SKYSCRAPER-02: Tiragolumab in Combination With Atezolizumab Plus Chemotherapy in Untreated Extensive-Stage Small-Cell Lung Cancer

Tiragolumab; Chemotherapy; Small-cell lung cancerTiragolumab; Quimioteràpia; Càncer de pulmó de cèl·lules petitesTiragolumab; Quimioterapia; Cáncer de pulmón de células pequeñasPurpose The phase III SKYSCRAPER-02 study determined whether the benefits of atezolizumab plus carboplatin and etoposide (CE) could be enhanced by the addition of tiragolumab in untreated extensive-stage small-cell lung cancer (ES-SCLC). We report final progression-free survival (PFS) and overall survival (OS) analyses. Methods Patients received tiragolumab 600 mg/placebo, plus atezolizumab 1,200 mg and CE (four cycles), then maintenance tiragolumab/placebo plus atezolizumab. Primary end points were investigator-assessed PFS and OS in patients without history/presence of brain metastases (primary analysis set [PAS]). Additional end points included PFS and OS in all patients regardless of brain metastases status (full analysis set [FAS]), response, and safety. Results Four hundred ninety patients were randomly assigned (FAS): 243 to tiragolumab arm and 247 to control arm. At the cutoff date (February 6, 2022; median duration of follow-up, 14.3 months [PAS] and 13.9 months [FAS]), final analysis of PFS in the PAS (n = 397) did not reach statistical significance (stratified hazard ratio [HR], 1.11; P = .3504; median, 5.4 months tiragolumab v 5.6 months control). At the cutoff date (September 6, 2022; median duration of follow-up, 21.2 months [FAS]), median OS in the PAS at final OS analysis was 13.1 months in both arms (stratified HR, 1.14; P = .2859). Median PFS and OS in the FAS were consistent with the PAS. The proportion of patients with immune-mediated adverse events (AEs) in the tiragolumab and control arms was 54.4% and 49.2%, respectively (grade 3/4: 7.9% and 7.7%). AEs leading to treatment withdrawal occurred in 8.4% and 9.3% of tiragolumab- and control-treated patients, respectively. Conclusion Tiragolumab did not provide additional benefit over atezolizumab and CE in untreated ES-SCLC. The combination was well tolerated with no new safety signals.Supported by Genentech Inc and F. Hoffmann-La Roche Ltd. C.M.D.'s work on small cell lung cancer is supported by NIH R35CA263816, U24CA13274, and P30CA008748

Local Behavior of Sparse Analysis Regularization: Applications to Risk Estimation

In this paper, we aim at recovering an unknown signal x0 from noisy L1measurements y=Phi*x0+w, where Phi is an ill-conditioned or singular linear operator and w accounts for some noise. To regularize such an ill-posed inverse problem, we impose an analysis sparsity prior. More precisely, the recovery is cast as a convex optimization program where the objective is the sum of a quadratic data fidelity term and a regularization term formed of the L1-norm of the correlations between the sought after signal and atoms in a given (generally overcomplete) dictionary. The L1-sparsity analysis prior is weighted by a regularization parameter lambda>0. In this paper, we prove that any minimizers of this problem is a piecewise-affine function of the observations y and the regularization parameter lambda. As a byproduct, we exploit these properties to get an objectively guided choice of lambda. In particular, we develop an extension of the Generalized Stein Unbiased Risk Estimator (GSURE) and show that it is an unbiased and reliable estimator of an appropriately defined risk. The latter encompasses special cases such as the prediction risk, the projection risk and the estimation risk. We apply these risk estimators to the special case of L1-sparsity analysis regularization. We also discuss implementation issues and propose fast algorithms to solve the L1 analysis minimization problem and to compute the associated GSURE. We finally illustrate the applicability of our framework to parameter(s) selection on several imaging problems

Treatment of Small-Cell Lung Cancer: American Society of Clinical Oncology Endorsement of the American College of Chest Physicians Guideline

PURPOSE: The American College of Chest Physicians (ACCP) produced an evidence-based guideline on treatment of patients with small-cell lung cancer (SCLC). Because of the relevance of this guideline to American Society of Clinical Oncology (ASCO) membership, ASCO reviewed the guideline, applying a set of procedures and policies used to critically examine guidelines developed by other organizations. METHODS: The ACCP guideline on the treatment of SCLC was reviewed for developmental rigor by methodologists. An ASCO Endorsement Panel updated the literature search, reviewed the content, and considered additional recommendations. RESULTS: The ASCO Endorsement Panel determined that the recommendations from the ACCP guideline, published in 2013, are clear, thorough, and based on current scientific evidence. ASCO endorses the ACCP guideline on the treatment of SCLC, with the addition of qualifying statements. RECOMMENDATIONS: Surgery is indicated for selected stage I SCLC. Limited-stage disease should be treated with concurrent chemoradiotherapy in patients with good performance status. Thoracic radiotherapy should be administered early in the course of treatment, preferably beginning with cycle one or two of chemotherapy. Chemotherapy should consist of four cycles of a platinum agent and etoposide. Extensive-stage disease should be treated primarily with chemotherapy consisting of a platinum agent plus etoposide or irinotecan. Prophylactic cranial irradiation prolongs survival in patients with limited-stage disease who achieve a complete or partial response to initial therapy and may do so in similarly responding patients with extensive-stage disease as well. Additional information is available at http://www.asco.org/endorsements/sclc and http://www.asco.org/guidelineswiki

Inhibition of glycolysis modulates prednisolone resistance in acute lymphoblastic leukemia cells

Treatment failure in pediatric acute lymphoblastic leukemia (ALL) is related to cellular resistance to glucocorticoids (eg, prednisolone). Recently, we demonstrated that genes associated with glucose metabolism are differentially expressed between prednisolone-sensitive and prednisolone-resistant precursor B-lineage leukemic patients. Here, we show that prednisolone resistance is associated with increased glucose consumption and that inhibition of glycolysis sensitizes prednisolone-resistant ALL cell lines to glucocorticoids. Treatment of prednisolone-resistant Jurkat and Molt4 cells with 2-deoxy-D-glucose (2-DG), lonidamine (LND), or3-bromopyruvate (3-BrPA) increased the in vitro sensitivity to glucocorticoids, while treatment of the prednisolone-sensitive cell lines Tom-1 and RS4; 11 did not influence drug cyto-toxicity. This sensitizing effect of the glycolysis inhibitors in glucocorticoid-resistant ALL cells was not found for other classes of antileukemic drugs (ie, vincris-tine and daunorubicin). Moreover, down-regulation of the expression of GAPDH by RNA interference also sensitized to prednisolone, comparable with treatment with glycolytic inhibitors. Importantly, the ability of 2-DG to reverse glucocorticoid resistance was not limited to cell lines, but was also observed in isolated primary ALL cells from patients. Together, these findings indicate the importance of the glycolytic pathway in glucocorticoid resistance in ALL and suggest that targeting glycolysis is a viable strategy for modulating prednisolone resistance in ALL

Alterations of immune response of non-small lung cancer with azacytidine

Innovative therapies are needed for advanced Non-Small Cell Lung Cancer (NSCLC). We have undertaken a genomics based, hypothesis driving, approach to query an emerging potential that epigenetic therapy may sensitize to immune checkpoint therapy targeting PD-L1/PD-1 interaction. NSCLC cell lines were treated with the DNA hypomethylating agent azacytidine (AZA - Vidaza) and genes and pathways altered were mapped by genome-wide expression and DNA methylation analyses. AZA-induced pathways were analyzed in The Cancer Genome Atlas (TCGA) project by mapping the derived gene signatures in hundreds of lung adeno (LUAD) and squamous cell carcinoma (LUSC) samples. AZA up-regulates genes and pathways related to both innate and adaptive immunity and genes related to immune evasion in a several NSCLC lines. DNA hypermethylation and low expression of IRF7, an interferon transcription factor, tracks with this signature particularly in LUSC. In concert with these events, AZA up-regulates PD-L1 transcripts and protein, a key ligand-mediator of immune tolerance. Analysis of TCGA samples demonstrates that a significant proportion of primary NSCLC have low expression of AZA-induced immune genes, including PD-L1. We hypothesize that epigenetic therapy combined with blockade of immune checkpoints - in particular the PD-1/PD-L1 pathway - may augment response of NSCLC by shifting the balance between immune activation and immune inhibition, particularly in a subset of NSCLC with low expression of these pathways. Our studies define a biomarker strategy for response in a recently initiated trial to examine the potential of epigenetic therapy to sensitize patients with NSCLC to PD-1 immune checkpoint blockade

N-Linked Glycosylation on Anthrax Toxin Receptor 1 Is Essential for Seneca Valley Virus Infection

Seneca Valley virus (SVV) is a picornavirus with potency in selectively infecting and lysing cancerous cells. The cellular receptor for SVV mediating the selective tropism for tumors is anthrax toxin receptor 1 (ANTXR1), a type I transmembrane protein expressed in tumors. Similar to other mammalian receptors, ANTXR1 has been shown to harbor N-linked glycosylation sites in its extracellular vWA domain. However, the exact role of ANTXR1 glycosylation on SVV attachment and cellular entry was unknown. Here we show that N-linked glycosylation in the ANTXR1 vWA domain is necessary for SVV attachment and entry. In our study, tandem mass spectrometry analysis of recombinant ANTXR1-Fc revealed the presence of complex glycans at N166, N184 in the vWA domain, and N81 in the Fc domain. Symmetry-expanded cryo-EM reconstruction of SVV-ANTXR1-Fc further validated the presence of N166 and N184 in the vWA domain. Cell blocking, co-immunoprecipitation, and plaque formation assays confirmed that deglycosylation of ANTXR1 prevents SVV attachment and subsequent entry. Overall, our results identified N-glycosylation in ANTXR1 as a necessary post-translational modification for establishing stable interactions with SVV. We anticipate our findings will aid in selecting patients for future cancer therapeutics, where screening for both ANTXR1 and its glycosylation could lead to an improved outcome from SVV therapy

A mobile health + health coaching application for the management of chronic non-cancer pain in older adults: Results from a pilot randomized controlled study

IntroductionThe rapid growth of mobile health (mHealth) devices holds substantial potential for improving care and care outcomes in aging adults with chronic non-cancer pain (CNCP), however, research evaluating these devices in older adults remains limited.ObjectiveTo ascertain the feasibility and preliminary efficacy of an mHealth intervention (Mymee) that combines symptom, diet, and behavior tracking via a smartphone application with data analytics to detect associations between symptoms and lifestyle factors along with weekly health coaching sessions to mitigate CNCP in adults 55 years of age and older.MethodsParticipants (N = 31) in this pilot study were recruited from one primary care practice in New York City and randomized to an intervention [app + up to 12 health coaching sessions (scheduled approximately once weekly) + usual care] or a control (app + usual care) arm. Feasibility measures included recruitment (proportion of eligible persons who enrolled) and retention rates (proportion of subjects completing a follow-up assessment) as well as adherence with the weekly coaching sessions and logging daily data on the app. Efficacy outcomes (e.g., pain intensity, self-efficacy, disability, anxiety) were assessed at baseline and follow-up (~16 weeks after baseline). Descriptive statistics were obtained and general linear mixed models used for primary analyses.ResultsParticipants had a mean (standard deviation) age of 67.32 (9.17) and were mostly female (61%). Feasibility outcomes were mixed as evidenced by recruitment and retention rates of 74% and 65%, respectively. The mean number of weekly coaching sessions attended by intervention participants was 6.05 (SD = 5.35), while the average number of days logging data on the app was 44.82 (34.02). We found a consistent trend in favor of the intervention, where pain intensity, affect, and quality of life measures improved considerably more among intervention (vs. control) participants. Finally, the proportion of participants with GAD-7 scores at follow up decreased by 0.35 to 0, whereas controls did not change, a significant effect in favor of the intervention (p = 0.02).ConclusionsThis study supports the need for future research that seeks to enhance feasibility outcomes and confirm the efficacy of the Mymee intervention among aging adults with CNCP

第647回千葉医学会例会・第5回千葉大学小児外科教室例会 6.

<p>(A) A schematic describing the experimental process used to test the four cell separation techniques. A single tumor from each PDX line was processed using a gentleMACS^™ Octo Dissociator to obtain a single cell suspension comprising a heterogeneous mixture of human cells (blue) and mouse cells (orange). The suspension was divided in five samples. The pre-sort sample received no further processing. The remaining 4 tubes were processed using each method to obtain separate human and mouse cell populations. Each resulting human fraction and the pre-sort sample were analyzed using ssPAL. (B) ssPAL analysis results for primer pair 5 and 43 were averaged together to obtain the human DNA percentage for each separation method. After performing ssPAL analysis, results indicate that on average, MCD yields the highest sample purity over FACS, EpCAM-M and EpCAM-SC. The starting amount of murine stromal contamination also influences the effectiveness of the kit used, with EpCAM-M and EpCAM-SC performing poorly with higher initial murine content. Error bars represent standard error.</p