Medical Abstracts ( IF > 20 )

1. N Engl J Med. 2020 Sep 19. doi: 10.1056/NEJMoa2027071. Online ahead of print.

Osimertinib in Resected EGFR-Mutated Non-Small-Cell Lung Cancer.

Wu YL(1), Tsuboi M(1), He J(1), John T(1), Grohe C(1), Majem M(1), Goldman

JW(1), Laktionov K(1), Kim SW(1), Kato T(1), Vu HV(1), Lu S(1), Lee KY(1),

Akewanlop C(1), Yu CJ(1), de Marinis F(1), Bonanno L(1), Domine M(1), Shepherd

FA(1), Zeng L(1), Hodge R(1), Atasoy A(1), Rukazenkov Y(1), Herbst RS(1); ADAURA

Investigators.

Author information:

(1)From the Guangdong Lung Cancer Institute, Guangdong Provincial People's

Hospital, and Guangdong Academy of Medical Sciences, Guangzhou (Y.-L.W.), the

Thoracic Surgery Department, National Cancer Center-National Clinical Research

Center for Cancer-Cancer Hospital, Chinese Academy of Medical Sciences and

Peking Union Medical College, Beijing (J.H.),…

BACKGROUND: Osimertinib is standard-of-care therapy for previously untreated

epidermal growth factor receptor (EGFR) mutation-positive advanced

non-small-cell lung cancer (NSCLC). The efficacy and safety of osimertinib as

adjuvant therapy are unknown.

METHODS: In this double-blind, phase 3 trial, we randomly assigned patients with

completely resected EGFR mutation-positive NSCLC in a 1:1 ratio to receive

either osimertinib (80 mg once daily) or placebo for 3 years. The primary end

point was disease-free survival among patients with stage II to IIIA disease

(according to investigator assessment). The secondary end points included

disease-free survival in the overall population of patients with stage IB to

IIIA disease, overall survival, and safety.

RESULTS: A total of 682 patients underwent randomization (339 to the osimertinib

group and 343 to the placebo group). At 24 months, 90% of the patients with

stage II to IIIA disease in the osimertinib group (95% confidence interval [CI],

84 to 93) and 44% of those in the placebo group (95% CI, 37 to 51) were alive

and disease-free (overall hazard ratio for disease recurrence or death, 0.17;

99.06% CI, 0.11 to 0.26; P<0.001). In the overall population, 89% of the

patients in the osimertinib group (95% CI, 85 to 92) and 52% of those in the

placebo group (95% CI, 46 to 58) were alive and disease-free at 24 months

(overall hazard ratio for disease recurrence or death, 0.20; 99.12% CI, 0.14 to

0.30; P<0.001). At 24 months, 98% of the patients in the osimertinib group (95%

CI, 95 to 99) and 85% of those in the placebo group (95% CI, 80 to 89) were

alive and did not have central nervous system disease (overall hazard ratio for

disease recurrence or death, 0.18; 95% CI, 0.10 to 0.33). Overall survival data

were immature; 29 patients died (9 in the osimertinib group and 20 in the

placebo group). No new safety concerns were noted.

CONCLUSIONS: In patients with stage IB to IIIA EGFR mutation-positive NSCLC,

disease-free survival was significantly longer among those who received

osimertinib than among those who received placebo. (Funded by AstraZeneca;

ADAURA ClinicalTrials.gov number, NCT02511106.).

Copyright © 2020 Massachusetts Medical Society.

DOI: 10.1056/NEJMoa2027071

PMID: 32955177

2. N Engl J Med. 2020 Sep 3;383(10):944-957. doi: 10.1056/NEJMoa2002787.

Capmatinib in MET Exon 14-Mutated or MET-Amplified Non-Small-Cell Lung Cancer.

Wolf J(1), Seto T(1), Han JY(1), Reguart N(1), Garon EB(1), Groen HJM(1), Tan

DSW(1), Hida T(1), …

Author information:

(1)From the Department I of Internal Medicine, Center for Integrated Oncology,

University Hospital Cologne and University of Cologne, Cologne (J.W.),

Internistische Onkologie der Thoraxtumoren, Thoraxklinik im Universitätsklinikum

Heidelberg, Translational Lung Research Center Heidelberg, Heidelberg (M.T.),

the Department of Hematology and Medical Oncology, University Medical Center

Göttingen, Göttingen (T.R.O.), …

BACKGROUND: Among patients with non-small-cell lung cancer (NSCLC), MET exon 14

skipping mutations occur in 3 to 4% and MET amplifications occur in 1 to 6%.

Capmatinib, a selective inhibitor of the MET receptor, has shown activity in

cancer models with various types of MET activation.

METHODS: We conducted a multiple-cohort, phase 2 study evaluating capmatinib in

patients with MET-dysregulated advanced NSCLC. Patients were assigned to cohorts

on the basis of previous lines of therapy and MET status (MET exon 14 skipping

mutation or MET amplification according to gene copy number in tumor tissue).

Patients received capmatinib (400-mg tablet) twice daily. The primary end point

was overall response (complete or partial response), and the key secondary end

point was response duration; both end points were assessed by an independent

review committee whose members were unaware of the cohort assignments.

RESULTS: A total of 364 patients were assigned to the cohorts. Among patients

with NSCLC with a MET exon 14 skipping mutation, overall response was observed

in 41% (95% confidence interval [CI], 29 to 53) of 69 patients who had received

one or two lines of therapy previously and in 68% (95% CI, 48 to 84) of 28

patients who had not received treatment previously; the median duration of

response was 9.7 months (95% CI, 5.6 to 13.0) and 12.6 months (95% CI, 5.6 to

could not be estimated), respectively. Limited efficacy was observed in

previously treated patients with MET amplification who had a gene copy number of

less than 10 (overall response in 7 to 12% of patients). Among patients with MET

amplification and a gene copy number of 10 or higher, overall response was

observed in 29% (95% CI, 19 to 41) of previously treated patients and in 40%

(95% CI, 16 to 68) of those who had not received treatment previously. The most

frequently reported adverse events were peripheral edema (in 51%) and nausea (in

45%); these events were mostly of grade 1 or 2.

CONCLUSIONS: Capmatinib showed substantial antitumor activity in patients with

advanced NSCLC with a MET exon 14 skipping mutation, particularly in those not

treated previously. The efficacy in MET-amplified advanced NSCLC was higher in

tumors with a high gene copy number than in those with a low gene copy number.

Low-grade peripheral edema and nausea were the main toxic effects. (Funded by

Novartis Pharmaceuticals; GEOMETRY mono-1 ClinicalTrials.gov number,

NCT02414139.).

Copyright © 2020 Massachusetts Medical Society.

DOI: 10.1056/NEJMoa2002787

PMID: 32877583 [Indexed for MEDLINE]

3. Nat Biotechnol. 2020 Oct;38(10):1194-1202. doi: 10.1038/s41587-020-0505-4. Epub

2020 Apr 27.

Analyzing the Mycobacterium tuberculosis immune response by T-cell receptor

clustering with GLIPH2 and genome-wide antigen screening.

Huang H(1), Wang C(1), Rubelt F(1), Scriba TJ(2), Davis MM(3)(4)(5).

Author information:

(1)Institute for Immunity, Transplantation and Infection, Stanford University

School of Medicine, Stanford, CA, USA.

(2)South African Tuberculosis Vaccine Initiative, Institute of Infectious

Disease and Molecular Medicine and Division of Immunology, Department of

Pathology, University of Cape Town, Cape Town, South Africa.

(3)Institute for Immunity, Transplantation and Infection, Stanford University

School of Medicine, Stanford, CA, USA. mmdavis@stanford.edu.…

CD4+ T cells are critical to fighting pathogens, but a comprehensive analysis of

human T-cell specificities is hindered by the diversity of HLA alleles (>20,000)

and the complexity of many pathogen genomes. We previously described GLIPH, an

algorithm to cluster T-cell receptors (TCRs) that recognize the same epitope and

to predict their HLA restriction, but this method loses efficiency and accuracy

when >10,000 TCRs are analyzed. Here we describe an improved algorithm, GLIPH2,

that can process millions of TCR sequences. We used GLIPH2 to analyze 19,044

unique TCRβ sequences from 58 individuals latently infected with Mycobacterium

tuberculosis (Mtb) and to group them according to their specificity. To identify

the epitopes targeted by clusters of Mtb-specific T cells, we carried out a

screen of 3,724 distinct proteins covering 95% of Mtb protein-coding genes using

artificial antigen-presenting cells (aAPCs) and reporter T cells. We found that

at least five PPE (Pro-Pro-Glu) proteins are targets for T-cell recognition in

Mtb.

DOI: 10.1038/s41587-020-0505-4

PMCID: PMC7541396

PMID: 32341563

4. N Engl J Med. 2020 Aug 27;383(9):813-824. doi: 10.1056/NEJMoa2005653.

Efficacy of Selpercatinib in RET Fusion-Positive Non-Small-Cell Lung Cancer.

Drilon A(1), Oxnard GR(1), Tan DSW(1), Loong HHF(1), Johnson M(1), Gainor J(1),…

Author information:

(1)From Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College

(A.D., E.R.) and New York University Langone Medical Center (V.V.), New York,

and Roswell Park Comprehensive Cancer Center, Buffalo (G.K.D.) - all in New

York; Dana-Farber Cancer Institute (G.R.O.) …

Comment in

N Engl J Med. 2020 Aug 27;383(9):868-869.

BACKGROUND: RET fusions are oncogenic drivers in 1 to 2% of non-small-cell lung

cancers (NSCLCs). In patients with RET fusion-positive NSCLC, the efficacy and

safety of selective RET inhibition are unknown.

METHODS: We enrolled patients with advanced RET fusion-positive NSCLC who had

previously received platinum-based chemotherapy and those who were previously

untreated separately in a phase 1-2 trial of selpercatinib. The primary end

point was an objective response (a complete or partial response) as determined

by an independent review committee. Secondary end points included the duration

of response, progression-free survival, and safety.

RESULTS: In the first 105 consecutively enrolled patients with RET

fusion-positive NSCLC who had previously received at least platinum-based

chemotherapy, the percentage with an objective response was 64% (95% confidence

interval [CI], 54 to 73). The median duration of response was 17.5 months (95%

CI, 12.0 to could not be evaluated), and 63% of the responses were ongoing at a

median follow-up of 12.1 months. Among 39 previously untreated patients, the

percentage with an objective response was 85% (95% CI, 70 to 94), and 90% of the

responses were ongoing at 6 months. Among 11 patients with measurable central

nervous system metastasis at enrollment, the percentage with an objective

intracranial response was 91% (95% CI, 59 to 100). The most common adverse

events of grade 3 or higher were hypertension (in 14% of the patients), an

increased alanine aminotransferase level (in 12%), an increased aspartate

aminotransferase level (in 10%), hyponatremia (in 6%), and lymphopenia (in 6%).

A total of 12 of 531 patients (2%) discontinued selpercatinib because of a

drug-related adverse event.

CONCLUSIONS: Selpercatinib had durable efficacy, including intracranial

activity, with mainly low-grade toxic effects in patients with RET

fusion-positive NSCLC who had previously received platinum-based chemotherapy

and those who were previously untreated. (Funded by Loxo Oncology and others;

LIBRETTO-001 ClinicalTrials.gov number, NCT03157128.).

Copyright © 2020 Massachusetts Medical Society.

DOI: 10.1056/NEJMoa2005653

PMCID: PMC7506467

PMID: 32846060 [Indexed for MEDLINE]

5. N Engl J Med. 2020 Sep 3;383(10):931-943. doi: 10.1056/NEJMoa2004407. Epub 2020 May 29.

Tepotinib in Non-Small-Cell Lung Cancer with MET Exon 14 Skipping Mutations.

Paik PK(1), Felip E(1), Veillon R(1), Sakai H(1), Cortot AB(1), Garassino MC(1),

…

Author information:

(1)From Memorial Sloan Kettering Cancer Center, New York (P.K.P.); the Oncology

Department, Vall d'Hebron University Hospital, Vall d'Hebron Institute of

Oncology (E.F.), and Dr. Rosell Oncology Institute, Dexeus University Hospital,

Quirónsalud Group (S.V.), Barcelona; Centre Hospitaliere Universitaire (CHU)

…

BACKGROUND: A splice-site mutation that results in a loss of transcription of

exon 14 in the oncogenic driver MET occurs in 3 to 4% of patients with

non-small-cell lung cancer (NSCLC). We evaluated the efficacy and safety of

tepotinib, a highly selective MET inhibitor, in this patient population.

METHODS: In this open-label, phase 2 study, we administered tepotinib (at a dose

of 500 mg) once daily in patients with advanced or metastatic NSCLC with a

confirmed MET exon 14 skipping mutation. The primary end point was the objective

response by independent review among patients who had undergone at least 9

months of follow-up. The response was also analyzed according to whether the

presence of a MET exon 14 skipping mutation was detected on liquid biopsy or

tissue biopsy.

RESULTS: As of January 1, 2020, a total of 152 patients had received tepotinib,

and 99 patients had been followed for at least 9 months. The response rate by

independent review was 46% (95% confidence interval [CI], 36 to 57), with a

median duration of response of 11.1 months (95% CI, 7.2 to could not be

estimated) in the combined-biopsy group. The response rate was 48% (95% CI, 36

to 61) among 66 patients in the liquid-biopsy group and 50% (95% CI, 37 to 63)

among 60 patients in the tissue-biopsy group; 27 patients had positive results

according to both methods. The investigator-assessed response rate was 56% (95%

CI, 45 to 66) and was similar regardless of the previous therapy received for

advanced or metastatic disease. Adverse events of grade 3 or higher that were

considered by investigators to be related to tepotinib therapy were reported in

28% of the patients, including peripheral edema in 7%. Adverse events led to

permanent discontinuation of tepotinib in 11% of the patients. A molecular

response, as measured in circulating free DNA, was observed in 67% of the

patients with matched liquid-biopsy samples at baseline and during treatment.

CONCLUSIONS: Among patients with advanced NSCLC with a confirmed MET exon 14

skipping mutation, the use of tepotinib was associated with a partial response

in approximately half the patients. Peripheral edema was the main toxic effect

of grade 3 or higher. (Funded by Merck [Darmstadt, Germany]; VISION

ClinicalTrials.gov number, NCT02864992.).

Copyright © 2020 Massachusetts Medical Society.

DOI: 10.1056/NEJMoa2004407

PMID: 32469185 [Indexed for MEDLINE]

6. Nat Med. 2020 Sep;26(9):1435-1443. doi: 10.1038/s41591-020-0940-2. Epub 2020 Jun 29.

Bacterial and host determinants of cough aerosol culture positivity in patients

with drug-resistant versus drug-susceptible tuberculosis.

Theron G(1)(2), Limberis J(1), Venter R(2), Smith L(1)(2), Pietersen E(1),

Esmail A(1), Calligaro G(1), Te Riele J(3), de Kock M(2), van Helden P(2), Gumbo

T(4), Clark TG(5)(6), Fennelly K(7), Warren R(2), Dheda K(8)(9).

Author information:

(1)Centre for Lung Infection and Immunity, Division of Pulmonology, Department

of Medicine and UCT Lung Institute & 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 and South

African Medical Research Centre for Tuberculosis Research, Division of Molecular

Biology and Human Genetics, Faculty of Medicine and Health Sciences,

Stellenbosch University, Cape Town, South Africa.

(3)Brooklyn Chest Hospital, Cape Town, South Africa.

…

A burgeoning epidemic of drug-resistant tuberculosis (TB) threatens to derail

global control efforts. Although the mechanisms remain poorly clarified,

drug-resistant strains are widely believed to be less infectious than

drug-susceptible strains. Consequently, we hypothesized that lower proportions

of patients with drug-resistant TB would have culturable Mycobacterium

tuberculosis from respirable, cough-generated aerosols compared to patients with

drug-susceptible TB, and that multiple factors, including mycobacterial genomic

variation, would predict culturable cough aerosol production. We enumerated the

colony forming units in aerosols (≤10 µm) from 452 patients with TB (227 with

drug resistance), compared clinical characteristics, and performed mycobacterial

whole-genome sequencing, dormancy phenotyping and drug-susceptibility analyses

on M. tuberculosis from sputum. After considering treatment duration, we found

that almost half of the patients with drug-resistant TB were cough aerosol

culture-positive. Surprisingly, neither mycobacterial genomic variants, lineage,

nor dormancy status predicted cough aerosol culture positivity. However,

mycobacterial sputum bacillary load and clinical characteristics, including a

lower symptom score and stronger cough, were strongly predictive, thereby

supporting targeted transmission-limiting interventions. Effective treatment

largely abrogated cough aerosol culture positivity; however, this was not always

rapid. These data question current paradigms, inform public health strategies

and suggest the need to redirect TB transmission-associated research efforts

toward host-pathogen interactions.

DOI: 10.1038/s41591-020-0940-2

PMID: 32601338

7. Lancet Oncol. 2020 Sep 24:S1470-2045(20)30453-8. doi:

10.1016/S1470-2045(20)30453-8. Online ahead of print.

Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer

(NADIM): an open-label, multicentre, single-arm, phase 2 trial.

Provencio M(1), Nadal E(2), Insa A(3), García-Campelo MR(4), Casal-Rubio J(5),…

Author information:

(1)Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain.

Electronic address: mprovenciop@gmail.com.

(2)Institut Català d'Oncologia, L'Hospitalet de Llobregat, Barcelona, Spain.

(3)Fundación INCLIVA, Hospital Clínico Universitario de Valencia, Valencia,

Spain. …

BACKGROUND: Non-small-cell lung cancer (NSCLC) is terminal in most patients with

locally advanced stage disease. We aimed to assess the antitumour activity and

safety of neoadjuvant chemoimmunotherapy for resectable stage IIIA NSCLC.

METHODS: This was an open-label, multicentre, single-arm phase 2 trial done at

18 hospitals in Spain. Eligible patients were aged 18 years or older with

histologically or cytologically documented treatment-naive American Joint

Committee on Cancer-defined stage IIIA NSCLC that was deemed locally to be

surgically resectable by a multidisciplinary clinical team, and an Eastern

Cooperative Oncology Group performance status of 0 or 1. Patients received

neoadjuvant treatment with intravenous paclitaxel (200 mg/m2) and carboplatin

(area under curve 6; 6 mg/mL per min) plus nivolumab (360 mg) on day 1 of each

21-day cycle, for three cycles before surgical resection, followed by adjuvant

intravenous nivolumab monotherapy for 1 year (240 mg every 2 weeks for 4 months,

followed by 480 mg every 4 weeks for 8 months). The primary endpoint was

progression-free survival at 24 months, assessed in the modified

intention-to-treat population, which included all patients who received

neoadjuvant treatment, and in the per-protocol population, which included all

patients who had tumour resection and received at least one cycle of adjuvant

treatment. Safety was assessed in the modified intention-to-treat population.

This study is registered with ClinicalTrials.gov, NCT03081689, and is ongoing

but no longer recruiting patients.

FINDINGS: Between April 26, 2017, and Aug 25, 2018, we screened 51 patients for

eligibility, of whom 46 patients were enrolled and received neoadjuvant

treatment. At the time of data cutoff (Jan 31, 2020), the median duration of

follow-up was 24·0 months (IQR 21·4-28·1) and 35 of 41 patients who had tumour

resection were progression free. At 24 months, progression-free survival was

77·1% (95% CI 59·9-87·7). 43 (93%) of 46 patients had treatment-related adverse

events during neoadjuvant treatment, and 14 (30%) had treatment-related adverse

events of grade 3 or worse; however, none of the adverse events were associated

with surgery delays or deaths. The most common grade 3 or worse

treatment-related adverse events were increased lipase (three [7%]) and febrile

neutropenia (three [7%]).

INTERPRETATION: Our results support the addition of neoadjuvant nivolumab to

platinum-based chemotherapy in patients with resectable stage IIIA NSCLC.

Neoadjuvant chemoimmunotherapy could change the perception of locally advanced

lung cancer as a potentially lethal disease to one that is curable.

FUNDING: Bristol-Myers Squibb, Instituto de Salud Carlos III, European Union's

Horizon 2020 research and innovation programme.

Copyright © 2020 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1470-2045(20)30453-8

PMID: 32979984

8. Lancet Oncol. 2020 Sep;21(9):1224-1233. doi: 10.1016/S1470-2045(20)30461-7.

Carboplatin plus etoposide versus topotecan as second-line treatment for

patients with sensitive relapsed small-cell lung cancer: an open-label,

multicentre, randomised, phase 3 trial.

Baize N(1), Monnet I(2), Greillier L(3), Geier M(4), Lena H(5), Janicot H(6),

Vergnenegre A(7), Crequit J(8), Lamy R(9), Auliac JB(2), Letreut J(10), Le Caer

H(11), Gervais R(12), Dansin E(13), Madroszyk A(14), Renault PA(15), Le Garff

G(11), Falchero L(16), Berard H(17), Schott R(18), Saulnier P(19), Chouaid

C(20); Groupe Français de Pneumo-Cancérologie 01–13 investigators.

Author information:

(1)Service de Cancérologie, Centre Hospitalier Universitaire d'Angers, Angers,

France.

(2)Service de Pneumologie, CHI Créteil, Créteil, France.

(3)Aix-Marseille University, Marseille, France; Department of Multidisciplinary

Oncology and Therapeutic Innovations, APHM, Hôpital Nord, Marseille, France;

Department of Multidisciplinary Oncology and Therapeutic Innovations, Hôpital

Nord, Marseille, France.…

Comment in

Lancet Oncol. 2020 Sep;21(9):1132-1134.

BACKGROUND: Topotecan is currently the only drug approved in Europe in a

second-line setting for the treatment of small-cell lung cancer. This study

investigated whether the doublet of carboplatin plus etoposide was superior to

topotecan as a second-line treatment in patients with sensitive relapsed

small-cell lung cancer.

METHODS: In this open-label, randomised, phase 3 trial done in 38 hospitals in

France, we enrolled patients with histologically or cytologically confirmed

advanced stage IV or locally relapsed small-cell lung cancer, who responded to

first-line platinum plus etoposide treatment, but who had disease relapse or

progression at least 90 days after completion of first-line treatment. Eligible

patients were aged 18 years or older and had an Eastern Cooperative Oncology

Group performance status 0-2. Enrolled patients were randomly assigned (1:1) to

receive combination carboplatin plus etoposide (six cycles of intravenous

carboplatin [area under the curve 5 mg/mL per min] on day 1 plus intravenous

etoposide [100 mg/m2 from day 1 to day 3]) or oral topotecan (2·3 mg/m2 from day

1 to day 5, for six cycles). Randomisation was done using the minimisation

method with biased-coin balancing for ECOG performance status, response to the

first-line chemotherapy, and treatment centre. The primary endpoint was

progression-free survival, which was centrally reviewed and analysed in the

intention-to-treat population. This trial is registered with ClinicalTrials.gov,

NCT02738346.

FINDINGS: Between July 18, 2013, and July 2, 2018, we enrolled and randomly

assigned 164 patients (82 in each study group). One patient from each group

withdrew consent, therefore 162 patients (81 in each group) were included in the

intention-to-treat population. With a median follow-up of 22·7 months (IQR

20·0-37·3), median progression-free survival was significantly longer in the

combination chemotherapy group than in the topotecan group (4·7 months, 90% CI

3·9-5·5 vs 2·7 months, 2·3-3·2; stratified hazard ratio 0·57, 90% CI 0·41-0·73;

p=0·0041). The most frequent grade 3-4 adverse events were neutropenia (18 [22%]

of 81 patients in the topotecan group vs 11 [14%] of 81 patients in the

combination chemotherapy group), thrombocytopenia (29 [36%] vs 25 [31%]),

anaemia (17 [21%] vs 20 [25%]), febrile neutropenia (nine [11%] vs five [6%]),

and asthenia (eight [10%] vs seven [9%]). Two treatment-related deaths occurred

in the topotecan group (both were febrile neutropenia with sepsis) and no

treatment-related deaths occurred in the combination group.

INTERPRETATION: Our results suggest that carboplatin plus etoposide rechallenge

can be considered as a reasonable second-line chemotherapy option for patients

with sensitive relapsed small-cell lung cancer.

FUNDING: Amgen and the French Lung Cancer Group (Groupe Français de

Pneumo-Cancérologie).

Copyright © 2020 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1470-2045(20)30461-7

PMID: 32888454 [Indexed for MEDLINE]

9. Lancet Infect Dis. 2020 Jul 13:S1473-3099(20)30276-0. doi:

10.1016/S1473-3099(20)30276-0. Online ahead of print.

Interferon-γ release assays or tuberculin skin test for detection and management

of latent tuberculosis infection: a systematic review and meta-analysis.

Zhou G(1), Luo Q(2), Luo S(1), Teng Z(3), Ji Z(1), Yang J(1), Wang F(1), Wen

S(1), Ding Z(1), Li L(1), Chen T(1), Abi ME(1), Jian M(4), Luo L(4), Liu A(5),

Bao F(6).

Author information:

(1)Department of Microbiology and Immunology, Kunming Medical University,

Kunming, Yunnan Province, China.

(2)School of Basic Medical Sciences, Department of Medical Imaging, Affiliated

Yanan Hospital, Kunming Medical University, Kunming, Yunnan Province, China.

(3)Department of Orthopedic Surgery, The 6th Affiliated Hospital, Kunming

Medical University, Kunming, Yunnan Province, China.…

BACKGROUND: Use of an interferon-γ (IFN-γ) release assay or tuberculin skin test

for detection and management of latent tuberculosis infection is controversial.

For both types of test, we assessed their predictive value for the progression

of latent infection to active tuberculosis disease, the targeting value of

preventive treatment, and the necessity of dual testing.

METHODS: In this systematic review and meta-analysis, we searched PubMed,

Embase, Web of Science, and the Cochrane Library, with no start date or language

restrictions, on Oct 18, 2019, using the keywords ("latent tuberculosis" OR

"latent tuberculosis infection" OR "LTBI") AND ("interferon gamma release

assays" OR "Interferon-gamma Release Test" OR "IGRA" OR "QuantiFERON®-TB in

tube" OR "QFT" OR "T-SPOT.TB") AND ("tuberculin skin test" OR "tuberculin test"

OR "Mantoux test" OR "TST"). We included articles that used a cohort study

design; included information that individuals with latent tuberculosis infection

detected by IFN-γ release assay, tuberculin skin test, or both, progressed to

active tuberculosis; reported information about treatment; and were limited to

high-risk populations. We excluded studies that included patients with active or

suspected tuberculosis at baseline, evaluated a non-commercial IFN-γ release

assay, and had follow-up of less than 1 year. We extracted study details (study

design, population investigated, tests used, follow-up period) and the number of

individuals observed at baseline, who progressed to active tuberculosis, and who

were treated. We then calculated the pooled risk ratio (RR) for disease

progression, positive predictive value (PPV), and negative predictive value

(NPV) of IFN-γ release assay versus tuberculin skin test.

FINDINGS: We identified 1823 potentially eligible studies after exclusion of

duplicates, of which 256 were eligible for full-text screening. From this

screening, 40 studies (50?592 individuals in 41 cohorts) were identified as

eligible and included in our meta-analysis. Pooled RR for the rate of disease

progression in untreated individuals who were positive by IFN-γ release assay

versus those were negative was 9·35 (95% CI 6·48-13·49) compared with 4·24

(3·30-5·46) for tuberculin skin test. Pooled PPV for IFN-γ release assay was

4·5% (95% CI 3·3-5·8) compared with 2·3% (1·5-3·1) for tuberculin skin test.

Pooled NPV for IFN-γ release assay was 99·7% (99·5-99·8) compared with 99·3%

(99·0-99·5) for tuberculin skin test. Pooled RR for rates of disease progression

in individuals positive by IFN-γ release assay who were untreated versus those

who were treated was 3·09 (95% CI 2·08-4·60) compared with 1·11 (0·69-1·79) for

the same populations who were positive by tuberculin skin test. Pooled

proportion of disease progression for individuals who were positive by IFN-γ

release assay and tuberculin skin test was 6·1 (95% CI 2·3-11·5). Pooled RR for

rates of disease progression in individuals who were positive by IFN-γ release

assay and tuberculin skin test who were untreated versus those who were treated

was 7·84 (95% CI 4·44-13·83).

INTERPRETATION: IFN-γ release assays have a better predictive ability than

tuberculin skin tests. Individuals who are positive by IFN-γ release assay might

benefit from preventive treatment, but those who are positive by tuberculin skin

test probably will not. Dual testing might improve detection, but further

confirmation is needed.

FUNDING: National Natural Science Foundation of China and Natural Foundation of

Yunnan Province.

Copyright © 2020 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1473-3099(20)30276-0

PMID: 32673595

10. Clin Microbiol Rev. 2020 Jul 1;33(4):e00036-20. doi: 10.1128/CMR.00036-20. Print

2020 Sep 16.

The Echo of Pulmonary Tuberculosis: Mechanisms of Clinical Symptoms and Other

Disease-Induced Systemic Complications.

Luies L(1), du Preez I(2).

Author information:

(1)Human Metabolomics, North-West University, Potchefstroom, North West, South

Africa laneke.luies@nwu.ac.za.

(2)Human Metabolomics, North-West University, Potchefstroom, North West, South

Africa.

Clinical symptoms of active tuberculosis (TB) can range from a simple cough to

more severe reactions, such as irreversible lung damage and, eventually, death,

depending on disease progression. In addition to its clinical presentation, TB

has been associated with several other disease-induced systemic complications,

such as hyponatremia and glucose intolerance. Here, we provide an overview of

the known, although ill-described, underlying biochemical mechanisms responsible

for the clinical and systemic presentations associated with this disease and

discuss novel hypotheses recently generated by various omics technologies. This

summative update can assist clinicians to improve the tentative diagnosis of TB

based on a patient's clinical presentation and aid in the development of

improved treatment protocols specifically aimed at restoring the disease-induced

imbalance for overall homeostasis while simultaneously eradicating the pathogen.

Furthermore, future applications of this knowledge could be applied to

personalized diagnostic and therapeutic options, bettering the treatment outcome

and quality of life of TB patients.

Copyright © 2020 American Society for Microbiology.

DOI: 10.1128/CMR.00036-20

PMCID: PMC7331478

PMID: 32611585

11. Lancet Infect Dis. 2020 Jun 23:S1473-3099(20)30177-8. doi:

10.1016/S1473-3099(20)30177-8. Online ahead of print.

Advanced imaging tools for childhood tuberculosis: potential applications and

research needs.

Jain SK(1), Andronikou S(2), Goussard P(3), Antani S(4), Gomez-Pastrana D(5),

Delacourt C(6), Starke JR(7), Ordonez AA(8), Jean-Philippe P(9), Browning RS(9),

Perez-Velez CM(10).

Author information:

(1)Department of Pediatrics, Johns Hopkins University School of Medicine,

Baltimore, MD, USA; Center for Infection and Inflammation Imaging Research,

Johns Hopkins University School of Medicine, Baltimore, MD, USA; Center for

Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore,

MD, USA; Russell H Morgan Department of Radiology and Radiological Science,

Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic

address: sjain5@jhmi.edu.

(2)Department of Radiology, Children's Hospital of Philadelphia, Philadelphia,

PA, USA; Perelman School of Medicine University of Pennsylvania, Philadelphia,

PA, USA.

(3)Tygerberg Hospital, Stellenbosch University, Cape Town, South Africa.…

Tuberculosis is the leading cause of death globally that is due to a single

pathogen, and up to a fifth of patients with tuberculosis in high-incidence

countries are children younger than 16 years. Unfortunately, the diagnosis of

childhood tuberculosis is challenging because the disease is often

paucibacillary and it is difficult to obtain suitable specimens, causing poor

sensitivity of currently available pathogen-based tests. Chest radiography is

important for diagnostic evaluations because it detects abnormalities consistent

with childhood tuberculosis, but several limitations exist in the interpretation

of such results. Therefore, other imaging methods need to be systematically

evaluated in children with tuberculosis, although current data suggest that when

available, cross-sectional imaging, such as CT, should be considered in the

diagnostic evaluation for tuberculosis in a symptomatic child. Additionally,

much of the understanding of childhood tuberculosis stems from clinical

specimens that might not accurately represent the lesional biology at infection

sites. By providing non-invasive measures of lesional biology, advanced imaging

tools could enhance the understanding of basic biology and improve on the poor

sensitivity of current pathogen detection systems. Finally, there are key

knowledge gaps regarding the use of imaging tools for childhood tuberculosis

that we outlined in this Personal View, in conjunction with a proposed roadmap

for future research.

Copyright © 2020 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1473-3099(20)30177-8

PMID: 32589869

12. Ann Intern Med. 2020 Aug 4;173(3):169-178. doi: 10.7326/M19-3741. Epub 2020 Jun 16.

Health System Costs of Treating Latent Tuberculosis Infection With Four Months

of Rifampin Versus Nine Months of Isoniazid in Different Settings.

Bastos ML(1), Campbell JR(2), Oxlade O(3), Adjobimey M(4), Trajman A(5), Ruslami

R(6), Kim HJ(7), Baah JO(8), Toelle BG(9), Long R(10), Hoeppner V(11), Elwood

K(12), Al-Jahdali H(13), Apriani L(14), Benedetti A(2), Schwartzman K(2),

Menzies D(2).

Author information:

(1)State University of Rio de Janeiro, Rio de Janeiro, Brazil, and McGill

University, Montreal, Quebec, Canada (M.L.B.).

(2)McGill University, Montreal, Quebec, Canada (J.R.C., A.B., K.S., D.M.).

(3)McGill International TB Center, Montreal, Quebec, Canada (O.O.).…

BACKGROUND: Four months of rifampin treatment for latent tuberculosis infection

is safer, has superior treatment completion rates, and is as effective as 9

months of isoniazid. However, daily medication costs are higher for a 4-month

rifampin regimen than a 9-month isoniazid regimen.

OBJECTIVE: To compare health care use and associated costs of 4 months of

rifampin and 9 months of isoniazid.

DESIGN: Health system cost comparison using all health care activities recorded

during 2 randomized clinical trials. (ClinicalTrials.gov: NCT00931736 and

NCT00170209).

SETTING: High-income countries (Australia, Canada, Saudi Arabia, and South

Korea), middle-income countries (Brazil and Indonesia), and African countries

(Benin, Ghana, and Guinea).

PARTICIPANTS: Adults and children with clinical or epidemiologic factors

associated with increased risk for developing tuberculosis that warranted

treatment for latent tuberculosis infection.

MEASUREMENTS: Health system costs per participant.

RESULTS: A total of 6012 adults and 829 children were included. In both adults

and children, greater health system use and higher costs were observed with 9

months of isoniazid than with 4 months of rifampin. In adults, the ratios of

costs of 4 months of rifampin versus 9 months of isoniazid were 0.76 (95% CI,

0.70 to 0.82) in high-income countries, 0.90 (CI, 0.85 to 0.96) in middle-income

countries, and 0.80 (CI, 0.78 to 0.81) in African countries. Similar findings

were observed in the pediatric population.

LIMITATION: Costs may have been overestimated because the trial protocol

required a minimum number of follow-up visits, although fewer than recommended

by many authoritative guidelines.

CONCLUSION: A 4-month rifampin regimen was safer and less expensive than 9

months of isoniazid in all settings. This regimen could be adopted by

tuberculosis programs in many countries as first-line therapy for latent

tuberculosis infection.

PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research.

DOI: 10.7326/M19-3741

PMID: 32539440