1)Fifth Medical Center, Chinese PLA General Hospital, Beijing, China.
(2)National Cancer Center Hospital, Tokyo, Japan.
(3)Centre Hospitalier Paris Saint-Joseph, Paris, France.
…
BACKGROUND: The options for first-line treatment of advanced oesophageal
squamous cell carcinoma are scarce, and the outcomes remain poor. The anti-PD-1
antibody, tislelizumab, has shown antitumour activity in previously treated
patients with advanced oesophageal squamous cell carcinoma. We report interim
analysis results from the RATIONALE-306 study, which aimed to assess
tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line
treatment for advanced or metastatic oesophageal squamous cell carcinoma.
METHODS: This global, randomised, double-blind, parallel-arm,
placebo-controlled, phase 3 study was conducted at 162 medical centres across
Asia, Europe, Oceania, and North America. Patients (aged ≥18 years) with
unresectable, locally advanced, recurrent or metastatic oesophageal squamous
cell carcinoma (regardless of PD-L1 expression), Eastern Cooperative Oncology
Group performance status of 0-1, and measurable or evaluable disease per
Response Evaluation Criteria in Solid Tumours (version 1.1) were recruited.
Patients were randomly assigned (1:1), using permuted block randomisation (block
size of four) and stratified by investigator-chosen chemotherapy, region, and
previous definitive therapy, to tislelizumab 200 mg or placebo intravenously
every 3 weeks on day 1, together with an investigator-chosen chemotherapy
doublet, comprising a platinum agent (cisplatin 60-80 mg/m2 intravenously on day
1 or oxaliplatin 130 mg/m2 intravenously on day 1) plus a fluoropyrimidine
(fluorouracil [750-800 mg/m2 intravenously on days 1-5] or capecitabine [1000
mg/m2 orally twice daily on days 1-14]) or paclitaxel (175 mg/m2 intravenously
on day 1). Treatment was continued until disease progression or unacceptable
toxicity. Investigators, patients, and sponsor staff or designees were masked to
treatment. The primary endpoint was overall survival. The efficacy analysis was
done in the intention-to-treat population (ie, all randomly assigned patients)
and safety was assessed in all patients who received at least one dose of study
treatment. The trial is registered with ClinicalTrials.gov, NCT03783442.
FINDINGS: Between Dec 12, 2018, and Nov 24, 2020, 869 patients were screened, of
whom 649 were randomly assigned to tislelizumab plus chemotherapy (n=326) or
placebo plus chemotherapy (n=323). Median age was 64·0 years (IQR 59·0-69·0),
563 (87%) of 649 participants were male, 86 (13%) were female, 486 (75%) were
Asian, and 155 (24%) were White. 324 (99%) of 326 patients in the tislelizumab
group and 321 (99%) of 323 in the placebo group received at least one dose of
the study drug. As of data cutoff (Feb 28, 2022), median follow-up was 16·3
months (IQR 8·6-21·8) in the tislelizumab group and 9·8 months (IQR 5·8-19·0)
in the placebo group, and 196 (60%) of 326 patients in the tislelizumab group
versus 226 (70%) of 323 in the placebo group had died. Median overall survival
in the tislelizumab group was 17·2 months (95% CI 15·8-20·1) and in the placebo
group was 10·6 months (9·3-12·1; stratified hazard ratio 0·66 [95% CI
0·54-0·80]; one-sided p<0·0001). 313 (97%) of 324 patients in the tislelizumab
group and 309 (96%) of 321 in the placebo group had treatment-related
treatment-emergent adverse events. The most common grade 3 or 4
treatment-related treatment-emergent adverse events were decreased neutrophil
count (99 [31%] in the tislelizumab group vs 105 [33%] in the placebo group),
decreased white blood cell count (35 [11%] vs 50 [16%]), and anaemia (47 [15%]
vs 41 [13%]). Six deaths in the tislelizumab group (gastrointestinal and upper
gastrointestinal haemorrhage [n=2], myocarditis [n=1], pulmonary tuberculosis
[n=1], electrolyte imbalance [n=1], and respiratory failure [n=1]) and four
deaths in the placebo group (pneumonia [n=1], septic shock [n=1], and
unspecified death [n=2]) were determined to be treatment-related.
INTERPRETATION: Tislelizumab plus chemotherapy as a first-line treatment for
advanced or metastatic oesophageal squamous cell carcinoma provided superior
overall survival with a manageable safety profile versus placebo plus
chemotherapy. Given that the interim analysis met its superiority boundary for
the primary endpoint, as confirmed by the independent data monitoring committee,
this Article represents the primary study analysis.
FUNDING: BeiGene.
Copyright © 2023 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1470-2045(23)00108-0
PMID: 37080222 [Indexed for MEDLINE]
33. Nat Immunol. 2023 May;24(5):855-868. doi: 10.1038/s41590-023-01476-3. Epub 2023 Apr 3.
Antigen-specific B cells direct T follicular-like helper cells into lymphoid
follicles to mediate Mycobacterium tuberculosis control.
Swanson RV(#)(1), Gupta A(#)(1)(2), Foreman TW(3)(4), Lu L(1), Choreno-Parra
JA(5), Mbandi SK(6), Rosa BA(7)(8), Akter S(1)(2), Das S(1), Ahmed M(1)(2),
Garcia-Hernandez ML(9), Singh DK(10), Esaulova E(11), Artyomov MN(11), Gommerman
J(12), Mehra S(3)(10), Zuniga J(5)(13), Mitreva M(7)(8), Scriba TJ(6),
Rangel-Moreno J(9), Kaushal D(14), Khader SA(15)(16).
Author information:
(1)Department of Molecular Microbiology, Washington University in St. Louis, St.
Louis, MO, USA.
(2)Department of Microbiology, University of Chicago, Chicago, IL, USA.
(3)Divisions of Bacteriology and Parasitology, Tulane National Primate Research
Center, Covington, LA, USA.
…
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a global cause
of death. Granuloma-associated lymphoid tissue (GrALT) correlates with
protection during TB, but the mechanisms of protection are not understood.
During TB, the transcription factor IRF4 in T cells but not B cells is required
for the generation of the TH1 and TH17 subsets of helper T cells and follicular
helper T (TFH)-like cellular responses. A population of IRF4+ T cells coexpress
the transcription factor BCL6 during Mtb infection, and deletion of Bcl6
(Bcl6fl/fl) in CD4+ T cells (CD4cre) resulted in reduction of TFH-like cells,
impaired localization within GrALT and increased Mtb burden. In contrast, the
absence of germinal center B cells, MHC class II expression on B cells,
antibody-producing plasma cells or interleukin-10-expressing B cells, did not
increase Mtb susceptibility. Indeed, antigen-specific B cells enhance cytokine
production and strategically localize TFH-like cells within GrALT via
interactions between programmed cell death 1 (PD-1) and its ligand PD-L1 and
mediate Mtb control in both mice and macaques.
© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.
DOI: 10.1038/s41590-023-01476-3
PMID: 37012543 [Indexed for MEDLINE]
34. Nat Med. 2023 Apr;29(4):1009-1016. doi: 10.1038/s41591-023-02247-1. Epub 2023
Mar 9.
Comparison of two diagnostic intervention packages for community-based active
case finding for tuberculosis: an open-label randomized controlled trial.
Esmail A(1), Randall P(1), Oelofse S(1), Tomasicchio M(1), Pooran A(1), Meldau
R(1), Makambwa E(1), Mottay L(1), Jaumdally S(1), Calligaro G(1), Meier S(1), de
Kock M(2), Gumbo T(3), Warren RM(2), Dheda K(4)(5)(6).
Author information:
(1)Centre for Lung Infection and Immunity, Division of Pulmonology, Department
of Medicine and UCT Lung Institute and South African MRC/UCT Centre for the
Study of Antimicrobial Resistance, University of Cape Town, Cape Town, South
Africa.
(2)DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research/SAMRC
Centre for Tuberculosis Research, Division of Molecular Biology and Human
Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University,
Stellenbosch, South Africa.
(3)Praedicare Laboratories, Dallas, TX, USA.
…
Two in every five patients with active tuberculosis (TB) remain undiagnosed or
unreported. Therefore community-based, active case-finding strategies require
urgent implementation. However, whether point-of-care (POC), portable
battery-operated, molecular diagnostic tools deployed at a community level,
compared with conventionally used POC smear microscopy, can shorten
time-to-treatment initiation, thus potentially curtailing transmission, remains
unclear. To clarify this issue, we performed an open-label, randomized
controlled trial in periurban informal settlements of Cape Town, South Africa,
where we TB symptom screened 5,274 individuals using a community-based scalable
mobile clinic. Some 584 individuals with HIV infection or symptoms of TB
underwent targeted diagnostic screening and were randomized (1:1) to same-day
smear microscopy (n = 296) or on-site DNA-based molecular diagnosis (n = 288;
GeneXpert). The primary aim was to compare time to TB treatment initiation
between the arms. Secondary aims included feasibility and detection of probably
infectious people. Of participants who underwent targeted screening, 9.9% (58 of
584) had culture-confirmed TB. Time-to-treatment initiation occurred
significantly earlier in the Xpert versus the smear-microscopy arm (8 versus
41 d, P = 0.002). However, overall, Xpert detected only 52% of individuals with
culture-positive TB. Notably, Xpert detected almost all of the probably
infectious patients compared with smear microscopy (94.1% versus 23.5%,
P = <0.001). Xpert was associated with a shorter median time to treatment of
probably infectious patients (7 versus 24 d, P = 0.02) and a greater proportion
of infectious patients were on treatment at 60 d compared with the probably
noninfectious patients (76.5% versus 38.2%, P < 0.01). Overall, a greater
proportion of POC Xpert-positive participants were on treatment at 60 d compared
with all culture-positive participants (100% versus 46.5%, P < 0.01). These
findings challenge the traditional paradigm of a passive case-finding, public
health strategy and argues for the implementation of portable DNA-based
diagnosis with linkage to care as a community-oriented,
transmission-interruption strategy. The study was registered with the South
African National Clinical Trials Registry (application ID 4367;
DOH-27-0317-5367) and ClinicalTrials.gov (NCT03168945).
© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.
DOI: 10.1038/s41591-023-02247-1
PMID: 36894651 [Indexed for MEDLINE]
