2021年
No.9
Medical Abstracts
Filters applied: from 2021/8/1 - 2021/8/31
Key words: tuberculosis ; lung cancer
1. Cell. 2021 Aug 5;184(16):4348-4371.e40. doi: 10.1016/j.cell.2021.07.016.
A proteogenomic portrait of lung squamous cell carcinoma.
Satpathy S(1), Krug K(2), Jean Beltran PM(2), Savage SR(3), Petralia F(4),
Kumar-Sinha C(5), Dou Y(3), Reva B(4), Kane MH(2), Avanessian SC(2), Vasaikar
SV(6), Krek A(4), Lei JT(3), Jaehnig EJ(3),
…
Author information:
(1)Broad Institute of Massachusetts Institute of Technology and Harvard,
Cambridge, MA 02142, USA. Electronic address: shankha@broadinstitute.org.
(2)Broad Institute of Massachusetts Institute of Technology and Harvard,
Cambridge, MA 02142, USA.
(3)Lester and Sue Smith Breast Center, Department of Molecular and Human
Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
…
Lung squamous cell carcinoma (LSCC) remains a leading cause of cancer death with
few therapeutic options. We characterized the proteogenomic landscape of LSCC,
providing a deeper exposition of LSCC biology with potential therapeutic
implications. We identify NSD3 as an alternative driver in FGFR1-amplified
tumors and low-p63 tumors overexpressing the therapeutic target survivin. SOX2
is considered undruggable, but our analyses provide rationale for exploring
chromatin modifiers such as LSD1 and EZH2 to target SOX2-overexpressing tumors.
Our data support complex regulation of metabolic pathways by crosstalk between
post-translational modifications including ubiquitylation. Numerous
immune-related proteogenomic observations suggest directions for further
investigation. Proteogenomic dissection of CDKN2A mutations argue for more
nuanced assessment of RB1 protein expression and phosphorylation before
declaring CDK4/6 inhibition unsuccessful. Finally, triangulation between LSCC,
LUAD, and HNSCC identified both unique and common therapeutic vulnerabilities.
These observations and proteogenomics data resources may guide research into the
biology and treatment of LSCC.
Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.cell.2021.07.016
PMCID: PMC8475722
PMID: 34358469
2. Cell. 2021 Aug 19;184(17):4579-4592.e24. doi: 10.1016/j.cell.2021.06.033. Epub
2021 Jul 22.
Genome-wide gene expression tuning reveals diverse vulnerabilities of
M. tuberculosis.
Bosch B(1), DeJesus MA(1), Poulton NC(1), Zhang W(2), Engelhart CA(3), Zaveri
A(3), Lavalette S(3), Ruecker N(3), Trujillo C(3), Wallach JB(3), Li S(1), Ehrt
S(3), Chait BT(2), Schnappinger D(4), Rock JM(5).
Author information:
(1)Laboratory of Host-Pathogen Biology, The Rockefeller University, New York, NY
10065, USA.
(2)Laboratory of Mass Spectrometry and Gaseous Ion Chemistry, The Rockefeller
University, New York, NY 10065, USA.
(3)Department of Microbiology and Immunology, Weill Cornell Medicine, New York,
NY 10065, USA.
(4)Department of Microbiology and Immunology, Weill Cornell Medicine, New York,
NY 10065, USA. Electronic address: dis2003@med.cornell.edu.
(5)Laboratory of Host-Pathogen Biology, The Rockefeller University, New York, NY
10065, USA. Electronic address: rock@rockefeller.edu.
Antibacterial agents target the products of essential genes but rarely achieve
complete target inhibition. Thus, the all-or-none definition of essentiality
afforded by traditional genetic approaches fails to discern the most attractive
bacterial targets: those whose incomplete inhibition results in major fitness
costs. In contrast, gene "vulnerability" is a continuous, quantifiable trait
that relates the magnitude of gene inhibition to the effect on bacterial
fitness. We developed a CRISPR interference-based functional genomics method to
systematically titrate gene expression in Mycobacterium tuberculosis (Mtb) and
monitor fitness outcomes. We identified highly vulnerable genes in various
processes, including novel targets unexplored for drug discovery. Equally
important, we identified invulnerable essential genes, potentially explaining
failed drug discovery efforts. Comparison of vulnerability between the reference
and a hypervirulent Mtb isolate revealed incomplete conservation of
vulnerability and that differential vulnerability can predict differential
antibacterial susceptibility. Our results quantitatively redefine essential
bacterial processes and identify high-value targets for drug development.
Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.cell.2021.06.033
PMCID: PMC8382161
PMID: 34297925
3. Chem Rev. 2021 Aug 11;121(15):9554-9643. doi: 10.1021/acs.chemrev.1c00043. Epub 2021 Jun 30.
Chemical Synthesis of Cell Wall Constituents of Mycobacterium tuberculosis.
Holzheimer M(1), Buter J(1), Minnaard AJ(1).
Author information:
(1)Stratingh Institute for Chemistry, University of Groningen, 9747 AG
Groningen, The Netherlands.
The pathogen Mycobacterium tuberculosis (Mtb), causing tuberculosis disease,
features an extraordinary thick cell envelope, rich in Mtb-specific lipids,
glycolipids, and glycans. These cell wall components are often directly involved
in host-pathogen interaction and recognition, intracellular survival, and
virulence. For decades, these mycobacterial natural products have been of great
interest for immunology and synthetic chemistry alike, due to their complex
molecular structure and the biological functions arising from it. The synthesis
of many of these constituents has been achieved and aided the elucidation of
their function by utilizing the synthetic material to study Mtb immunology. This
review summarizes the synthetic efforts of a quarter century of total synthesis
and highlights how the synthesis layed the foundation for immunological studies
as well as drove the field of organic synthesis and catalysis to efficiently
access these complex natural products.
DOI: 10.1021/acs.chemrev.1c00043
PMCID: PMC8361437
PMID: 34190544
4. Cancer Cell. 2021 Sep 13;39(9):1279-1291.e3. doi: 10.1016/j.ccell.2021.07.005.
Epub 2021 Aug 12.
Bevacizumab plus erlotinib in Chinese patients with untreated, EGFR-mutated,
advanced NSCLC (ARTEMIS-CTONG1509): A multicenter phase 3 study.
Zhou Q(1), Xu CR(1), Cheng Y(2), Liu YP(3), Chen GY(4), Cui JW(5), Yang N(6),
Song Y(7), Li XL(8), Lu S(9), Zhou JY(10), Ma ZY(11), Yu SY(12), Huang C(13),
Shu YQ(14), Wang Z(1), Yang JJ(1), Tu HY(1), Zhong WZ(1), Wu YL(15).
Author information:
(1)Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer,
Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital and
Guangdong Academy of Medical Sciences, Guangzhou, China.
(2)Department of Thoracic Oncology, Jilin Provincial Tumor Hospital, Changchun,
China.
(3)Department of Medical Oncology, First Hospital of China Medical University,
Shenyang, China.
…
Dual inhibition of epidermal growth factor receptor (EGFR) and vascular
endothelial growth factor (VEGF) pathways may delay therapeutic resistance in
advanced non-small cell lung cancer (NSCLC). This phase 3 study investigated the
efficacy and safety of an erlotinib plus bevacizumab regimen in untreated
patients with advanced NSCLC. In total, 311 patients received bevacizumab plus
erlotinib (n = 157) or erlotinib only (n = 154). Progression-free survival (PFS)
was 17.9 months (95% confidence interval [CI], 15.2-19.9) for bevacizumab plus
erlotinib and 11.2 months (95% CI, 9.7-13.8) for erlotinib only (hazard ratio
[HR] = 0.55; 95% CI, 0.41-0.73; p < 0.001). A brain metastases subgroup treated
with bevacizumab plus erlotinib also showed improved PFS (HR = 0.48; 95% CI,
0.27-0.84; p = 0.008). Grade ≥3 treatment-related adverse events occurred in 86
(54.8%) and 40 (26.1%) patients, respectively. Bevacizumab plus erlotinib
significantly improved PFS in patients with untreated metastatic EGFR-mutated
NSCLC, including those with brain metastases at baseline.
Copyright © 2021 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ccell.2021.07.005
PMID: 34388377
5. Cancer Cell. 2021 Sep 13;39(9):1245-1261.e6. doi: 10.1016/j.ccell.2021.07.006.
Epub 2021 Aug 12.
Targeting Aurora B kinase prevents and overcomes resistance to EGFR inhibitors
in lung cancer by enhancing BIM- and PUMA-mediated apoptosis.
Tanaka K(1), Yu HA(2), Yang S(1), Han S(1), Selcuklu SD(1), Kim K(3), Ramani
S(1), Ganesan YT(1), Moyer A(4), Sinha S(1), Xie Y(5), Ishizawa K(1),
Osmanbeyoglu HU(6), Lyu Y(7), Roper N(8), Guha U(9), Rudin CM(10), Kris MG(2),
Hsieh JJ(7), Cheng EH(11).
Author information:
(1)Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer
Center, New York, NY 10065, USA.
(2)Thoracic Oncology Service, Department of Medicine, Memorial Sloan Kettering
Cancer Center, Department of Medicine, Weill Cornell Medical College, New York,
NY 10065, USA.
(3)Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
10065, USA.
…
The clinical success of EGFR inhibitors in EGFR-mutant lung cancer is limited by
the eventual development of acquired resistance. We hypothesize that enhancing
apoptosis through combination therapies can eradicate cancer cells and reduce
the emergence of drug-tolerant persisters. Through high-throughput screening of
a custom library of ∼1,000 compounds, we discover Aurora B kinase inhibitors as
potent enhancers of osimertinib-induced apoptosis. Mechanistically, Aurora B
inhibition stabilizes BIM through reduced Ser87 phosphorylation, and
transactivates PUMA through FOXO1/3. Importantly, osimertinib resistance caused
by epithelial-mesenchymal transition (EMT) activates the ATR-CHK1-Aurora B
signaling cascade and thereby engenders hypersensitivity to respective kinase
inhibitors by activating BIM-mediated mitotic catastrophe. Combined inhibition
of EGFR and Aurora B not only efficiently eliminates cancer cells but also
overcomes resistance beyond EMT.
Copyright © 2021 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ccell.2021.07.006
PMCID: PMC8440494
PMID: 34388376
6. Nat Med. 2021 Aug;27(8):1410-1418. doi: 10.1038/s41591-021-01462-y. Epub 2021
Aug 12.
Tumor-infiltrating lymphocyte treatment for anti-PD-1-resistant metastatic lung
cancer: a phase 1 trial.
Creelan BC(#)(1), Wang C(#)(2), Teer JK(3), Toloza EM(2), Yao J(3), Kim S(4),
Landin AM(5), Mullinax JE(6), Saller JJ(7), Saltos AN(2), Noyes DR(4), Montoya
LB(8), Curry W(8), Pilon-Thomas SA(4), Chiappori AA(2), Tanvetyanon T(2), Kaye
FJ(9), Thompson ZJ(2), Yoder SJ(10), Fang B(10), Koomen JM(10), Sarnaik AA(2),
Chen DT(3), Conejo-Garcia JR(2), Haura EB(#)(2), Antonia SJ(#)(11).
Author information:
(1)Department of Thoracic Oncology, H. Lee Moffitt Cancer Center & Research
Institute, Tampa, FL, USA. ben.creelan@moffitt.org.
(2)Department of Thoracic Oncology, H. Lee Moffitt Cancer Center & Research
Institute, Tampa, FL, USA.
(3)Department of Bioinformatics and Biostatistics, H. Lee Moffitt Cancer Center
& Research Institute, Tampa, FL, USA.
…
Comment in
Nat Med. 2021 Aug;27(8):1339-1341.
Nat Rev Clin Oncol. 2021 Oct;18(10):603.
Adoptive cell therapy using tumor-infiltrating lymphocytes (TILs) has shown
activity in melanoma, but has not been previously evaluated in metastatic
non-small cell lung cancer. We conducted a single-arm open-label phase 1 trial (
NCT03215810 ) of TILs administered with nivolumab in 20 patients with advanced
non-small cell lung cancer following initial progression on nivolumab
monotherapy. The primary end point was safety and secondary end points included
objective response rate, duration of response and T cell persistence. Autologous
TILs were expanded ex vivo from minced tumors cultured with interleukin-2.
Patients received cyclophosphamide and fludarabine lymphodepletion, TIL infusion
and interleukin-2, followed by maintenance nivolumab. The end point of safety
was met according to the prespecified criteria of ≤17% rate of severe toxicity
(95% confidence interval, 3-29%). Of 13 evaluable patients, 3 had confirmed
responses and 11 had reduction in tumor burden, with a median best change of
35%. Two patients achieved complete responses that were ongoing 1.5 years later.
In exploratory analyses, we found T cells recognizing multiple types of cancer
mutations were detected after TIL treatment and were enriched in responding
patients. Neoantigen-reactive T cell clonotypes increased and persisted in
peripheral blood after treatment. Cell therapy with autologous TILs is generally
safe and clinically active and may constitute a new treatment strategy in
metastatic lung cancer.
© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.
DOI: 10.1038/s41591-021-01462-y
PMID: 34385708 [Indexed for MEDLINE]
7. Nat Med. 2021 Aug;27(8):1345-1356. doi: 10.1038/s41591-021-01450-2. Epub 2021
Aug 12.
Toward personalized treatment approaches for non-small-cell lung cancer.
Wang M(1), Herbst RS(2), Boshoff C(3)(4).
Author information:
(1)Yale Comprehensive Cancer Center, Yale School of Medicine, New Haven, CT,
USA.
(2)Yale Comprehensive Cancer Center, Yale School of Medicine, New Haven, CT,
USA. roy.herbst@yale.edu.
(3)Yale Comprehensive Cancer Center, Yale School of Medicine, New Haven, CT,
USA. christoffer.boshoff@pfizer.com.
(4)Pfizer Inc., New York City, NY, USA. christoffer.boshoff@pfizer.com.
Worldwide, lung cancer is the most common cause of cancer-related deaths.
Molecular targeted therapies and immunotherapies for non-small-cell lung cancer
(NSCLC) have improved outcomes markedly over the past two decades. However, the
vast majority of advanced NSCLCs become resistant to current treatments and
eventually progress. In this Perspective, we discuss some of the recent
breakthrough therapies developed for NSCLC, focusing on immunotherapies and
targeted therapies. We highlight our current understanding of mechanisms of
resistance and the importance of incorporating genomic analyses into clinical
studies to decipher these further. We underscore the future role of neoadjuvant
and maintenance combination therapy approaches to potentially cure early
disease. A major challenge to successful development of rational combination
therapies will be the application of robust predictive biomarkers for clear-cut
patient stratification, and we provide our views on clinical research areas that
could influence how NSCLC will be managed over the coming decade.
© 2021. Springer Nature America, Inc.
DOI: 10.1038/s41591-021-01450-2
PMID: 34385702 [Indexed for MEDLINE]
8. J Clin Oncol. 2021 Aug 26:JCO2003318. doi: 10.1200/JCO.20.03318. Online ahead of print.
Veliparib in Combination With Platinum-Based Chemotherapy for First-Line
Treatment of Advanced Squamous Cell Lung Cancer: A Randomized, Multicenter Phase
III Study.
Ramalingam SS(1), Novello S(2), Guclu SZ(3)(4), Bentsion D(5), Zvirbule Z(6),
Szilasi M(7), Bernabe R(8), Syrigos K(9), Byers LA(10), Clingan P(11), Bar
J(12), Vokes EE(13), Govindan R(14), Dunbar M(15), Ansell P(15), He L(15), Huang
X(15), Sehgal V(15), Glasgow J(15), Bach BA(15), Mazieres J(16).
Author information:
(1)Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA.
(2)Department of Oncology, University of Turin, AOU San Luigi Gonzaga,
Orbassano, Torino, Italy.
(3)Chest Diseases Clinic, Izmir Chest Diseases Research Hospital, Izmir, Turkey.
…
PURPOSE: Squamous non-small-cell lung cancer (sqNSCLC) is genetically complex
with evidence of DNA damage. This phase III study investigated the efficacy and
safety of poly (ADP-ribose) polymerase inhibitor veliparib in combination with
conventional chemotherapy for advanced sqNSCLC (NCT02106546).
PATIENTS AND METHODS: Patients age ≥ 18 years with untreated, advanced sqNSCLC
were randomly assigned 1:1 to carboplatin and paclitaxel with veliparib 120 mg
twice daily (twice a day) or placebo twice a day for up to six cycles. The
primary end point was overall survival (OS) in the veliparib arm versus the
control arm in current smokers, based on phase II findings. Archival tumor
samples were provided for biomarker analysis using a 52-gene expression
histology classifier (LP52).
RESULTS: Overall, 970 patients were randomly assigned to carboplatin and
paclitaxel plus either veliparib (n = 486) or placebo (n = 484); 57% were
current smokers. There was no significant OS benefit with veliparib in current
smokers, with median OS 11.9 versus 11.1 months (hazard ratio [HR], 0.905; 95%
CI, 0.744 to 1.101; P = .266). In the overall population, OS favored veliparib;
median OS was 12.2 versus 11.2 months (HR, 0.853; 95% CI, 0.747 to 0.974), with
no difference in progression-free survival (median 5.6 months per arm). In
patients with biomarker-evaluable tumor samples (n = 360), OS favored veliparib
in the LP52-positive population (median 14.0 v 9.6 months; HR, 0.66; 95% CI,
0.49 to 0.89), but favored placebo in the LP52-negative population (median 11.0
v 14.4 months; HR, 1.33; 95% CI, 0.95 to 1.86). No new safety signals were
observed in the experimental arm.
CONCLUSION: In current smokers with advanced sqNSCLC, there was no therapeutic
benefit of adding veliparib to first-line chemotherapy. The LP52 signature may
identify a subgroup of patients likely to derive benefit from veliparib with
chemotherapy.
DOI: 10.1200/JCO.20.03318
PMID: 34436928
9. Nat Commun. 2021 Aug 20;12(1):5060. doi: 10.1038/s41467-021-24994-w.
Detection and characterization of lung cancer using cell-free DNA fragmentomes.
Mathios D(#)(1)(2), Johansen JS(#)(3), Cristiano S(#)(1)(4), Medina JE(#)(1),
Phallen J(#)(1), Larsen KR(5), Bruhm DC(1), Niknafs N(1), Ferreira L(1), Adleff
V(1), Chiao JY(1), Leal A(1), Noe M(1), White JR(1), Arun AS(1), Hruban C(1),
Annapragada AV(1), Jensen SØ(6), Ørntoft MW(6), Madsen AH(7), Carvalho B(8), de
Wit M(8), Carey J(9), Dracopoli NC(9), Maddala T(9), Fang KC(9), Hartman AR(9),
Forde PM(1), Anagnostou V(1), Brahmer JR(1), Fijneman RJA(8), Nielsen HJ(10),
Meijer GA(8), Andersen CL(7), Mellemgaard A(3), Bojesen SE(11), Scharpf
RB(12)(13), Velculescu VE(14).
Author information:
(1)The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University
School of Medicine, Baltimore, MD, USA.
(2)Department of Neurosurgery, Johns Hopkins University School of Medicine,
Baltimore, MD, USA.
(3)Department of Oncology, Herlev and Gentofte Hospital, Copenhagen, Denmark.
…
Comment in
Nat Rev Clin Oncol. 2021 Oct;18(10):603.
Non-invasive approaches for cell-free DNA (cfDNA) assessment provide an
opportunity for cancer detection and intervention. Here, we use a machine
learning model for detecting tumor-derived cfDNA through genome-wide analyses of
cfDNA fragmentation in a prospective study of 365 individuals at risk for lung
cancer. We validate the cancer detection model using an independent cohort of
385 non-cancer individuals and 46 lung cancer patients. Combining fragmentation
features, clinical risk factors, and CEA levels, followed by CT imaging,
detected 94% of patients with cancer across stages and subtypes, including 91%
of stage I/II and 96% of stage III/IV, at 80% specificity. Genome-wide
fragmentation profiles across ~13,000 ASCL1 transcription factor binding sites
distinguished individuals with small cell lung cancer from those with non-small
cell lung cancer with high accuracy (AUC = 0.98). A higher fragmentation score
represented an independent prognostic indicator of survival. This
approach provides a facile avenue for non-invasive detection of lung cancer.
© 2021. The Author(s).
DOI: 10.1038/s41467-021-24994-w
PMCID: PMC8379179
PMID: 34417454 [Indexed for MEDLINE]
10. Am J Respir Crit Care Med. 2021 Aug 17. doi: 10.1164/rccm.202103-0534OC. Online ahead of print.
A Semi-Mechanistic Model of the Bactericidal Activity of High-Dose Isoniazid
Against Multi-Drug-Resistant Tuberculosis: Results from a Randomized Clinical
Trial.
Gausi K(1), Ignatius EH(2), Sun X(3), Kim S(4), Moran L(5), Wiesner L(1), von
Groote-Bidlingmaier F(6), Hafner R(7), Donahue K(8), Vanker N(6), Rosenkranz
SL(3)(8), Swindells S(9), Diacon AH(6), Nuermberger EL(10), Dooley KE(10), Denti
P(11); A5312 Study Team.
Author information:
(1)University of Cape Town Faculty of Health Sciences, 63726, Observatory,
Western Cape, South Africa.
(2)Johns Hopkins University, Baltimore, Maryland, United States.
(3)Harvard University T H Chan School of Public Health, 1857, Boston,
Massachusetts, United States.
…
RATIONALE: There is accumulating evidence that higher-than-standard doses of
isoniazid are effective against low-to-intermediate-level isoniazid-resistant
strains of Mycobacterium tuberculosis, but the optimal dose remains unknown.
OBJECTIVE: Characterizing the association between isoniazid pharmacokinetics
(standard or high-dose) and early bactericidal activity against M. tuberculosis
(drug-sensitive and inhA-mutated) and N-acetyltransferase 2 status.
METHODS: ACTG A5312/INHindsight is 7-day early bactericidal activity study with
isoniazid at normal dose (5 mg/kg) for patients with drug-sensitive bacteria and
5, 10, and 15 mg/kg doses for patients with inhA mutants. Participants with
pulmonary TB received daily isoniazid monotherapy and collected sputum daily.
Colony-forming units (CFU) on solid culture and time-to-positivity (TTP) in
liquid culture were jointly analyzed using nonlinear mixed-effects modeling.
RESULTS: Fifty-nine adults were included in this analysis. Decline in sputum CFU
was described by a one-compartment model, while an exponential bacterial growth
model was used to interpret TTP data. The model found bacterial kill is
modulated by isoniazid concentration using an effect compartment and a sigmoidal
Emax relationship. The model predicted lower potency but similar maximum-kill of
isoniazid against inhA-mutated isolates compared to drug-sensitive. Based on
simulations from the PK/PD model, to achieve a drop in bacterial load comparable
to 5mg/kg against drug-sensitive TB, 10- and 15-mg/kg doses are necessary
against inhA-mutated isolates in slow and intermediate N-acetyltransferase 2
acetylators, respectively. Fast acetylators underperformed even at 15 mg/kg.
CONCLUSIONS: Dosing of isoniazid based on N-acetyltransferase 2 acetylator
status may help patients attain effective exposures against inhA-mutated
isolates while mitigating toxicity risks associated with higher doses. Clinical
trial registration available at www.clinicaltrials.gov, ID: NCT01936831.
DOI: 10.1164/rccm.202103-0534OC
PMID: 34403326
11. J Natl Cancer Inst. 2021 Aug 17:djab157. doi: 10.1093/jnci/djab157. Online ahead of print.
Clinical Implications of Inter- and Intra-Tumor Heterogeneity of Immune Cell
Markers in Lung Cancer.
Zhao W(1), Zhu B(2), Hutchinson A(3), Pesatori AC(4)(5), Consonni D(5), Caporaso
NE(6), Zhang T(1), Wang D(3), Shi J(2), Landi MT(1).
Author information:
(1)Integrative Epidemiology Branch, Division of Cancer Epidemiology and
Genetics, National Cancer Institute, NIH, DHHS, Bethesda, MD, USA.
(2)Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National
Cancer Institute, NIH, DHHS, Bethesda, MD, USA.
(3)Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer
Research, Frederick, MD, USA.
…
BACKGROUND: Immune cell transcriptome signatures have been widely used to study
the lung tumor microenvironment (TME). However, it is unclear to what extent the
immune cell composition in the lung TME varies across histological and molecular
subtypes (inter-tumor heterogeneity or Inter-TH) and within tumors (intratumor
heterogeneity or ITH), and whether ITH has any prognostic relevance.
METHODS: Using RNA sequencing in 269 tumor samples from 160 lung cancer patients
we quantified the Inter-TH of immune gene expression and immune cell abundance
and evaluated the association of median immune cell abundance with
clinical/pathological features and overall survival. In 39 tumors with 132
multi-region samples, we also analyzed the ITH of immune cell abundance in
relation to overall survival using a variance-weighted multivariate Cox model
not biased by the number of samples per tumor.
RESULTS: Substantial Inter-TH of 14 immune cell types was observed even within
the same histological and molecular subtypes, but early-stage tumors had higher
lymphocyte infiltration across all tumor types. In multi-region samples, an
unbiased estimate of low ITH of overall immune cell composition (hazard ratio
[HR] = 0.40, 95% confidence interval [CI] = 0.21 to 0.78; P = .007), dendritic
cells (HR = 0.24, 95% CI = 0.096 to 0.58; P = .002) and macrophages (HR = 0.50,
95% CI = 0.30 to 0.84; P = .009) was strongly associated with poor survival. The
ITH of three markers, including CD163 and CD68 (macrophages) and CCL13
(dendritic cells), was enough to characterize the ITH of the corresponding
immune cell abundances and its association with overall survival.
CONCLUSION: This study suggests that lack of immune cell diversity may
facilitate tumor evasion and progression. ITH inferred from CCL13, CD163 and
CD68 could be used as a prognostic tool in clinical practice.
Published by Oxford University Press 2021.
DOI: 10.1093/jnci/djab157
PMID: 34402912
12. J Clin Oncol. 2021 Oct 1;39(28):3118-3127. doi: 10.1200/JCO.21.00639. Epub 2021 Aug 11.
Randomized Phase III Trial of Prophylactic Cranial Irradiation With or Without
Hippocampal Avoidance for Small-Cell Lung Cancer (PREMER): A GICOR-GOECP-SEOR
Study.
Rodríguez de Dios N(1)(2)(3), Couñago F(4), Murcia-Mejía M(5), Rico-Oses M(6),
Calvo-Crespo P(7), Samper P(8), Vallejo C(9), Luna J(10), Trueba I(11), Sotoca
A(12), Cigarral C(13), Farré N(14), Manero RM(15), Durán X(2), Gispert
JD(2)(3)(16)(17), Sánchez-Benavides G(2)(16)(18), Rognoni T(19), Torrente
M(20)(21), Capellades J(22), Jiménez M(23), Cabada T(24), Blanco M(25), Alonso
A(26), Martínez-San Millán J(27), Escribano J(28), González B(13), López-Guerra
JL(29).
Author information:
(1)Radiation Oncology, Hospital del Mar, Barcelona, Spain.
(2)IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.
(3)Pompeu Fabra University, Barcelona, Spain.
…
PURPOSE: Radiation dose received by the neural stem cells of the hippocampus
during whole-brain radiotherapy has been associated with neurocognitive decline.
The key concern using hippocampal avoidance-prophylactic cranial irradiation
(HA-PCI) in patients with small-cell lung cancer (SCLC) is the incidence of
brain metastasis within the hippocampal avoidance zone.
METHODS: This phase III trial enrolled 150 patients with SCLC (71.3% with
limited disease) to standard prophylactic cranial irradiation (PCI; 25 Gy in 10
fractions) or HA-PCI. The primary objective was the delayed free recall (DFR) on
the Free and Cued Selective Reminding Test (FCSRT) at 3 months; a decrease of 3
points or greater from baseline was considered a decline. Secondary end points
included other FCSRT scores, quality of life (QoL), evaluation of the incidence
and location of brain metastases, and overall survival (OS). Data were recorded
at baseline, and 3, 6, 12, and 24 months after PCI.
RESULTS: Participants' baseline characteristics were well balanced between the
two groups. The median follow-up time for living patients was 40.4 months.
Decline on DFR from baseline to 3 months was lower in the HA-PCI arm (5.8%)
compared with the PCI arm (23.5%; odds ratio, 5; 95% CI, 1.57 to 15.86; P =
.003). Analysis of all FCSRT scores showed a decline on the total recall (TR;
8.7% v 20.6%) at 3 months; DFR (11.1% v 33.3%), TR (20.3% v 38.9%), and total
free recall (14.8% v 31.5%) at 6 months, and TR (14.2% v 47.6%) at 24 months.
The incidence of brain metastases, OS, and QoL were not significantly different.
CONCLUSION: Sparing the hippocampus during PCI better preserves cognitive
function in patients with SCLC. No differences were observed with regard to
brain failure, OS, and QoL compared with standard PCI.
DOI: 10.1200/JCO.21.00639
PMID: 34379442
13. Am J Respir Crit Care Med. 2021 Aug 10. doi: 10.1164/rccm.202103-0564OC. Online ahead of print.
A Rapid Pharmacogenomic Assay to Detect NAT2 Polymorphisms and Guide Isoniazid
Dosing for Tuberculosis Treatment.
Verma R(1), Patil S(2), Zhang N(3), Moreira FMF(4), Vitorio MT(4), Santos
ADS(4), Wallace E(5), Gnanashanmugam D(5), Persing D(5), Savic R(6), Croda J(7),
Andrews JR(8).
Author information:
(1)Stanford University School of Medicine, 10624, Infectious Diseases and
Geographic Medicine, Stanford, California, United States.
(2)Stanford University School of Medicine, 10624, Infectious Diseases, Stanford,
California, United States.
(3)University of California San Francisco, 8785, Department of Bioengineering
and Therapeutic Sciences, San Francisco, California, United States.
…
RATIONALE: Standardized dosing of anti-tubercular drugs contributes to a
substantial incidence of toxicities, inadequate treatment response, and relapse,
in part due to variable drug levels achieved. Single nucleotide polymorphisms
(SNPs) in the N-acetyltransferase-2 (NAT2) gene explain the majority of
interindividual pharmacokinetic variability of isoniazid (INH). However, an
obstacle to implementing pharmacogenomic-guided dosing is the lack of a
point-of-care assay.
OBJECTIVES: To develop and test a NAT2 classification algorithm, validate its
performance in predicting isoniazid clearance, and develop a prototype
pharmacogenomic assay.
METHODS: We trained random forest models to predict NAT2 acetylation genotype
from unphased SNP data using a global collection of 8,561 phased genomes. We
enrolled 48 pulmonary TB patients, performed sparse pharmacokinetic sampling,
and tested the acetylator prediction algorithm accuracy against estimated INH
clearance. We then developed a cartridge-based multiplex qPCR assay on the
GeneXpert platform and assessed its analytical sensitivity on whole blood
samples from healthy individuals.
MEASUREMENTS AND MAIN RESULTS: With a 5-SNP model trained on two-thirds of the
data (n=5,738), out-of-sample acetylation genotype prediction accuracy on the
remaining third (n=2,823) was 100%. Among the 48 TB patients, predicted
acetylator types were: 27 (56.2%) slow, 16 (33.3%) intermediate and 5 (10.4%)
rapid. INH clearance rates were lowest in predicted slow acetylators (median
14.5 L/hr), moderate in intermediate acetylators (median 40.3 L/hr) and highest
in fast acetylators (median 53.0 L/hr). The cartridge-based assay accurately
detected all allele patterns directly from 25 ul of whole blood.
CONCLUSIONS: An automated pharmacogenomic assay on a platform widely used
globally for tuberculosis diagnosis could enable personalized dosing of
isoniazid.
DOI: 10.1164/rccm.202103-0564OC
PMID: 34375564
14. Lancet Infect Dis. 2021 Aug 4:S1473-3099(21)00052-9. doi:
10.1016/S1473-3099(21)00052-9. Online ahead of print.
Initiation and completion of treatment for latent tuberculosis infection in
migrants globally: a systematic review and meta-analysis.
Rustage K(1), Lobe J(1), Hayward SE(2), Kristensen KL(3), Margineanu I(4),
Stienstra Y(5), Goletti D(6), Zenner D(7), Noori T(8), Pareek M(9), Greenaway
C(10), Friedland JS(1), Nellums LB(11), Hargreaves S(12); ESGITM and ESGMYC
study groups.
Author information:
(1)The Migrant Health Research Group, Institute for Infection and Immunity, St
George's University of London, London, UK.
(2)The Migrant Health Research Group, Institute for Infection and Immunity, St
George's University of London, London, UK; Faculty of Public Health and Policy,
London School of Hygiene & Tropical Medicine, London, UK.
(3)Research Centre for Migration, Ethnicity and Health, University of
Copenhagen, Copenhagen, Denmark; International Reference Laboratory of
Mycobacteriology, Statens Serum Institut, Copenhagen, Denmark.
…
BACKGROUND: Latent tuberculosis infection (LTBI) is one of the most prevalent
infections globally and can lead to the development of active tuberculosis
disease. In many low-burden countries, LTBI is concentrated within migrant
populations often because of a higher disease burden in the migrant's country of
origin. National programmes consequently focus on screening and treating LTBI in
migrants to prevent future tuberculosis cases; however, how effective these
programmes are is unclear. We aimed to assess LTBI treatment initiation and
outcomes among migrants, and the factors that influence both.
METHODS: For this systematic review and meta-analysis, we searched Embase,
MEDLINE, and Global Health, and manually searched grey literature from Jan 1,
2000, to April 21, 2020. We included primary research articles reporting on LTBI
treatment initiation or completion, or both, in migrants and excluded articles
in which data were not stratified by migrant status, or in which the data were
related to outcomes before 2000. There were no geographical or language
restrictions. All included studies were quality appraised using recognised tools
depending on their design, and we assessed the heterogeneity of analyses using
I2. We extracted data on the numbers of migrants initiating and completing
treatment. Our primary outcomes were LTBI treatment initiation and completion in
migrants (defined as foreign-born). We used random-effects meta-regression to
examine the influence of factors related to these outcomes. The study is
registered with PROSPERO (CRD42019140338).
FINDINGS: 2199 publications were retrieved screened, after which 39 publications
from 13 mostly high-income, low-burden countries were included in our analyses,
with treatment initiation and completion data reported for 31 598 migrants
positive for LTBI, with not all articles reporting the full pathway from
initiation to completion. The pooled estimate for the true proportion of
migrants testing positive who initiated treatment was 69% (95% CI 51-84; I2=
99·62%; 4409 of 8764). The pooled estimate for the true proportion of migrants
on treatment in datasets, who subsequently completed it was 74% (95% CI = 66-81;
I2= 99·19%; 15 516 of 25 629). Where data were provided for the entire treatment
pathway, the pooled estimate for the true proportion of migrants who initiated
and completed treatment after a positive test was only 52% (95% CI 40-64; I2=
98·90%; 3289 of 6652). Meta-regression showed that LTBI programmes are
improving, with more recent reported data (2010-20) associated with better rates
of treatment initiation and completion, with multiple complex factors affecting
treatment outcomes in migrants.
INTERPRETATION: Although our analysis highlights that LTBI treatment initiation
and completion in migrants has improved considerably from 2010-20, there is
still room for improvement, with drop out reported along the entire treatment
pathway. The delivery of these screening and treatment programmes will require
further strengthening if the targets to eradicate tuberculosis in low-incidence
countries are to be met, with greater focus needed on engaging migrants more
effectively in the clinic and understanding the diverse and unique barriers and
facilitators to migrants initiating and completing treatment.
FUNDING: European Society of Clinical Microbiology and Infectious Diseases, the
Rosetrees Trust, the National Institute for Health Research, and the Academy of
Medical Sciences.
Copyright © 2021 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(21)00052-9
PMID: 34363771
15. Nat Commun. 2021 Aug 4;12(1):4702. doi: 10.1038/s41467-021-25055-y.
Reversible gene silencing through frameshift indels and frameshift scars provide
adaptive plasticity for Mycobacterium tuberculosis.
Gupta A(1), Alland D(2).
Author information:
(1)Center for Emerging Pathogens, New Jersey Medical School, Rutgers University,
Newark, NJ, USA. aditi9783@gmail.com.
(2)Center for Emerging Pathogens, New Jersey Medical School, Rutgers University,
Newark, NJ, USA. david.alland@rutgers.edu.
Mycobacterium tuberculosis can adapt to changing environments by non-heritable
mechanisms. Frame-shifting insertions and deletions (indels) may also
participate in adaptation through gene disruption, which could be reversed by
secondary introduction of a frame-restoring indel. We present ScarTrek, a
program that scans genomic data for indels, including those that together
disrupt and restore a gene's reading frame, producing "frame-shift scars"
suggestive of reversible gene inactivation. We use ScarTrek to analyze 5977
clinical M. tuberculosis isolates. We show that indel frequency inversely
correlates with genomic linguistic complexity and varies with gene-position and
gene-essentiality. Using ScarTrek, we detect 74 unique frame-shift scars in 48
genes, with a 3.74% population-level incidence of unique scar events. We find
multiple scars in the ESX-1 gene cluster. Six scars show evidence of convergent
evolution while the rest shared a common ancestor. Our results suggest that
sequential indels are a mechanism for reversible gene silencing and adaptation
in M. tuberculosis.
© 2021. The Author(s).
DOI: 10.1038/s41467-021-25055-y
PMCID: PMC8339072
PMID: 34349104 [Indexed for MEDLINE]
16. J Exp Med. 2021 Oct 4;218(10):e20210469. doi: 10.1084/jem.20210469. Epub 2021 Aug 4.
Eosinophils are part of the granulocyte response in tuberculosis and promote
host resistance in mice.
Bohrer AC(#)(1), Castro E(#)(1), Hu Z(#)(2)(3), Queiroz ATL(4), Tocheny CE(1),
Assmann M(1), Sakai S(5), Nelson C(5), Baker PJ(1), Ma H(2)(3), Wang L(3)(6),
Zilu W(3)(6), du Bruyn E(7), Riou C(7), Kauffman KD(5); Tuberculosis Imaging
Program, Moore IN(8), Del Nonno F(9), Petrone L(10), Goletti D(10), Martineau
AR(11), Lowe DM(11), Cronan MR(12)(13), Wilkinson RJ(7)(14)(15), Barry
CE(7)(16), Via LE(17)(16), Barber DL(5), Klion AD(18), Andrade BB(4), Song
Y(3)(6), Wong KW(2)(3), Mayer-Barber KD(1).
Author information:
(1)Inflammation and Innate Immunity Unit, Laboratory of Clinical Immunology and
Microbiology, National Institute of Allergy and Infectious Diseases, National
Institutes of Health, Bethesda, MD.
(2)Department of Scientific Research, Shanghai Public Health Clinical Center,
Fudan University, Shanghai, China.
(3)Tuberculosis Center, Shanghai Emerging and Re-emerging Infectious Disease
Institute, Fudan University, Shanghai, China.
…
Host resistance to Mycobacterium tuberculosis (Mtb) infection requires the
activities of multiple leukocyte subsets, yet the roles of the different innate
effector cells during tuberculosis are incompletely understood. Here we uncover
an unexpected association between eosinophils and Mtb infection. In humans,
eosinophils are decreased in the blood but enriched in resected human
tuberculosis lung lesions and autopsy granulomas. An influx of eosinophils is
also evident in infected zebrafish, mice, and nonhuman primate granulomas, where
they are functionally activated and degranulate. Importantly, using
complementary genetic models of eosinophil deficiency, we demonstrate that in
mice, eosinophils are required for optimal pulmonary bacterial control and host
survival after Mtb infection. Collectively, our findings uncover an unexpected
recruitment of eosinophils to the infected lung tissue and a protective role for
these cells in the control of Mtb infection in mice.
© 2021 Bohrer et al.
DOI: 10.1084/jem.20210469
PMCID: PMC8348215
PMID: 34347010
17. Am J Respir Crit Care Med. 2021 Aug 4. doi: 10.1164/rccm.202101-0117OC. Online ahead of print.
Precision-enhancing Risk Stratification Tools for Selecting Optimal Treatment
Durations in Tuberculosis Clinical Trials.
Imperial MZ(1), Phillips PPJ(2), Nahid P(3), Savic RM(4).
Author information:
(1)University of California San Francisco, 8785, San Francisco, California,
United States.
(2)University of California San Francisco, 8785, Medicine, San Francisco,
California, United States.
(3)University of California San Francisco, 8785, Pulmonary and Critical Care
Medicine, San Francisco, California, United States.
(4)University of California San Francisco, 8785, Pulmonary and Critical Care
Medicine, San Francisco, California, United States; rada.savic@ucsf.edu.
RATIONALE: No evidence-based tools exist to enhance precision in selection of
patient-specific optimal treatment durations to study in tuberculosis clinical
trials.
OBJECTIVES: Develop risk stratification tools that assigns tuberculosis patients
into risk groups of unfavorable outcome and informs selection of optimal
treatment duration for each patient strata to study in clinical trials.
METHODS: Publicly-available data from four phase 3 trials, each evaluating
treatment duration shortening from 6 to 4 months, were used to develop
parametric time-to-event models that describe unfavorable outcomes. Regimen,
baseline, and on-treatment characteristics were evaluated as predictors of
outcomes. Exact regression coefficients of predictors were used to assign risk
groups and predict optimal treatment durations.
MAIN RESULTS: The parametric model had an area under the receiver operating
characteristic curve of 0.72. A six-item risk score (HIV status, smear grade,
sex, cavitary disease status, BMI and month 2 culture status) successfully
grouped participants into low (1060/3791,28%), moderate (1740/3791,46%), and
high (991/3791,26%) risk, requiring treatment durations of 4, 6 and greater than
6 months, respectively, to reach a target cure rate of 93% when receiving
standard-dose rifamycin-containing regimens. With current one-duration-fits-all
approaches, high risk groups have 3.7-fold (95%CI: 2.7-5.1) and 2.4-fold
(1.9-2.9) higher hazard risk of unfavorable outcome compared to low and moderate
groups, respectively. Four-month regimens were noninferior to the standard
6-month regimen in the low risk group.
CONCLUSIONS: Our model discrimination was modest but consistent with current
models of unfavorable outcomes. Our results showed that stratified medicine
approaches is feasible and may achieve high cure rates in all tuberculosis
patients. An interactive risk stratification tool is provided to facilitate
decision making in the regimen development pathway. This article is open access
and distributed under the terms of the Creative Commons Attribution
Non-Commercial No Derivatives License 4.0
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
DOI: 10.1164/rccm.202101-0117OC
PMID: 34346856
18. Am J Respir Crit Care Med. 2021 Aug 3. doi: 10.1164/rccm.202101-0136OC. Online ahead of print.
Indoor Air Pollution and Susceptibility to Tuberculosis Infection in Urban
Vietnamese Children.
Blount RJ(1), Phan H(2)(3), Trinh T(2)(3), Dang H(2)(3), Merrifield C(4)(5)(6),
Zavala M(7), Zabner J(7), Comellas AP(8), Stapleton EM(9), Segal MR(10), Balmes
J(11)(12), Nhung NV(2)(13), Nahid P(4)(14)(15).
Author information:
(1)UI Carver College of Medicine, 12243, Pulmonary and Critical Care Medicine,
Iowa City, Iowa, United States; robert-blount@uiowa.edu.
(2)Vietnam National Tuberculosis Program - University of California San
Francisco Research Collaboration Unit, Hanoi, Viet Nam.
(3)Center for Promotion of Advancement of Society, Vietnam, Hanoi, Viet Nam.
…
RATIONALE: The Southeast Asian tuberculosis burden is high, and it remains
unclear if urban indoor air pollution in this setting is exacerbating the
epidemic.
OBJECTIVES: To determine the associations of latent tuberculosis with common
urban indoor air pollution sources (secondhand smoke, indoor motorcycle
emissions, and cooking) in Southeast Asia.
METHODS: We enrolled child household contacts of patients with microbiologically
confirmed active tuberculosis in Vietnam, July 2017-December 2019. We tested
children for latent tuberculosis and evaluated air pollution exposures with
questionnaires and personal aerosol sampling. We tested hypotheses using
generalized estimating equations.
MEASUREMENTS AND MAIN RESULTS: We enrolled 72 tuberculosis patients (27% with
cavitary disease) and 109 of their child household contacts. Of household
contacts, 58 (53%) were diagnosed with latent tuberculosis at baseline visit.
Children experienced a 2.56-fold increased odds of latent tuberculosis for each
additional household member who smoked (95%CI 1.27-5.16). Odds were highest
among children exposed to indoor smokers and children under five years old
exposed to household smokers. Each residential floor above street-level
pollution decreased the odds of latent tuberculosis by 36% (aOR 0.64, 95%CI
0.42-0.96). Motorcycles parked inside children's homes and cooking with liquid
petroleum gas compared to electricity increased the odds of latent tuberculosis
while kitchen ventilation decreased the effect, but these findings were not
statistically significant.
CONCLUSION: Common urban indoor air pollution sources were associated with
increased odds of latent tuberculosis infection in child household contacts of
active tuberculosis patients.
DOI: 10.1164/rccm.202101-0136OC
PMID: 34343025
19. J Clin Oncol. 2021 Aug 2:JCO2100662. doi: 10.1200/JCO.21.00662. Online ahead of print.
Amivantamab in EGFR Exon 20 Insertion-Mutated Non-Small-Cell Lung Cancer
Progressing on Platinum Chemotherapy: Initial Results From the CHRYSALIS Phase I Study.
Park K(1), Haura EB(2), Leighl NB(3), Mitchell P(4), Shu CA(5), Girard N(6),
Viteri S(7), Han JY(8), Kim SW(9), Lee CK(10), Sabari JK(11), Spira AI(12), Yang
TY(13), Kim DW(14), Lee KH(15), Sanborn RE(16), Trigo J(17), Goto K(18), Lee
JS(19), Yang JC(20), Govindan R(21), Bauml JM(22), Garrido P(23), Krebs MG(24),
Reckamp KL(25), Xie J(26), Curtin JC(26), Haddish-Berhane N(26), Roshak A(26),
Millington D(26), Lorenzini P(26), Thayu M(26), Knoblauch RE(26), Cho BC(27).
Author information:
(1)Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul,
South Korea.
(2)H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
(3)Princess Margaret Cancer Centre, Toronto, Canada.
…
Comment in
Nat Rev Clin Oncol. 2021 Oct;18(10):604.
PURPOSE: Non-small-cell lung cancer (NSCLC) with epidermal growth factor
receptor (EGFR) exon 20 insertion (Exon20ins) mutations exhibits inherent
resistance to approved tyrosine kinase inhibitors. Amivantamab, an EGFR-MET
bispecific antibody with immune cell-directing activity, binds to each
receptor's extracellular domain, bypassing resistance at the tyrosine kinase
inhibitor binding site.
METHODS: CHRYSALIS is a phase I, open-label, dose-escalation, and dose-expansion
study, which included a population with EGFR Exon20ins NSCLC. The primary end
points were dose-limiting toxicity and overall response rate. We report findings
from the postplatinum EGFR Exon20ins NSCLC population treated at the recommended
phase II dose of 1,050 mg amivantamab (1,400 mg, ≥ 80 kg) given once weekly for
the first 4 weeks and then once every 2 weeks starting at week 5.
RESULTS: In the efficacy population (n = 81), the median age was 62 years
(range, 42-84 years); 40 patients (49%) were Asian, and the median number of
previous lines of therapy was two (range, 1-7). The overall response rate was
40% (95% CI, 29 to 51), including three complete responses, with a median
duration of response of 11.1 months (95% CI, 6.9 to not reached). The median
progression-free survival was 8.3 months (95% CI, 6.5 to 10.9). In the safety
population (n = 114), the most common adverse events were rash in 98 patients
(86%), infusion-related reactions in 75 (66%), and paronychia in 51 (45%). The
most common grade 3-4 adverse events were hypokalemia in six patients (5%) and
rash, pulmonary embolism, diarrhea, and neutropenia in four (4%) each.
Treatment-related dose reductions and discontinuations were reported in 13% and
4% of patients, respectively.
CONCLUSION: Amivantamab, via its novel mechanism of action, yielded robust and
durable responses with tolerable safety in patients with EGFR Exon20ins
mutations after progression on platinum-based chemotherapy.
DOI: 10.1200/JCO.21.00662
PMID: 34339292
20. J Clin Invest. 2021 Aug 2;131(15):e151810. doi: 10.1172/JCI151810.
Tuberculosis lymph node granulomas: using transcriptomics to discover
immunopathology paradigms and guide host-directed therapy.
Phelan JJ, O'Leary S, Keane J.
Comment on
Integrated transcriptomic analysis of human tuberculosis granulomas and a
biomimetic model identifies therapeutic targets.
Immunometabolism is a burgeoning field of investigation in tuberculosis host
defense, susceptibility, and pathophysiology. Unbiased approaches to studying
tuberculosis have, as expected, confirmed that pathways of immunometabolism are
crucial in these disease processes. In this issue of the JCI, Reichmann et al.
studied carefully controlled human lymph node tuberculosis and uncovered
Sphingosine kinase 1 as a druggable target of interest that could support the
infected host. Future host-directed therapy research might seek to establish the
different cellular consequences of sphingolipid pathway manipulation. Animal
models will be especially useful to establish the role of this pathway, which
might target diseased organs to improve mycobactericidal effect and limit
pathology.
DOI: 10.1172/JCI151810
PMCID: PMC8321565
PMID: 34338227
21. Immunity. 2021 Aug 10;54(8):1758-1771.e7. doi: 10.1016/j.immuni.2021.06.009.
Epub 2021 Jul 12.
Macrophage and neutrophil death programs differentially confer resistance to
tuberculosis.
Stutz MD(1), Allison CC(1), Ojaimi S(1), Preston SP(1), Doerflinger M(1),
Arandjelovic P(1), Whitehead L(1), Bader SM(1), Batey D(1), Asselin-Labat ML(1),
Herold MJ(1), Strasser A(1), West NP(2), Pellegrini M(3).
Author information:
(1)The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052,
Australia; Department of Medical Biology, The University of Melbourne,
Parkville, VIC 3010, Australia.
(2)School of Chemistry and Molecular Bioscience, The University of Queensland,
St Lucia, QLD 4072, Australia.
(3)The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052,
Australia; Department of Medical Biology, The University of Melbourne,
Parkville, VIC 3010, Australia. Electronic address: pellegrini@wehi.edu.au.
Comment in
Immunity. 2021 Aug 10;54(8):1625-1627.
Apoptosis can potently defend against intracellular pathogens by directly
killing microbes and eliminating their replicative niche. However, the reported
ability of Mycobacterium tuberculosis to restrict apoptotic pathways in
macrophages in vitro has led to apoptosis being dismissed as a host-protective
process in tuberculosis despite a lack of in vivo evidence. Here we define
crucial in vivo functions of the death receptor-mediated and BCL-2-regulated
apoptosis pathways in mediating protection against tuberculosis by eliminating
distinct populations of infected macrophages and neutrophils and priming T cell
responses. We further show that apoptotic pathways can be targeted
therapeutically with clinical-stage compounds that antagonize inhibitor of
apoptosis (IAP) proteins to promote clearance of M. tuberculosis in mice. These
findings reveal that any inhibition of apoptosis by M. tuberculosis is
incomplete in vivo, advancing our understanding of host-protective responses to
tuberculosis (TB) and revealing host pathways that may be targetable for
treatment of disease.
Copyright © 2021 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.immuni.2021.06.009
PMID: 34256013 [Indexed for MEDLINE]
22. J Clin Invest. 2021 Aug 16;131(16):e141833. doi: 10.1172/JCI141833.
WNT6/ACC2-induced storage of triacylglycerols in macrophages is exploited by
Mycobacterium tuberculosis.
Brandenburg J(1)(2), Marwitz S(3)(4), Tazoll SC(1), Waldow F(2)(5), Kalsdorf
B(2)(6), Vierbuchen T(7), Scholzen T(8), Gross A(1), Goldenbaum S(1), Hölscher
A(9), Hein M(8), Linnemann L(10), Reimann M(6), Kispert A(11), Leitges M(12),
Rupp J(2)(13), Lange C(2)(6)(14)(15), Niemann S(2)(16), Behrends J(8), Goldmann
T(3)(4), Heine H(7), Schaible UE(2)(10), Hölscher C(2)(9), Schwudke D(2)(4)(5),
Reiling N(1)(2).
Author information:
(1)Microbial Interface Biology, Research Center Borstel, Leibniz Lung Center,
Borstel, Germany.
(2)German Center for Infection Research (DZIF), Site
Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany.
(3)Pathology, Research Center Borstel, Borstel, Germany.
…
In view of emerging drug-resistant tuberculosis (TB), host-directed adjunct
therapies are urgently needed to improve treatment outcomes with currently
available anti-TB therapies. One approach is to interfere with the formation of
lipid-laden "foamy" macrophages in the host, as they provide a nutrient-rich
host cell environment for Mycobacterium tuberculosis (Mtb). Here, we provide
evidence that Wnt family member 6 (WNT6), a ligand of the evolutionarily
conserved Wingless/Integrase 1 (WNT) signaling pathway, promotes foam cell
formation by regulating key lipid metabolic genes including acetyl-CoA
carboxylase 2 (ACC2) during pulmonary TB. Using genetic and pharmacological
approaches, we demonstrated that lack of functional WNT6 or ACC2 significantly
reduced intracellular triacylglycerol (TAG) levels and Mtb survival in
macrophages. Moreover, treatment of Mtb-infected mice with a combination of a
pharmacological ACC2 inhibitor and the anti-TB drug isoniazid (INH) reduced lung
TAG and cytokine levels, as well as lung weights, compared with treatment with
INH alone. This combination also reduced Mtb bacterial numbers and the size of
mononuclear cell infiltrates in livers of infected mice. In summary, our
findings demonstrate that Mtb exploits WNT6/ACC2-induced storage of TAGs in
macrophages to facilitate its intracellular survival, a finding that opens new
perspectives for host-directed adjunctive treatment of pulmonary TB.
DOI: 10.1172/JCI141833
PMCID: PMC8363280
PMID: 34255743
23. J Clin Oncol. 2021 Aug 10;39(23):2574-2585. doi: 10.1200/JCO.20.02574. Epub 2021 Jun 2.
Benefits and Harms of Lung Cancer Screening by Chest Computed Tomography: A
Systematic Review and Meta-Analysis.
Passiglia F(1), Cinquini M(2), Bertolaccini L(3), Del Re M(4), Facchinetti F(5),
Ferrara R(6), Franchina T(7), Larici AR(8), Malapelle U(9), Menis J(10)(11),
Passaro A(12), Pilotto S(13), Ramella S(14), Rossi G(15), Trisolini R(16),
Novello S(1).
Author information:
(1)Department of Oncology, San Luigi Hospital, University of Turin, Orbassano
(TO), Italy.
(2)Mario Negri Institute for Pharmacological Research IRCCS, Milan, Italy.
(3)Division of Thoracic Surgery, IEO, European Institute of Oncology IRCCS,
Milan, Italy.
…
Erratum in
J Clin Oncol. 2021 Oct 1;39(28):3192-3193.
PURPOSE: This meta-analysis aims to combine and analyze randomized clinical
trials comparing computed tomography lung screening (CTLS) versus either no
screening (NS) or chest x-ray (CXR) in subjects with cigarette smoking history,
to provide a precise and reliable estimation of the benefits and harms
associated with CTLS.
MATERIALS AND METHODS: Data from all published randomized trials comparing CTLS
versus either NS or CXR in a highly tobacco-exposed population were collected,
according to the Preferred Reporting Items for Systematic Reviews and
Meta-Analyses guidelines. Subgroup analyses by comparator (NS or CXR) were
performed. Pooled risk ratio (RR) and relative 95% CIs were calculated for
dichotomous outcomes. The certainty of the evidence was assessed using the GRADE
approach.
RESULTS: Nine eligible trials (88,497 patients) were included. Pooled analysis
showed that CTLS is associated with: a significant reduction of lung
cancer-related mortality (overall RR, 0.87; 95% CI, 0.78 to 0.98; NS RR, 0.80;
95% CI, 0.69 to 0.92); a significant increase of early-stage tumors diagnosis
(overall RR, 2.84; 95% CI 1.76 to 4.58; NS RR, 3.33; 95% CI, 2.27 to 4.89; CXR
RR, 1.52; 95% CI, 1.04 to 2.23); a significant decrease of late-stage tumors
diagnosis (overall RR, 0.75; 95% CI, 0.68 to 0.83; NS RR, 0.67; 95% CI, 0.56 to
0.80); a significant increase of resectability rate (NS RR, 2.57; 95% CI, 1.76
to 3.74); a nonsignificant reduction of all-cause mortality (overall RR, 0.99;
95% CI, 0.94 to 1.05); and a significant increase of overdiagnosis rate (NS,
38%; 95% CI, 14 to 63). The analysis of lung cancer-related mortality by sex
revealed nonsignificant differences between men and women (P = .21; I-squared =
33.6%).
CONCLUSION: Despite there still being uncertainty about overdiagnosis estimate,
this meta-analysis suggested that the CTLS benefits outweigh harms, in subjects
with cigarette smoking history, ultimately supporting the systematic
implementation of lung cancer screening worldwide.
DOI: 10.1200/JCO.20.02574
PMID: 34236916
24. J Clin Invest. 2021 Aug 2;131(15):e148136. doi: 10.1172/JCI148136.
Integrated transcriptomic analysis of human tuberculosis granulomas and a
biomimetic model identifies therapeutic targets.
Reichmann MT(1), Tezera LB(1)(2), Vallejo AF(1), Vukmirovic M(3)(4), Xiao R(5),
Reynolds J(6), Jogai S(1), Wilson S(1), Marshall B(1), Jones MG(1), Leslie
A(2)(7), D'Armiento JM(5), Kaminski N(4), Polak ME(1)(8), Elkington P(1)(8).
Author information:
(1)NIHR Biomedical Research Center, School of Clinical and Experimental
Sciences, Faculty of Medicine, University of Southampton, Southampton, United
Kingdom.
(2)Department of Infection and Immunity, University College London, London,
United Kingdom.
(3)Firestone Institute for Respiratory Health-Division of Respirology,
Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
…
Comment in
Tuberculosis lymph node granulomas: using transcriptomics to discover
immunopathology paradigms and guide host-directed therapy.
Tuberculosis (TB) is a persistent global pandemic, and standard treatment for it
has not changed for 30 years. Mycobacterium tuberculosis (Mtb) has undergone
prolonged coevolution with humans, and patients can control Mtb even after
extensive infection, demonstrating the fine balance between protective and
pathological host responses within infected granulomas. We hypothesized that
whole transcriptome analysis of human TB granulomas isolated by laser capture
microdissection could identify therapeutic targets, and that comparison with a
noninfectious granulomatous disease, sarcoidosis, would identify
disease-specific pathological mechanisms. Bioinformatic analysis of RNAseq data
identified numerous shared pathways between TB and sarcoidosis lymph nodes, and
also specific clusters demonstrating TB results from a dysregulated inflammatory
immune response. To translate these insights, we compared 3 primary human cell
culture models at the whole transcriptome level and demonstrated that the 3D
collagen granuloma model most closely reflected human TB disease. We
investigated shared signaling pathways with human disease and identified 12
intracellular enzymes as potential therapeutic targets. Sphingosine kinase 1
inhibition controlled Mtb growth, concurrently reducing intracellular pH in
infected monocytes and suppressing inflammatory mediator secretion.
Immunohistochemical staining confirmed that sphingosine kinase 1 is expressed in
human lung TB granulomas, and therefore represents a host therapeutic target to
improve TB outcomes.
DOI: 10.1172/JCI148136
PMCID: PMC8321576
PMID: 34128839
25. Lancet Infect Dis. 2021 Aug;21(8):1175-1183. doi: 10.1016/S1473-3099(20)30732-5. Epub 2021 Mar 23.
Measuring health-care delays among privately insured patients with tuberculosis
in the USA: an observational cohort study.
El Halabi J(1), Palmer N(1), McDuffie M(1), Golub JJ(2), Fox K(1), Kohane I(1),
Farhat MR(3).
Author information:
(1)Department of Biomedical Informatics, Harvard Medical School, Boston, MA,
USA.
(2)Center for Tuberculosis Research, Johns Hopkins University, Baltimore, MD,
USA.
(3)Department of Biomedical Informatics, Harvard Medical School, Boston, MA,
USA; Division of Pulmonary and Critical Care Medicine, Massachusetts General
Hospital, Boston, MA, USA. Electronic address: maha_farhat@hms.harvard.edu.
BACKGROUND: A high index of suspicion is needed to initiate appropriate testing
for tuberculosis due to its protean symptoms, yet health-care providers in
low-incidence settings are becoming less familiar with the disease as rates
decline. We aimed to estimate delays in tuberculosis diagnosis and treatment at
the US national level between 2008 and 2016.
METHODS: In this retrospective observational cohort study, we repurposed private
insurance claims data provided by Aetna (Connecticut, USA), to measure
health-care delays in tuberculosis diagnosis in the USA in 2008-16. Active
tuberculosis was determined by diagnosis codes and the filling of
anti-tuberculosis treatment prescriptions. Health-care delays were defined as
the duration between the first health-care visit for a tuberculosis symptom and
the initiation of anti-tuberculosis treatment. We assessed if delays varied over
time, and by patient and system variables, using multivariable regression. We
estimated household tuberculosis transmission and respiratory complications
after treatment initiation.
FINDINGS: We confirmed 738 active tuberculosis cases (incidence 1·45 per 100 000 person-years) with a median health-care delay of 24 days (IQR 10-45).
Multivariable regression analysis showed that longer delays were associated with
older age (8·4% per 10 year increase [95% CI 4·0 to 13·1]; p<0·0086) and non-HIV immunosuppression (19·2% [15·1 to 60·0]; p=0·0432). Presenting with three or more symptoms was associated with a shorter delay (-22·5% [-39·1 to -2·0]; p=0·0415), relative to presenting with one symptom, as did use of chest imaging (-24·9% [-37·9 to -8·9]; p<0·0098), tuberculosis nucleic acid amplification tests (-19·2% [-32·7 to -3·1]; p=0·0241), and care by a tuberculosis specialist provider (-17·2% [-33·1 to -22·3]; p<0·0087). Longer delays were associated with an increased rate of respiratory complications even after controlling for patient characteristics, and an increased rate of secondary tuberculosis among dependents.
INTERPRETATION: In the USA, the median health-care delay for privately insured
patients with tuberculosis exceeds WHO-recommended levels of 21 days (3 weeks).
The results suggest the need for health-care provider education on best
practices in tuberculosis diagnosis, including the use of molecular tests and
the maintenance of a high index of suspicion for the disease.
FUNDING: US National Institutes of Health.
Copyright © 2021 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1473-3099(20)30732-5
PMID: 33770534 [Indexed for MEDLINE]
26. Am J Respir Crit Care Med. 2021 Aug 1;204(3):347-356. doi:
10.1164/rccm.202007-2634OC.
Glycemic Trajectories and Treatment Outcomes of Patients with Newly Diagnosed
Tuberculosis: A Prospective Study in Eastern China.
Liu Q(1)(2), You N(1)(3), Pan H(4), Shen Y(5), Lu P(1), Wang J(2), Lu W(1), Zhu
L(1), Martinez L(6).
Author information:
(1)Department of Chronic Communicable Disease, Center for Disease Control and
Prevention of Jiangsu Province, Nanjing, People's Republic of China.
(2)Department of Epidemiology, School of Public Health, Nanjing Medical
University, Nanjing, People's Republic of China.
(3)The Second Affiliated Hospital of Zhejiang Chinese Medical University,
Hangzhou, People's Republic of China.
(4)Department of Tuberculosis, The Third People's Hospital of Zhenjiang
Affiliated to Jiangsu University, Zhenjiang, People's Republic of China.
(5)Department of Epidemiology and Biostatistics, School of Public Health,
University of Georgia, Athens, Georgia; and.
(6)Department of Epidemiology, School of Public Health, Boston University,
Boston, Massachusetts.
Comment in
Am J Respir Crit Care Med. 2021 Aug 1;204(3):254-255.
Rationale: Patients with newly diagnosed tuberculosis often have inconsistent
glycemic measurements during and after treatment. Distinct glycemic trajectories
after the diagnosis of tuberculosis are not well characterized, and whether
patients with stress hyperglycemia have poor treatment outcomes is not
known.Objectives: To identify distinct glycemic trajectories from the point of
tuberculosis diagnosis to the posttreatment period and to assess the
relationship between glycemic trajectories and tuberculosis treatment
outcomes.Methods: Patients with newly diagnosed, drug-susceptible tuberculosis
and with at least three fasting plasma glucose tests at tuberculosis diagnosis
and during the third and sixth month of treatment were identified and included
from Jiangsu Province, China. Patients were also given an additional fasting
plasma glucose test at 2 and 4 months after treatment.Measurements and Main
Results: Several distinct glycemic trajectories from the point of tuberculosis
diagnosis to the posttreatment period were found, including consistently normal
glycemic testing results (43%), transient hyperglycemia (24%), erratic glycemic
instability (12%), diabetes (16%), and consistent hyperglycemia without diabetes
(6%). Compared with participants with a consistently normal glycemic trajectory,
patients with transient hyperglycemia were more likely to experience treatment
failure (adjusted odds ratio [AOR], 4.20; 95% confidence interval [CI],
1.57-11.25; P = 0.004) or erratic glycemic instability (AOR, 5.98; 95% CI,
2.00-17.87; P = 0.001). Patients living with diabetes also had a higher risk of
experiencing treatment failure (AOR, 6.56; 95% CI, 2.22-19.35; P = 0.001), and
this was modified by glycemic control and metformin use.Conclusions: Among
patients with tuberculosis without diabetes, glycemic changes were common and
may represent an important marker for patient response to tuberculosis
treatment.
DOI: 10.1164/rccm.202007-2634OC
PMID: 33705666 [Indexed for MEDLINE]
