Medical Abstracts ( IF > 10)

1. N Engl J Med. 2020 Nov 19;383(21):2018-2029. doi: 10.1056/NEJMoa2027187.

First-Line Lorlatinib or Crizotinib in Advanced ALK-Positive Lung Cancer.

Shaw AT(1), Bauer TM(1), de Marinis F(1), Felip E(1), Goto Y(1), Liu G(1),

Mazieres J(1), Kim DW(1), Mok T(1), Polli A(1), Thurm H(1), Calella AM(1), Peltz

G(1), Solomon BJ(1); CROWN Trial Investigators.

Author information:

(1)From the Massachusetts General Hospital Cancer Center (A.T.S.) and Pfizer

(G.P.) - both in Boston; Sarah Cannon Research Institute-Tennessee Oncology,

Nashville (T.M.B.); European Institute of Oncology, IRCCS (F.M.), and Pfizer

(A.P., A.M.C.) - both in Milan; Vall d'Hebron University Hospital and Institute

of Oncology, International Oncology Bureau-Quirón, Barcelona (E.F.); National

Cancer Center Hospital, Tokyo (Y.G.); Princess Margaret Cancer Centre, Toronto

(G.L.); Toulouse University Hospital, Toulouse, France (J.M.); Seoul National

University College of Medicine and Seoul National University Hospital, Seoul,

South Korea (D.-W.K.); State Key Laboratory of Translational Oncology, Chinese

University of Hong Kong, Hong Kong (T.M.); Pfizer, La Jolla, CA (H.T.); and

Peter MacCallum Cancer Centre, Melbourne, VIC, Australia (B.J.S.).

BACKGROUND: Lorlatinib, a third-generation inhibitor of anaplastic lymphoma

kinase (ALK), has antitumor activity in previously treated patients with

ALK-positive non-small-cell lung cancer (NSCLC). The efficacy of lorlatinib, as

compared with that of crizotinib, as first-line treatment for advanced

ALK-positive NSCLC is unclear.

METHODS: We conducted a global, randomized, phase 3 trial comparing lorlatinib

with crizotinib in 296 patients with advanced ALK-positive NSCLC who had

received no previous systemic treatment for metastatic disease. The primary end

point was progression-free survival as assessed by blinded independent central

review. Secondary end points included independently assessed objective response

and intracranial response. An interim analysis of efficacy was planned after

approximately 133 of 177 (75%) expected events of disease progression or death

had occurred.

RESULTS: The percentage of patients who were alive without disease progression

at 12 months was 78% (95% confidence interval [CI], 70 to 84) in the lorlatinib

group and 39% (95% CI, 30 to 48) in the crizotinib group (hazard ratio for

disease progression or death, 0.28; 95% CI, 0.19 to 0.41; P<0.001). An objective

response occurred in 76% (95% CI, 68 to 83) of the patients in the lorlatinib

group and 58% (95% CI, 49 to 66) of those in the crizotinib group; among those

with measurable brain metastases, 82% (95% CI, 57 to 96) and 23% (95% CI, 5 to

54), respectively, had an intracranial response, and 71% of the patients who

received lorlatinib had an intracranial complete response. The most common

adverse events with lorlatinib were hyperlipidemia, edema, increased weight,

peripheral neuropathy, and cognitive effects. Lorlatinib was associated with

more grade 3 or 4 adverse events (mainly altered lipid levels) than crizotinib

(in 72% vs. 56%). Discontinuation of treatment because of adverse events

occurred in 7% and 9% of the patients, respectively.

CONCLUSIONS: In an interim analysis of results among patients with previously

untreated advanced ALK-positive NSCLC, those who received lorlatinib had

significantly longer progression-free survival and a higher frequency of

intracranial response than those who received crizotinib. The incidence of grade

3 or 4 adverse events was higher with lorlatinib than with crizotinib because of

the frequent occurrence of altered lipid levels. (Funded by Pfizer; CROWN

ClinicalTrials.gov number, NCT03052608.).

Copyright © 2020 Massachusetts Medical Society.

DOI: 10.1056/NEJMoa2027187

PMID: 33207094 [Indexed for MEDLINE]

2. Nat Med. 2020 Dec;26(12):1941-1949. doi: 10.1038/s41591-020-1076-0. Epub 2020

Oct 19.

Discovery and validation of a personalized risk predictor for incident

tuberculosis in low transmission settings.

Gupta RK(1), Calderwood CJ(1), Yavlinsky A(2), Krutikov M(1), Quartagno M(3),

Aichelburg MC(4), Altet N(5)(6), Diel R(7)(8), Dobler CC(9)(10), Dominguez

J(11)(12)(13), Doyle JS(14)(15), Erkens C(16), Geis S(17), Haldar P(18), Hauri

AM(19), Hermansen T(20), Johnston JC(21), Lange C(22)(23)(24)(25), Lange B(26),

van Leth F(24)(27)(28), Muñoz L(29), Roder C(14)(15), Romanowski K(21), Roth

D(21), Sester M(24)(30), Sloot R(31), Sotgiu G(24)(32), Woltmann G(18),

Yoshiyama T(33), Zellweger JP(24)(34), Zenner D(1), Aldridge RW(2), Copas

A(1)(3), Rangaka MX(1)(3)(35)(36), Lipman M(37)(38), Noursadeghi M(39), Abubakar

I(40).

Author information:

(1)Institute for Global Health, University College London, London, UK.

(2)Institute of Health Informatics, University College London, London, UK.

(3)MRC Clinical Trials Unit, Institute of Clinical Trials and Methodology,

University College London, London, UK.

...

The risk of tuberculosis (TB) is variable among individuals with latent

Mycobacterium tuberculosis infection (LTBI), but validated estimates of

personalized risk are lacking. In pooled data from 18 systematically identified

cohort studies from 20 countries, including 80,468 individuals tested for LTBI,

5-year cumulative incident TB risk among people with untreated LTBI was 15.6%

(95% confidence interval (CI), 8.0-29.2%) among child contacts, 4.8% (95% CI,

3.0-7.7%) among adult contacts, 5.0% (95% CI, 1.6-14.5%) among migrants and 4.8%

(95% CI, 1.5-14.3%) among immunocompromised groups. We confirmed highly variable

estimates within risk groups, necessitating an individualized approach to risk

stratification. Therefore, we developed a personalized risk predictor for

incident TB (PERISKOPE-TB) that combines a quantitative measure of T cell

sensitization and clinical covariates. Internal-external cross-validation of the

model demonstrated a random effects meta-analysis C-statistic of 0.88 (95% CI,

0.82-0.93) for incident TB. In decision curve analysis, the model demonstrated

clinical utility for targeting preventative treatment, compared to treating all,

or no, people with LTBI. We challenge the current crude approach to TB risk

estimation among people with LTBI in favor of our evidence-based and

patient-centered method, in settings aiming for pre-elimination worldwide.

DOI: 10.1038/s41591-020-1076-0

PMID: 33077958

3. Lancet Oncol. 2020 Dec 4:S1470-2045(20)30539-8. doi:

10.1016/S1470-2045(20)30539-8. Online ahead of print.

Durvalumab, with or without tremelimumab, plus platinum-etoposide versus

platinum-etoposide alone in first-line treatment of extensive-stage small-cell

lung cancer (CASPIAN): updated results from a randomised, controlled,

open-label, phase 3 trial.

Goldman JW(1), Dvorkin M(2), Chen Y(3), Reinmuth N(4), Hotta K(5), Trukhin D(6),

Statsenko G(7), Hochmair MJ(8), Özgüro?lu M(9), Ji JH(10), Garassino MC(11),

Voitko O(12), Poltoratskiy A(13), Ponce S(14), Verderame F(15), Havel L(16),

Bondarenko I(17), Ka?arnowicz A(18), Losonczy G(19), Conev NV(20), Armstrong

J(21), Byrne N(21), Thiyagarajah P(21), Jiang H(22), Paz-Ares L(23); CASPIAN

investigators.

Author information:

(1)David Geffen School of Medicine at University of California Los Angeles, Los

Angeles, CA, USA.

(2)BHI of Omsk Region Clinical Oncology Dispensary, Omsk, Russia.

(3)Cancer and Hematology Centers of Western Michigan, Grand Rapids, MI, USA.

...

BACKGROUND: First-line durvalumab plus etoposide with either cisplatin or

carboplatin (platinum-etoposide) showed a significant improvement in overall

survival versus platinum-etoposide alone in patients with extensive-stage

small-cell lung cancer (ES-SCLC) in the CASPIAN study. Here we report updated

results, including the primary analysis for overall survival with durvalumab

plus tremelimumab plus platinum-etoposide versus platinum-etoposide alone.

METHODS: CASPIAN is an ongoing, open-label, sponsor-blind, randomised,

controlled phase 3 trial at 209 cancer treatment centres in 23 countries

worldwide. Eligible patients were aged 18 years or older (20 years in Japan) and

had treatment-naive, histologically or cytologically documented ES-SCLC, with a

WHO performance status of 0 or 1. Patients were randomly assigned (1:1:1) in

blocks of six, stratified by planned platinum, using an interactive

voice-response or web-response system to receive intravenous durvalumab plus

tremelimumab plus platinum-etoposide, durvalumab plus platinum-etoposide, or

platinum-etoposide alone. In all groups, patients received etoposide 80-100

mg/m2 on days 1-3 of each cycle with investigator's choice of either carboplatin

area under the curve 5-6 mg/mL/min or cisplatin 75-80 mg/m2 on day 1 of each

cycle. Patients in the platinum-etoposide group received up to six cycles of

platinum-etoposide every 3 weeks and optional prophylactic cranial irradiation

(investigator's discretion). Patients in the immunotherapy groups received four

cycles of platinum-etoposide plus durvalumab 1500 mg with or without

tremelimumab 75 mg every 3 weeks followed by maintenance durvalumab 1500 mg

every 4 weeks. The two primary endpoints were overall survival for durvalumab

plus platinum-etoposide versus platinum-etoposide and for durvalumab plus

tremelimumab plus platinum-etoposide versus platinum-etoposide in the

intention-to-treat population. Safety was assessed in all patients who received

at least one dose of study treatment. This study is registered at

ClinicalTrials.gov, NCT03043872.

FINDINGS: Between March 27, 2017, and May 29, 2018, 972 patients were screened

and 805 were randomly assigned (268 to durvalumab plus tremelimumab plus

platinum-etoposide, 268 to durvalumab plus platinum-etoposide, and 269 to

platinum-etoposide). As of Jan 27, 2020, the median follow-up was 25·1 months

(IQR 22·3-27·9). Durvalumab plus tremelimumab plus platinum-etoposide was not

associated with a significant improvement in overall survival versus

platinum-etoposide (hazard ratio [HR] 0·82 [95% CI 0·68-1·00]; p=0·045); median

overall survival was 10·4 months (95% CI 9·6-12·0) versus 10·5 months

(9·3-11·2). Durvalumab plus platinum-etoposide showed sustained improvement in

overall survival versus platinum-etoposide (HR 0·75 [95% CI 0·62-0·91]; nominal

p=0·0032); median overall survival was 12·9 months (95% CI 11·3-14·7) versus

10·5 months (9·3-11·2). The most common any-cause grade 3 or worse adverse

events were neutropenia (85 [32%] of 266 patients in the durvalumab plus

tremelimumab plus platinum-etoposide group, 64 [24%] of 265 patients in the

durvalumab plus platinum-etoposide group, and 88 [33%] of 266 patients in the

platinum-etoposide group) and anaemia (34 [13%], 24 [9%], and 48 [18%]).

Any-cause serious adverse events were reported in 121 (45%) patients in the

durvalumab plus tremelimumab plus platinum-etoposide group, 85 (32%) in the

durvalumab plus platinum-etoposide group, and 97 (36%) in the platinum-etoposide

group. Treatment-related deaths occurred in 12 (5%) patients in the durvalumab

plus tremelimumab plus platinum-etoposide group (death, febrile neutropenia, and

pulmonary embolism [n=2 each]; enterocolitis, general physical health

deterioration and multiple organ dysfunction syndrome, pneumonia, pneumonitis

and hepatitis, respiratory failure, and sudden death [n=1 each]), six (2%)

patients in the durvalumab plus platinum-etoposide group (cardiac arrest,

dehydration, hepatotoxicity, interstitial lung disease, pancytopenia, and sepsis

[n=1 each]), and two (1%) in the platinum-etoposide group (pancytopenia and

thrombocytopenia [n=1 each]).

INTERPRETATION: First-line durvalumab plus platinum-etoposide showed sustained

overall survival improvement versus platinum-etoposide but the addition of

tremelimumab to durvalumab plus platinum-etoposide did not significantly improve

outcomes versus platinum-etoposide. These results support the use of durvalumab

plus platinum-etoposide as a new standard of care for the first-line treatment

of ES-SCLC.

FUNDING: AstraZeneca.

Copyright © 2020 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1470-2045(20)30539-8

PMID: 33285097

4. J Clin Oncol. 2020 Dec 17:JCO2001820. doi: 10.1200/JCO.20.01820. Online ahead of

print.

Gefitinib Versus Vinorelbine Plus Cisplatin as Adjuvant Treatment for Stage

II-IIIA (N1-N2) EGFR-Mutant NSCLC: Final Overall Survival Analysis of CTONG1104

Phase III Trial.

Zhong WZ(1), Wang Q(2), Mao WM(3), Xu ST(2), Wu L(4), Wei YC(5), Liu YY(6), Chen

C(7), Cheng Y(8), Yin R(9), Yang F(10), Ren SX(11), Li XF(12), Li J(13), Huang

C(14), Liu ZD(15), Xu S(16), Chen KN(17), Xu SD(18), Liu LX(19), Yu P(20), Wang

BH(21), Ma HT(22), Yang JJ(1), Yan HH(1), Yang XN(1), Liu SY(1), Zhou Q(1), Wu

YL(1).

Author information:

(1)Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, and

Guangdong Academy of Medical Sciences, Guangzhou, China.

(2)Fudan University Affiliated Zhongshan Hospital, Shanghai, China.

(3)Zhejiang Cancer Hospital, Hangzhou, China.

...

PURPOSE: ADJUVANT-CTONG1104 (ClinicalTrials.gov identifier: NCT01405079), a

randomized phase III trial, showed that adjuvant gefitinib treatment

significantly improved disease-free survival (DFS) versus vinorelbine plus

cisplatin (VP) in patients with epidermal growth factor receptor (EGFR)

mutation-positive resected stage II-IIIA (N1-N2) non-small-cell lung cancer

(NSCLC). Here, we report the final overall survival (OS) results.

METHODS: From September 2011 to April 2014, 222 patients from 27 sites were

randomly assigned 1:1 to adjuvant gefitinib (n = 111) or VP (n = 111). Patients

with resected stage II-IIIA (N1-N2) NSCLC and EGFR-activating mutation were

enrolled, receiving gefitinib for 24 months or VP every 3 weeks for four cycles.

The primary end point was DFS (intention-to-treat [ITT] population). Secondary

end points included OS, 3-, 5-year (y) DFS rates, and 5-year OS rate. Post hoc

analysis was conducted for subsequent therapy data.

RESULTS: Median follow-up was 80.0 months. Median OS (ITT) was 75.5 and 62.8

months with gefitinib and VP, respectively (hazard ratio [HR], 0.92; 95% CI,

0.62 to 1.36; P = .674); respective 5-year OS rates were 53.2% and 51.2% (P =

.784). Subsequent therapy was administered upon progression in 68.4% and 73.6%

of patients receiving gefitinib and VP, respectively. Subsequent targeted

therapy contributed most to OS (HR, 0.23; 95% CI, 0.14 to 0.38) compared with no

subsequent therapy. Updated 3y DFS rates were 39.6% and 32. 5% with gefitinib

and VP (P = .316) and 5y DFS rates were 22. 6% and 23.2% (P = .928),

respectively.

CONCLUSION: Adjuvant therapy with gefitinib in patients with early-stage NSCLC

and EGFR mutation demonstrated improved DFS over standard of care chemotherapy.

Although this DFS advantage did not translate to a significant OS difference, OS

with adjuvant gefitinib was one of the longest observed in this patient group

compared with historic data.

DOI: 10.1200/JCO.20.01820

PMID: 33332190

5. J Clin Oncol. 2020 Nov 20;38(33):3883-3894. doi: 10.1200/JCO.19.03010. Epub 2020

Oct 13.

Molecular Landscape and Actionable Alterations in a Genomically Guided Cancer

Clinical Trial: National Cancer Institute Molecular Analysis for Therapy Choice

(NCI-MATCH).

Flaherty KT(1), Gray RJ(2), Chen AP(3), Li S(2), McShane LM(3), Patton D(4),

Hamilton SR(5), Williams PM(6), Iafrate AJ(1)(7), Sklar J(8), Mitchell EP(9),

Harris LN(3), Takebe N(3), Sims DJ(6), Coffey B(10), Fu T(6), Routbort M(5),

Zwiebel JA(3), Rubinstein LV(3), Little RF(3), Arteaga CL(11), Comis R(12)(13),

Abrams JS(3), O'Dwyer PJ(3), Conley BA(3); NCI-MATCH team.

Author information:

(1)Massachusetts General Hospital, Boston, MA.

(2)ECOG-ACRIN Cancer Research Group Biostatistics Center, Dana Farber Cancer

Institute Boston, MA.

(3)Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI),

National Institutes of Health (NIH), Bethesda, MD.

...

PURPOSE: Therapeutically actionable molecular alterations are widely distributed

across cancer types. The National Cancer Institute Molecular Analysis for

Therapy Choice (NCI-MATCH) trial was designed to evaluate targeted therapy

antitumor activity in underexplored cancer types. Tumor biopsy specimens were

analyzed centrally with next-generation sequencing (NGS) in a master screening

protocol. Patients with a tumor molecular alteration addressed by a targeted

treatment lacking established efficacy in that tumor type were assigned to 1 of

30 treatments in parallel, single-arm, phase II subprotocols.

PATIENTS AND METHODS: Tumor biopsy specimens from 5,954 patients with refractory

malignancies at 1,117 accrual sites were analyzed centrally with NGS and

selected immunohistochemistry in a master screening protocol. The

treatment-assignment rate to treatment arms was assessed. Molecular alterations

in seven tumors profiled in both NCI-MATCH trial and The Cancer Genome Atlas

(TCGA) of primary tumors were compared.

RESULTS: Molecular profiling was successful in 93.0% of specimens. An actionable

alteration was found in 37.6%. After applying clinical and molecular exclusion

criteria, 17.8% were assigned (26.4% could have been assigned if all

subprotocols were available simultaneously). Eleven subprotocols reached their

accrual goal as of this report. Actionability rates differed among histologies

(eg, > 35% for urothelial cancers and < 6% for pancreatic and small-cell lung

cancer). Multiple actionable or resistance-conferring tumor mutations were seen

in 11.9% and 71.3% of specimens, respectively. Known resistance mutations to

targeted therapies were numerically more frequent in NCI-MATCH than TCGA tumors,

but not markedly so.

CONCLUSION: We demonstrated feasibility of screening large numbers of patients

at numerous accruing sites in a complex trial to test investigational therapies

for moderately frequent molecular targets. Co-occurring resistance mutations

were common and endorse investigation of combination targeted-therapy regimens.

DOI: 10.1200/JCO.19.03010

PMCID: PMC7676882

PMID: 33048619

6. J Clin Oncol. 2020 Dec 1;38(34):4076-4085. doi: 10.1200/JCO.20.01149. Epub 2020

Oct 6.

Randomized Trial of Afatinib Plus Cetuximab Versus Afatinib Alone for First-Line

Treatment of EGFR-Mutant Non-Small-Cell Lung Cancer: Final Results From SWOG

S1403.

Goldberg SB(1), Redman MW(2), Lilenbaum R(1), Politi K(1), Stinchcombe TE(3),

Horn L(4), Chen EH(5), Mashru SH(6), Gettinger SN(1), Melnick MA(1), Herbst

RS(1), Baumgart MA(7), Miao J(2), Moon J(2), Kelly K(8), Gandara DR(8).

Author information:

(1)Yale School of Medicine, New Haven, CT.

(2)SWOG Statistical Center, Seattle, WA.

(3)Duke Cancer Center, Durham, NC.

...

PURPOSE: The irreversible ErbB family tyrosine kinase inhibitor (TKI) afatinib

plus the EGFR monoclonal antibody cetuximab was previously shown to overcome

resistance to EGFR TKIs. We studied whether the combination of afatinib plus

cetuximab compared with afatinib alone would improve progression-free survival

(PFS) in patients with treatment-naive EGFR-mutant non-small-cell lung cancer

(NSCLC) by preventing or delaying resistance.

METHODS: Patients with EGFR-mutant NSCLC without prior treatment of advanced

disease were enrolled in this phase II, multicenter trial and randomly assigned

to receive afatinib 40 mg orally daily plus cetuximab 500 mg/m2 intravenously

every 2 weeks or afatinib alone. The primary end point was PFS.

RESULTS: Between March 25, 2015 and April 23, 2018, 174 patients were randomly

assigned, and 168 (83 on afatinib + cetuximab and 85 on afatinib) were eligible.

There was no improvement in PFS in patients receiving afatinib plus cetuximab

compared with afatinib alone (hazard ratio [HR], 1.01; 95% CI, 0.72 to 1.43; P =

.94; median, 11.9 months v 13.4 months). Similarly, there was no difference in

response rate (67% v 74%; P = .38) or overall survival (HR, 0.82; 95% CI, 0.50

to 1.36; P = .44). Toxicity was greater with the combination: grade ≥ 3 adverse

events related to treatment occurred in 72% of patients receiving afatinib plus

cetuximab compared with 40% of those receiving afatinib alone, most commonly

rash and diarrhea. Dose reductions were more common in patients receiving the

combination, and 30% of patients in this arm discontinued cetuximab due to

toxicity. At interim analysis, there was insufficient evidence to support

continued accrual, and the trial was closed.

CONCLUSIONS: The addition of cetuximab to afatinib did not improve outcomes in

previously untreated EGFR-mutant NSCLC, despite recognized activity in the

acquired resistance setting.

DOI: 10.1200/JCO.20.01149

PMID: 33021871

7. J Clin Oncol. 2020 Dec 1;38(34):4055-4063. doi: 10.1200/JCO.20.00890. Epub 2020

Oct 6.

Association Between a National Insurer's Pay-for-Performance Program for

Oncology and Changes in Prescribing of Evidence-Based Cancer Drugs and Spending.

Bekelman JE(1)(2)(3)(4)(5), Gupta A(3)(4)(6), Fishman E(7), Debono D(8), Fisch

MJ(9)(10), Liu Y(11), Sylwestrzak G(11), Barron J(11), Navathe AS(2)(3)(4)(5).

Author information:

(1)Department of Radiation Oncology, Perelman School of Medicine, University of

Pennsylvania, Philadelphia, PA.

(2)Department of Medical Ethics and Health Policy, Perelman School of Medicine,

University of Pennsylvania, Philadelphia, PA.

(3)Penn Center for Cancer Care Innovation at the Abramson Cancer Center,

Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

...

PURPOSE: Cancer drug prescribing by medical oncologists accounts for the

greatest variation in practice and the largest portion of spending on cancer

care. We evaluated the association between a national commercial insurer's

ongoing pay-for-performance (P4P) program for oncology and changes in the

prescribing of evidence-based cancer drugs and spending.

METHODS: We conducted an observational difference-in-differences study using

administrative claims data covering 6.7% of US adults. We leveraged the

geographically staggered, time-varying rollout of the P4P program to simulate a

stepped-wedge study design. We included patients age 18 years or older with

breast, colon, or lung cancer who were prescribed cancer drug regimens by 1,867

participating oncologists between 2013 and 2017. The exposure was a time-varying

dichotomous variable equal to 1 for patients who were prescribed a cancer drug

regimen after the P4P program was offered. The primary outcome was whether a

patient's drug regimen was a program-endorsed, evidence-based regimen. We also

evaluated spending over a 6-month episode period.

RESULTS: The P4P program was associated with an increase in evidence-based

regimen prescribing from 57.1% of patients in the preintervention period to

62.2% in the intervention period, for a difference of +5.1 percentage point (95%

CI, 3.0 percentage points to 7.2 percentage points; P < .001). The P4P program

was also associated with a differential $3,339 (95% CI, $1,121 to $5,557; P =

.003) increase in cancer drug spending and a differential $253 (95% CI, $100 to

$406; P = .001) increase in patient out-of-pocket spending, but no significant

changes in total health care spending ($2,772; 95% CI, -$181 to $5,725; P = .07)

over the 6-month episode period.

CONCLUSION: P4P programs may be effective in increasing evidence-based cancer

drug prescribing, but may not yield cost savings.

DOI: 10.1200/JCO.20.00890

PMID: 33021865

8. J Clin Oncol. 2020 Nov 20;38(33):3863-3873. doi: 10.1200/JCO.20.00131. Epub 2020

Sep 10.

Continuous Versus 1-Year Fixed-Duration Nivolumab in Previously Treated Advanced

Non-Small-Cell Lung Cancer: CheckMate 153.

Waterhouse DM(1), Garon EB(2), Chandler J(3), McCleod M(4), Hussein M(5), Jotte

R(6), Horn L(7), Daniel DB(8), Keogh G(9), Creelan B(10), Einhorn LH(11), Baker

J(12), Kasbari S(13), Nikolinakos P(14), Babu S(15), Couture F(16), Leighl

NB(17), Reynolds C(18), Blumenschein G Jr(19), Gunuganti V(20), Li A(21), Aanur

N(21), Spigel DR(22).

Author information:

(1)The US Oncology Network/Oncology Hematology Care, Cincinnati, OH.

(2)David Geffen School of Medicine at UCLA/Translational Research in Oncology-US

Network, Los Angeles, CA.

(3)West Cancer Center, Memphis, TN.

PURPOSE: Limited data exist on the optimal duration of immunotherapy, including

for non-small-cell lung cancer (NSCLC). We present an exploratory analysis of

CheckMate 153, a largely community-based phase IIIb/IV study, to evaluate the

impact of 1-year fixed-duration versus continuous therapy on the efficacy and

safety of nivolumab.

METHODS: Patients with previously treated advanced NSCLC received nivolumab

monotherapy (3 mg/kg every 2 weeks). Those still receiving treatment at 1 year,

including patients perceived to be deriving benefit despite radiographic

progression, were randomly assigned to continue nivolumab until disease

progression or unacceptable toxicity or to stop nivolumab with the option of

on-study retreatment after disease progression (1-year fixed duration).

RESULTS: Of 1,428 patients treated, 252 were randomly assigned to continuous (n

= 127) or 1-year fixed-duration (n = 125) treatment (intent-to-treat [ITT]

population). Of these, 89 and 85 patients in the continuous and 1-year

fixed-duration arms, respectively, had not progressed (progression-free survival

[PFS] population). With minimum post-random assignment follow-up of 13.5 months,

median PFS was longer with continuous versus 1-year fixed-duration treatment

(PFS population: 24.7 months v 9.4 months; hazard ratio [HR], 0.56 [95% CI, 0.37

to 0.84]). Median overall survival from random assignment was longer with

continuous versus 1-year fixed-duration treatment in the PFS (not reached v 32.5

months; HR, 0.61 [95% CI, 0.37 to 0.99]) and ITT (not reached v 28.8 months; HR,

0.62 [95% CI, 0.42 to 0.92]) populations. Few new-onset treatment-related

adverse events occurred. No new safety signals were identified.

CONCLUSION: To our knowledge, these findings from an exploratory analysis

represent the first randomized data on continuous versus fixed-duration

immunotherapy in previously treated advanced NSCLC and suggest that continuing

nivolumab beyond 1 year improves outcomes.

DOI: 10.1200/JCO.20.00131

PMCID: PMC7676888

PMID: 32910710

9. J Clin Invest. 2020 Dec 10:130319. doi: 10.1172/JCI130319. Online ahead of

print.

The integrated stress response mediates necrosis in murine Mycobacterium

tuberculosis granulomas.

Bhattacharya B(1), Xiao S(2), Chatterjee S(1), Urbanowski ME(2), Ordonez AA(2),

Ihms EA(2), Agrahari G(1), Lun S(2), Berland R(3), Pichugin A(4), Gao Y(5),

Connor JH(6), Ivanov AR(7), Yan BS(8), Kobzik L(9), Koo BB(1), Jain SK(2),

Bishai WR(2), Kramnik I(1).

Author information:

(1)The National Emerging Infectious Disease Laboratory, Boston University School

of Medicine, Boston, United States of America.

(2)Center for TB Research, Johns Hopkins University School of Medicine,

Baltimore, United States of America.

(3)Department of Integrative Physiology and Pathobiology, Tufts University

School of Medicine, Boston, United States of America.

...

The mechanism by which only some individuals infected with M. tuberculosis (Mtb)

develop necrotic granulomas with progressive disease while others form

controlled granulomas that contain the infection remains poorly defined. Mice

carrying the sst1-suscepible (sst1S) genotype develop necrotic inflammatory lung

lesions, similar to human TB granulomas, which are linked to macrophage

dysfunction while their congenic counterparts (B6) mice do not. In this study we

report that (i) sst1S macrophages developed aberrant, biphasic responses to TNF

characterized by super-induction of stress and type I interferon pathways after

prolonged TNF stimulation; (ii) the late-stage TNF response was driven via a JNK

- IFNβ - PKR circuit; and (iii) induced the integrated stress response (ISR) via

PKR-mediated eIF2α phosphorylation and the subsequent hyper-induction of ATF3

and ISR-target genes Chac1, Trib3, Ddit4. The administration of ISRIB, a small

molecule inhibitor of the ISR, blocked the development of necrosis in lung

granulomas of Mtb-infected sst1S mice and concomitantly reduced the bacterial

burden. Hence induction of the ISR and the locked-in state of escalating stress

driven by type I IFN pathway in sst1S macrophages plays a causal role in the

development of necrosis in TB granulomas. Interruption of the aberrant stress

response with inhibitors such as ISRIB may offer novel host-directed therapy

strategies.

DOI: 10.1172/JCI130319

PMID: 33301427

10. J Clin Invest. 2020 Nov 19:145157. doi: 10.1172/JCI145157. Online ahead of

print.

BCG vaccination history associates with decreased SARS-CoV-2 seroprevalence

across a diverse cohort of healthcare workers.

Noval Rivas M(1), Ebinger JE(2), Wu M(3), Sun N(3), Braun J(4), Sobhani K(5),

Van Eyk JE(6), Cheng S(7), Arditi M(1).

Author information:

(1)Departments of Pediatrics, Division of Infectious Diseases and Immunologic ,

Cedars-Sinai Medical Center, Los Angeles, United States of America.

(2)Department of Cardiology, Cedars-Siani Medical Center, Los Angeles, United

States of America.

(3)Department of Cardiology, Cedars-Sinai Medical Center, Los Angeles, United

States of America.

...

BACKGROUND: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has

caused over one million deaths worldwide, thus there is an urgent need to

develop preventive and therapeutic strategies. The anti-tuberculosis vaccine

Bacillus Calmette-Guérin (BCG) demonstrates non-specific protective innate

immune-boosting effects. Here, we determined if history of BCG vaccination was

associated with decreased SARS-CoV-2 infection and seroconversion in a

retrospective observational study of a diverse cohort of health care workers

(HCWs).

METHODS: We assessed SARS-CoV-2 seroprevalence and collected medical

questionnaires, including BCG vaccination status and pre-existing demographic

and clinical characteristics, from an observational cohort of HCWs in a

multi-site Los Angeles healthcare organization. We used multi-variate analysis

to estimate if history of BCG vaccination was associated with decreased rates of

SARS-CoV-2 infection and seroconversion.

RESULTS: Of the 6,201 HCWs, 29.6% reported a history of BCG vaccination whereas

68.9% did not receive BCG vaccination. Seroprevalence of anti-SARS-CoV-2 IgG as

well as incidence of self-reported clinical symptoms associated with COVID-19

were significantly decreased among HCWs with a history of BCG vaccination

compared to those without BCG vaccination. After adjusting for age and sex, we

found that history of BCG vaccination, but not meningococcal, pneumococcal or

influenza vaccination, was associated with decreased SARS-CoV-2 IgG

seroconversion.

CONCLUSIONS: History of BCG vaccination was associated with decreased

seroprevalence of anti-SARS-CoV-2 IgG and reduced reported COVID-19-related

clinical symptoms in this cohort of HCWs. Therefore, large randomized

prospective clinical trials of BCG vaccination are urgently needed to confirm if

BCG vaccination can induced a protective effect against SARS-CoV2 infection.

FUNDING: This work was supported by the National Institutes of Health, National

Cancer Institute (U54 CA26059) and the Erika J. Glazer Family Foundation. Key

words: SARS-CoV-2, COVID-19, Bacillus Calmette-Guérin, BCG, anti-SARS-CoV-2 IgG,

healthcare workers, trained immunity.

DOI: 10.1172/JCI145157

PMID: 33211672

11. Clin Microbiol Rev. 2020 Oct 14;34(1):e00141-20. doi: 10.1128/CMR.00141-20.

Print 2020 Dec 16.

Mechanisms of Drug-Induced Tolerance in Mycobacterium tuberculosis.

Goossens SN(1), Sampson SL(2), Van Rie A(3).

Author information:

(1)Family Medicine and Population Health (FAMPOP), Faculty of Medicine and

Health Sciences, University of Antwerp, Wilrijk, Belgium

sander.goossens@uantwerpen.be.

(2)DSI/NRF Centre of Excellence for Biomedical Tuberculosis Research/SA MRC

Centre for Tuberculosis Research, Division of Molecular Biology and Human

Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape

Town, South Africa.

(3)Family Medicine and Population Health (FAMPOP), Faculty of Medicine and

Health Sciences, University of Antwerp, Wilrijk, Belgium.

SUMMARY Successful treatment of tuberculosis (TB) can be hampered by

Mycobacterium tuberculosis populations that are temporarily able to survive

antibiotic pressure in the absence of drug resistance-conferring mutations, a

phenomenon termed drug tolerance. We summarize findings on M. tuberculosis

tolerance published in the past 20 years. Key M. tuberculosis responses to drug

pressure are reduced growth rates, metabolic shifting, and the promotion of

efflux pump activity. Metabolic shifts upon drug pressure mainly occur in M.

tuberculosis's lipid metabolism and redox homeostasis, with reduced

tricarboxylic acid cycle activity in favor of lipid anabolism. Increased lipid

anabolism plays a role in cell wall thickening, which reduces sensitivity to

most TB drugs. In addition to these general mechanisms, drug-specific mechanisms

have been described. Upon isoniazid exposure, M. tuberculosis reprograms several

pathways associated with mycolic acid biosynthesis. Upon rifampicin exposure, M.

tuberculosis upregulates the expression of its drug target rpoB Upon bedaquiline

exposure, ATP synthesis is stimulated, and the transcription factors Rv0324 and

Rv0880 are activated. A better understanding of M. tuberculosis's responses to

drug pressure will be important for the development of novel agents that prevent

the development of drug tolerance following treatment initiation. Such agents

could then contribute to novel TB treatment-shortening strategies.

Copyright © 2020 American Society for Microbiology.

DOI: 10.1128/CMR.00141-20

PMCID: PMC7566895

PMID: 33055230

12. Cell Host Microbe. 2020 Dec 16:S1931-3128(20)30635-1. doi:

10.1016/j.chom.2020.11.013. Online ahead of print.

The immune landscape in tuberculosis reveals populations linked to disease and

latency.

Esaulova E(1), Das S(2), Singh DK(3), Choreño-Parra JA(4), Swain A(1), Arthur

L(1), Rangel-Moreno J(5), Ahmed M(2), Singh B(3), Gupta A(2), Fernández-López

LA(4), de la Luz Garcia-Hernandez M(5), Bucsan A(6), Moodley C(6), Mehra S(6),

García-Latorre E(7), Zuniga J(8), Atkinson J(9), Kaushal D(10), Artyomov MN(11),

Khader SA(12).

Author information:

(1)Department of Pathology and Immunology, Washington University School of

Medicine, St Louis, MO 63110, USA.

(2)Department of Molecular Microbiology, Washington University School of

Medicine, St. Louis, MO 63110, USA.

(3)Southwest National Primate Research Center, Texas Biomedical Research

Institute, San Antonio, TX 78227, USA.

...

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) latently infects

approximately one-fourth of the world's population. The immune mechanisms that

govern progression from latent (LTBI) to active pulmonary TB (PTB) remain poorly

defined. Experimentally Mtb-infected non-human primates (NHP) mirror the disease

observed in humans and recapitulate both PTB and LTBI. We characterized the lung

immune landscape in NHPs with LTBI and PTB using high-throughput technologies.

Three defining features of PTB in macaque lungs include the influx of

plasmacytoid dendritic cells (pDCs), an Interferon (IFN)-responsive macrophage

population, and activated T cell responses. In contrast, a CD27+ Natural killer

(NK) cell subset accumulated in the lungs of LTBI macaques. This NK cell

population was also detected in the circulation of LTBI individuals. This

comprehensive analysis of the lung immune landscape will improve the

understanding of TB immunopathogenesis, providing potential targets for

therapies and vaccines for TB control.

Copyright © 2020 Elsevier Inc. All rights reserved.

DOI: 10.1016/j.chom.2020.11.013

PMID: 33340449

13. Cancer Discov. 2020 Dec;10(12):1826-1841. doi: 10.1158/2159-8290.CD-20-0282.

Epub 2020 Oct 18.

KEAP1/NFE2L2 Mutations Predict Lung Cancer Radiation Resistance That Can Be

Targeted by Glutaminase Inhibition.

Binkley MS(#)(1), Jeon YJ(#)(2)(3), Nesselbush M(4), Moding EJ(1), Nabet

BY(1)(2), Almanza D(4), Kunder C(5), Stehr H(5), Yoo CH(1), Rhee S(6), Xiang

M(7), Chabon JJ(2), Hamilton E(4), Kurtz DM(8), Gojenola L(5), Owen SG(1), Ko

RB(1), Shin JH(2), Maxim PG(1), Lui NS(9), Backhus LM(9), Berry MF(9), Shrager

JB(9), Ramchandran KJ(2)(8), Padda SK(2)(8), Das M(2)(8), Neal JW(2)(8), Wakelee

HA(2)(8), Alizadeh AA(2)(8), Loo BW Jr(1)(2), Diehn M(10)(2)(11).

Author information:

(1)Department of Radiation Oncology, Stanford University, Stanford, California.

(2)Stanford Cancer Institute, Stanford, California.

(3)Department of Integrative Biotechnology, Sungkyunkwan University, Suwon,

Republic of Korea.

...

Tumor genotyping is not routinely performed in localized non-small cell lung

cancer (NSCLC) due to lack of associations of mutations with outcome. Here, we

analyze 232 consecutive patients with localized NSCLC and demonstrate that KEAP1

and NFE2L2 mutations are predictive of high rates of local recurrence (LR) after

radiotherapy but not surgery. Half of LRs occurred in tumors with KEAP1/NFE2L2

mutations, indicating that they are major molecular drivers of clinical

radioresistance. Next, we functionally evaluate KEAP1/NFE2L2 mutations in our

radiotherapy cohort and demonstrate that only pathogenic mutations are

associated with radioresistance. Furthermore, expression of NFE2L2 target genes

does not predict LR, underscoring the utility of tumor genotyping. Finally, we

show that glutaminase inhibition preferentially radiosensitizes KEAP1-mutant

cells via depletion of glutathione and increased radiation-induced DNA damage.

Our findings suggest that genotyping for KEAP1/NFE2L2 mutations could facilitate

treatment personalization and provide a potential strategy for overcoming

radioresistance conferred by these mutations. SIGNIFICANCE: This study shows

that mutations in KEAP1 and NFE2L2 predict for LR after radiotherapy but not

surgery in patients with NSCLC. Approximately half of all LRs are associated

with these mutations and glutaminase inhibition may allow personalized

radiosensitization of KEAP1/NFE2L2-mutant tumors.This article is highlighted in

the In This Issue feature, p. 1775.

©2020 American Association for Cancer Research.

DOI: 10.1158/2159-8290.CD-20-0282

PMCID: PMC7710558

PMID: 33071215

14. Annu Rev Genet. 2020 Nov 23;54:511-537. doi:

10.1146/annurev-genet-022820-085940. Epub 2020 Sep 14.

Genetic Diversity in Mycobacterium tuberculosis Clinical Isolates and Resulting

Outcomes of Tuberculosis Infection and Disease.

Peters JS(1), Ismail N(2), Dippenaar A(2)(3), Ma S(4), Sherman DR(4), Warren

RM(2), Kana BD(1).

Author information:

(1)Department of Science and Innovation-National Research Foundation Centre of

Excellence for Biomedical Tuberculosis Research, School of Pathology, Faculty of

Health Sciences, University of the Witwatersrand and the National Health

Laboratory Service, Johannesburg 2000, South Africa; email:

petersjulian8@gmail.com, bavesh.kana@wits.ac.za.

(2)Department of Science and Innovation-National Research Foundation Centre of

Excellence for Biomedical Tuberculosis Research, South African Medical Research

Council Centre for Tuberculosis Research, Division of Molecular Biology and

Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch

University, Tygerberg 7505, South Africa; email: nabilai@sun.ac.za,

rw1@sun.ac.za.

(3)Family Medicine and Population Health (FAMPOP), Faculty of Medicine and

Health Sciences, University of Antwerp, Antwerp, 2000, Belgium; email:

Anzaan.Dippenaar@uantwerpen.be.

Tuberculosis claims more human lives than any other bacterial infectious disease

and represents a clear and present danger to global health as new tools for

vaccination, treatment, and interruption of transmission have been slow to

emerge. Additionally, tuberculosis presents with notable clinical heterogeneity,

which complicates diagnosis, treatment, and the establishment of nonrelapsing

cure. How this heterogeneity is driven by the diversity ofclinical isolates of

the causative agent, Mycobacterium tuberculosis, has recently garnered

attention. Herein, we review advances in the understanding of how naturally

occurring variation in clinical isolates affects transmissibility, pathogenesis,

immune modulation, and drug resistance. We also summarize how specific changes

in transcriptional responses can modulate infection or disease outcome, together

with strain-specific effects on gene essentiality. Further understanding of how

this diversity of M. tuberculosis isolates affects disease and treatment

outcomes will enable the development of more effective therapeutic options and

vaccines for this dreaded disease.

DOI: 10.1146/annurev-genet-022820-085940

PMID: 32926793

15. Angew Chem Int Ed Engl. 2020 Nov 20. doi: 10.1002/anie.202013987. Online ahead

of print.

An ER-Targeting Iridium(III) Complex which Induces Immunogenic Cell Death in

Non-Small Cell Lung Cancer.

Chao H(1), Wang L(2), Guan R(2), Xie L(2), Liao X(2), Xiong K(2), Rees TW(2),

Chen Y(2), Ji L(3).

Author information:

(1)Sun Yat-Sen University, Chemistry, Xingang Xilu 135#, 510275, Guangzhou,

CHINA.

(2)Sun Yat-Sen University, School of Chemistry, CHINA.

(3)Sun Yat-Sen University Cancer Prevention and Treatment Center: Sun Yat-sen

University Cancer Center, School of Chemistry, CHINA.

Immunogenic cell death (ICD) is a vital component of therapeutically induced

anti-tumor immunity. An iridium(III) complex ( Ir1 ), containing an N , N

-bis(2-chloroethyl)-azane derivate, as an endoplasmic reticulum-localized ICD

inducer for non-small cell lung cancer (NSCLC) is herein reported. The

characteristic discharge of damage-associated molecular patterns (DAMPs), i.e.

cell surface exposure of calreticulin (CRT), extracellular exclusion of high

mobility group box 1 (HMGB1) and ATP, were generated by Ir1 in A549 lung cancer

cells, accompanied by an increase in endoplasmic reticulum stress and reactive

oxygen species (ROS). The vaccination of immunocompetent mice with Ir1 -treated

dying cells elicited an antitumor CD8 + T cell response and Foxp3 + T cell

depletion, which eventually resulted in long-acting anti-tumor immunity by the

activation of ICD in lung cancer cells. With the dual actions of ICD and

chemotherapy against NSCLC, Ir1 has great potential as an antitumor agent. To

the best of our knowledge, Ir1 is the first iridium-based complex that is

capable of developing an immunomodulatory response by immunogenic cell death.

© 2020 Wiley-VCH GmbH.

DOI: 10.1002/anie.202013987

PMID: 33217194

16. Angew Chem Int Ed Engl. 2020 Dec 1;59(49):21965-21970. doi:

10.1002/anie.202009983. Epub 2020 Sep 29.

Discovery of a Chiral DNA-Targeted Platinum-Acridine Agent with Potent

Enantioselective Anticancer Activity.

Zhang S(1), Yao X(1), Watkins NH(1), Rose PK(1), Caruso SR(1), Day CS(2),

Bierbach U(1).

Author information:

(1)Department of Chemistry, Wake Forest University, Wake Downtown, 455 Vine St.,

Winston-Salem, NC, 27101, USA.

(2)Department of Chemistry, Wake Forest University, 1834 Wake Forest Rd.,

Winston-Salem, NC, 27109, USA.

A structure-activity relationship study was performed for a set of rigidified

platinum-acridine anticancer agents containing linkers derived from chiral

pyrrolidine and piperidine scaffolds. Screening a library of microscale

reactions and selected resynthesized compounds in non-small-cell lung cancer

(NSCLC) cells showed that cytotoxicities varied by more than three orders of

magnitude. A potent hit compound was discovered containing a

(R)-N-(piperidin-3-yl) linker (P2-6R), which killed NCI-H460 and A549 lung

cancer cells 100 times more effectively than the S enantiomer (P2-6S). P2-6R

accumulated in A549 cells significantly faster and produced 50-fold higher DNA

adduct levels than P2-6S. Ligand similarity analysis suggests that only module

6R may be compatible with strainless monofunctional intercalative binding.

NCI-60 screening and COMPARE analysis highlights the spectrum of activity and

potential utility of P2-6R for treating NSCLC and other solid tumors.

© 2020 Wiley-VCH GmbH.

DOI: 10.1002/anie.202009983

PMID: 32835419

17. Am J Respir Crit Care Med. 2020 Dec 1;202(11):1567-1575. doi:

10.1164/rccm.202003-0526OC.

Impact of Effective Global Tuberculosis Control on Health and Economic Outcomes

in the United States.

Menzies NA(1), Bellerose M(1), Testa C(1), Swartwood NA(1), Malyuta Y(1), Cohen

T(2), Marks SM(3), Hill AN(3), Date AA(4), Maloney SA(4), Bowden SE(5), Grills

AW(5), Salomon JA(6).

Author information:

(1)Department of Global Health and Population, Harvard T.H. Chan School of

Public Health, Boston, Massachusetts.

(2)Department of Epidemiology of Microbial Diseases, Yale School of Public

Health, New Haven, Connecticut.

(3)Division of Tuberculosis Elimination.

...

Comment in

Am J Respir Crit Care Med. 2020 Dec 1;202(11):1499-1500.

Rationale: Most U.S. residents who develop tuberculosis (TB) were born abroad,

and U.S. TB incidence is increasingly driven by infection risks in other

countries.Objectives: To estimate the potential impact of effective global TB

control on health and economic outcomes in the United States.Methods: We

estimated outcomes using linked mathematical models of TB epidemiology in the

United States and migrants' birth countries. A base-case scenario extrapolated

country-specific TB incidence trends. We compared this with scenarios in which

countries achieve 90% TB incidence reductions between 2015 and 2035, as targeted

by the World Health Organization's End TB Strategy ("effective global TB

control"). We also considered pessimistic scenarios of flat TB incidence trends

in individual countries.Measurements and Main Results: We estimated TB cases,

deaths, and costs and the total economic burden of TB in the United States.

Compared with the base-case scenario, effective global TB control would avert

40,000 (95% uncertainty interval, 29,000-55,000) TB cases in the United States

in 2020-2035. TB incidence rates in 2035 would be 43% (95% uncertainty interval,

34-54%) lower than in the base-case scenario, and 49% (95% uncertainty interval,

44-55%) lower than in 2020. Summed over 2020-2035, this represents 0.8 billion

dollars (95% uncertainty interval, 0.6-1.0 billion dollars) in averted

healthcare costs and $2.5 billion dollars (95% uncertainty interval, 1.7-3.6

billion dollars) in productivity gains. The total U.S. economic burden of TB

(including the value of averted TB deaths) would be 21% (95% uncertainty

interval, 16-28%) lower (18 billion dollars [95% uncertainty level, 8-32 billion

dollars]).Conclusions: In addition to producing major health benefits for

high-burden countries, strengthened efforts to achieve effective global TB

control could produce substantial health and economic benefits for the United

States.

DOI: 10.1164/rccm.202003-0526OC

PMCID: PMC7706168

PMID: 32645277 [Indexed for MEDLINE]

18. Am J Respir Crit Care Med. 2020 Dec 1;202(11):1551-1559. doi:

10.1164/rccm.202001-0002OC.

Chronic Effects of High Fine Particulate Matter Exposure on Lung Cancer in

China.

Li J(1)(2), Lu X(1)(2), Liu F(1), Liang F(1), Huang K(1), Yang X(1), Xiao Q(3),

Chen J(1), Liu X(4), Cao J(1), Chen S(1), Shen C(5), Yu L(6), Lu F(7), Wu X(8),

Zhao L(1), Wu X(1), Li Y(1), Hu D(9)(10), Huang J(1), Zhu M(5)(11), Liu Y(12),

Shen H(5)(11), Gu D(1)(2)(13).

Author information:

(1)Department of Epidemiology, Fuwai Hospital, National Center for

Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union

Medical College, Beijing, China.

(2)Key Laboratory of Cardiovascular Epidemiology, Chinese Academy of Medical

Sciences, Beijing, China.

(3)School of Environment, Tsinghua University, Beijing, China.

...

Rationale: Limited cohort studies have evaluated chronic effects of high fine

particulate matter (particulate matter with an aerodynamic diameter ≤2.5 μm

[PM2.5]) exposure on lung cancer.Objectives: To investigate the response pattern

of lung cancer associated with high PM2.5 exposure.Methods: A Chinese cohort of

118,551 participants was followed up from 1992 to 2015. By incorporating PM2.5

exposure at 1 km spatial resolution generated using the satellite-based model

during 2000-2015, we estimated the association between lung cancer and

time-weighted average PM2.5 concentration using Cox proportional hazard

models.Measurements and Main Results: A total of 844 incident lung cancer cases

were identified during 915,053 person-years of follow-up. Among them, 701 lung

cancer deaths occurred later. The exposure-response curves for lung cancer

associated with PM2.5 exposure were nonlinear, with steeper slopes at the higher

concentrations. Adjusted for age, sex, geographical region, urbanization,

education level, smoking status, alcohol consumption, work-related physical

activity, and body mass index, participants exposed to the second-fifth

quintiles of PM2.5 had higher risk for lung cancer incidence than those exposed

to the first quintile, with hazard ratios of 1.44 (95% confidence interval [CI],

1.10-1.88), 1.49 (95% CI, 1.12-1.99), 2.08 (95% CI, 1.42-3.04), and 2.45 (95%

CI, 1.83-3.29), respectively. The corresponding hazard ratios for lung cancer

mortality were 1.83 (95% CI, 1.33-2.50), 1.80 (95% CI, 1.29-2.53), 2.50 (95% CI,

1.62-3.86), and 2.95 (95% CI, 2.09-4.17), respectively.Conclusions: We provide

strong evidence that high PM2.5 exposure leads to an elevated risk of lung

cancer incidence and mortality, highlighting that remarkable public health

benefits could be obtained from the improvement of air quality in highly

polluted regions.

DOI: 10.1164/rccm.202001-0002OC

PMID: 32614242 [Indexed for MEDLINE]

19. ACS Nano. 2020 Dec 21. doi: 10.1021/acsnano.0c07132. Online ahead of print.

Sequential Treatment of Bioresponsive Nanoparticles Elicits Antiangiogenesis and

Apoptosis and Synergizes with a CD40 Agonist for Antitumor Immunity.

Ling X(1), Jiang X(1), Li Y(1), Han W(1), Rodriguez M(1), Xu Z(1), Lin W(1)(2).

Author information:

(1)Department of Chemistry, The University of Chicago, Chicago, Illinois 60637,

United States.

(2)Department of Radiation and Cellular Oncology and Ludwig Center for

Metastasis Research, The University of Chicago, Chicago, Illinois 60637, United

States.

The combination of antiangiogenesis and chemotherapy regimens with cancer

immunotherapy has the potential to synergistically boost antitumor immunity.

Herein, we report the construction of two bioresponsive nanoparticles, namely,

Podo-NP and CbP-NP, comprising prodrugs of podophyllotoxin (Podo) and

carboplatin, respectively. Sequential treatment with esterase-responsive

Podo-NP, redox-sensitive CbP-NP, and a CD40 agonist promotes antitumor T cell

response. Podo-NP suppresses angiogenesis by preventing proliferation and

migration of endothelial cells, sprouting of neovessels, formation of tubules,

and stabilization of newly formed vessels. Vascular endothelial growth factor

blockade and endostatin stimulation normalize tortuous tumor vasculatures to

allow efficient infiltration of effector immune cells. Subsequent treatment with

CbP-NP arrests the cell-division cycle and elicits the apoptosis of tumor cells.

CD40 agonist activates antigen-presenting cells to process the released

tumor-associated antigens from dying tumor cells, thus reversing

immunosuppressive tumor microenvironments. Sequential delivery of antiangiogenic

and chemotherapeutic agents with bioresponsive NPs activates tumor

microenvironments and synergizes with CD40 agonist to regress transplanted

tumors and inhibit disseminated tumors in a lung cancer mouse model.

DOI: 10.1021/acsnano.0c07132

PMID: 33347262