Global prognostic impact of driver genetic alterations in patients with lung adenocarcinoma: a real-life study

Background Advanced lung adenocarcinoma (LAC) is one of the most lethal malignancies worldwide. The aim of this study was to evaluate the global survival in a real-life cohort of patients with LAC harboring driver genetic alterations. Methods A series of 1282 consecutive Sardinian LAC patients who underwent genetic testing from January 2011 through July 2016 was collected. Molecular tests were based on the clinical needs of each single case (EGFR-exon18/19/21, ALK, and, more recently, BRAF-exon15), and the availability of tissue (KRAS, MET, and presence of low-frequency EGFR-T790M mutated alleles at baseline). Results The mean follow-up time of the patients was 46 months. EGFR, KRAS, and BRAF mutations were detected in 13.7%, 21.3%, and 3% of tested cases, respectively; ALK rearrangements and MET amplifications were found respectively in 4.7% and 2% of tested cases. As expected, cases with mutations in exons 18–21 of EGFR, sensitizing to anti-EGFR tyrosine kinase inhibitors (TKIs) agents, had a significantly longer survival in comparison to those without (p < 0.0001); conversely, KRAS mutations were associated with a significantly lower survival (p = 0.0058). Among LAC patients with additional tissue section available for next-generation sequencing (NGS)-based analysis, 26/193 (13.5%) patients found positive for even low-rate EGFR-T790M mutated alleles at baseline were associated with a highly significant lower survival in comparison to those without (8.7 vs. 47.4 months, p < 0.0001). Conclusions In addition to its predictive value for addressing targeted therapy approaches, the assessment of as more inclusive mutation analysis at baseline may provide clues about factors significantly impacting on global survival in advanced LAC patients.

Combined mRNAs and clinical factors model on predicting prognosis in patients with triple-negative breast cancer

Objective Triple-negative breast cancer (TNBC) is aggressive cancer usually diagnosed in young women with no effective prognosis prediction model to use. The present study was performed to develop a useful prognostic model for predicting overall survival (OS) for TNBC patients. Methods The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) databases were used as training and validation data sets, respectively, in which the gene expression levels and clinical prognostic information of TNBC were collected. Differentially expressed genes (DEGs) between TNBC and non-TNBC (NTNBC) were identified with the thresholds of false discovery rate < 0.05 and |log2 Fold Change| > 1. DEGs in AmiGO2 and the Kyoto Encyclopedia of Genes and Genomes (KEGG) databases were retained for further study. Univariate, multivariate Cox, and logistic regression analysis were conducted for detecting DEG signature with the threshold of log-rank P < 0.05. The prognosis models of mRNA signature, clinical factors were constructed and compared. Results One five-DEG signature, including CHST4, COCH, CST9, SOX11, and TDGF1 was identified in DEG prognosis model. Stratified analysis showed that the patients aged over 60, with higher pathologic stage (III-IV) and recurrence induced a significantly lower survival rate than those aged below 60, lower pathologic stage and without recurrence. Compared with patients with low-risk scores, those presented high-risk scores demonstrated significantly lower survival rate in the subgroup aged over 60 [HR = 3.780 (1.801–7.933), P < 0.0001]. For patients who obtained a higher pathologic stage and recurrence, high-risk scores were correlated with a significantly lower survival rate than patients with low-risk scores. The five-mRNA signature combined with clinical model (AUC = 0.950) predicted better than single clinical model (AUC = 0.795) or five-mRNA signature model (AUC = 0.823). Conclusion Our present study identified a prognostic prediction model (combined with five-mRNA signature and clinical factors) for TNBC patients receiving immunotherapy, which will benefit future research and clinical therapies.

Offspring of first-generation hatchery steelhead trout (Oncorhynchus mykiss) grow faster in the hatchery than offspring of wild fish, but survive worse in the wild: Possible mechanisms for inadvertent domestication and fitness loss in hatchery salmon

Salmonid fish raised in hatcheries often have lower fitness (number of returning adult offspring) than wild fish when both spawn in the wild. Body size at release from hatcheries is positively correlated with survival at sea. So one explanation for reduced fitness is that hatcheries inadvertently select for trait values that enhance growth rate under the unnatural environment of a hatchery, but that are maladaptive in the wild environment. A simple prediction of this hypothesis is that juveniles of hatchery origin should grow more quickly than fish of wild origin under hatchery conditions, but should have lower survival under wild conditions. We tested that hypothesis using multiple full sibling families of steelhead (Oncorhynchus mykiss) that were spawned using either two wild parents (WxW) or two first-generation hatchery (HxH) parents. Offspring from all the families were grown together under hatchery conditions and under semi-natural conditions in artificial streams. HxH families grew significantly faster in the hatchery, but had significantly lower survival in the streams. That we see this tradeoff after only a single generation of selection suggests that the traits involved are under very strong selection. We also considered one possible alteration to the hatchery environment that might reduce the intensity of selection among families in size at release. Here we tested whether reducing the fat content of hatchery feed would reduce the variance among families in body size. Although fish raised under a low-fat diet were slightly smaller, the variation among families in final size was unchanged. Thus, there is no evidence that reducing the fat content of hatchery feed would reduce the opportunity for selection among families on size at release.

591 Survival rates in Stage IV melanoma patients treated with radiation and immunotherapy differ depending on age and radiation treatment site

BackgroundMelanoma is difficult to treat due to its propensity of evading the immune system. Radiation can be combined with immune checkpoint inhibitors to potentially prolong survival. Radiation has been shown to reduce tumor sizes both at the site of radiation and at non-irradiated lesions, also known as the abscopal effect. However, the interaction of immunotherapy and radiation treatment in melanoma cancer is not well-defined. This study seeks to better characterize factors influencing survival in Stage IV melanoma patients treated with both radiation and immunotherapy.MethodsRetrospective data was collected from melanoma patients receiving both radiation and immunotherapy within 6 months of each other between 2008–2021 at our institution. Patient and treatment characteristics were examined for their influence on overall survival and progression-free survival using the log-rank test on Kaplan Meier survival curves. Radiographic response was assessed according to PERCIST/RECIST criteria and analyzed against patient/treatment characteristics using the Mann-Whitney U Test. For the abscopal effect, the percent changes both before and after radiation treatment were subtracted in non-irradiated lesions to produce a ”delta-delta” percent change to reflect the rate of change in tumor response to radiation treatment.ResultsYounger patients trended towards worse overall (p=0.141) and progression free (p=0.06) survival as well as less favorable PERCIST/RECIST response to radiation (p=.0562) compared to older patients. Combination CTLA-4 and PD-1 inhibition therapy tended to produce better PERCIST/RECIST tumor response (p=0.09), but it did not significantly affect survival times. In addition, there was some lower overall (p=0.22) and significantly lower progression free (p=0.012) survival among patients with intracranial irradiated lesions. However, no difference was found in PERCIST/RECIST response in the irradiated lesions between the intra- or extracranial groups. Non-irradiated lesions in patients with extracranial irradiated lesions had a pattern of less favorable rate of change in tumor size (p=0.16).ConclusionsLower survival times in younger patients is unexpected and may reflect differences in immunotherapy response in patients receiving both radiotherapy and immunotherapy, which requires further investigation. Combination CTLA-4 and PD-1 inhibition therapy correlating with better tumor response confirms the effect is still present in this cohort receiving radiotherapy. The lower survival times among intracranial lesion patients is most likely due to lower expectancy of brain metastasized patients; however, it could also be the brain is less responsive to immunotherapy. Further research in a larger cohort is needed for deeper analysis, but this series is still comparable in size to other published series.Ethics ApprovalThis retrospective review was approved by the University IRB, UMCIRB 15-001726. Consent of participants was waived due to the retrospective nature of this review.

Socioeconomic factors and outcomes from exercise-related sudden cardiac arrest in high school student-athletes in the USA

ObjectiveMinority student-athletes have a lower survival rate from sudden cardiac arrest (SCA) than non-minority student-athletes. This study examined the relationship between high school indicators of socioeconomic status (SES) and survival in student-athletes with exercise-related SCA.MethodsHigh school student-athletes in the USA with exercise-related SCA on school campuses were prospectively identified from 1 July 2014 to 30 June 2018 by the National Center for Catastrophic Sports Injury Research. High school indicators of SES included the following: median household and family income, proportion of students on free/reduced lunch and percent minority students. Resuscitation details included witnessed arrest, presence of an athletic trainer, bystander cardiopulmonary resuscitation and use of an on-site automated external defibrillator (AED). The primary outcome was survival to hospital discharge. Differences in survival were analysed using risk ratios (RR) and univariate general log-binomial regression models.ResultsOf 111 cases identified (mean age 15.8 years, 88% male, 49% white non-Hispanic), 75 (68%) survived. Minority student-athletes had a lower survival rate compared with white non-Hispanic student-athletes (51.1% vs 75.9%; RR 0.67, 95% CI 0.49 to 0.92). A non-significant monotonic increase in survival was observed with increasing median household or family income and with decreasing percent minority students or proportion on free/reduced lunch. The survival rate was 83% if an athletic trainer was on-site at the time of SCA and 85% if an on-site AED was used.ConclusionsMinority student-athletes with exercise-related SCA on high school campuses have lower survival rates than white non-Hispanic athletes, but this difference is not fully explained by SES markers of the school.

High expression levels and the C3435T SNP of the ABCB1 gene are associated with lower survival in adult patients with acute myeloblastic leukemia in Mexico City

Background Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by different genetic alterations that cause changes in the normal mechanisms of differentiation, which are associated with chemoresistance. The ABCB1 gene is part of a family of ATP-binding cassette (ABC) transporter genes involved in the progression of various types of cancer. The following work aimed to evaluate the expression levels of the ABCB1 gene and the C3435T SNP with the response to first-line treatment and survival in patients with AML. Methods In total 135 samples were taken to isolate total RNA and DNA at the beginning of the treatment. Expression analysis by RT-qPCR and SNP C3435T assessment method were performed for real-time Polymerase chain reaction (qPCR). Results The expression levels impact on the survival of patients with AML compared to low or absent levels; the CC genotype was found in 22.9%, the CT genotype was found in 47.4%, and the TT genotype was found in 29.6%, the presence of the C3435T SNP, the TT genotype also impacts with a lower survival compared to CT and CC genotypes. In addition, it was shown that the dominant model significantly impacts survival. Conclusion In conclusion, we have found that the overexpression of the ABCB1 gene, as well as the presence of the TT genotype of the C3435T SNP, contributes to a worse prognosis in AML.

ASXL1 and STAG2 are Common Mutations in GATA2 Deficiency Patients with Bone Marrow Disease and Myelodysplastic Syndrome

GATA2 Deficiency patients harbor de novo or inherited germline mutations in the GATA2 transcription factor gene, predisposing them to myeloid malignancies. There is considerable variation in disease progression, even among family members with the same mutation in GATA2. We investigated somatic mutations in 106 patients with GATA2 Deficiency to identify acquired mutations that are associated with myeloid malignancies. Myelodysplastic Syndrome (MDS) was the most common diagnosis (~44%), followed by GATA2 bone marrow immunodeficiency disorder (G2BMID) (~37%). Thirteen percent of the cohort had GATA2 mutations but displayed no disease manifestations. There were no correlations between patient age or sex with disease progression or survival. Cytogenetic analyses showed a high incidence of abnormalities (~43%)- notably trisomy 8 (~23%) and monosomy 7 (~12%), but these changes did not correlate with lower survival. Somatic mutations in ASXL1 and STAG2 were detected in ~25% of patients, though these mutations were rarely concomitant. Mutations in DNMT3A were found in ~10% of patients. These somatic mutations were found similarly in G2BMID and MDS, suggesting clonal hematopoiesis in early stages of disease, before the onset of MDS. ASXL1 mutations conferred a lower survival probability and were more prevalent in female patients. STAG2 mutations also conferred a lower survival probability, but did not show a statistically significant sex bias. There was a conspicuous absence of many commonly mutated genes associated with myeloid malignancies, including TET2, IDH1/2, and the splicing factor genes. Notably, somatic mutations in chromatin-related genes and cohesin genes characterized disease progression in GATA2 Deficiency

The age distribution of business firms

We investigate upon the shape and the determinants of the age distribution of business firms. By employing a novel dataset covering the population of French businesses, we highlight that a geometric law provides a reasonable approximation for the age distribution. However, relevant systematic deviations and sectoral heterogeneity appear. We develop a stochastic model of firm dynamics to explain the mechanisms behind this evidence and relate them to business dynamism. Results reveal a long-term decline in entry rates and lower survival probabilities of young firms. Our findings bear important implications for aggregate outcomes, notably employment growth.

Epidemiology of Geographic Disparities of Myocardial Infarction Among Older Adults in the United States: Analysis of 2000–2017 Medicare Data

Background: There are substantial geographic disparities in the life expectancy (LE) across the U.S. with myocardial infarction (MI) contributing significantly to the differences between the states with highest (leading) and lowest (lagging) LE. This study aimed to systematically investigate the epidemiology of geographic disparities in MI among older adults.Methods: Data on MI outcomes among adults aged 65+ were derived from the Center for Disease Control and Prevention-sponsored Wide-Ranging Online Data for Epidemiologic Research database and a 5% sample of Medicare Beneficiaries for 2000–2017. Death certificate-based mortality from MI as underlying/multiple cause of death (CBM-UCD/CBM-MCD), incidence-based mortality (IBM), incidence, prevalence, prevalence at age 65, and 1-, 3-, and 5-year survival, and remaining LE at age 65 were estimated and compared between the leading and lagging states. Cox model was used to investigate the effect of residence in the lagging states on MI incidence and survival.Results: Between 2000 and 2017, MI mortality was higher in the lagging than in the leading states (per 100,000, CBM-UCD: 236.7–583.7 vs. 128.2–357.6, CBM-MCD: 322.7–707.7 vs. 182.4–437.7, IBM: 1330.5–1518.9 vs. 1003.3–1197.0). Compared to the leading states, lagging states had higher MI incidence (1.1–2.0% vs. 0.9–1.8%), prevalence (10.2–13.1% vs. 8.3–11.9%), pre-existing prevalence (2.5–5.1% vs. 1.4–3.6%), and lower survival (70.4 vs. 77.2% for 1-year, 63.2 vs. 67.2% for 3-year, and 52.1 vs. 58.7% for 5-year), and lower remaining LE at age 65 among MI patients (years, 8.8–10.9 vs. 9.9–12.8). Cox model results showed that the lagging states had greater risk of MI incidence [Adjusted hazards ratio, AHR (95% Confidence Interval, CI): 1.18 (1.16, 1.19)] and death after MI diagnosis [1.22 (1.21, 1.24)]. Study results also showed alarming declines in survival and remaining LE at age 65 among MI patients.Conclusion: There are substantial geographic disparities in MI outcomes, with lagging states having higher MI mortality, incidence, and prevalence, lower survival and remaining LE at age 65. Disparities in MI mortality in a great extent could be due to between-the-state differences in MI incidence, prevalence at age 65 and survival. Observed declines in survival and remaining LE require an urgent analysis of contributing factors that must be addressed.

Offspring of first-generation hatchery steelhead trout (Oncorhynchus mykiss) grow faster in the hatchery than offspring of wild fish, but survive worse in the wild: possible mechanisms for inadvertent domestication and fitness loss in hatchery salmon

Salmonid fish raised in hatcheries often have lower fitness (number of returning adult offspring) than wild fish when both spawn in the wild. Body size at release from hatcheries is positively correlated with survival at sea. So one explanation for reduced fitness is that hatcheries inadvertently select for trait values that enhance growth rate under the unnatural environment of a hatchery, but that are maladaptive in the wild environment. A simple prediction of this hypothesis is that juveniles of hatchery origin should grow more quickly than fish of wild origin under hatchery conditions, but should have lower survival under wild conditions. We tested that hypothesis using multiple full sibling families of steelhead ( Oncorhynchus mykiss ) that were spawned using either two wild parents (WxW) or two first-generation hatchery (HxH) parents. Offspring from all the families were grown together under hatchery conditions and under semi-natural conditions in artificial streams. HxH families grew significantly faster in the hatchery, but had significantly lower survival in the streams. That we see this tradeoff after only a single generation of selection suggests that the traits involved are under very strong selection. We also considered one possible alteration to the hatchery environment that might reduce the intensity of selection among families in size at release. Here we tested whether reducing the fat content of hatchery feed would reduce the variance among families in body size. Although fish raised under a low-fat diet were slightly smaller, the variation among families in final size was unchanged. Thus, there is no evidence that reducing the fat content of hatchery feed would reduce the opportunity for selection among families on size at release.