Medical Abstracts

Filters applied: from 2021/6/1 - 2021/6/30

1. Chem Rev. 2021 Jun 30. doi: 10.1021/acs.chemrev.1c00043. Online ahead of print.

Chemical Synthesis of Cell Wall Constituents of Mycobacterium tuberculosis.

Holzheimer M(1), Buter J(1), Minnaard AJ(1).

Author information:

(1)Stratingh Institute for Chemistry, University of Groningen, 9747 AG

Groningen, The Netherlands.

The pathogen Mycobacterium tuberculosis (Mtb), causing tuberculosis disease,

features an extraordinary thick cell envelope, rich in Mtb-specific lipids,

glycolipids, and glycans. These cell wall components are often directly involved

in host-pathogen interaction and recognition, intracellular survival, and

virulence. For decades, these mycobacterial natural products have been of great

interest for immunology and synthetic chemistry alike, due to their complex

molecular structure and the biological functions arising from it. The synthesis

of many of these constituents has been achieved and aided the elucidation of

their function by utilizing the synthetic material to study Mtb immunology. This

review summarizes the synthetic efforts of a quarter century of total synthesis

and highlights how the synthesis layed the foundation for immunological studies

as well as drove the field of organic synthesis and catalysis to efficiently

access these complex natural products.

DOI: 10.1021/acs.chemrev.1c00043

PMID: 34190544

2. N Engl J Med. 2021 Jun 24;384(25):2382-2393. doi: 10.1056/NEJMoa2105281.

Acquired Resistance to KRAS(G12C) Inhibition in Cancer.

Awad MM(1), Liu S(1), Rybkin II(1), Arbour KC(1), Dilly J(1), Zhu VW(1), Johnson

ML(1), Heist RS(1), Patil T(1), Riely GJ(1), Jacobson JO(1), Yang X(1), Persky

NS(1), Root DE(1), Lowder KE(1), Feng H(1), Zhang SS(1), Haigis KM(1), Hung

YP(1), Sholl LM(1), Wolpin BM(1), Wiese J(1), Christiansen J(1), Lee J(1),

Schrock AB(1), Lim LP(1), Garg K(1), Li M(1), Engstrom LD(1), Waters L(1),

Lawson JD(1), Olson P(1), Lito P(1), Ou SI(1), Christensen JG(1), Jänne PA(1),

Aguirre AJ(1).

Author information:

(1)From Dana-Farber Cancer Institute (M.M.A., S.L., J.D., J.O.J., K.E.L., H.F.,

K.M.H., B.M.W., P.A.J., A.J.A.), Massachusetts General Hospital (R.S.H.,

Y.P.H.), and Brigham and Women's Hospital (L.M.S., A.J.A.), Boston, and Broad

Institute of MIT and Harvard (S.L., X.Y., N.S.P., D.E.R., K.M.H., A.J.A.) and

Foundation Medicine (J.L., A.B.S.), Cambridge - all in Massachusetts; Henry Ford

Cancer Institute, Detroit (I.I.R.); Memorial Sloan Kettering Cancer Center, New

York (K.C.A., G.J.R., P.L.); Chao Family Comprehensive Cancer Center, University

of California, Irvine, School of Medicine, Orange (V.W.Z., S.S.Z., S.-H.I.O.),

Boundless Bio, La Jolla (J.W., J.C.), and Mirati Therapeutics, San Diego

(L.D.E., L.W., J.D.L., P.O., J.G.C.) - all in California; Sarah Cannon Research

Institute, Tennessee Oncology/OneOncology, Nashville (M.L.J.); the University of

Colorado, Aurora (T.P.); and Resolution Bioscience, Kirkland, WA (L.P.L., K.G.,

M.L.).

Comment in

    N Engl J Med. 2021 Jun 24;384(25):2447-2449.

BACKGROUND: Clinical trials of the KRAS inhibitors adagrasib and sotorasib have

shown promising activity in cancers harboring KRAS glycine-to-cysteine amino

acid substitutions at codon 12 (KRASG12C). The mechanisms of acquired resistance

to these therapies are currently unknown.

METHODS: Among patients with KRASG12C -mutant cancers treated with adagrasib

monotherapy, we performed genomic and histologic analyses that compared

pretreatment samples with those obtained after the development of resistance.

Cell-based experiments were conducted to study mutations that confer resistance

to KRASG12C inhibitors.

RESULTS: A total of 38 patients were included in this study: 27 with

non-small-cell lung cancer, 10 with colorectal cancer, and 1 with appendiceal

cancer. Putative mechanisms of resistance to adagrasib were detected in 17

patients (45% of the cohort), of whom 7 (18% of the cohort) had multiple

coincident mechanisms. Acquired KRAS alterations included G12D/R/V/W, G13D,

Q61H, R68S, H95D/Q/R, Y96C, and high-level amplification of the KRASG12C allele.

Acquired bypass mechanisms of resistance included MET amplification; activating

mutations in NRAS, BRAF, MAP2K1, and RET; oncogenic fusions involving ALK, RET,

BRAF, RAF1, and FGFR3; and loss-of-function mutations in NF1 and PTEN. In two of

nine patients with lung adenocarcinoma for whom paired tissue-biopsy samples

were available, histologic transformation to squamous-cell carcinoma was

observed without identification of any other resistance mechanisms. Using an in

vitro deep mutational scanning screen, we systematically defined the landscape

of KRAS mutations that confer resistance to KRASG12C inhibitors.

CONCLUSIONS: Diverse genomic and histologic mechanisms impart resistance to

covalent KRASG12C inhibitors, and new therapeutic strategies are required to

delay and overcome this drug resistance in patients with cancer. (Funded by

Mirati Therapeutics and others; ClinicalTrials.gov number, NCT03785249.).

Copyright © 2021 Massachusetts Medical Society.

DOI: 10.1056/NEJMoa2105281

PMID: 34161704 [Indexed for MEDLINE]

3. Nature. 2021 Jul;595(7868):578-584. doi: 10.1038/s41586-021-03651-8. Epub 2021

Jun 16.

Tissue-resident macrophages provide a pro-tumorigenic niche to early NSCLC

cells.

Casanova-Acebes M(1)(2)(3)(4), Dalla E(#)(5)(6)(7)(8), Leader AM(#)(9)(10)(11),

LeBerichel J(#)(9)(10)(11), Nikolic J(12), Morales BM(13), Brown M(13), Chang

C(9)(10)(11), Troncoso L(9)(10)(11), Chen ST(9)(10)(11), Sastre-Perona

A(14)(15), Park MD(9)(10)(11), Tabachnikova A(9)(10)(11), Dhainaut

M(10)(11)(16), Hamon P(9)(10)(11), Maier B(9)(10)(11)(17), Sawai CM(18),

Agulló-Pascual E(19), Schober M(14), Brown BD(10)(11)(16)(20), Reizis B(21),

Marron T(9)(10)(11)(5)(22), Kenigsberg E(10)(20), Moussion C(13), Benaroch

P(12), Aguirre-Ghiso JA(9)(10)(11)(5)(6)(7)(8), Merad M(23)(24)(25)(26).

Author information:

(1)Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai,

New York, NY, USA. mcasanova@cnio.es.

(2)Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New

York, NY, USA. mcasanova@cnio.es.

(3)Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York,

NY, USA. mcasanova@cnio.es.

…

Macrophages have a key role in shaping the tumour microenvironment (TME), tumour

immunity and response to immunotherapy, which makes them an important target for

cancer treatment1,2. However, modulating macrophages has proved extremely

difficult, as we still lack a complete understanding of the molecular and

functional diversity of the tumour macrophage compartment. Macrophages arise

from two distinct lineages. Tissue-resident macrophages self-renew locally,

independent of adult haematopoiesis3-5, whereas short-lived monocyte-derived

macrophages arise from adult haematopoietic stem cells, and accumulate mostly in

inflamed lesions1. How these macrophage lineages contribute to the TME and

cancer progression remains unclear. To explore the diversity of the macrophage

compartment in human non-small cell lung carcinoma (NSCLC) lesions, here we

performed single-cell RNA sequencing of tumour-associated leukocytes. We

identified distinct populations of macrophages that were enriched in human and

mouse lung tumours. Using lineage tracing, we discovered that these macrophage

populations differ in origin and have a distinct temporal and spatial

distribution in the TME. Tissue-resident macrophages accumulate close to tumour

cells early during tumour formation to promote epithelial-mesenchymal transition

and invasiveness in tumour cells, and they also induce a potent regulatory T

cell response that protects tumour cells from adaptive immunity. Depletion of

tissue-resident macrophages reduced the numbers and altered the phenotype of

regulatory T cells, promoted the accumulation of CD8+ T cells and reduced tumour

invasiveness and growth. During tumour growth, tissue-resident macrophages

became redistributed at the periphery of the TME, which becomes dominated by

monocyte-derived macrophages in both mouse and human NSCLC. This study

identifies the contribution of tissue-resident macrophages to early lung cancer

and establishes them as a target for the prevention and treatment of early lung

cancer lesions.

© 2021. The Author(s), under exclusive licence to Springer Nature Limited.

DOI: 10.1038/s41586-021-03651-8

PMID: 34135508

4. N Engl J Med. 2021 Jun 24;384(25):2371-2381. doi: 10.1056/NEJMoa2103695. Epub

2021 Jun 4.

Sotorasib for Lung Cancers with KRAS p.G12C Mutation.

Skoulidis F(1), Li BT(1), Dy GK(1), Price TJ(1), Falchook GS(1), Wolf J(1),

Italiano A(1), Schuler M(1), Borghaei H(1), Barlesi F(1), Kato T(1),

Curioni-Fontecedro A(1), Sacher A(1), Spira A(1), Ramalingam SS(1), Takahashi

T(1), Besse B(1), Anderson A(1), Ang A(1), Tran Q(1), Mather O(1), Henary H(1),

Ngarmchamnanrith G(1), Friberg G(1), Velcheti V(1), Govindan R(1).

Author information:

(1)From the University of Texas M.D. Anderson Cancer Center, Houston (F.S.), and

U.S. Oncology Research, the Woodlands (A. Spira) - both in Texas; Memorial Sloan

Kettering Cancer Center and Weill Cornell Medicine (B.T.L.) and Thoracic Medical

Oncology, Perlmutter Cancer Center, New York University (V.V.), New York, and

Roswell Park Cancer Institute, Buffalo (G.K.D.) - all in New York; the Queen

Elizabeth Hospital and University of Adelaide, Woodville, SA, Australia

(T.J.P.); …

Comment in

    N Engl J Med. 2021 Jun 24;384(25):2447-2449.

BACKGROUND: Sotorasib showed anticancer activity in patients with KRAS

p.G12C-mutated advanced solid tumors in a phase 1 study, and particularly

promising anticancer activity was observed in a subgroup of patients with

non-small-cell lung cancer (NSCLC).

METHODS: In a single-group, phase 2 trial, we investigated the activity of

sotorasib, administered orally at a dose of 960 mg once daily, in patients with

KRAS p.G12C-mutated advanced NSCLC previously treated with standard therapies.

The primary end point was objective response (complete or partial response)

according to independent central review. Key secondary end points included

duration of response, disease control (defined as complete response, partial

response, or stable disease), progression-free survival, overall survival, and

safety. Exploratory biomarkers were evaluated for their association with

response to sotorasib therapy.

RESULTS: Among the 126 enrolled patients, the majority (81.0%) had previously

received both platinum-based chemotherapy and inhibitors of programmed death 1

(PD-1) or programmed death ligand 1 (PD-L1). According to central review, 124

patients had measurable disease at baseline and were evaluated for response. An

objective response was observed in 46 patients (37.1%; 95% confidence interval

[CI], 28.6 to 46.2), including in 4 (3.2%) who had a complete response and in 42

(33.9%) who had a partial response. The median duration of response was 11.1

months (95% CI, 6.9 to could not be evaluated). Disease control occurred in 100

patients (80.6%; 95% CI, 72.6 to 87.2). The median progression-free survival was

6.8 months (95% CI, 5.1 to 8.2), and the median overall survival was 12.5 months

(95% CI, 10.0 to could not be evaluated). Treatment-related adverse events

occurred in 88 of 126 patients (69.8%), including grade 3 events in 25 patients

(19.8%) and a grade 4 event in 1 (0.8%). Responses were observed in subgroups

defined according to PD-L1 expression, tumor mutational burden, and co-occurring

mutations in STK11, KEAP1, or TP53.

CONCLUSIONS: In this phase 2 trial, sotorasib therapy led to a durable clinical

benefit without new safety signals in patients with previously treated KRAS

p.G12C-mutated NSCLC. (Funded by Amgen and the National Institutes of Health;

CodeBreaK100 ClinicalTrials.gov number, NCT03600883.).

Copyright © 2021 Massachusetts Medical Society.

DOI: 10.1056/NEJMoa2103695

PMID: 34096690 [Indexed for MEDLINE]

5. Nat Med. 2021 Jun 28. doi: 10.1038/s41591-021-01388-5. Online ahead of print.

Inherited PD-1 deficiency underlies tuberculosis and autoimmunity in a child.

Ogishi M(1)(2), Yang R(3), Aytekin C(4), Langlais D(5), Bourgey M(6), Khan T(7),

Ali FA(7), Rahman M(7), Delmonte OM(8), …

Author information:

(1)St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller

Branch, Rockefeller University, New York, NY, USA. mogishi@rockefeller.edu.

(2)The David Rockefeller Graduate Program, Rockefeller University, New York, NY,

USA. mogishi@rockefeller.edu.

(3)St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller

Branch, Rockefeller University, New York, NY, USA.

(4)Department of Pediatric Immunology, Dr. Sami Ulus Maternity and Children's

Health and Diseases Training and Research Hospital, Ankara, Turkey.

(5)Department of Human Genetics, McGill University, Montreal, Quebec, Canada.

(6)McGill University Genome Center, Montreal, Quebec, Canada.

…

The pathophysiology of adverse events following programmed cell death protein 1

(PD-1) blockade, including tuberculosis (TB) and autoimmunity, remains poorly

characterized. We studied a patient with inherited PD-1 deficiency and TB who

died of pulmonary autoimmunity. The patient's leukocytes did not express PD-1 or

respond to PD-1-mediated suppression. The patient's lymphocytes produced only

small amounts of interferon (IFN)-γ upon mycobacterial stimuli, similarly to

patients with inborn errors of IFN-γ production who are vulnerable to TB. This

phenotype resulted from a combined depletion of Vδ2+ γδ T, mucosal-associated

invariant T and CD56bright natural killer lymphocytes and dysfunction of other T

lymphocyte subsets. Moreover, the patient displayed hepatosplenomegaly and an

expansion of total, activated and RORγT+ CD4-CD8- double-negative αβ T cells,

similar to patients with STAT3 gain-of-function mutations who display

lymphoproliferative autoimmunity. This phenotype resulted from excessive amounts

of STAT3-activating cytokines interleukin (IL)-6 and IL-23 produced by activated

T lymphocytes and monocytes, and the STAT3-dependent expression of RORγT by

activated T lymphocytes. Our work highlights the indispensable role of human

PD-1 in governing both antimycobacterial immunity and self-tolerance, while

identifying potentially actionable molecular targets for the diagnostic and

therapeutic management of TB and autoimmunity in patients on PD-1 blockade.

DOI: 10.1038/s41591-021-01388-5

PMID: 34183838

6. Lancet Oncol. 2021 Jul;22(7):959-969. doi: 10.1016/S1470-2045(21)00247-3. Epub

2021 Jun 9.

Pralsetinib for RET fusion-positive non-small-cell lung cancer (ARROW): a

multi-cohort, open-label, phase 1/2 study.

Gainor JF(1), Curigliano G(2), Kim DW(3), Lee DH(4), Besse B(5), Baik CS(6),

Doebele RC(7), Cassier PA(8), Lopes G(9), Tan DSW(10), Garralda E(11), Paz-Ares

LG(12), Cho BC(13), Gadgeel SM(14), Thomas M(15), Liu SV(16), Taylor MH(17),

Mansfield AS(18), Zhu VW(19), Clifford C(20), Zhang H(21), Palmer M(22), Green

J(23), Turner CD(23), Subbiah V(24).

Author information:

(1)Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.

Electronic address: jgainor@partners.org.

(2)Department of Oncology and Hemato-Oncology, University of Milan and European

Institute of Oncology, IRCCS, Milan, Italy.

(3)Department of Internal Medicine, Seoul National University College of

Medicine and Seoul National University Hospital, Seoul, South Korea.

(4)Department of Oncology, University of Ulsan College of Medicine, Asan Medical

Center, Seoul, South Korea.

…

BACKGROUND: Oncogenic alterations in RET have been identified in multiple tumour

types, including 1-2% of non-small-cell lung cancers (NSCLCs). We aimed to

assess the safety, tolerability, and antitumour activity of pralsetinib, a

highly potent, oral, selective RET inhibitor, in patients with RET

fusion-positive NSCLC.

METHODS: ARROW is a multi-cohort, open-label, phase 1/2 study done at 71 sites

(community and academic cancer centres) in 13 countries (Belgium, China, France,

Germany, Hong Kong, Italy, Netherlands, Singapore, South Korea, Spain, Taiwan,

the UK, and the USA). Patients aged 18 years or older with locally advanced or

metastatic solid tumours, including RET fusion-positive NSCLC, and an Eastern

Cooperative Oncology Group performance status of 0-2 (later limited to 0-1 in a

protocol amendment) were enrolled. In phase 2, patients received 400 mg

once-daily oral pralsetinib, and could continue treatment until disease

progression, intolerance, withdrawal of consent, or investigator decision. Phase

2 primary endpoints were overall response rate (according to Response Evaluation

Criteria in Solid Tumours version 1·1 and assessed by blinded independent

central review) and safety. Tumour response was assessed in patients with RET

fusion-positive NSCLC and centrally adjudicated baseline measurable disease who

had received platinum-based chemotherapy or were treatment-naive because they

were ineligible for standard therapy. This ongoing study is registered with

ClinicalTrials.gov, NCT03037385, and enrolment of patients with treatment-naive

RET fusion-positive NSCLC was ongoing at the time of this interim analysis.

FINDINGS: Of 233 patients with RET fusion-positive NSCLC enrolled between March

17, 2017, and May 22, 2020 (data cutoff), 92 with previous platinum-based

chemotherapy and 29 who were treatment-naive received pralsetinib before July

11, 2019 (efficacy enrolment cutoff); 87 previously treated patients and 27

treatment-naive patients had centrally adjudicated baseline measurable disease.

Overall responses were recorded in 53 (61%; 95% CI 50-71) of 87 patients with

previous platinum-based chemotherapy, including five (6%) patients with a

complete response; and 19 (70%; 50-86) of 27 treatment-naive patients, including

three (11%) with a complete response. In 233 patients with RET fusion-positive

NSCLC, common grade 3 or worse treatment-related adverse events were neutropenia

(43 patients [18%]), hypertension (26 [11%]), and anaemia (24 [10%]); there were

no treatment-related deaths in this population.

INTERPRETATION: Pralsetinib is a new, well-tolerated, promising, once-daily oral

treatment option for patients with RET fusion-positive NSCLC.

FUNDING: Blueprint Medicines.

Copyright © 2021 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1470-2045(21)00247-3

PMID: 34118197 [Indexed for MEDLINE]

7. Lancet Oncol. 2021 Jun;22(6):824-835. doi: 10.1016/S1470-2045(21)00149-2. Epub

2021 May 18.

Neoadjuvant durvalumab with or without stereotactic body radiotherapy in

patients with early-stage non-small-cell lung cancer: a single-centre,

randomised phase 2 trial.

Altorki NK(1), McGraw TE(2), Borczuk AC(3), Saxena A(4), Port JL(5), Stiles

BM(5), Lee BE(5), Sanfilippo NJ(6), Scheff RJ(4), Pua BB(7), Gruden JF(7),

Christos PJ(8), Spinelli C(5), Gakuria J(5), Uppal M(9), Binder B(9), Elemento

O(3), Ballman KV(8), Formenti SC(6).

Author information:

(1)Department of Cardiothoracic Surgery, Weill Cornell Medicine-New York

Presbyterian Hospital, New York, NY, USA. Electronic address:

nkaltork@med.cornell.edu.

(2)Department of Biochemistry, Weill Cornell Medicine-New York Presbyterian

Hospital, New York, NY, USA.

(3)Department of Pathology and Laboratory Medicine, Weill Cornell Medicine-New

York Presbyterian Hospital, New York, NY, USA.

…

Comment in

    Lancet Oncol. 2021 Jun;22(6):744-746.

BACKGROUND: Previous phase 2 trials of neoadjuvant anti-PD-1 or anti-PD-L1

monotherapy in patients with early-stage non-small-cell lung cancer have

reported major pathological response rates in the range of 15-45%. Evidence

suggests that stereotactic body radiotherapy might be a potent immunomodulator

in advanced non-small-cell lung cancer (NSCLC). In this trial, we aimed to

evaluate the use of stereotactic body radiotherapy in patients with early-stage

NSCLC as an immunomodulator to enhance the anti-tumour immune response

associated with the anti-PD-L1 antibody durvalumab.

METHODS: We did a single-centre, open-label, randomised, controlled, phase 2

trial, comparing neoadjuvant durvalumab alone with neoadjuvant durvalumab plus

stereotactic radiotherapy in patients with early-stage NSCLC, at

NewYork-Presbyterian and Weill Cornell Medical Center (New York, NY, USA). We

enrolled patients with potentially resectable early-stage NSCLC (clinical stages

I-IIIA as per the 7th edition of the American Joint Committee on Cancer) who

were aged 18 years or older with an Eastern Cooperative Oncology Group

performance status of 0 or 1. Eligible patients were randomly assigned (1:1) to

either neoadjuvant durvalumab monotherapy or neoadjuvant durvalumab plus

stereotactic body radiotherapy (8 Gy × 3 fractions), using permuted blocks with

varied sizes and no stratification for clinical or molecular variables.

Patients, treating physicians, and all study personnel were unmasked to

treatment assignment after all patients were randomly assigned. All patients

received two cycles of durvalumab 3 weeks apart at a dose of 1·12 g by

intravenous infusion over 60 min. Those in the durvalumab plus radiotherapy

group also received three consecutive daily fractions of 8 Gy stereotactic body

radiotherapy delivered to the primary tumour immediately before the first cycle

of durvalumab. Patients without systemic disease progression proceeded to

surgical resection. The primary endpoint was major pathological response in the

primary tumour. All analyses were done on an intention-to-treat basis. This

trial is registered with ClinicalTrial.gov, NCT02904954, and is ongoing but

closed to accrual.

FINDINGS: Between Jan 25, 2017, and Sept 15, 2020, 96 patients were screened and

60 were enrolled and randomly assigned to either the durvalumab monotherapy

group (n=30) or the durvalumab plus radiotherapy group (n=30). 26 (87%) of 30

patients in each group had their tumours surgically resected. Major pathological

response was observed in two (6·7% [95% CI 0·8-22·1]) of 30 patients in the

durvalumab monotherapy group and 16 (53·3% [34·3-71·7]) of 30 patients in the

durvalumab plus radiotherapy group. The difference in the major pathological

response rates between both groups was significant (crude odds ratio 16·0 [95%

CI 3·2-79·6]; p<0·0001). In the 16 patients in the dual therapy group with a

major pathological response, eight (50%) had a complete pathological response.

The second cycle of durvalumab was withheld in three (10%) of 30 patients in the

dual therapy group due to immune-related adverse events (grade 3 hepatitis,

grade 2 pancreatitis, and grade 3 fatigue and thrombocytopaenia). Grade 3-4

adverse events occurred in five (17%) of 30 patients in the durvalumab

monotherapy group and six (20%) of 30 patients in the durvalumab plus

radiotherapy group. The most frequent grade 3-4 events were hyponatraemia (three

[10%] patients in the durvalumab monotherapy group) and hyperlipasaemia (three

[10%] patients in the durvalumab plus radiotherapy group). Two patients in each

group had serious adverse events (pulmonary embolism [n=1] and stroke [n=1] in

the durvalumab monotherapy group, and pancreatitis [n=1] and fatigue [n=1] in

the durvalumab plus radiotherapy group). No treatment-related deaths or deaths

within 30 days of surgery were reported.

INTERPRETATION: Neoadjuvant durvalumab combined with stereotactic body

radiotherapy is well tolerated, safe, and associated with a high major

pathological response rate. This neoadjuvant strategy should be validated in a

larger trial.

FUNDING: AstraZeneca.

Copyright © 2021 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1470-2045(21)00149-2

PMID: 34015311 [Indexed for MEDLINE]

8. J Clin Oncol. 2021 Jun 2:JCO2002574. doi: 10.1200/JCO.20.02574. Online ahead of

print.

Benefits and Harms of Lung Cancer Screening by Chest Computed Tomography: A

Systematic Review and Meta-Analysis.

Passiglia F(1), Cinquini M(2), Bertolaccini L(3), Del Re M(4), Facchinetti F(5),

Ferrara R(6), Franchina T(7), Larici AR(8), Malapelle U(9), Menis J(10)(11),

Passaro A(12), Pilotto S(13), Ramella S(14), Rossi G(15), Trisolini R(16),

Novello S(1).

Author information:

(1)Department of Oncology, San Luigi Hospital, University of Turin, Orbassano

(TO), Italy.

(2)Mario Negri Institute for Pharmacological Research IRCCS, Milan, Italy.

(3)Division of Thoracic Surgery, IEO, European Institute of Oncology IRCCS,

Milan, Italy.

…

PURPOSE: This meta-analysis aims to combine and analyze randomized clinical

trials comparing computed tomography lung screening (CTLS) versus either no

screening (NS) or chest x-ray (CXR) in subjects with cigarette smoking history,

to provide a precise and reliable estimation of the benefits and harms

associated with CTLS.

MATERIALS AND METHODS: Data from all published randomized trials comparing CTLS

versus either NS or CXR in a highly tobacco-exposed population were collected,

according to the Preferred Reporting Items for Systematic Reviews and

Meta-Analyses guidelines. Subgroup analyses by comparator (NS or CXR) were

performed. Pooled risk ratio (RR) and relative 95% CIs were calculated for

dichotomous outcomes. The certainty of the evidence was assessed using the GRADE

approach.

RESULTS: Nine eligible trials (88,497 patients) were included. Pooled analysis

showed that CTLS is associated with: a significant reduction of lung

cancer-related mortality (overall RR, 0.87; 95% CI, 0.78 to 0.98; NS RR, 0.80;

95% CI, 0.69 to 0.92); a significant increase of early-stage tumors diagnosis

(overall RR, 2.84; 95% CI 1.76 to 4.58; NS RR, 3.33; 95% CI, 2.27 to 4.89; CXR

RR, 1.52; 95% CI, 1.04 to 2.23); a significant decrease of late-stage tumors

diagnosis (overall RR, 0.75; 95% CI, 0.68 to 0.83; NS RR, 0.67; 95% CI, 0.56 to

0.80); a significant increase of resectability rate (NS RR, 2.57; 95% CI, 1.76

to 3.74); a nonsignificant reduction of all-cause mortality (overall RR, 0.99;

95% CI, 0.94 to 1.05); and a significant increase of overdiagnosis rate (NS,

38%; 95% CI, 14 to 63). The analysis of lung cancer-related mortality by sex

revealed nonsignificant differences between men and women (P = .21; I-squared =

33.6%).

CONCLUSION: Despite there still being uncertainty about overdiagnosis estimate,

this meta-analysis suggested that the CTLS benefits outweigh harms, in subjects

with cigarette smoking history, ultimately supporting the systematic

implementation of lung cancer screening worldwide.

DOI: 10.1200/JCO.20.02574

PMID: 34236916

9. Mol Cell. 2021 Jul 15;81(14):2887-2900.e5. doi: 10.1016/j.molcel.2021.06.002.

Epub 2021 Jun 24.

Structural insights into the functional divergence of WhiB-like proteins in

Mycobacterium tuberculosis.

Wan T(1), Horová M(1), Beltran DG(1), Li S(1), Wong HX(1), Zhang LM(2).

Author information:

(1)Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, NE

68588, USA.

(2)Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, NE

68588, USA; Redox Biology Center, University of Nebraska-Lincoln, Lincoln, NE

68588, USA; Nebraska Center for Integrated Biomolecular Communication,

University of Nebraska-Lincoln, Lincoln, NE 68588, USA. Electronic address:

lzhang30@unl.edu.

WhiB7 represents a distinct subclass of transcription factors in the WhiB-Like

(Wbl) family, a unique group of iron-sulfur (4Fe-4S] cluster-containing proteins

exclusive to the phylum of Actinobacteria. In Mycobacterium tuberculosis (Mtb),

WhiB7 interacts with domain 4 of the primary sigma factor (σA4) in the RNA

polymerase holoenzyme and activates genes involved in multiple drug resistance

and redox homeostasis. Here, we report crystal structures of the WhiB7:σA4

complex alone and bound to its target promoter DNA at 1.55-Å and 2.6-Å

resolution, respectively. These structures show how WhiB7 regulates gene

expression by interacting with both σA4 and the AT-rich sequence upstream of the

-35 promoter DNA via its C-terminal DNA-binding motif, the AT-hook. By combining

comparative structural analysis of the two high-resolution σA4-bound Wbl

structures with molecular and biochemical approaches, we identify the structural

basis of the functional divergence between the two distinct subclasses of Wbl

proteins in Mtb.

Copyright © 2021 Elsevier Inc. All rights reserved.

DOI: 10.1016/j.molcel.2021.06.002

PMID: 34171298

10. Mol Cell. 2021 Jul 15;81(14):2875-2886.e5. doi: 10.1016/j.molcel.2021.05.017.

Epub 2021 Jun 24.

Structural basis of transcriptional activation by the Mycobacterium tuberculosis

intrinsic antibiotic-resistance transcription factor WhiB7.

Lilic M(1), Darst SA(1), Campbell EA(2).

Author information:

(1)Laboratory of Molecular Biophysics, The Rockefeller University, 1230 York

Avenue, New York, NY 10065, USA.

(2)Laboratory of Molecular Biophysics, The Rockefeller University, 1230 York

Avenue, New York, NY 10065, USA. Electronic address: campbee@rockefeller.edu.

In pathogenic mycobacteria, transcriptional responses to antibiotics result in

induced antibiotic resistance. WhiB7 belongs to the Actinobacteria-specific

family of Fe-S-containing transcription factors and plays a crucial role in

inducible antibiotic resistance in mycobacteria. Here, we present cryoelectron

microscopy structures of Mycobacterium tuberculosis transcriptional regulatory

complexes comprising RNA polymerase σA-holoenzyme, global regulators CarD and

RbpA, and WhiB7, bound to a WhiB7-regulated promoter. The structures reveal how

WhiB7 interacts with σA-holoenzyme while simultaneously interacting with an

AT-rich sequence element via its AT-hook. Evidently, AT-hooks, rare elements in

bacteria yet prevalent in eukaryotes, bind to target AT-rich DNA sequences

similarly to the nuclear chromosome binding proteins. Unexpectedly, a subset of

particles contained a WhiB7-stabilized closed promoter complex, revealing this

intermediate's structure, and we apply kinetic modeling and biochemical assays

to rationalize how WhiB7 activates transcription. Altogether, our work presents

a comprehensive view of how WhiB7 serves to activate gene expression leading to

antibiotic resistance.

Copyright © 2021 Elsevier Inc. All rights reserved.

DOI: 10.1016/j.molcel.2021.05.017

PMCID: PMC8311663

PMID: 34171296

11. Nat Commun. 2021 Jun 17;12(1):3697. doi: 10.1038/s41467-021-23912-4.

Identification of optimal dosing schedules of dacomitinib and osimertinib for a

phase I/II trial in advanced EGFR-mutant non-small cell lung cancer.

Poels KE(1)(2), Schoenfeld AJ(3), Makhnin A(3), Tobi Y(3), Wang Y(4),

Frisco-Cabanos H(5), Chakrabarti S(1)(2)(6), Shi M(4), Napoli C(5), McDonald

TO(1)(2)(6)(7), Tan W(8), Hata A(5)(9)(10), Weinrich SL(4), Yu HA(11), Michor

F(12)(13)(14)(15)(16)(17).

Author information:

(1)Department of Biostatistics, Harvard T.H. Chan School of Public Health,

Boston, MA, USA.

(2)Department of Data Science, Dana Farber Cancer Institute, Boston, MA, USA.

(3)Division of Solid Tumor Oncology, Department of Medicine, Thoracic Oncology

Service, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College,

New York, NY, USA.

(4)Oncology Research and Development, Pfizer Inc, La Jolla, CA, USA.

(5)Massachusetts General Hospital Cancer Center, Boston, MA, USA.

…

Despite the clinical success of the third-generation EGFR inhibitor osimertinib

as a first-line treatment of EGFR-mutant non-small cell lung cancer (NSCLC),

resistance arises due to the acquisition of EGFR second-site mutations and other

mechanisms, which necessitates alternative therapies. Dacomitinib, a pan-HER

inhibitor, is approved for first-line treatment and results in different

acquired EGFR mutations than osimertinib that mediate on-target resistance. A

combination of osimertinib and dacomitinib could therefore induce more durable

responses by preventing the emergence of resistance. Here we present an

integrated computational modeling and experimental approach to identify an

optimal dosing schedule for osimertinib and dacomitinib combination therapy. We

developed a predictive model that encompasses tumor heterogeneity and

inter-subject pharmacokinetic variability to predict tumor evolution under

different dosing schedules, parameterized using in vitro dose-response data.

This model was validated using cell line data and used to identify an optimal

combination dosing schedule. Our schedule was subsequently confirmed tolerable

in an ongoing dose-escalation phase I clinical trial (NCT03810807), with some

dose modifications, demonstrating that our rational modeling approach can be

used to identify appropriate dosing for combination therapy in the clinical

setting.

DOI: 10.1038/s41467-021-23912-4

PMCID: PMC8211846

PMID: 34140482 [Indexed for MEDLINE]

12. J Clin Invest. 2021 Jun 15:141895. doi: 10.1172/JCI141895. Online ahead of

print.

Doxycycline host-directed therapy in human pulmonary tuberculosis.

Miow QH(1), Vallejo AF(2), Wang Y(1), Hong JM(1), Bai C(1), Teo FS(3), Wang

AD(4), Loh HR(1), Tan TZ(5), Ding Y(6), She HW(7), Gan SH(7), Paton NI(1), Lum

J(8), Tay A(8), Chee CB(7), Tambyah PA(1), Polak ME(9), Wang YT(7), Singhal

A(8), Elkington P(10), Friedland JS(11), Ong CW(1).

Author information:

(1)Department of Medicine, Yong Loo Ling School of Medicine, National University

of Singapore, Singapore, Singapore.

(2)Department of Clinical and Experimental Sciences, University of Southampton,

Faculty of Medicine, Southampton, United Kingdom.

(3)Division of Respiratory and Critical Care Medicine, National University

Hospital, National University Health System, Singapore, Singapore.

…

BACKGROUND: Matrix metalloproteinases (MMPs) are implicated as key regulators of

tissue destruction in tuberculosis (TB) and may be a target for host-directed

therapy. Here, we conducted a Phase 2 randomized, double-blind,

placebo-controlled trial investigating doxycycline, a licensed broad spectrum

MMP inhibitor, in pulmonary TB patients.

METHODS: Thirty pulmonary TB patients were enrolled within 7 days of initiating

anti-TB treatment and randomly assigned to receive either doxycycline 100 mg or

placebo twice a day for 14 days in addition to standard care.

RESULTS: There were significant changes in the host transcriptome, and

suppression of systemic and respiratory markers of tissue destruction with the

doxycycline intervention. Whole blood RNA-sequencing demonstrated that

doxycycline accelerated restoration of dysregulated gene expression patterns in

TB towards normality, with more rapid down-regulation of type I and II

interferon and innate immune response genes and concurrent up-regulation of

B-cell modules relative to placebo. The effects persisted for 6 weeks after

doxycycline was discontinued, concurrent with suppression of plasma MMP-1. In

respiratory samples, doxycycline reduced MMP-1, -8, -9, -12 and -13

concentrations, suppressed type I collagen and elastin destruction, and reduced

pulmonary cavity volume despite unchanged sputum Mycobacterium tuberculosis

loads between the study arms. Two weeks of adjunctive doxycycline with standard

anti-TB treatment was well-tolerated, with no serious adverse events related to

doxycycline.

CONCLUSION: These data demonstrate that adjunctive doxycycline with standard

anti-TB treatment suppresses pathological MMPs in pulmonary tuberculosis

patients, and suggest that larger studies on adjunctive doxycycline to limit

immunopathology in TB are merited.

DOI: 10.1172/JCI141895

PMID: 34128838

13. Am J Respir Crit Care Med. 2021 Jun 9. doi: 10.1164/rccm.202009-3527OC. Online

ahead of print.

Evidence-based Definition for Extensively Drug-resistant Tuberculosis.

Roelens M(1), Battista Migliori G(2), Rozanova L(1), Estill J(1)(3), Campbell

JR(4), Cegielski JP(5), Tiberi S(6)(7), Palmero D(8), Fox GJ(9), Guglielmetti

L(10)(11), Sotgiu G(12), Brust JCM(13), Bang D(14)(15), Lienhardt C(16)(17),

Lange C(18)(19)(20), Menzies D(21), Keiser O(1), Raviglione M(22)(23).

Author information:

(1)University of Geneva Institute of Global Health, 30492, Geneve, Switzerland.

(2)Istituti Clinici Scientifici Maugeri IRCCS, Tradate, Italy.

(3)University of Bern, 27210, Institute of Mathematical Statistics and Actuarial

Science, Bern, Switzerland.

(4)McGill University, 5620, Montreal, Quebec, Canada.

(5)Rollins School of Public Health, 25798, Department of Epidemiology, Atlanta,

Georgia, United States.

…

RATIONALE: Until 2020, extensively drug-resistant tuberculosis (XDR-TB) was

defined as resistance to rifampicin and isoniazid (multidrug-resistant

tuberculosis, MDR-TB), any fluoroquinolone (FQ) and any second-line injectable

drug (SLID). In 2019 the World Health Organization issued new recommendations

for managing patients with drug-resistant tuberculosis, substantially limiting

the role of SLID in MDR-TB treatment and thus putting that XDR-TB definition

into question.

OBJECTIVE: To propose an up-to-date definition for XDR-TB.

METHODS: We used a large dataset to assess treatment outcomes for MDR-TB

patients exposed to any type of longer regimen. We included patients with

bacteriologically confirmed MDR-TB and known FQ and SLID resistance results. We

did logistic regression to estimate adjusted odds ratios (aORs) for unfavourable

treatment outcome (failure, relapse, death, loss-to-follow-up) by resistance

pattern (FQ, SLID) and Group A drug use (moxifloxacin/levofloxacin, linezolid,

bedaquiline).

MEASUREMENTS AND MAIN RESULTS: We included 11,666 patients with MDR-TB; 4653

(39.9%) had an unfavourable treatment outcome. Resistance to FQs increased the

odds of an unfavourable treatment outcome (aOR 1.91; 95% confidence interval

[95%CI] 1.63-2.23). Administration of bedaquiline and/or linezolid improved

treatment outcomes regardless of resistance to FQ and/or SLID. Among XDR-TB

patients, compared to persons receiving no Group A drug, aORs for unfavourable

outcome were 0.37 (95%CI 0.20-0.69) with linezolid only, 0.40 (95%CI 0.21-0.77)

with bedaquiline only, and 0.21 (95%CI 0.12-0.38) with both.

CONCLUSIONS: Our study supports a new definition of XDR-TB as MDR plus

additional resistance to FQ plus bedaquiline and/or linezolid, and helps assess

the adequacy of this definition for surveillance and treatment choice.NOTE: This

article has been updated on July 16, 2021. When it was initially posted on June

9, 2021, the name of one of the coauthors, Dr. Christian Lienhardt, was

inadvertently omitted. This version includes Dr. Lienhardt's affilations and

contributions; the affiliations have therefore been renumbered.

DOI: 10.1164/rccm.202009-3527OC

PMID: 34107231

14. J Clin Oncol. 2021 Jun 2:JCO2003307. doi: 10.1200/JCO.20.03307. Online ahead of print.

Clinicopathologic Features and Response to Therapy of NRG1 Fusion-Driven Lung

Cancers: The eNRGy1 Global Multicenter Registry.

Drilon A(1), Duruisseaux M(2)(3)(4), Han JY(5), Ito M(6)(7)(8), Falcon C(1),

Yang SR(1), Murciano-Goroff YR(9), Chen H(10)(11), Okada M(8), Molina MA(12),

Wislez M(13)(14), Brun P(15), Dupont C(2), Branden E(16)(17), Rossi G(18)(19),

Schrock A(20), Ali S(20), Gounant V(21), Magne F(22), Blum TG(23), Schram AM(9),

Monnet I(24), Shih JY(25), Sabari J(26), Pérol M(27), Zhu VW(28), Nagasaka

M(29)(30), Doebele R(31), Camidge DR(31), Arcila M(1), Ou SI(32), Moro-Sibilot

D(33), Rosell R(34), Muscarella LA(35), Liu SV(36), Cadranel J(37).

Author information:

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

York, NY.

(2)Respiratory Department, Louis Pradel Hospital, Hospices Civils de Lyon Cancer

Institute, Lyon, France.

(3)Anticancer Antibodies Laboratory, Cancer Research Center of Lyon, Lyon,

France.

(4)Université Claude Bernard Lyon UMR INSERM 1052 CNRS 5286, Université de Lyon,

Lyon, France.

(5)National Cancer Center, Korea, Goyang-si, South Korea.

…

PURPOSE: Although NRG1 fusions are oncogenic drivers across multiple tumor types

including lung cancers, these are difficult to study because of their rarity.

The global eNRGy1 registry was thus established to characterize NRG1

fusion-positive lung cancers in the largest and most diverse series to date.

METHODS: From June 2018 to February 2020, a consortium of 22 centers from nine

countries in Europe, Asia, and the United States contributed data from patients

with pathologically confirmed NRG1 fusion-positive lung cancers. Profiling

included DNA-based and/or RNA-based next-generation sequencing and fluorescence

in situ hybridization. Anonymized clinical, pathologic, molecular, and response

(RECIST v1.1) data were centrally curated and analyzed.

RESULTS: Although the typified never smoking (57%), mucinous adenocarcinoma

(57%), and nonmetastatic (71%) phenotype predominated in 110 patients with NRG1

fusion-positive lung cancer, further diversity, including in smoking history

(43%) and histology (43% nonmucinous and 6% nonadenocarcinoma), was elucidated.

RNA-based testing identified most fusions (74%). Molecularly, six (of 18) novel

5' partners, 20 unique epidermal growth factor domain-inclusive chimeric events,

and heterogeneous 5'/3' breakpoints were found. Platinum-doublet and

taxane-based (post-platinum-doublet) chemotherapy achieved low objective

response rates (ORRs 13% and 14%, respectively) and modest progression-free

survival medians (PFS 5.8 and 4.0 months, respectively). Consistent with a low

programmed death ligand-1 expressing (28%) and low tumor mutational burden

(median: 0.9 mutations/megabase) immunophenotype, the activity of

chemoimmunotherapy and single-agent immunotherapy was poor (ORR 0%/PFS 3.3

months and ORR 20%/PFS 3.6 months, respectively). Afatinib achieved an ORR of

25%, not contingent on fusion type, and a 2.8-month median PFS.

CONCLUSION: NRG1 fusion-positive lung cancers were molecularly, pathologically,

and clinically more heterogeneous than previously recognized. The activity of

cytotoxic, immune, and targeted therapies was disappointing. Further research

examining NRG1-rearranged tumor biology is needed to develop new therapeutic

strategies.

DOI: 10.1200/JCO.20.03307

PMID: 34077268

15. Am J Respir Crit Care Med. 2021 Jun 15;203(12):1556-1565. doi:

10.1164/rccm.202007-2686OC.

Antigen-Specific T-Cell Activation Distinguishes between Recent and Remote

Tuberculosis Infection.

Mpande CAM(1), Musvosvi M(1), Rozot V(1), Mosito B(1), Reid TD(1), Schreuder

C(1), Lloyd T(1), Bilek N(1), Huang H(2), Obermoser G(2), Davis MM(2), Ruhwald

M(3)(4), Hatherill M(1), Scriba TJ(1), Nemes E(1); ACS Study Team.

Collaborators: Mahomed H, Hanekom WA, Kafaar F, Workman L, Mulenga H, Ehrlich R,

Erasmus M, Abrahams D, Hawkridge A, Hughes EJ, Moyo S, Gelderbloem S, Tameris M,

Geldenhuys H, Hussey G.

Author information:

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

Disease and Molecular Medicine, Division of Immunology, Department of Pathology,

University of Cape Town, Cape Town, South Africa.

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

School of Medicine, Stanford, California.

(3)Statens Serum Institute, Copenhagen, Denmark; and.

(4)Foundation of Innovative New Diagnostics, Geneva, Switzerland.

Comment in

    Am J Respir Crit Care Med. 2021 Jun 15;203(12):1460-1461.

Rationale: Current diagnostic tests fail to identify individuals at higher risk

of progression to tuberculosis disease, such as those with recent Mycobacterium

tuberculosis infection, who should be prioritized for targeted preventive

treatment. Objectives: To define a blood-based biomarker, measured with a simple

flow cytometry assay, that can stratify different stages of tuberculosis

infection to infer risk of disease. Methods: South African adolescents were

serially tested with QuantiFERON-TB Gold to define recent (QuantiFERON-TB

conversion<6 and="" persistent="" for="">1 yr) infection. We

defined the ΔHLA-DR median fluorescence intensity biomarker as the difference in

HLA-DR expression between IFN-γ+ TNF+ Mycobacterium tuberculosis-specific T

cells and total CD3+ T cells. Biomarker performance was assessed by blinded

prediction in untouched test cohorts with recent versus persistent infection or

tuberculosis disease and by unblinded analysis of asymptomatic adolescents with

tuberculosis infection who remained healthy (nonprogressors) or who progressed

to microbiologically confirmed disease (progressors). Measurements and Main

Results: In the test cohorts, frequencies of Mycobacterium tuberculosis-specific

T cells differentiated between QuantiFERON-TB- (n = 25) and QuantiFERON-TB+

(n = 47) individuals (area under the receiver operating characteristic curve,

0.94; 95% confidence interval, 0.87-1.00). ΔHLA-DR significantly discriminated

between recent (n = 20) and persistent (n = 22) QuantiFERON-TB+ (0.91;

0.83-1.00); persistent QuantiFERON-TB+ and newly diagnosed tuberculosis (n = 19;

0.99; 0.96-1.00); and tuberculosis progressors (n = 22) and nonprogressors

(n = 34; 0.75; 0.63-0.87). However, ΔHLA-DR median fluorescent intensity could

not discriminate between recent QuantiFERON-TB+ and tuberculosis (0.67;

0.50-0.84). Conclusions: The ΔHLA-DR biomarker can identify individuals with

recent QuantiFERON-TB conversion and those with disease progression, allowing

targeted provision of preventive treatment to those at highest risk of

tuberculosis. Further validation studies of this novel immune biomarker in

various settings and populations at risk are warranted.

DOI: 10.1164/rccm.202007-2686OC

PMID: 33406011