Gas phase hydrogen permeation in alpha titanium and carbon steels

Commercially pure titanium and heats of Armco ingot iron and steels containing from 0.008-1.23 w/oC were annealed or normalized and machined into hollow cylinders. Coefficients of diffusion for alpha-Ti and alpha-Fe were determined by the lag-time technique. Steady state permeation experiments yield first power pressure dependence for alpha-Ti and Sievert's law square root dependence for Armco iron and carbon steels. As in the case of diffusion, permeation data confirm that alpha-titanium is subject to at least partial phase boundary reaction control while the steels are purely diffusion controlled. The permeation rate in steels also decreases as the carbon content increases. As a consequence of Sievert's law, the computed hydrogen solubility decreases as the carbon content increases. This decreases in explained in terms of hydrogen trapping at carbide interfaces. Oxidizing and nitriding the surfaces of alpha-titanium membranes result in a decrease in the permeation rate for such treatment on the gas inlet surfaces but resulted in a slight increase in the rate for such treatment on the gas outlet surfaces. This is explained in terms of a discontinuous TiH2 layer

1544P Pre-treatment CT radiomics predicts survival in chemo-immunotherapy-treated small cell lung cancer

Background: The addition of checkpoint inhibitors to chemotherapy in SCLC patients provides modest benefit, with a median survival of 12 months. Development of non-invasive imaging predictors to identify patients most likely to benefit from chemo-immunotherapy would enable personalized management of SCLC. Methods: A cohort of 31 extensive-stage SCLC patients treated with atezolizumab, carboplatin, and etoposide from June 2020 to May 2021 were identified and pre-treatment CT scans were curated. The axial slice at the level of the carina (S1) was identified and center-cropped. 304 3D radiomic features from 5 slices surrounding S1 were extracted for analysis. After feature selection, the most discriminative radiomic feature was used to train and evaluate a random forest machine classifier for mortality prediction using leave-one-out cross-validation (LOOCV). A baseline classifier was trained using clinical variables. LOOCV mortality probabilities were recorded for each patient and used to stratify patient risk. Overall survival (OS) analysis was performed using Cox modeling. Results: Median follow-up was 343 days. Patient data included median age of 67 (46-85), race (24 white, 7 black), 58% female, and liver metastases at diagnosis in 29%. The Haralick difference variance feature had an AUC of 0.77 (c-index: 0.70) compared to the clinical baseline AUC of 0.56 (c-index: 0.64) for mortality and OS. The radiomic classifier identified low (N=12) and high (N=19) risk cohorts with median OS of 519.5 and 194 days, respectively (p=.01). There was no significant difference in OS for low and high risk cohorts identified by clinical features (p=0.47). Conclusions: Patient survival following chemo-immunotherapy in SCLC can be predicted using computational analysis of pre-treatment images. Our results encourage study of larger patient cohorts to further understand the relationship between imaging signatures and survival in SCLC, potentially leading to improved personalized disease management

CD20+ T Cells in Primary Mediastinal Large B Cell Lymphoma Microenvironment

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153656/1/cytob21832.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153656/2/cytob21832_am.pd

Severe macrothrombocytopenia with platelet CD9 deficiency responsive to romiplostim

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156447/2/bjh16812_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156447/1/bjh16812.pd

Clonal T-cell large granular lymphocyte proliferations in childhood and young adult immune dysregulation conditions

BackgroundProliferation of large granular lymphocytes (LGL) and T- cell LGL (T- LGL) in peripheral blood along with demonstration of clonality are the hallmarks of a heterogeneous group of disorders, including T- LGL leukemia or T- LGL lymphocytosis. They are often associated with neutropenia and responsive to immunosuppression. The true nature of this entity is not well understood. Some cases are reported as reactive phenomena with very limited experience in pediatric population.MethodsHematology/Oncology Flow Cytometry Laboratory database has been reviewed retrospectively. Patients with identifiable distinct CD5- dim T- cell population and positive clonal T- cell receptor rearrangement were included in the analysis. Clinical and laboratory data were then reviewed.ResultsSixteen cases of children and young adults with increased peripheral blood clonal T- LGL population characterized by dim CD5 expression with wide range of underlying immune dysregulation/stimulation disorders were reviewed. Extended follow up with repeat testing suggested the reactive nature of persistent clonal T- LGL proliferations in this group.ConclusionsOur observations indicate that clonal T- LGL proliferations in children and young adults are reactive in nature and some can be persistent with an indolent course with unknown consequentiality. Clonal T- LGL cells could be targeting the most prominent immunogenic stressor(s) involved as a control mechanism.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154679/1/pbc28231.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154679/2/pbc28231_am.pd

Pembrolizumab Plus Pemetrexed and Platinum in Nonsquamous Non–Small-Cell Lung Cancer: 5-Year Outcomes From the Phase 3 KEYNOTE-189 Study

Pembrolizumab; Non-small-cell lung cancerPembrolizumab; Cáncer de pulmón de células no pequeñasPembrolizumab; Càncer de pulmó de cèl·lules no petitesClinical 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

Up-Regulation of Sonic Hedgehog Contributes to TGF-β1-Induced Epithelial to Mesenchymal Transition in NSCLC Cells

BACKGROUND:Lung cancer, especially non-small cell lung cancer (NSCLC) is the major cause of cancer-related deaths in the United States. The aggressiveness of NSCLC has been shown to be associated with the acquisition of epithelial-to-mesenchymal transition (EMT). The acquisition of EMT phenotype induced by TGF-β1in several cancer cells has been implicated in tumor aggressiveness and resistance to conventional therapeutics; however, the molecular mechanism of EMT and tumor aggressiveness in NSCLC remains unknown. METHODOLOGY/PRINCIPAL FINDINGS:In this study we found for the first time that the induction of EMT by chronic exposure of A549 NSCLC cells to TGF-β1 (A549-M cells) led to the up-regulation of sonic hedgehog (Shh) both at the mRNA and protein levels causing activation of hedgehog signaling. These results were also reproduced in another NSCLC cell line (H2030). Induction of EMT was found to be consistent with aggressive characteristics such as increased clonogenic growth, cell motility and invasion. The aggressiveness of these cells was attenuated by the treatment of A549-M cells with pharmacological inhibitors of Hh signaling in addition to Shh knock-down by siRNA. The inhibition of Hh signaling by pharmacological inhibitors led to the reversal of EMT phenotype as confirmed by the reduction of mesenchymal markers such as ZEB1 and Fibronectin, and induction of epithelial marker E-cadherin. In addition, knock-down of Shh by siRNA significantly attenuated EMT induction by TGF-β1. CONCLUSIONS/SIGNIFICANCE:Our results show for the first time the transcriptional up-regulation of Shh by TGF-β1, which is mechanistically associated with TGF-β1 induced EMT phenotype and aggressive behavior of NSCLC cells. Thus the inhibitors of Shh signaling could be useful for the reversal of EMT phenotype, which would inhibit the metastatic potential of NSCLC cells and also make these tumors more sensitive to conventional therapeutics

Atezolizumab versus chemotherapy in advanced or metastatic NSCLC with high blood-based tumor mutational burden: primary analysis of BFAST cohort C randomized phase 3 trial

Non-small-cell lung cancer; Predictive markersCàncer de pulmó de cèl·lules no petites; Marcadors predictiusCáncer de pulmón de células no pequeñas; Marcadores predictivosTumor mutational burden (TMB) is being explored as a predictive biomarker for cancer immunotherapy outcomes in non-small cell lung cancer. BFAST (NCT03178552)—an open-label, global, multicohort trial—evaluated the safety and efficacy of first-line targeted therapies or immunotherapy in patients with unresectable Stage IIIB or IV advanced or metastatic non-small cell lung cancer who were selected for biomarker status using blood-based targeted next-generation sequencing. In the Phase 3 cohort C evaluating blood-based (b)TMB as a biomarker of atezolizumab efficacy, patients with bTMB of ≥10 (N = 471) were randomized 1:1 to receive atezolizumab or platinum-based chemotherapy per local standard of care. Cohort C did not meet its primary endpoint of investigator-assessed progression-free survival in the population with bTMB of ≥16 (hazard ratio, 0.77; 95% confidence interval: 0.59, 1.00; P = 0.053). Adverse events leading to treatment withdrawal occurred in 10% of patients in the atezolizumab arm and 20% in the chemotherapy arm. Adverse events of special interest occurred in 42% of patients in the atezolizumab arm and 26% in the chemotherapy arm. A prespecified exploratory analysis compared the bTMB clinical trial assay with the FoundationOne Liquid Companion Diagnostic assay and showed high concordance between assays. Additional exploration of bTMB to identify optimal cutoffs, confounding factors, assay improvements or cooperative biomarkers is warranted

Associations of Tissue Tumor Mutational Burden and Mutational Status With Clinical Outcomes With Pembrolizumab Plus Chemotherapy Versus Chemotherapy For Metastatic NSCLC

Biomarker; Pembrolizumab; Tissue tumor mutational burdenBiomarcador; Pembrolizumab; Càrrega mutacional del tumor tissularBiomarcador; Pembrolizumab; Carga mutacional del tumor tisularIntroduction We evaluated tissue tumor mutational burden (tTMB) and mutations in STK11, KEAP1, and KRAS as biomarkers for outcomes with pembrolizumab plus platinum-based chemotherapy (pembrolizumab-combination) for NSCLC among patients in the phase 3 KEYNOTE-189 (ClinicalTrials.gov, NCT02578680; nonsquamous) and KEYNOTE-407 (ClinicalTrials.gov, NCT02775435; squamous) trials. Methods This retrospective exploratory analysis evaluated prevalence of high tTMB and STK11, KEAP1, and KRAS mutations in patients enrolled in KEYNOTE-189 and KEYNOTE-407 and the relationship between these potential biomarkers and clinical outcomes. tTMB and STK11, KEAP1, and KRAS mutation status was assessed using whole-exome sequencing in patients with available tumor and matched normal DNA. The clinical utility of tTMB was assessed using a prespecified cutpoint of 175 mutations/exome. Results Among patients with evaluable data from whole-exome sequencing for evaluation of tTMB (KEYNOTE-189, n = 293; KEYNOTE-407, n = 312) and matched normal DNA, no association was found between continuous tTMB score and overall survival (OS) or progression-free survival for pembrolizumab-combination (Wald test, one-sided p > 0.05) or placebo-combination (Wald test, two-sided p > 0.05) in patients with squamous or nonsquamous histology. Pembrolizumab-combination improved outcomes for patients with tTMB greater than or equal to 175 compared with tTMB less than 175 mutations/exome in KEYNOTE-189 (OS, hazard ratio = 0.64 [95% confidence interval (CI): 0.38‒1.07] and 0.64 [95% CI: 0.42‒0.97], respectively) and KEYNOTE-407 (OS, hazard ratio = 0.74 [95% CI: 0.50‒1.08 and 0.86 [95% CI: 0.57‒1.28], respectively) versus placebo-combination. Treatment outcomes were similar regardless of KEAP1, STK11, or KRAS mutation status. Conclusions These findings support pembrolizumab-combination as first-line treatment in patients with metastatic NSCLC and do not suggest the utility of tTMB, STK11, KEAP1, or KRAS mutation status as a biomarker for this regimen.All authors’ institutions received research funding from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, for the conduct of this study

1317P Renal toxicity in black patients with non-squamous non-small cell lung cancer treated with combination platinum-pemetrexed-pembrolizumab therapy

Background: In Keynote 189, an increased incidence of renal toxicity was observed with combination platinum-pemetrexed-pembrolizumab (PPP) therapy compared to chemotherapy alone. Studies have shown that compared to White Americans, Black Americans are at higher risk of morbidity and mortality associated with chronic kidney disease (CKD). We conducted a retrospective analysis of patients treated with PPP to assess the rate of renal toxicity in Black and White patients. Methods: Data of self-identified non-hispanic (NH) Black and NH White patients with advanced NS-NSCLC who were treated with PPP between January 1, 2017, and November 1, 2020, at the Henry Ford Health System was analyzed. Serum creatinine (Cr) and calculated glomerular filtration rate (GFR) before the first cycle of PPP and over the duration of PPP therapy were assessed. Acute kidney injury (AKI) was defined as an increase in Cr 1.5 times the baseline value. Reduction in GFR of ≥ 30% was considered significant. Multiple variables and outcomes were analyzed by two-group comparisons, univariate analysis, and Cox regression. Results: A total of 134 patients were included in the analysis. The mean age was 66.5 (SD 8.6) years, and 65 (48.5%) patients were men. A total of 33 (24%) patients were NH Black and 101 (75.4%) were NH White. There were 10 (8.1%) patients who developed AKI, and the median time to development of AKI was 4.5 months. No significant association of Black (3) or White (7) ethnicity with AKI was observed (p =.57). The odds of developing AKI was not increased in patients with a history of hypertension (p =.67), diabetes mellitus (p =.33), cardiovascular disease (p =.68), or CKD (p =.33). A total of 17 out of 127 (13.4%) patients had significantly reduced GFR, and patients with CKD were more likely to have reduced GFR (OR 4.8, p =.02). At the median follow-up of 24.5 months, the median survival was 15.2 months (95% CI, 12.7-22.2). Black ethnicity (HR 1.21, p =.46) and development of AKI (HR 1.13; 95% CI, 0.45–2.86) were not associated with increased mortality. Conclusions: Black patients with NS-NSCLC treated with PPP are not at higher risk of AKI or death than White patients. Development of AKI after PPP therapy was not associated with increased mortality