2023年
No.3
PubMed
(tuberculosis[Title/Abstract]) OR (lung cancer[Title/Abstract])
Filters applied: from 2023/3/1 - 2023/3/31.
1. Nature. 2023 Mar;615(7953):712-719. doi: 10.1038/s41586-023-05793-3. Epub 2023
Mar 15.
Spatial mapping of mitochondrial networks and bioenergetics in lung cancer.
Han M(1), Bushong EA(2)(3), Segawa M(4), Tiard A(5), Wong A(6), Brady MR(1),
Momcilovic M(1), Wolf DM(4)(7), Zhang R(1), Petcherski A(8), Madany M(2)(3), Xu
S(9)(10)(11), Lee JT(9)(10)(11)(12), Poyurovsky MV(13), Olszewski K(13),
Holloway T(9), Gomez A(14), John MS(11)(15), Dubinett SM(1)(9)(11)(16)(17),
Koehler CM(14)(18), Shirihai OS(8)(9)(11), Stiles L(8)(9), Lisberg A(11)(19),
Soatto S(5), Sadeghi S(20), Ellisman MH(2)(3), Shackelford DB(21)(22).
Author information:
(1)Pulmonary and Critical Care Medicine, David Geffen School of Medicine
(DGSOM), University of California Los Angeles (UCLA), Los Angeles, CA, USA.
(2)Department of Neurosciences, University of California San Diego (UCSD), San
Diego, CA, USA.
(3)National Center for Microscopy and Imaging Research, UCSD, San Diego, CA,
USA.
…
Mitochondria are critical to the governance of metabolism and bioenergetics in
cancer cells1. The mitochondria form highly organized networks, in which their
outer and inner membrane structures define their bioenergetic capacity2,3.
However, in vivo studies delineating the relationship between the structural
organization of mitochondrial networks and their bioenergetic activity have been
limited. Here we present an in vivo structural and functional analysis of
mitochondrial networks and bioenergetic phenotypes in non-small cell lung cancer
(NSCLC) using an integrated platform consisting of positron emission tomography
imaging, respirometry and three-dimensional scanning block-face electron
microscopy. The diverse bioenergetic phenotypes and metabolic dependencies we
identified in NSCLC tumours align with distinct structural organization of
mitochondrial networks present. Further, we discovered that mitochondrial
networks are organized into distinct compartments within tumour cells. In
tumours with high rates of oxidative phosphorylation (OXPHOSHI) and fatty acid
oxidation, we identified peri-droplet mitochondrial networks wherein
mitochondria contact and surround lipid droplets. By contrast, we discovered
that in tumours with low rates of OXPHOS (OXPHOSLO), high glucose flux regulated
perinuclear localization of mitochondria, structural remodelling of cristae and
mitochondrial respiratory capacity. Our findings suggest that in NSCLC,
mitochondrial networks are compartmentalized into distinct subpopulations that
govern the bioenergetic capacity of tumours.
© 2023. The Author(s).
DOI: 10.1038/s41586-023-05793-3
PMCID: PMC10033418
PMID: 36922590 [Indexed for MEDLINE]
2. CA Cancer J Clin. 2023 Mar 1. doi: 10.3322/caac.21774. Online ahead of print.
Acquiring tissue for advanced lung cancer diagnosis and comprehensive biomarker
testing: A National Lung Cancer Roundtable best-practice guide.
Fox AH(1), Nishino M(2)(3), Osarogiagbon RU(4), Rivera MP(5), Rosenthal LS(6),
Smith RA(6), Farjah F(7), Sholl LM(8), Silvestri GA(1), Johnson BE(9).
Author information:
(1)Division of Pulmonary Critical Care, Allergy and Sleep Medicine, Medical
University of South Carolina, Charleston, South Carolina, USA.
(2)Department of Imaging, Dana-Farber Cancer Institute, Boston, Massachusetts,
USA.
(3)Department of Radiology, Brigham and Women's Hospital, Boston, Massachusetts,
USA.
…
Advances in biomarker-driven therapies for patients with nonsmall cell lung
cancer (NSCLC) both provide opportunities to improve the treatment (and thus
outcomes) for patients and pose new challenges for equitable care delivery. Over
the last decade, the continuing development of new biomarker-driven therapies
and evolving indications for their use have intensified the importance of
interdisciplinary communication and coordination for patients with or suspected
to have lung cancer. Multidisciplinary teams are challenged with completing
comprehensive and timely biomarker testing and navigating the constantly
evolving evidence base for a complex and time-sensitive disease. This guide
provides context for the current state of comprehensive biomarker testing for
NSCLC, reviews how biomarker testing integrates within the diagnostic continuum
for patients, and illustrates best practices and common pitfalls that influence
the success and timeliness of biomarker testing using a series of case
scenarios.
© 2023 The Authors. CA: A Cancer Journal for Clinicians published by Wiley
Periodicals LLC on behalf of American Cancer Society.
DOI: 10.3322/caac.21774
PMID: 36859638
3. Cell. 2023 Mar 2;186(5):1013-1025.e24. doi: 10.1016/j.cell.2023.01.043. Epub
2023 Feb 23.
Discovery of natural-product-derived sequanamycins as potent oral
anti-tuberculosis agents.
Zhang J(1), Lair C(2), Roubert C(2), Amaning K(1), Barrio MB(3), Benedetti Y(1),
Cui Z(4), Xing Z(4), Li X(4), Franzblau SG(5), Baurin N(1), Bordon-Pallier F(1),
Cantalloube C(6), Sans S(2), Silve S(2), Blanc I(2), Fraisse L(2), Rak A(1),
Jenner LB(7), Yusupova G(7), Yusupov M(7), Zhang J(4), Kaneko T(8), Yang TJ(8),
Fotouhi N(8), Nuermberger E(9), Tyagi S(9), Betoudji F(9), Upton A(10),
Sacchettini JC(11), Lagrange S(2).
Author information:
(1)Sanofi R&D, Integrated Drug Discovery, CRVA, 94403 Vitry-sur-Seine, France.
(2)Evotec ID (LYON) SAS, Lyon, France; Sanofi R&D, Infectious Diseases TSU,
31036 Toulouse, France.
(3)Sanofi R&D, Infectious Diseases TSU, 31036 Toulouse, France.
…
The emergence of drug-resistant tuberculosis has created an urgent need for new
anti-tubercular agents. Here, we report the discovery of a series of macrolides
called sequanamycins with outstanding in vitro and in vivo activity against
Mycobacterium tuberculosis (Mtb). Sequanamycins are bacterial ribosome
inhibitors that interact with the ribosome in a similar manner to classic
macrolides like erythromycin and clarithromycin, but with binding
characteristics that allow them to overcome the inherent macrolide resistance of
Mtb. Structures of the ribosome with bound inhibitors were used to optimize
sequanamycin to produce the advanced lead compound SEQ-9. SEQ-9 was efficacious
in mouse models of acute and chronic TB as a single agent, and it demonstrated
bactericidal activity in a murine TB infection model in combination with other
TB drugs. These results support further investigation of this series as TB
clinical candidates, with the potential for use in new regimens against
drug-susceptible and drug-resistant TB.
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.cell.2023.01.043
PMCID: PMC9994261
PMID: 36827973 [Indexed for MEDLINE]
4. N Engl J Med. 2023 Mar 9;388(10):873-887. doi: 10.1056/NEJMoa2212537. Epub 2023 Feb 20.
Treatment Strategy for Rifampin-Susceptible Tuberculosis.
Paton NI(1), Cousins C(1), Suresh C(1), Burhan E(1), Chew KL(1), Dalay VB(1), Lu
Q(1), Kusmiati T(1), Balanag VM(1), Lee SL(1), Ruslami R(1), Pokharkar Y(1),
Djaharuddin I(1), Sugiri JJR(1), Veto RS(1), Sekaggya-Wiltshire C(1),
Avihingsanon A(1), Sarin R(1), Papineni P(1), Nunn AJ(1), Crook AM(1);
TRUNCATE-TB Trial Team.
Author information:
(1)From the Infectious Diseases Translational Research Programme and Yong Loo
Lin School of Medicine, National University of Singapore (N.I.P., C.C., C.S.,
P.P.), National University Hospital (K.L.C.), and Singapore Clinical Research
Institute (Q.L., S.L.L., Y.P.) - all in Singapore; the Faculty of Medicine,
Universitas Indonesia, and Persahabatan General Hospital, Jakarta (E.B.), Dr.
Soetomo Hospital, …
BACKGROUND: Tuberculosis is usually treated with a 6-month rifampin-based
regimen. Whether a strategy involving shorter initial treatment may lead to
similar outcomes is unclear.
METHODS: In this adaptive, open-label, noninferiority trial, we randomly
assigned participants with rifampin-susceptible pulmonary tuberculosis to
undergo either standard treatment (rifampin and isoniazid for 24 weeks with
pyrazinamide and ethambutol for the first 8 weeks) or a strategy involving
initial treatment with an 8-week regimen, extended treatment for persistent
clinical disease, monitoring after treatment, and retreatment for relapse. There
were four strategy groups with different initial regimens; noninferiority was
assessed in the two strategy groups with complete enrollment, which had initial
regimens of high-dose rifampin-linezolid and bedaquiline-linezolid (each with
isoniazid, pyrazinamide, and ethambutol). The primary outcome was a composite of
death, ongoing treatment, or active disease at week 96. The noninferiority
margin was 12 percentage points.
RESULTS: Of the 674 participants in the intention-to-treat population, 4 (0.6%)
withdrew consent or were lost to follow-up. A primary-outcome event occurred in
7 of the 181 participants (3.9%) in the standard-treatment group, as compared
with 21 of the 184 participants (11.4%) in the strategy group with an initial
rifampin-linezolid regimen (adjusted difference, 7.4 percentage points; 97.5%
confidence interval [CI], 1.7 to 13.2; noninferiority not met) and 11 of the 189
participants (5.8%) in the strategy group with an initial bedaquiline-linezolid
regimen (adjusted difference, 0.8 percentage points; 97.5% CI, -3.4 to 5.1;
noninferiority met). The mean total duration of treatment was 180 days in the
standard-treatment group, 106 days in the rifampin-linezolid strategy group, and
85 days in the bedaquiline-linezolid strategy group. The incidences of grade 3
or 4 adverse events and serious adverse events were similar in the three groups.
CONCLUSIONS: A strategy involving initial treatment with an 8-week
bedaquiline-linezolid regimen was noninferior to standard treatment for
tuberculosis with respect to clinical outcomes. The strategy was associated with
a shorter total duration of treatment and with no evident safety concerns.
(Funded by the Singapore National Medical Research Council and others;
TRUNCATE-TB ClinicalTrials.gov number, NCT03474198.).
Copyright © 2023 Massachusetts Medical Society.
DOI: 10.1056/NEJMoa2212537
PMID: 36808186 [Indexed for MEDLINE]
5. Lancet. 2023 Mar 4;401(10378):733-746. doi: 10.1016/S0140-6736(23)00221-0. Epub 2023 Feb 7.
Sotorasib versus docetaxel for previously treated non-small-cell lung cancer
with KRAS(G12C) mutation: a randomised, open-label, phase 3 trial.
de Langen AJ(1), Johnson ML(2), Mazieres J(3), Dingemans AC(4), Mountzios G(5),
Pless M(6), Wolf J(7), Schuler M(8), Lena H(9), Skoulidis F(10), Yoneshima
Y(11), Kim SW(12), Linardou H(13), Novello S(14), van der Wekken AJ(15), Chen
Y(16), Peters S(17), Felip E(18), Solomon BJ(19), Ramalingam SS(20), Dooms
C(21), Lindsay CR(22), Ferreira CG(23), Blais N(24), Obiozor CC(25), Wang Y(25),
Mehta B(25), Varrieur T(25), Ngarmchamnanrith G(25), Stollenwerk B(26),
Waterhouse D(27), Paz-Ares L(28); CodeBreaK 200 Investigators.
Author information:
(1)Netherlands Cancer Institute, Amsterdam, Netherlands.
(2)Sarah Cannon Research Institute at Tennessee Oncology, Nashville, TN, USA.
(3)Centre Hospitalier Universitaire de Toulouse, Toulouse, France.
…
Comment in
Lancet. 2023 Mar 4;401(10378):706-707.
BACKGROUND: Sotorasib is a specific, irreversible inhibitor of the GTPase
protein, KRASG12C. We compared the efficacy and safety of sotorasib with a
standard-of-care treatment in patients with non-small-cell lung cancer (NSCLC)
with the KRASG12C mutation who had been previously treated with other anticancer
drugs.
METHODS: We conducted a randomised, open-label phase 3 trial at 148 centres in
22 countries. We recruited patients aged at least 18 years with KRASG12C-mutated
advanced NSCLC, who progressed after previous platinum-based chemotherapy and a
PD-1 or PD-L1 inhibitor. Key exclusion criteria included new or progressing
untreated brain lesions or symptomatic brain lesions, previously identified
oncogenic driver mutation other than KRASG12C for which an approved therapy is
available (eg EGFR or ALK), previous treatment with docetaxel (neoadjuvant or
adjuvant docetaxel was allowed if the tumour did not progress within 6 months
after the therapy was terminated), previous treatment with a direct KRASG12C
inhibitor, systemic anticancer therapy within 28 days of study day 1, and
therapeutic or palliative radiation therapy within 2 weeks of treatment
initiation. We randomly assigned (1:1) patients to oral sotorasib (960 mg once
daily) or intravenous docetaxel (75 mg/m2 once every 3 weeks) in an open-label
manner using interactive response technology. Randomisation was stratified by
number of previous lines of therapy in advanced disease (1 vs 2 vs >2),
ethnicity (Asian vs non-Asian), and history of CNS metastases (present or
absent). Treatment continued until an independent central confirmation of
disease progression, intolerance, initiation of another anticancer therapy,
withdrawal of consent, or death, whichever occurred first. The primary endpoint
was progression-free survival, which was assessed by a blinded, independent
central review in the intention-to-treat population. Safety was assessed in all
treated patients. This trial is registered at ClinicalTrials.gov, NCT04303780,
and is active but no longer recruiting.
FINDINGS: Between June 4, 2020, and April 26, 2021, 345 patients were randomly
assigned to receive sotorasib (n=171 [50%]) or docetaxel (n=174 [50%]). 169
(99%) patients in the sotorasib group and 151 (87%) in the docetaxel group
received at least one dose. After a median follow-up of 17·7 months (IQR
16·4-20·1), the study met its primary endpoint of a statistically significant
increase in the progression-free survival for sotorasib, compared with docetaxel
(median progression-free survival 5·6 months [95% CI 4·3-7·8] vs 4·5 months
[3·0-5·7]; hazard ratio 0·66 [0·51-0·86]; p=0·0017). Sotorasib was well
tolerated, with fewer grade 3 or worse (n=56 [33%] vs n=61 [40%]) and serious
treatment-related adverse events compared with docetaxel (n=18 [11%] vs n=34
[23%]). For sotorasib, the most common treatment-related adverse events of grade
3 or worse were diarrhoea (n= 20 [12%]), alanine aminotransferase increase (n=13
[8%]), and aspartate aminotransferase increase (n=9 [5%]). For docetaxel, the
most common treatment-related adverse events of grade 3 or worse were
neutropenia (n=13 [9%]), fatigue (n=9 [6%]), and febrile neutropenia (n=8 [5%]).
INTERPRETATION: Sotorasib significantly increased progression-free survival and
had a more favourable safety profile, compared with docetaxel, in patients with
advanced NSCLC with the KRASG12C mutation and who had been previously treated
with other anticancer drugs.
FUNDING: Amgen.
Copyright © 2023 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S0140-6736(23)00221-0
PMID: 36764316 [Indexed for MEDLINE]
6. Nat Med. 2023 Mar;29(3):593-604. doi: 10.1038/s41591-022-02189-0. Epub 2023 Mar 16.
Neoadjuvant chemotherapy plus nivolumab with or without ipilimumab in operable
non-small cell lung cancer: the phase 2 platform NEOSTAR trial.
Cascone T(1), Leung CH(2), Weissferdt A(3)(4), Pataer A(4), Carter BW(5), Godoy
MCB(5), Feldman H(4), William WN Jr(6)(7), Xi Y(8), Basu S(9), Sun JJ(9), …
Author information:
(1)Department of Thoracic/Head and Neck Medical Oncology, The University of
Texas MD Anderson Cancer Center, Houston, TX, USA. tcascone@mdanderson.org.
(2)Department of Biostatistics, The University of Texas MD Anderson Cancer
Center, Houston, TX, USA.
(3)Department of Pathology, The University of Texas MD Anderson Cancer Center,
Houston, TX, USA.
…
Neoadjuvant ipilimumab + nivolumab (Ipi+Nivo) and nivolumab + chemotherapy
(Nivo+CT) induce greater pathologic response rates than CT alone in patients
with operable non-small cell lung cancer (NSCLC). The impact of adding
ipilimumab to neoadjuvant Nivo+CT is unknown. Here we report the results and
correlates of two arms of the phase 2 platform NEOSTAR trial testing neoadjuvant
Nivo+CT and Ipi+Nivo+CT with major pathologic response (MPR) as the primary
endpoint. MPR rates were 32.1% (7/22, 80% confidence interval (CI) 18.7-43.1%)
in the Nivo+CT arm and 50% (11/22, 80% CI 34.6-61.1%) in the Ipi+Nivo+CT arm;
the primary endpoint was met in both arms. In patients without known tumor
EGFR/ALK alterations, MPR rates were 41.2% (7/17) and 62.5% (10/16) in the
Nivo+CT and Ipi+Nivo+CT groups, respectively. No new safety signals were
observed in either arm. Single-cell sequencing and multi-platform immune
profiling (exploratory endpoints) underscored immune cell populations and
phenotypes, including effector memory CD8+ T, B and myeloid cells and markers of
tertiary lymphoid structures, that were preferentially increased in the
Ipi+Nivo+CT cohort. Baseline fecal microbiota in patients with MPR were enriched
with beneficial taxa, such as Akkermansia, and displayed reduced abundance of
pro-inflammatory and pathogenic microbes. Neoadjuvant Ipi+Nivo+CT enhances
pathologic responses and warrants further study in operable NSCLC.
(ClinicalTrials.gov registration: NCT03158129 .).
© 2023. The Author(s).
DOI: 10.1038/s41591-022-02189-0
PMCID: PMC10033402
PMID: 36928818 [Indexed for MEDLINE]
7. Nat Med. 2023 Mar 16. doi: 10.1038/s41591-023-02226-6. Online ahead of print.
A longitudinal circulating tumor DNA-based model associated with survival in
metastatic non-small-cell lung cancer.
Assaf ZJF(1), Zou W(2), Fine AD(3), Socinski MA(4), Young A(3), Lipson D(3),
Freidin JF(3), Kennedy M(3), Polisecki E(3), Nishio M(5), Fabrizio D(3), Oxnard
GR(3), Cummings C(2), Rode A(6), Reck M(7), Patil NS(2), Lee M(2), Shames DS(8),
Schulze K(9).
Author information:
(1)Genentech Inc., South San Francisco, CA, USA. assaf.zoe-june@gene.com.
(2)Genentech Inc., South San Francisco, CA, USA.
(3)Foundation Medicine Inc., Cambridge, MA, USA.
…
One of the great challenges in therapeutic oncology is determining who might
achieve survival benefits from a particular therapy. Studies on longitudinal
circulating tumor DNA (ctDNA) dynamics for the prediction of survival have
generally been small or nonrandomized. We assessed ctDNA across 5 time points in
466 non-small-cell lung cancer (NSCLC) patients from the randomized phase 3
IMpower150 study comparing chemotherapy-immune checkpoint inhibitor (chemo-ICI)
combinations and used machine learning to jointly model multiple ctDNA metrics
to predict overall survival (OS). ctDNA assessments through cycle 3 day 1 of
treatment enabled risk stratification of patients with stable disease (hazard
ratio (HR) = 3.2 (2.0-5.3), P < 0.001; median 7.1 versus 22.3 months for high-
versus low-intermediate risk) and with partial response (HR = 3.3 (1.7-6.4),
P < 0.001; median 8.8 versus 28.6 months). The model also identified high-risk
patients in an external validation cohort from the randomized phase 3 OAK study
of ICI versus chemo in NSCLC (OS HR = 3.73 (1.83-7.60), P = 0.00012).
Simulations of clinical trial scenarios employing our ctDNA model suggested that
early ctDNA testing outperforms early radiographic imaging for predicting trial
outcomes. Overall, measuring ctDNA dynamics during treatment can improve patient
risk stratification and may allow early differentiation between competing
therapies during clinical trials.
© 2023. The Author(s).
DOI: 10.1038/s41591-023-02226-6
PMID: 36928816
8. Nat Med. 2023 Mar 9. doi: 10.1038/s41591-023-02247-1. Online ahead of print.
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
9. Nat Commun. 2023 Mar 31;14(1):1803. doi: 10.1038/s41467-023-37183-8.
Genome-wide tiled detection of circulating Mycobacterium tuberculosis cell-free
DNA using Cas13.
Thakku SG(1), Lirette J(1), Murugesan K(2), Chen J(1), Theron G(3), Banaei
N(2)(4)(5), Blainey PC(1)(6)(7), Gomez J(1), Wong SY(1), Hung DT(8)(9)(10).
Author information:
(1)Broad Institute of MIT and Harvard, Cambridge, MA, USA.
(2)Department of Pathology, Stanford University School of Medicine, Stanford,
CA, USA.
(3)DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research and SAMRC
Centre for Tuberculosis Research, Division of Molecular Biology and Human
Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape
Town, South Africa.
…
Detection of microbial cell-free DNA (cfDNA) circulating in the bloodstream has
emerged as a promising new approach for diagnosing infection. Microbial
diagnostics based on cfDNA require assays that can detect rare and highly
fragmented pathogen nucleic acids. We now report WATSON (Whole-genome Assay
using Tiled Surveillance Of Nucleic acids), a method to detect low amounts of
pathogen cfDNA that couples pooled amplification of genomic targets tiled across
the genome with pooled CRISPR/Cas13-based detection of these targets. We
demonstrate that this strategy of tiling improves cfDNA detection compared to
amplification and detection of a single targeted locus. WATSON can detect cfDNA
from Mycobacterium tuberculosis in plasma of patients with active pulmonary
tuberculosis, a disease that urgently needs accurate, minimally-invasive,
field-deployable diagnostics. We thus demonstrate the potential for translating
WATSON to a lateral flow platform. WATSON demonstrates the ability to capitalize
on the strengths of targeting microbial cfDNA to address the need for
point-of-care diagnostic tests for infectious diseases.
© 2023. The Author(s).
DOI: 10.1038/s41467-023-37183-8
PMCID: PMC10064635
PMID: 37002219 [Indexed for MEDLINE]
10. J Clin Oncol. 2023 Mar 28:JCO2201997. doi: 10.1200/JCO.22.01997. Online ahead of print.
Randomized Double-Blind Placebo-Controlled Study of Olanzapine for
Chemotherapy-Related Anorexia in Patients With Locally Advanced or Metastatic
Gastric, Hepatopancreaticobiliary, and Lung Cancer.
Sandhya L(1), Devi Sreenivasan N(1), Goenka L(1), Dubashi B(1), Kayal S(1),
Solaiappan M(2), Govindarajalou R(3), Kt H(4), Ganesan P(1).
Author information:
(1)Department of Medical Oncology, Jawaharlal Institute of Postgraduate Medical
Education and Research (JIPMER), Puducherry, India.
(2)Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical
Education and Research (JIPMER), Puducherry, India.
(3)Radiodiagnosis, Jawaharlal Institute of Postgraduate Medical Education and
Research (JIPMER), Puducherry, India.
(4)Biostatistics, Jawaharlal Institute of Postgraduate Medical Education and
Research (JIPMER), Puducherry, India.
PURPOSE: Anorexia occurs in 30%-80% of patients with advanced malignancies,
which may be worsened with chemotherapy. This trial assessed the efficacy of
olanzapine in stimulating appetite and improving weight gain in patients
receiving chemotherapy.
METHODS: Adults (≥18 years) with untreated, locally advanced, or metastatic
gastric, hepatopancreaticobiliary (HPB), and lung cancers were randomly assigned
(double-blind) to receive olanzapine (2.5 mg once a day for 12 weeks) or placebo
along with chemotherapy. Both groups received standard nutritional assessment
and dietary advice. The primary outcomes were the proportion of patients with
weight gain > 5% and the improvement in appetite (assessed by the visual analog
scale [VAS] and the Functional Assessment of Chronic Illness Therapy system of
Quality-of-Life questionnaires Anorexia Cachexia subscale [FAACT ACS]).
Secondary end points were change in nutritional status, quality of life (QOL),
and chemotherapy toxicity.
RESULTS: We enrolled 124 patients (olanzapine, 63 and placebo, 61) with a median
age of 55 years (18-78 years), of whom 112 (olanzapine, 58 and placebo, 54) were
analyzable. The majority (n = 99, 80%) had metastatic cancer (gastric [n = 68,
55%] > lung [n = 43, 35%] > HPB [n = 13, 10%]). The olanzapine arm had a greater
proportion of patients with a weight gain of > 5% (35 of 58 [60%] v 5 of 54
[9%], P < .001) and improvement in appetite by VAS (25 of 58 [43%] v 7 of 54
[13%], P < .001) and by FAACT ACS (scores ≥37:13 of 58 [22%] v 2 of 54 [4%], P = .004).
Patients on olanzapine had better QOL, nutritional status, and lesser
chemotoxicity. Side effects attributable to olanzapine were minimal.
CONCLUSION: Low-dose, daily olanzapine is a simple, inexpensive, well-tolerated
intervention that significantly improves appetite and weight gain in newly
diagnosed patients on chemotherapy.
DOI: 10.1200/JCO.22.01997
PMID: 36977285
11. Lancet Infect Dis. 2023 Mar 23:S1473-3099(23)00067-1. doi:
10.1016/S1473-3099(23)00067-1. Online ahead of print.
Rosuvastatin adjunctive therapy for rifampicin-susceptible pulmonary
tuberculosis: a phase 2b, randomised, open-label, multicentre trial.
Cross GB(1), Sari IP(2), Kityo C(3), Lu Q(4), Pokharkar Y(4), Moorakonda RB(4),
Thi HN(5), Do Q(5), Dalay VB(6), Gutierrez E(6), Balanag VM(7), Castillo RJ(7),
Mugerwa H(3), Fanusi F(8), Kwan P(8), Chew KL(9), Paton NI(10); ROSETTA trial
team.
Author information:
(1)Infectious Disease Translational Research Programme, National University of
Singapore, Singapore; Department of Medicine, National University Health
Systems, Singapore. Electronic address: gail.cross@burnet.edu.au.
(2)Department of Medicine, National University Health Systems, Singapore.
(3)Joint Clinical Research Centre, Kampala, Uganda.
…
BACKGROUND: Shorter treatments are needed for drug-susceptible tuberculosis.
Adjunctive statins increase bactericidal activity in preclinical tuberculosis
models. We investigated the safety and efficacy of adjunctive rosuvastatin in
people with tuberculosis. We tested the hypothesis that adjunctive rosuvastatin
accelerates sputum culture conversion within the first 8 weeks of treatment of
rifampicin-susceptible tuberculosis.
METHODS: This phase 2b, randomised, open-label, multicentre trial conducted in
five hospitals or clinics in three countries with high tuberculosis burden (ie,
the Philippines, Viet Nam, and Uganda) enrolled adult participants aged 18-75
years with sputum smear or Xpert MTB/RIF positive, rifampicin-susceptible
tuberculosis who had received less than 7 days of previous tuberculosis
treatment. Participants were randomly assigned via a web-based system to receive
either 10 mg rosuvastatin once per day for 8 weeks plus standard tuberculosis
therapy (rifampicin, isoniazid, pyrazinamide, and ethambutol; rosuvastatin
group) or standard tuberculosis therapy alone (control group). Randomisation was
stratified by trial site, history of diabetes, and HIV co-infection. Laboratory
staff and central investigators involved in data cleaning and analysis were
masked to treatment allocation, but study participants and site investigators
were not. Both groups continued standard treatment to week 24. Sputum samples
were collected once per week for the first 8 weeks after randomisation, and then
at weeks 10, 12, and 24. The primary efficacy outcome was time to culture
conversion (TTCC; days) in liquid culture by week 8, assessed in randomised
participants who had microbiological confirmation of tuberculosis, took at least
one dose of rosuvastatin, and who did not show resistance to rifampicin
(modified intention-to-treat population), for which groups were compared with
the Cox proportional hazards model. The main safety outcome was grade 3-5
adverse events by week 24, assessed in the intention-to-treat population, for
which groups were compared with Fisher's exact test. All participants completed
24 weeks of follow-up. This trial is registered with ClinicalTrials.gov
(NCT04504851).
FINDINGS: Between Sept 2, 2020, and Jan 14, 2021, 174 participants were screened
and 137 were randomly assigned to the rosuvastatin group (70 participants) or
control group (67 participants). In the modified intention-to-treat population
of 135 participants, 102 (76%) were men and 33 (24%) were women. Median TTCC in
liquid media was 42 days (95% CI 35-49) in the rosuvastatin group (68
participants) and 42 days (36-53) in the control group (67 participants; hazard
ratio 1·30 [0·88-1·91], p=0·19). Grade 3-5 adverse events occurred in six (9%)
of 70 in the rosuvastatin group (none were considered related to rosuvastatin)
and four (6%) of 67 in the control group (p=0·75). There were no serious adverse
events that were considered to be related to rosuvastatin.
INTERPRETATION: Adjunctive rosuvastatin at 10 mg once per day was safe but did
not produce substantive benefits on culture conversion in the overall study
population. Future trials could explore the safety and efficacy of higher doses
of adjunctive rosuvastatin.
FUNDING: National Medical Research Council, Singapore.
Copyright © 2023 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1473-3099(23)00067-1
PMID: 36966799
12. Nat Commun. 2023 Mar 24;14(1):1639. doi: 10.1038/s41467-023-37314-1.
Transmission modeling to infer tuberculosis incidence prevalence and mortality
in settings with generalized HIV epidemics.
Dodd PJ(1), Shaweno D(2), Ku CC(2), Glaziou P(3), Pretorius C(4), Hayes RJ(5),
MacPherson P(6)(7), Cohen T(8), Ayles H(7)(9).
Author information:
(1)School of Health and Related Research, University of Sheffield, Sheffield,
UK. p.j.dodd@sheffield.ac.uk.
(2)School of Public Health, Infectious Disease Epidemiology, Imperial College
London, London, UK.
(3)Global TB Programme, World Health Organization, Geneva, Switzerland.
(4)Avenir Health, Glastonbury, CT, USA.
(5)Department of Infectious Disease Epidemiology, Faculty of Epidemiology and
Population Health, London School of Hygiene and Tropical Medicine, London, UK.
(6)School of Health & Wellbeing, University of Glasgow, Glasgow, UK.
(7)Clinical Research Department, Faculty of Infectious and Tropical Diseases,
London School of Hygiene and Tropical Medicine, London, UK.
(8)Department of Epidemiology of Microbial Diseases, Yale School of Public
Health, New Haven, CT, USA.
(9)ZAMBART Project, Ridgeway Campus, University of Zambia, Lusaka, Zambia.
Tuberculosis (TB) killed more people globally than any other single pathogen
over the past decade. Where surveillance is weak, estimating TB burden estimates
uses modeling. In many African countries, increases in HIV prevalence and
antiretroviral therapy have driven dynamic TB epidemics, complicating estimation
of burden, trends, and potential intervention impact. We therefore develop a
novel age-structured TB transmission model incorporating evolving demographic,
HIV and antiretroviral therapy effects, and calibrate to TB prevalence and
notification data from 12 African countries. We use Bayesian methods to include
uncertainty for all TB model parameters, and estimate age-specific annual risks
of TB infection, finding up to 16.0%/year in adults, and the proportion of TB
incidence from recent (re)infection, finding a mean across countries of 34%.
Rapid reduction of the unacceptably high burden of TB in high HIV prevalence
settings will require interventions addressing progression as well as
transmission.
© 2023. The Author(s).
DOI: 10.1038/s41467-023-37314-1
PMCID: PMC10037365
PMID: 36964130 [Indexed for MEDLINE]
13. Nat Commun. 2023 Mar 18;14(1):1517. doi: 10.1038/s41467-023-37184-7.
The evolution of antibiotic resistance is associated with collateral drug
phenotypes in Mycobacterium tuberculosis.
Waller NJE(1)(2), Cheung CY(1), Cook GM(1)(2), McNeil MB(3)(4).
Author information:
(1)Department of Microbiology and Immunology, University of Otago, Dunedin, New
Zealand.
(2)Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland,
Auckland, New Zealand.
(3)Department of Microbiology and Immunology, University of Otago, Dunedin, New
Zealand. matthew.mcneil@otago.ac.nz.
(4)Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland,
Auckland, New Zealand. matthew.mcneil@otago.ac.nz.
The increasing incidence of drug resistance in Mycobacterium tuberculosis has
diminished the efficacy of almost all available antibiotics, complicating
efforts to combat the spread of this global health burden. Alongside the
development of new drugs, optimised drug combinations are needed to improve
treatment success and prevent the further spread of antibiotic resistance.
Typically, antibiotic resistance leads to reduced sensitivity, yet in some cases
the evolution of drug resistance can lead to enhanced sensitivity to unrelated
drugs. This phenomenon of collateral sensitivity is largely unexplored in M.
tuberculosis but has the potential to identify alternative therapeutic
strategies to combat drug-resistant strains that are unresponsive to current
treatments. Here, by using drug susceptibility profiling, genomics and
evolutionary studies we provide evidence for the existence of collateral drug
sensitivities in an isogenic collection M. tuberculosis drug-resistant strains.
Furthermore, in proof-of-concept studies, we demonstrate how collateral drug
phenotypes can be exploited to select against and prevent the emergence of
drug-resistant strains. This study highlights that the evolution of drug
resistance in M. tuberculosis leads to collateral drug responses that can be
exploited to design improved drug regimens.
© 2023. The Author(s).
DOI: 10.1038/s41467-023-37184-7
PMCID: PMC10024696
PMID: 36934122 [Indexed for MEDLINE]
14. Nat Commun. 2023 Mar 17;14(1):1431. doi: 10.1038/s41467-023-37149-w.
Ferroptosis hijacking by Mycobacterium tuberculosis.
Gan B(1)(2).
Author information:
(1)Department of Experimental Radiation Oncology, The University of Texas MD
Anderson Cancer Center, Houston, TX, USA. bgan@mdanderson.org.
(2)The University of Texas MD Anderson UTHealth Graduate School of Biomedical
Sciences, Houston, TX, USA. bgan@mdanderson.org.
A recent study from Nature Communications reveals that Mycobacterium
tuberculosis can hijack epigenetic machinery in host cells and induce host cell
ferroptosis, which promotes pathogen pathogenicity and spread. These findings
also suggest new therapeutic strategies to treat tuberculosis.
DOI: 10.1038/s41467-023-37149-w
PMCID: PMC10023749
PMID: 36932073 [Indexed for MEDLINE]
15. J Exp Med. 2023 Jun 5;220(6):e20221392. doi: 10.1084/jem.20221392. Epub 2023 Mar 15.
Spatial mapping reveals granuloma diversity and histopathological superstructure
in human tuberculosis.
Sawyer AJ(1)(2)(3), Patrick E(4)(5)(6), Edwards J(1)(7), Wilmott JS(1)(3)(7),
Fielder T(8), Yang Q(9), Barber DL(10), Ernst JD(11), Britton WJ(2)(12),
Palendira U(1)(2)(3), Chen X(13), Feng CG(1)(2)(3)(14).
Author information:
(1)School of Medical Sciences, Faculty of Medicine and Health, The University of
Sydney , Sydney, Australia.
(2)Centenary Institute, The University of Sydney , Sydney, Australia.
(3)Charles Perkins Centre, The University of Sydney , Sydney, Australia.
…
The hallmark of tuberculosis (TB) is the formation of immune cell-enriched
aggregates called granulomas. While granulomas are pathologically diverse, their
tissue-wide heterogeneity has not been spatially resolved at the single-cell
level in human tissues. By spatially mapping individual immune cells in every
lesion across entire tissue sections, we report that in addition to necrotizing
granulomas, the human TB lung contains abundant non-necrotizing leukocyte
aggregates surrounding areas of necrotizing tissue. These cellular lesions were
more diverse in composition than necrotizing lesions and could be stratified
into four general classes based on cellular composition and spatial distribution
of B cells and macrophages. The cellular composition of non-necrotizing
structures also correlates with their proximity to necrotizing lesions,
indicating these are foci of distinct immune reactions adjacent to necrotizing
granulomas. Together, we show that during TB, diseased lung tissue develops a
histopathological superstructure comprising at least four different types of
non-necrotizing cellular aggregates organized as satellites of necrotizing
granulomas.
© 2023 Sawyer et al.
DOI: 10.1084/jem.20221392
PMCID: PMC10035589
PMID: 36920308 [Indexed for MEDLINE]
16. J Clin Invest. 2023 Mar 15;133(6):e168366. doi: 10.1172/JCI168366.
The fat is in the lysosome: how Mycobacterium tuberculosis tricks macrophages
into storing lipids.
Rombouts Y, Neyrolles O.
Comment on
A terpene nucleoside from M. tuberculosis induces lysosomal lipid storage in
foamy macrophages.
Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), infects
primarily macrophages, causing them to differentiate into lipid-laden foamy
macrophages that are a primary source of tissue destruction in patients with TB.
In this issue of the JCI, Bedard et al. demonstrate that
1-tuberculosinyladenosine, a virulence factor produced by M. tuberculosis,
caused lysosomal dysfunction associated with lipid storage in the phagolysosome
of macrophages in a manner that mimicked lysosomal storage diseases. This work
sheds light on how M. tuberculosis manipulates host lipid metabolism for its
survival and opens avenues toward host-directed therapy against TB.
DOI: 10.1172/JCI168366
PMCID: PMC10014092
PMID: 36919697 [Indexed for MEDLINE]
17. Nat Commun. 2023 Mar 6;14(1):1138. doi: 10.1038/s41467-023-36789-2.
Safety and immunogenicity of a thermostable ID93 + GLA-SE tuberculosis vaccine
candidate in healthy adults.
Sagawa ZK(1), Goman C(1), Frevol A(1)(2), Blazevic A(3), Tennant J(3), Fisher
B(1)(4), Day T(1)(5), Jackson S(6), Lemiale F(6), Toussaint L(6), Kalisz I(6),
Jiang J(7), Ondrejcek L(7), Mohamath R(1), Vergara J(1)(8), Lew A(1), Beckmann
AM(1), Casper C(1)(9)(10)(11), Hoft DF(3), Fox CB(12)(13).
Author information:
(1)Access to Advanced Health Institute (formerly Infectious Disease Research
Institute), Seattle, WA, USA.
(2)HDT Bio, Seattle, WA, USA.
(3)Saint Louis University Center for Vaccine Development, St. Louis, MO, USA.
…
Adjuvant-containing subunit vaccines represent a promising approach for
protection against tuberculosis (TB), but current candidates require
refrigerated storage. Here we present results from a randomized, double-blinded
Phase 1 clinical trial (NCT03722472) evaluating the safety, tolerability, and
immunogenicity of a thermostable lyophilized single-vial presentation of the
ID93 + GLA-SE vaccine candidate compared to the non-thermostable two-vial
vaccine presentation in healthy adults. Participants were monitored for primary,
secondary, and exploratory endpoints following intramuscular administration of
two vaccine doses 56 days apart. Primary endpoints included local and systemic
reactogenicity and adverse events. Secondary endpoints included antigen-specific
antibody (IgG) and cellular immune responses (cytokine-producing peripheral
blood mononuclear cells and T cells). Both vaccine presentations are safe and
well tolerated and elicit robust antigen-specific serum antibody and Th1-type
cellular immune responses. Compared to the non-thermostable presentation, the
thermostable vaccine formulation generates greater serum antibody responses
(p < 0.05) and more antibody-secreting cells (p < 0.05). In this work, we show
the thermostable ID93 + GLA-SE vaccine candidate is safe and immunogenic in
healthy adults.
© 2023. The Author(s).
DOI: 10.1038/s41467-023-36789-2
PMCID: PMC9988862
PMID: 36878897 [Indexed for MEDLINE]
18. Nat Commun. 2023 Mar 4;14(1):1247. doi: 10.1038/s41467-023-36892-4.
CDK4/6 inhibition triggers ICAM1-driven immune response and sensitizes LKB1
mutant lung cancer to immunotherapy.
Bai X(#)(1), Guo ZQ(#)(1), Zhang YP(#)(1)(2), Fan ZZ(#)(3)(4), Liu LJ(#)(5), Liu
L(2)(6), Long LL(1), Ma SC(1)(2), Wang J(1), Fang Y(1), Tang XR(1), Zeng YJ(7),
Pan X(8), Wu DH(9), Dong ZY(10).
Author information:
(1)Department of Radiation Oncology, Nanfang Hospital, Southern Medical
University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China.
(2)Information Management and Big Data Center, Nanfang Hospital, Southern
Medical University, Guangzhou, 510515, China.
(3)CAS Key Laboratory of Genomics and Precision Medicine, Beijing Institute of
Genomics, University of Chinese Academy of Sciences, Chinese Academy of
Sciences, China National Center for Bioinformation, Beijing, 100101, China.
…
Liver kinase B1 (LKB1) mutation is prevalent and a driver of resistance to
immune checkpoint blockade (ICB) therapy for lung adenocarcinoma. Here
leveraging single cell RNA sequencing data, we demonstrate that trafficking and
adhesion process of activated T cells are defected in genetically engineered
Kras-driven mouse model with Lkb1 conditional knockout. LKB1 mutant cancer cells
result in marked suppression of intercellular adhesion molecule-1 (ICAM1).
Ectopic expression of Icam1 in Lkb1-deficient tumor increases homing and
activation of adoptively transferred SIINFEKL-specific CD8+ T cells, reactivates
tumor-effector cell interactions and re-sensitises tumors to ICB. Further
discovery proves that CDK4/6 inhibitors upregulate ICAM1 transcription by
inhibiting phosphorylation of retinoblastoma protein RB in LKB1 deficient cancer
cells. Finally, a tailored combination strategy using CDK4/6 inhibitors and
anti-PD-1 antibodies promotes ICAM1-triggered immune response in multiple
Lkb1-deficient murine models. Our findings renovate that ICAM1 on tumor cells
orchestrates anti-tumor immune response, especially for adaptive immunity.
© 2023. The Author(s).
DOI: 10.1038/s41467-023-36892-4
PMCID: PMC9985635
PMID: 36871040 [Indexed for MEDLINE]
19. J Clin Invest. 2023 Mar 15;133(6):e161944. doi: 10.1172/JCI161944.
A terpene nucleoside from M. tuberculosis induces lysosomal lipid storage in
foamy macrophages.
Bedard M(1), van der Niet S(2), Bernard EM(3), Babunovic G(1)(4), Cheng TY(1),
Aylan B(3), Grootemaat AE(2), Raman S(1), Botella L(3), Ishikawa E(5),
O'Sullivan MP(6), O'Leary S(6), Mayfield JA(1), Buter J(7), Minnaard AJ(7),
Fortune SM(4), Murphy LO(8), Ory DS(8), Keane J(6), Yamasaki S(5), Gutierrez
MG(3), van der Wel N(2), Moody DB(1).
Author information:
(1)Division of Rheumatology, Immunity and Inflammation, Brigham and Women's
Hospital, Harvard Medical School, Boston, Massachusetts, USA.
(2)Electron Microscopy Centre Amsterdam, Amsterdam University Medical Centre,
Amsterdam, Netherlands.
(3)Host-Pathogen Interactions in Tuberculosis Laboratory, The Francis Crick
Institute, London, United Kingdom.
…
Comment in
The fat is in the lysosome: How Mycobacterium tuberculosis tricks
macrophages into storing lipids.
Induction of lipid-laden foamy macrophages is a cellular hallmark of
tuberculosis (TB) disease, which involves the transformation of infected
phagolysosomes from a site of killing into a nutrient-rich replicative niche.
Here, we show that a terpenyl nucleoside shed from Mycobacterium tuberculosis,
1-tuberculosinyladenosine (1-TbAd), caused lysosomal maturation arrest and
autophagy blockade, leading to lipid storage in M1 macrophages. Pure 1-TbAd, or
infection with terpenyl nucleoside-producing M. tuberculosis, caused
intralysosomal and peribacillary lipid storage patterns that matched both the
molecules and subcellular locations known in foamy macrophages. Lipidomics
showed that 1-TbAd induced storage of triacylglycerides and cholesterylesters
and that 1-TbAd increased M. tuberculosis growth under conditions of restricted
lipid access in macrophages. Furthermore, lipidomics identified 1-TbAd-induced
lipid substrates that define Gaucher's disease, Wolman's disease, and other
inborn lysosomal storage diseases. These data identify genetic and molecular
causes of M. tuberculosis-induced lysosomal failure, leading to successful
testing of an agonist of TRPML1 calcium channels that reverses lipid storage in
cells. These data establish the host-directed cellular functions of an orphan
effector molecule that promotes survival in macrophages, providing both an
upstream cause and detailed picture of lysosome failure in foamy macrophages.
DOI: 10.1172/JCI161944
PMCID: PMC10014106
PMID: 36757797 [Indexed for MEDLINE]
20. Nat Rev Clin Oncol. 2023 Mar;20(3):143-159. doi: 10.1038/s41571-022-00718-x.
Epub 2023 Jan 13.
At the crossroads of immunotherapy for oncogene-addicted subsets of NSCLC.
Otano I(1)(2), Ucero AC(3)(4)(5), Zugazagoitia J(3)(4)(6), Paz-Ares L(7)(8)(9).
Author information:
(1)H12O-CNIO Lung Cancer Clinical Research Unit, Health Research Institute
Hospital 12 de Octubre (i+12)/Spanish National Cancer Research Center (CNIO),
Madrid, Spain. iotanoan@alumni.unav.es.
(2)Spanish Center for Biomedical Research Network in Oncology (CIBERONC),
Madrid, Spain. iotanoan@alumni.unav.es.
(3)H12O-CNIO Lung Cancer Clinical Research Unit, Health Research Institute
Hospital 12 de Octubre (i+12)/Spanish National Cancer Research Center (CNIO),
Madrid, Spain.
…
Non-small-cell lung cancer (NSCLC) has become a paradigm of precision medicine,
with the discovery of numerous disease subtypes defined by specific oncogenic
driver mutations leading to the development of a range of molecularly targeted
therapies. Over the past decade, rapid progress has also been made in the
development of immune-checkpoint inhibitors (ICIs), especially antagonistic
antibodies targeting the PD-L1-PD-1 axis, for the treatment of NSCLC. Although
many of the major oncogenic drivers of NSCLC are associated with intrinsic
resistance to ICIs, patients with certain oncogene-driven subtypes of the
disease that are highly responsive to specific targeted therapies might also
derive benefit from immunotherapy. However, the development of effective
immunotherapy approaches for oncogene-addicted NSCLC has been challenged by a
lack of predictive biomarkers for patient selection and limited knowledge of how
ICIs and oncogene-directed targeted therapies should be combined. Therefore,
whether ICIs alone or with chemotherapy or even in combination with molecularly
targeted agents would offer comparable benefit in the context of selected
oncogenic driver alterations to that observed in the general unselected NSCLC
population remains an open question. In this Review, we discuss the effects of
oncogenic driver mutations on the efficacy of ICIs and the immune tumour
microenvironment as well as the potential vulnerabilities that could be
exploited to overcome the challenges of immunotherapy for oncogene-addicted
NSCLC.
© 2023. Springer Nature Limited.
DOI: 10.1038/s41571-022-00718-x
PMID: 36639452 [Indexed for MEDLINE]
21. J Natl Cancer Inst. 2023 Mar 9;115(3):303-310. doi: 10.1093/jnci/djac208.
Association between imaging surveillance frequency and outcomes following
surgical treatment of early-stage lung cancer.
Heiden BT(1), Eaton DB(2), Chang SH(2)(3), Yan Y(2)(3), Schoen MW(2)(4), Thomas
TS(2)(5), Patel MR(2), Kreisel D(1)(2), Nava RG(1)(2), Meyers BF(1), Kozower
BD(1), Puri V(1)(2).
Author information:
(1)Division of Cardiothoracic Surgery, Department of Surgery, Washington
University School of Medicine, St. Louis, MO, USA.
(2)VA St. Louis Health Care System, St. Louis, MO, USA.
(3)Division of Public Health Sciences, Department of Surgery, Washington
University School of Medicine, St. Louis, MO, USA.
…
BACKGROUND: Recent studies have suggested that more frequent postoperative
surveillance imaging via computed tomography following lung cancer resection may
not improve outcomes. We sought to validate these findings using a uniquely
compiled dataset from the Veterans Health Administration, the largest integrated
health-care system in the United States.
METHODS: We performed a retrospective cohort study of veterans with pathologic
stage I non-small cell lung cancer receiving surgery (2006-2016). We assessed
the relationship between surveillance frequency (chest computed tomography scans
within 2 years after surgery) and recurrence-free survival and overall survival.
RESULTS: Among 6171 patients, 3047 (49.4%) and 3124 (50.6%) underwent
low-frequency (<2 scans per year; every 6-12 months) and high-frequency (≥2
scans per year; every 3-6 months) surveillance, respectively. Factors associated
with high-frequency surveillance included being a former smoker (vs current;
adjusted odds ratio [aOR] = 1.18, 95% confidence interval [CI] = 1.05 to 1.33),
receiving a wedge resection (vs lobectomy; aOR = 1.21, 95% CI = 1.05 to 1.39),
and having follow-up with an oncologist (aOR = 1.58, 95% CI = 1.42 to 1.77),
whereas African American race was associated with low-frequency surveillance (vs
White race; aOR = 0.64, 95% CI = 0.54 to 0.75). With a median (interquartile
range) follow-up of 7.3 (3.4-12.5) years, recurrence was detected in 1360
(22.0%) patients. High-frequency surveillance was not associated with longer
recurrence-free survival (adjusted hazard ratio = 0.93, 95% CI = 0.83 to 1.04,
P = .22) or overall survival (adjusted hazard ratio = 1.04, 95% CI = 0.96 to
1.12, P = .35).
CONCLUSIONS: We found that high-frequency surveillance does not improve outcomes
in surgically treated stage I non-small cell lung cancer. Future lung cancer
treatment guidelines should consider less frequent surveillance imaging in
patients with stage I disease.
© The Author(s) 2022. Published by Oxford University Press. All rights reserved.
For permissions, please email: journals.permissions@oup.com.
DOI: 10.1093/jnci/djac208
PMCID: PMC9996218
PMID: 36442509 [Indexed for MEDLINE]
22. Lancet Infect Dis. 2023 Mar;23(3):341-351. doi: 10.1016/S1473-3099(22)00668-5. Epub 2022 Nov 14.
Effect of systematic tuberculosis detection on mortality in young children with
severe pneumonia in countries with high incidence of tuberculosis: a
stepped-wedge cluster-randomised trial.
Marcy O(1), Wobudeya E(2), Font H(3), Vessière A(3), Chabala C(4), Khosa C(5),
Taguebue JV(6), Moh R(7), Mwanga-Amumpaire J(8), Lounnas M(9), Mulenga V(4),
…
Author information:
(1)Inserm UMR 1219, IRD EMR 271, University of Bordeaux, Bordeaux, France.
Electronic address: olivier.marcy@u-bordeaux.fr.
(2)Makerere University-Johns Hopkins University Research Collaboration, Kampala,
Uganda.
(3)Inserm UMR 1219, IRD EMR 271, University of Bordeaux, Bordeaux, France.
…
BACKGROUND: Tuberculosis diagnosis might be delayed or missed in children with
severe pneumonia because this diagnosis is usually only considered in cases of
prolonged symptoms or antibiotic failure. Systematic tuberculosis detection at
hospital admission could increase case detection and reduce mortality.
METHODS: We did a stepped-wedge cluster-randomised trial in 16 hospitals from
six countries (Cambodia, Cameroon, Côte d'Ivoire, Mozambique, Uganda, and
Zambia) with high incidence of tuberculosis. Children younger than 5 years with
WHO-defined severe pneumonia received either the standard of care (control
group) or standard of care plus Xpert MTB/RIF Ultra (Xpert Ultra; Cepheid,
Sunnyvale, CA, USA) on nasopharyngeal aspirate and stool samples (intervention
group). Clusters (hospitals) were progressively switched from control to
intervention at 5-week intervals, using a computer-generated random sequence,
stratified on incidence rate of tuberculosis at country level, and masked to
teams until 5 weeks before switch. We assessed the effect of the intervention on
primary (12-week all-cause mortality) and secondary (including tuberculosis
diagnosis) outcomes, using generalised linear mixed models. The primary analysis
was by intention to treat. We described outcomes in children with severe acute
malnutrition in a post hoc analysis. This study is registered with
ClinicalTrials.gov (NCT03831906) and the Pan African Clinical Trial Registry
(PACTR202101615120643).
FINDINGS: From March 21, 2019, to March 30, 2021, we enrolled 1401 children in
the control group and 1169 children in the intervention group. In the
intervention group, 1140 (97·5%) children had nasopharyngeal aspirates and 942
(80·6%) had their stool collected; 24 (2·1%) had positive Xpert Ultra. At 12
weeks, 110 (7·9%) children in the control group and 91 (7·8%) children in the
intervention group had died (adjusted odds ratio [OR] 0·986, 95% CI 0·597-1·630, p=0·957),
and 74 (5·3%) children in the control group and 88 (7·5%) children in the intervention group
had tuberculosis diagnosed (adjusted OR 1·238, 95% CI 0·696-2·202, p=0·467). In children
with severe acute malnutrition, 57 (23·8%) of 240 children in the control group and 53 (17·8%)
of 297 children in the intervention group died, and 36 (15·0%) of 240 children in the control
group and 56 (18·9%) of 297 children in the intervention group were diagnosed with
tuberculosis. The main adverse events associated with nasopharyngeal aspirates
were samples with blood in 312 (27·3%) of 1147 children with nasopharyngeal
aspirates attempted, dyspnoea or SpO2 less than 95% in 134 (11·4%) of children,
and transient respiratory distress or SpO2 less than 90% in 59 (5·2%) children.
There was no serious adverse event related to nasopharyngeal aspirates reported
during the trial.
INTERPRETATION: Systematic molecular tuberculosis detection at hospital
admission did not reduce mortality in children with severe pneumonia. High
treatment and microbiological confirmation rates support more systematic use of
Xpert Ultra in this group, notably in children with severe acute malnutrition.
FUNDING: Unitaid and L'Initiative.
TRANSLATION: For the French translation of the abstract see Supplementary
Materials section.
Copyright © 2023 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1473-3099(22)00668-5
PMID: 36395782 [Indexed for MEDLINE]
