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The Aspergilli of the series Versicolores include several airborne species to which we are exposed daily. Most of them synthesise sterigmatocystin, a mycotoxin precursor of aflatoxins recognised as potentially carcinogenic for humans (group 2B) by the International Agency for Research on Cancer. Our objective was to study the potential role of these moulds in the synthesis of extrolites of the aflatoxin biosynthetic pathway. A total of 124 isolates belonging to the eight species of the series Versicolores collected in French bioaerosols were studied: Aspergillus amoenus (n=1), Aspergillus creber (n=45), Aspergillus fructus (n=2), Aspergillus jensenii (n=39), Aspergillus protuberus (n=6), Aspergillus puulaauensis (n=5), Aspergillus sydowii (n=14) and Aspergillus tabacinus (n=2). All these isolates and a reference strain of each species were extracted using ethyl acetate acidified with 1% (v/v) acetic acid. In each extract, we screened for the following extrolites of the aflatoxin biosynthetic pathway by UPLC-HRMS: norsolorinic acid, versicolorin A, 6-demethylsterigmatocystin, sterigmatocystin, 8-O-methylsterigmatocystin, 5-methoxysterigmatocystin and aflatoxins B1, B2, G1 and G2. All extrolites, except aflatoxins, were found variably among species. Sterigmatocystin was found in extracts of all eight Versicolores species, including A. sydowii and A. tabacinus whose ability to synthesise sterigmatocystin was questioned or unknown, respectively.

Pembrolizumab; Non-small-cell lung cancer Pembrolizumab; Cáncer de pulmón de células no pequeñas Pembrolizumab; Càncer de pulmó de cèl·lules no petites Clinical trials frequently include multiple end points that mature at different times. The initial report, typically on the based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We present 5-year outcomes from the phase 3 KEYNOTE-189 study (ClinicalTrials.gov identifier: NCT02578680). Eligible patients with previously untreated metastatic nonsquamous non-small-cell lung cancer without EGFR/ALK alterations were randomly assigned 2:1 to pembrolizumab 200 mg or placebo once every 3 weeks for up to 35 cycles with pemetrexed and investigator's choice of carboplatin/cisplatin for four cycles, followed by maintenance pemetrexed until disease progression or unacceptable toxicity. Primary end points were overall survival (OS) and progression-free survival (PFS). Among 616 randomly assigned patients (n = 410, pembrolizumab plus pemetrexed-platinum; n = 206, placebo plus pemetrexed-platinum), median time from random assignment to data cutoff (March 8, 2022) was 64.6 (range, 60.1-72.4) months. Hazard ratio (95% CI) for OS was 0.60 (0.50 to 0.72) and PFS was 0.50 (0.42 to 0.60) for pembrolizumab plus platinum-pemetrexed versus placebo plus platinum-pemetrexed. 5-year OS rates were 19.4% versus 11.3%. Toxicity was manageable. Among 57 patients who completed 35 cycles of pembrolizumab, objective response rate was 86.0% and 3-year OS rate after completing 35 cycles (approximately 5 years after random assignment) was 71.9%. Pembrolizumab plus pemetrexed-platinum maintained OS and PFS benefits versus placebo plus pemetrexed-platinum, regardless of programmed cell death ligand-1 expression. These data continue to support pembrolizumab plus pemetrexed-platinum as a standard of care in previously untreated metastatic non-small-cell lung cancer without EGFR/ALK alterations.

Introduction: Capmatinib, a MET inhibitor, showed substantial antitumour activity with manageable side effects in patients with MET exon 14 (METex14)-mutated advanced non-small cell lung cancer (aNSCLC) in the GEOMETRY mono-1 study. We report patient-reported outcomes (PROs) from this study. Methods: Enrolled treatment-naïve (1L) or pre-treated (2L+) patients with aNSCLC with a METex14-skipping mutation received 400 mg capmatinib twice daily during 21-day treatment cycles. PROs were collected at baseline and every six weeks thereafter using EORTC QLQ-C30 global health status/quality of life (GHS/QoL), QLQ-LC13 symptoms, and EQ-5D-5L visual analogue scale (VAS) questionnaires. Results: As of 6 January 2020, 27/28 1L and 65/69 2L+ patients had completed PROs at baseline; compliance rates remained >70%. Cough improved early, with meaningful improvements (≥10-point change from baseline) observed throughout cycles (mean change from baseline [SD] by week 7: 1L −13.0 [39.9], 2L+ −8.2 [28.4]; week 43: 1L −28.2 [26.7], 2L+ −10.5 [27.3]). QoL, assessed by GHS/QoL and VAS, improved by week 7 in 1L and 2L+ patients, with improvements generally sustained over time. Median time to definitive deterioration (TTDD) in GHS/QoL was 16.6 months (95% CI: 9.7, not estimable [NE]) in 1L and 12.4 months (95% CI: 4.2, 19.4) in 2L+ patients. Median TTDD for dyspnoea was 19.4 months (95% CI: 12.4, NE) and 22.1 months (95% CI: 9.9, NE) for 1L and 2L+ patients, respectively, and NE for cough and chest pain. Conclusions: Capmatinib was associated with clinically meaningful improvements in cough and preserved QoL, further supporting its use in patients with METex14-mutated aNSCLC. Trial registration: ClinicalTrials.gov registry number: NCT02414139.

PURPOSE The open-label, phase III POSEIDON study evaluated tremelimumab plus durvalumab and chemotherapy (T + D + CT) and durvalumab plus chemotherapy (D + CT) versus chemotherapy alone (CT) in first-line metastatic non–small-cell lung cancer (mNSCLC). METHODS Patients (n = 1,013) with EGFR/ ALK wild-type mNSCLC were randomly assigned (1:1:1) to tremelimumab 75 mg plus durvalumab 1,500 mg and platinum-based chemotherapy for up to four 21-day cycles, followed by durvalumab once every 4 weeks until progression and one additional tremelimumab dose; durvalumab plus chemotherapy for up to four 21-day cycles, followed by durvalumab once every 4 weeks until progression; or chemotherapy for up to six 21-day cycles (with or without maintenance pemetrexed; all arms). Primary end points were progression-free survival (PFS) and overall survival (OS) for D + CT versus CT. Key alpha-controlled secondary end points were PFS and OS for T + D + CT versus CT. RESULTS PFS was significantly improved with D + CT versus CT (hazard ratio [HR], 0.74; 95% CI, 0.62 to 0.89; P = .0009; median, 5.5 v 4.8 months); a trend for improved OS did not reach statistical significance (HR, 0.86; 95% CI, 0.72 to 1.02; P = .0758; median, 13.3 v 11.7 months; 24-month OS, 29.6% v 22.1%). PFS (HR, 0.72; 95% CI, 0.60 to 0.86; P = .0003; median, 6.2 v 4.8 months) and OS (HR, 0.77; 95% CI, 0.65 to 0.92; P = .0030; median, 14.0 v 11.7 months; 24-month OS, 32.9% v 22.1%) were significantly improved with T + D + CT versus CT. Treatment-related adverse events were maximum grade 3/4 in 51.8%, 44.6%, and 44.4% of patients receiving T + D + CT, D + CT, and CT, respectively; 15.5%, 14.1%, and 9.9%, respectively, discontinued treatment because of treatment-related adverse events. CONCLUSION D + CT significantly improved PFS versus CT. A limited course of tremelimumab added to durvalumab and chemotherapy significantly improved OS and PFS versus CT, without meaningful additional tolerability burden, representing a potential new option in first-line mNSCLC.

Les pratiques de l’enseignant qui soutiennent les besoins d’autodétermination (autonomie, compétence, appartenance) des élèves favorisent leur motivation intrinsèque, leur engagement et leur réussite scolaire. Cette étude s’est intéressée aux pratiques de soutien aux besoins d’autodétermination déployées par un enseignant d’une classe primaire lors du retour en classe post confinement 2020. À l’aide d’une grille d’observation, 500 minutes de captation vidéo ont été examinées afin de dégager la fréquence et la nature des pratiques qui soutiennent le besoin d’autonomie, de compétence et d’appartenance des élèves. Les analyses descriptives montrent que cet enseignant utilise un grand nombre de pratiques qui soutiennent ces trois besoins, à plus forte raison lorsqu’il fait de l’enseignement magistral ou lorsque des interactions ont lieu avec les élèves. L’analyse du discours de l’enseignant a permis de mettre en lumière qu’il a opté pour une approche positive face aux changements induits par la Covid-19. S’il est possible de croire que cet enseignant utilisait déjà des pratiques soutenant l’autodétermination des élèves, le contexte pandémique semble avoir été pour lui une occasion d’être centré sur les besoins des élèves dans sa didactique et sa gestion de la classe.

Purpose: Immune checkpoint inhibitors (ICI) have revolutionized the treatment of non–small cell lung cancer (NSCLC), but predictive biomarkers of their efficacy are imperfect. The primary objective is to evaluate circulating immune predictors of pembrolizumab efficacy in patients with advanced NSCLC. Experimental Design: We used high-dimensional mass cytometry (CyTOF) in baseline blood samples of patients with advanced NSCLC treated with pembrolizumab. CyTOF data were analyzed by machine-learning algorithms (Citrus, tSNE) and confirmed by manual gating followed by principal component analysis (between-group analysis). Results: We analyzed 27 patients from the seminal KEYNOTE-001 study (median follow-up of 60.6 months). We demonstrate that blood baseline frequencies of classical monocytes, natural killer (NK) cells, and ICOS+ CD4+ T cells are significantly associated with improved objective response rates, progression-free survival, and overall survival (OS). In addition, we report that a baseline immune peripheral score combining these three populations strongly predicts pembrolizumab efficacy (OS: HR = 0.25; 95% confidence interval = 0.12–0.51; P < 0.0001). Conclusions: As this immune monitoring is easy in routine practice, we anticipate our findings may improve prediction of ICI benefit in patients with advanced NSCLC.

In an ongoing, open-label, single-arm phase II study (NCT02927301), 181 patients with untreated, resectable, stage IB–IIIB non-small cell lung cancer received two doses of neoadjuvant atezolizumab monotherapy. The primary end point was major pathological response (MPR; ≤10% viable malignant cells) in resected tumors withoutEGFRorALKalterations. Of the 143 patients in the primary end point analysis, the MPR was 20% (95% confidence interval, 14–28%). With a minimum duration of follow-up of 3 years, the 3-year survival rate of 80% was encouraging. The most common adverse events during the neoadjuvant phase were fatigue (39%, 71 of 181) and procedural pain (29%, 53 of 181), along with expected immune-related toxicities; there were no unexpected safety signals. In exploratory analyses, MPR was predicted using the pre-treatment peripheral blood immunophenotype based on 14 immune cell subsets. Immune cell subsets predictive of MPR in the peripheral blood were also identified in the tumor microenvironment and were associated with MPR. This study of neoadjuvant atezolizumab in a large cohort of patients with resectable non-small cell lung cancer was safe and met its primary end point of MPR ≥ 15%. Data from this single-arm, non-randomized trial suggest that profiles of innate immune cells in pre-treatment peripheral blood may predict pathological response after neoadjuvant atezolizumab, but additional studies are needed to determine whether these profiles can inform patient selection and new therapeutic approaches.

Background Adjuvant immune checkpoint blockade (ICB) following chemoradiotherapy and adding ICB to chemotherapy have been key advances for stages III-IV non-small cell lung cancer (NSCLC) treatment. However, known biomarkers like PD-L1 are not consistently indicative of ICB response. Other markers within the tumor immune microenvironment (TIME) may better reflect ICB response and/or resistance mechanisms, but an understanding of how TIMEs differ between stage III and IV NSCLC has not been explored. Methods Real-world data from unresectable, stage III-IV, non-squamous, pretreatment NSCLCs (stage III n = 106, stage IV n = 285) were retrospectively analyzed. PD-L1 immunohistochemistry (IHC) was compared to CD274 gene expression. Then, differential gene expression levels, pathway enrichment, and immune infiltrate between stages were calculated from whole-transcriptome RNA-seq. Analyses were stratified by EGFR status. Results PD-L1 IHC and CD274 expression in tumor cells were highly correlated (n = 295, P ⍴ = 0.74). CTLA4 expression was significantly increased in stage III tumors (P = 1.32e-04), while no differences were observed for other ICB-related genes. Metabolic pathway activity was significantly enriched in stage IV tumors (P = 0.004), whereas several immune-related KEGG pathways were enriched in stage III. Stage IV tumors had significantly increased macrophage infiltration (P = 0.0214), and stage III tumors had a significantly higher proportion of CD4 + T cells (P = 0.017). CD4 + T cells were also relatively more abundant in EGFR-mutant tumors vs. wild-type (P = 0.0081). Conclusion Directly comparing the TIMEs of stage III and IV NSCLC, these results carry implications for further studies of ICB response in non-resectable stage III NSCLC and guide further research of prognostic biomarkers and therapeutic targets.

Purpose In RELAY, ramucirumab plus erlotinib (RAM + ERL) improved progression-free survival (PFS) in patients with untreated, metastatic, EGFR-mutated, non-small cell lung cancer (NSCLC). Here, we present the exposure–response relationship of RAM from RELAY. Methods Patients received ERL (150 mg/day) with either RAM (10 mg/kg) or placebo (PBO + ERL) every 2 weeks (Q2W). A population pharmacokinetic model predicted RAM minimum concentration after first dose (Cmin,1), and at steady state (Cmin,ss), which were used to evaluate correlation between RAM exposure and efficacy and safety. The Kaplan–Meier method and Cox regression analyses were utilized to evaluate exposure–efficacy by Cmin,1 quartile. Exposure–safety was evaluated by assessing incidence rates for safety parameters by Cmin,ss quartile, with ordered categorical analysis used for ALT/AST only. Results Analyses included 216 patients treated with RAM + ERL and 225 patients treated with PBO + ERL. Adjusting for significant baseline covariates, no exposure–efficacy relationship was identified in RELAY: PFS hazard ratio (mean, 95% confidence intervals) for the Cmin,1 quartiles were 0.67 (0.45–0.99), 0.77 (0.53–1.12), 0.57 (0.38–0.84), and 0.50 (0.33–0.76). No apparent exposure–safety relationship was observed for selected safety endpoints, including Grade ≥ 3 hypertension, diarrhea, and dermatitis acneiform, and any grade hypertension, any grade and Grade ≥ 3 proteinuria, and any grade ALT/AST increased within liver failure/liver injury. Conclusions No association was observed between RAM exposure and response, suggesting that the RELAY regimen of RAM 10 mg/kg Q2W with ERL is an optimized, efficacious, and safe first-line treatment for patients with untreated, metastatic, EGFR-mutated NSCLC. Trial registration: ClinicalTrials.gov, NCT02411448.

Background COVID-19 has negatively impacted the mental health of frontline health care workers, including pharmacists. Objective(s) The aim of this longitudinal study was to assess the psychological impact of the COVID-19 outbreak in French owner community pharmacists. Methods We carried out a postal-based survey to assess the psychological difficulties of the COVID-19 outbreak in French owner community pharmacists based on three psychologically validated self-report questionnaires: Perceived Stress Scale (PSS), Impact of Event Scale-revised (IES-R) and Maslach Burnout Inventory. The baseline assessment was during the first sanitary lockdown period and the second one 5 months later. Results The sample consists of 135 owner community pharmacists. At follow-up, 67 answered the questionnaires (response rate: 49.6%). The mean scores of the PSS and IES-R significantly decreased (p=0.002). Fifteen pharmacists reported significant posttraumatic stress symptoms (23.1%) at baseline and eleven at follow-up (16.4%, p=0.02). Age and sex were not significantly associated with persistent posttraumatic stress or burnout symptoms. Conclusion This is the first longitudinal study that showed the psychological impact of owner community pharmacists as health care workers dealing with their community's COVID-19 outbreak. Based on validated self-report questionnaires, stress, posttraumatic stress and burnout symptoms decreased during follow-up. It is necessary to continue monitoring psychological difficulties for health care workers, especially during consecutive waves of the COVID-19 outbreak.

IntroductionChild attention skills are critical for supporting self-regulation abilities, especially during the first years of life. On the other hand, inattention symptoms in preschoolers have been associated with poor school readiness, literacy skills and academic achievement. Previous research has linked excessive screen time with increased inattention symptoms in early childhood. However, most research has only focused on TV exposure and did not investigate this association during the COVID-19 pandemic. This atypical context has increased screen time in children worldwide, including preschoolers. We hypothesize that higher levels of child screen media and parenting stress at age 3.5 will be associated with higher child inattention symptoms at age 4.5.MethodThis study draws on participants followed longitudinally over the span of 2-years for an investigation of Canadian preschoolers’ screen media use during the pandemic (N = 315, 2020). A follow-up with this sample was completed in 2021 (N = 264).ResultsAnalyses using multiple linear regression, revealed a positive association between child screen time at age 3.5 and inattention symptoms at 4.5 years. Parental stress was also positively associated with child inattention symptoms. Associations were observed above individual (child age, inhibitory control, and sex) and family (parent education and family income) characteristics.DiscussionThese results confirmed our hypothesis and highlight that preschooler screen use and parenting stress may undermine attentional skills. Since attention is a crucial component for children development, behavior and academic outcomes, our study reinforces the importance for parents of adopting healthy media habits.

We retrospectively analyzed non–small cell lung cancer (NSCLC) patients from a single center treated with pembrolizumab on the KEYNOTE-001 trial and evaluated the association between treatment-related adverse events (trAEs) and clinical outcomes. Investigators reported AEs on trial and graded them according to Common Terminology Criteria for Adverse Events v4.0, labeling them as unlikely, possibly, or probably treatment-related. AEs labeled as possibly/probably related were considered trAEs for this analysis. The relationship between the incidence of a trAE and clinical outcomes was evaluated. Ninety-seven NSCLC patients treated on KEYNOTE-001 at the University of California, Los Angeles were evaluated. Ten percent (85/826) of AEs were trAEs, occurring in 40% (39/97) of patients. The most frequent trAEs were rash (21% patients), fatigue (6% patients), and hypothyroidism (6% patients). The 39 patients that experienced a trAE had increased objective response rate (ORR, 38.5%), progression-free survival (PFS: median, 248 days), and overall survival (OS: median, 493 days), compared with the 58 patients that did not (ORR: 8.9%, PFS: median 60 days, OS: median 144.5 days). The observed association between trAEs and improved clinical outcome persisted when using Cox proportional hazards regression models to assess the confounding effect of covariates and mitigate guarantee-time bias. The association also remained when data were substratified by grade, degree of association, and treatment-related select AE designation. This single-center analysis revealed that trAEs predicted for improved clinical outcome with pembrolizumab, and when controlling for guarantee-time bias and plausible confounders, this association remained. This observed relationship adds to our understanding of anti–PD-1 therapy and could aid clinicians in identifying patients most likely to benefit from therapy. Cancer Immunol Res; 6(3); 288–94. ©2018 AACR.

Table S2: Demographics of the 97 NSCLC patients treated at UCLA on KEYNOTE-001 (N=97) compared with the demographics of the total KEYNOTE-001 study population (n=495). Of note, the UCLA cohort of 97 patients is included in the total KEYNOTE-001 study population of 495 patients.

Quantitative CD8+ Counts in patients with Liver and skin metastases.

Table S3: The occurrence of a treatment related AE (trAE) in the 97 patients treated at UCLA on the KEYNOTE-001 clinical trial, stratified by a history of thoracic radiation therapy (TRT) or prior radiation therapy to any location. P values computed via Fisher's exact test.

PDF file - 37K, Stable knockdown of c-myc expression by shRNA in NSCLC cells.

Supplementary Table S6a: Objective response rate (ORR) in the 95 NSCLC patients from the UCLA cohort that had at least 1 set of thyroid values obtained on trial available for analysis stratified by the presence or absence of an abnormal TSH value of varying qualities (Any, High, Low, Both High and Low noted).

Univariate Analysis of Pretreatment prognostic factors in the Discovery cohort.

PDF - 69K, Supplemental Figure Legend

Heat shock protein 90 (HSP90) is involved in protein folding and functions as a chaperone for numerous client proteins, many of which are important in non–small cell lung cancer (NSCLC) pathogenesis. We sought to define preclinical effects of the HSP90 inhibitor NVP-AUY922 and identify predictors of response. We assessed in vitro effects of NVP-AUY922 on proliferation and protein expression in NSCLC cell lines. We evaluated gene expression changes induced by NVP-AUY922 exposure. Xenograft models were evaluated for tumor control and biological effects. NVP-AUY922 potently inhibited in vitro growth in all 41 NSCLC cell lines evaluated with IC50 < 100 nmol/L. IC100 (complete inhibition of proliferation) < 40 nmol/L was seen in 36 of 41 lines. Consistent gene expression changes after NVP-AUY922 exposure involved a wide range of cellular functions, including consistently decreased dihydrofolate reductase after exposure. NVP-AUY922 slowed growth of A549 (KRAS-mutant) xenografts and achieved tumor stability and decreased EGF receptor (EGFR) protein expression in H1975 xenografts, a model harboring a sensitizing and a resistance mutation for EGFR-tyrosine kinase inhibitors in the EGFR gene. These data will help inform the evaluation of correlative data from a recently completed phase II NSCLC trial and a planned phase IB trial of NVP-AUY922 in combination with pemetrexed in NSCLCs. Mol Cancer Ther; 12(6); 890–900. ©2013 AACR.

PDF - 769K, Heat maps from microarray analyses of gene expression changes seen in at least 13 of 16 experiments after exposure to NVP-AUY922

Supplementary Table S5a: Cox proportional hazards models for progression-free survival (PFS) with number of treatment related select adverse events included as a time-varying covariate. Listed are results from both unadjusted models and adjusted models. Hazard ratio estimates marked '(+1)' correspond to the incremental effect of a unit increase in the relevant predictor.

Table S1: All adverse events occurring in > 5% of patients in the UCLA NSCLC cohort of 97 patients treated on KEYNOTE-001.

Supplementary Table 4a: Objective response rate (ORR), progression-free survival (PFS), and overall survival stratified by the incidence of a grade 2 or higher treatment related AE (trAE) or a trAE of varying degrees of attribution (possible or probable). Included are all 97 NSCLC patients treated at UCLA on KEYNOTE-001 with available follow-up data.

PDF file - 38K

Supplementary Figure S1A-B. ORR, PFS, and OS analysis for UCLA NSCLC cohort of KEYNOTE-001 trial. ORR, PFS, and OS for all 97 patients in the UCLA cohort of the KEYNOTE-001 trial stratified by the occurrence of a (A) treatment related adverse event (trAE) or (B) a treatment related select AE.

Aberrant expression of microRNAs (miRNA) with oncogenic capacities (oncomiRs) has been described for several different malignancies. The first identified oncomiR, miR-17-92, is frequently overexpressed in a variety of cancers and its targets include the tumor suppressor PTEN. The transcription factor c-Myc (MYC) plays a central role in proliferative control and is rapidly upregulated upon mitogenic stimulation. Expression of c-Myc is frequently deregulated in tumors, facilitating proliferation and inhibiting terminal differentiation. The c-Myc–regulated network comprises a large number of transcripts, including those encoding miRNAs. Here, prostaglandin E2 (PGE2) exposure rapidly upregulates the expression of the MYC gene followed by the elevation of miR-17-92 levels, which in turn suppresses PTEN expression, thus enhancing apoptosis resistance in non–small cell lung cancer (NSCLC) cells. Knockdown of MYC expression or the miR-17-92 cluster effectively reverses this outcome. Similarly, miR-17-92 levels are significantly elevated in NSCLC cells ectopically expressing COX-2. Importantly, circulating miR-17-92 was elevated in the blood of patients with lung cancer as compared with subjects at risk for developing lung cancer. Furthermore, in patients treated with celecoxib, miR-17-92 levels were significantly reduced. These data demonstrate that PGE2, abundantly produced by NSCLC and inflammatory cells in the tumor microenvironment, is able to stimulate cell proliferation and promote resistance to pharmacologically induced apoptosis in a c-Myc and miR-17-92–dependent manner.Implications: This study describes a novel mechanism, involving c-Myc and miR-17-92, which integrates cell proliferation and apoptosis resistance. Mol Cancer Res; 12(5); 765–74. ©2014 AACR.

PDF file - 47K, Patient characteristics.

PDF - 47B, A tabular demonstration of the efficacy and tolerability of NVP-AUY922 in 32 mice carrying subcutaneous A549 or H1975 xenograft tumors randomized

Purpose:Immune checkpoint inhibitors (ICI) have revolutionized the treatment of non–small cell lung cancer (NSCLC), but predictive biomarkers of their efficacy are imperfect. The primary objective is to evaluate circulating immune predictors of pembrolizumab efficacy in patients with advanced NSCLC. Experimental Design:We used high-dimensional mass cytometry (CyTOF) in baseline blood samples of patients with advanced NSCLC treated with pembrolizumab. CyTOF data were analyzed by machine-learning algorithms (Citrus, tSNE) and confirmed by manual gating followed by principal component analysis (between-group analysis).Results:We analyzed 27 patients from the seminal KEYNOTE-001 study (median follow-up of 60.6 months). We demonstrate that blood baseline frequencies of classical monocytes, natural killer (NK) cells, and ICOS+ CD4+ T cells are significantly associated with improved objective response rates, progression-free survival, and overall survival (OS). In addition, we report that a baseline immune peripheral score combining these three populations strongly predicts pembrolizumab efficacy (OS: HR = 0.25; 95% confidence interval = 0.12–0.51; P < 0.0001).Conclusions:As this immune monitoring is easy in routine practice, we anticipate our findings may improve prediction of ICI benefit in patients with advanced NSCLC.

Supplementary Figure 1: Graphical Abstract Supplementary Figure 2: Overall Survival in NSCLC patients treated with pembrolizumab in KEYNOTE-001 according to EGFR mutation Supplementary Figure 3: Recursive partitioning identified classical monocytes and NK as the main immune populations whose frequency splits patients into distinct patterns of overall survival Supplementary Figure 4: Classical monocytes, NK cells and ICOS+ CD4+ T cells are associated with improved pembrolizumab efficacy in advanced NSCLC patients. Supplementary Figure 5: Gating strategy of the 3 main immune populations associated with pembrolizumab efficacy. Supplementary Figure 6: Comparison side by side of Maxstat cut-offs with cut-off from Younden index for overall survival in the 3 populations of interest. Supplementary Figure 7: Survival outcomes in NSCLC patients treated with pembrolizumab in KEYNOTE-001 according to blood baseline frequency of classical monocytes. Supplementary Figure 8: Baseline immune peripheral score is also associated with PFS in melanoma patients treated with PD-1 inhibitors.

Unleashing the immune system to fight cancer has been a major breakthrough in cancer therapeutics since 2014 when anti-PD-1 antibodies (pembrolizumab and nivolumab) were approved for patients with metastatic melanoma. Therapeutic indications have rapidly expanded for many types of advanced cancer, including lung cancer. A variety of antibodies targeting the PD-1/PD-L1 checkpoint are contributing to this paradigm shift. The field now confronts two salient challenges: first, to improve the therapeutic outcome given the low response rate across the histologies; second, to identify biomarkers for improved patient selection. Pre-clinical and clinical studies are underway to evaluate combinatorial treatments to improve the therapeutic outcome paired with correlative studies to identify the factors associated with response and resistance. One of the emerging strategies is to combine epigenetic modifiers with immune checkpoint blockade (ICB) based on the evidence that targeting epigenetic elements can enhance anti-tumor immunity by reshaping the tumor microenvironment (TME). We will briefly review pleotropic biological functions of enhancer of zeste homolog 2 (EZH2), the enzymatic subunit of polycomb repressive complex 2 (PRC2), clinical developments of oral EZH2 inhibitors, and potentially promising approaches to combine EZH2 inhibitors and PD-1 blockade for patients with advanced solid tumors, focusing on lung cancer.

Background: Before immune checkpoint blockade therapy, chemotherapy with pemetrexed maintenance was the standard of care for patients with advanced nonsquamous non-small-cell lung cancer (NSQ-NSCLC) and remains such where immunotherapy is not applicable. This pooled analysis aimed to characterize overall survival (OS) and safety of pemetrexed +/- anti-VEGF maintenance, by treatment duration. Patients and Methods: Data from four randomized clinical trials (PARAMOUNT, PRONOUNCE, PointBreak, JVBL) of patients with NSQ-NSCLC receiving pemetrexed +/- anti-VEGF maintenance therapy were pooled as two groups (Group A: pemetrexed-only maintenance, n=486; and Group B: pemetrexed + anti-VEGF maintenance, n=329). OS and treatment-emergent adverse events (TEAEs) were analyzed in both groups by treatment duration. Results: Baseline characteristics were well balanced between both groups. Median OS did not significantly differ between Group A (16.1 months) and Group B (18.4 months; hazard ratio: 1.17, p-value=0.1417). A correlation between median OS and treatment duration was numerically stronger in Group A (r=0.72) versus B (r=0.62). Across treatment groups, TEAEs were largely grade 1-2 and, with few exceptions, did not increase with increased treatment duration. Conclusion: There was no significant OS difference between pemetrexed-only and pemetrexed ± anti-VEGF maintenance in patients with NSQ-NSCLC. Patients receiving pemetrexed + anti-VEGF experienced a slightly less favorable safety profile with more reported TEAEs compared to pemetrexed monotherapy. Pemetrexed +/- anti-VEGF maintenance therapy may be considered in NSQ-NSCLC, based on an individualized patient approach, particularly where immunotherapy is not clinically indicated.

The aim of this study was to investigate whether three facets of lung cancer stigma (internalized stigma, constrained disclosure, and perceived subtle discrimination) uniquely predicted psychological and physical health-related adjustment to lung cancer across 12 weeks. Additionally, self-compassion was tested as a moderator of the stigma-health relationship.Adults receiving oncologic treatment for lung cancer (N = 108) completed measures of lung cancer stigma, self-compassion, depressive symptoms, cancer-related stress, and physical symptom bother. Multivariable linear regression models were used to investigate cross-sectional and longitudinal relationships (at 6- and 12-week follow-up) between indicators of stigma and health-related outcomes, controlling for covariates. Self-compassion was tested as a moderator of these relationships.At study entry, higher internalized stigma, constrained disclosure, and perceived subtle discrimination were associated significantly and uniquely with higher depressive symptoms (all p.05). Constrained disclosure and perceived subtle discrimination were also associated significantly with higher cancer-related stress and higher physical symptom bother at study entry (all p.05). Furthermore, higher internalized stigma predicted significant increases in depressive symptoms across 12 weeks and in cancer-related stress across 6 and 12 weeks (all p.05). Higher self-compassion significantly moderated relationships between perceived discrimination and psychological health outcomes at study entry as well as between internalized stigma and increasing depressive symptoms across 12 weeks (all p.05).Results indicated robust relationships between distinct facets of stigma and health-related adjustment to lung cancer. Supportive care programs that bolster self-compassion may be useful for reducing lung cancer stigma. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Background and Purpose: Many psychotherapeutic drugs, including clozapine, display polypharmacology and act on GABA receptors. Patients with schizophrenia show alterations in function, structure and molecular composition of the hippocampus, and a recent study demonstrated aberrant levels of hippocampal a5 subunit-containing GABA receptors. The purpose of this study is to investigate tricyclic compounds in a5 subunit-containing receptor subtypes. Experimental Approach: Functional studies of effects by seven antipsychotic and antidepressant medications were performed in several GABA receptor subtypes by two‐electrode voltage‐clamp electrophysiology using Xenopus laevis oocytes. Computational structural analysis was employed to design mutated constructs of the a5 subunit, probing a novel binding site. Radioligand displacement data complemented the functional and mutational findings. Key Results: We show that the antipsychotic drugs clozapine and chlorpromazine exert functional inhibition on multiple GABA receptor subtypes, including a5-containing ones. Based on a chlorpromazine binding site observed in a GABA-gated bacterial homologue, we identified a novel site in a5 GABA receptor subunits and demonstrate differential usage of this and the orthosteric sites by these ligands. Conclusion and Implications: Despite high molecular and functional similarities among the tested ligands, they reduce GABA currents by differential usage of allosteric and orthosteric sites. The C C C C C C site we describe here is a new potential target for optimizing antipsychotic medications with beneficial polypharmacology. Further studies in defined subtypes are needed to substantiate mechanistic links between the therapeutic effects of clozapine and its action on certain GABA receptor subtypes.

Following successful school-based demonstration programs in 2014-2016, the human papillomavirus (HPV) vaccine was introduced nationwide in Senegal for 9-year-old girls in 2018, using a routine service delivery strategy at health facilities, schools, and other outreach sites. We reviewed the HPV vaccine introduction in Senegal to understand the successes, challenges, and lessons learned. Focusing on three key domains (program decision-making, planning, and implementation), we conducted ten semi-structured interviews during 2019-2020 with purposively selected national-level stakeholders (government, expert advisory committee, key technical and implementation partners) and comprehensive desk reviews of country documents on HPV vaccine introduction. Due to the global HPV vaccine shortage, the introduction was limited to a single-age cohort; therefore, 9-year-old girls were chosen. This strategy enabled Senegal to potentially reach more girls in primary education because school enrolment rates decline thereafter. Vaccination through routine delivery platforms (i.e., health facility, school-based, and community outreach) was perceived to be more cost-effective than a campaign approach. High-level political commitment and collaborations between immunization and education partners were frequently cited by key informants as reasons for a successful vaccine introduction. All key informants reported that the health care worker (HCW) strike, rumors, and vaccine hesitancy negatively impacted the introduction. Other challenges noted included insufficient information on attitudes towards HPV vaccination among HCWs, teachers, and community members. Senegal successfully introduced HPV vaccine into the national immunization schedule, using a routine delivery strategy. Strong leadership and a multi-sectoral approach likely contributed to this success. To build sustainability of the HPV vaccination program in the future, it is important to improve the understanding and engagement among all stakeholders, including HCWs and community members, and to strengthen and innovate communication and crisis management strategies. To better understand the efficiency and effectiveness of Senegal's vaccination strategy, additional assessments of the operational costs and coverage achieved are needed.

Purpose:Cell-free DNA (cfDNA) offers a noninvasive approach to monitor cancer. Here we develop a method using whole-exome sequencing (WES) of cfDNA for simultaneously monitoring the full spectrum of cancer treatment outcomes, including minimal residual disease (MRD), recurrence, evolution, and second primary cancers.Experimental Design:Three simulation datasets were generated from 26 patients with cancer to benchmark the detection performance of MRD/recurrence and second primary cancers. For further validation, cfDNA samples (n = 76) from patients with cancer (n = 35) with six different cancer types were used for performance validation during various treatments.Results:We present a cfDNA-based cancer monitoring method, named cfTrack. Taking advantage of the broad genome coverage of WES data, cfTrack can sensitively detect MRD and cancer recurrence by integrating signals across known clonal tumor mutations of a patient. In addition, cfTrack detects tumor evolution and second primary cancers by de novo identifying emerging tumor mutations. A series of machine learning and statistical denoising techniques are applied to enhance the detection power. On the simulation data, cfTrack achieved an average AUC of 99% on the validation dataset and 100% on the independent dataset in detecting recurrence in samples with tumor fractions ≥0.05%. In addition, cfTrack yielded an average AUC of 88% in detecting second primary cancers in samples with tumor fractions ≥0.2%. On real data, cfTrack accurately monitors tumor evolution during treatment, which cannot be accomplished by previous methods.Conclusions:Our results demonstrated that cfTrack can sensitively and specifically monitor the full spectrum of cancer treatment outcomes using exome-wide mutation analysis of cfDNA.

This case is based on the 2020 merger between Callaway Golf Company, a leader in the golf equipment and apparel industry, and Topgolf Entertainment Group, the top entertainment brand in the golf industry. Mergers have been known to provide greater efficiency and profitability, but they can also initiate a clash of corporate cultures, creating conflict which may result in a loss of employee satisfaction and brand equity. Along with reviewing the industry and potential outcomes, students will analyze the viability of this merger by conducting a value chain analysis of both companies to look for product alignment. This decision-based case asks students to play the role of Callaway Golf board member Sophia Berckman, who is preparing to make a statement on the prospective merger of the two companies at an emergency board meeting. As such, students will be expected to formulate a recommendation to the board of directors on whether this is a wise business decision using the information provided.

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