Intratumor heterogeneity (ITH) of genomic alterations may impact prognosis of lung adenocarcinoma (LUAD). Here, we investigate ITH of somatic copy number alterations (SCNAs), DNA methylation, and ...point mutations in lung cancer driver genes in 292 tumor samples from 84 patients with LUAD. LUAD samples show substantial SCNA and methylation ITH, and clonal architecture analyses present congruent evolutionary trajectories for SCNAs and DNA methylation aberrations. Methylation ITH mapping to gene promoter areas or tumor suppressor genes is low. Moreover, ITH composed of genetic and epigenetic mechanisms altering the same cancer driver genes is shown in several tumors. To quantify ITH for valid statistical association analyses, we develope an average pairwise ITH index (APITH), which does not depend on the number of samples per tumor. Both APITH indexes for SCNAs and methylation aberrations show significant associations with poor prognosis. This study further establishes the important clinical implications of genetic and epigenetic ITH in LUAD.
Abstract Context Despite the large body of literature on breakthrough cancer pain (BTcP), an accurate estimate of BTcP prevalence is still not available. Objectives To provide an estimate of BTcP ...prevalence and investigate the association between different prevalence rates and possible determinants. Methods We conducted MEDLINE and EMBASE searches for studies published from 1990 to 2012 reporting data on BTcP prevalence in adult cancer populations. Pooled prevalence rates from observational studies with an acceptable methodological quality were computed. The association between BTcP prevalence and possible predictors was investigated using subgroup analyses and meta-regression. Results Twenty-seven observational studies were identified. When quality criteria were applied, only 19 studies were included in the pooled analysis. The overall pooled prevalence was 59.2%, with high heterogeneity. The lowest prevalence rates were detected in studies conducted in outpatient clinics (39.9%), and the highest prevalence was reported in studies conducted in hospice (80.5%). The association between BTcP prevalence and other determinants such as publication year, age, gender, metastatic disease prevalence, or baseline pain intensity did not reach statistical significance. Conclusion In the context of a large between-studies heterogeneity, more than one in two patients with cancer pain also experiences BTcP, with some variability according to clinical and organizational variables.
In this large single-centre study, we report high prevalence (25%) of, small (<10%) and very small (<1%), paroxysmal nocturnal hemoglobinuria (PNH) clones by high-sensitive cytometry among 3085 ...patients tested. Given PNH association with bone marrow failures, we analyzed 869 myelodysplastic syndromes (MDS) and 531 aplastic anemia (AA) within the cohort. PNH clones were more frequent and larger in AA vs. MDS (p = 0.04). PNH clone, irrespective of size, was a good predictor of response to immunosuppressive therapy (IST) and to stem cell transplant (HSCT) (in MDS: 84% if PNH+ vs. 44.7% if PNH-, p = 0.01 for IST, and 71% if PNH+ vs. 56.6% if PNH- for HSCT; in AA: 78 vs. 50% for IST, p < 0.0001, and 97 vs. 77%, p = 0.01 for HSCT). PNH positivity had a favorable impact on disease progression (0.6% vs. 4.9% IPSS-progression in MDS, p < 0.005; and 2.1 vs. 6.9% progression to MDS in AA, p = 0.01), leukemic evolution (6.8 vs. 12.7%, p = 0.01 in MDS), and overall survival 73% (95% CI 68-77) vs. 51% (48-54), p < 0.0001, with a relative HR for mortality of 2.37 (95% CI 1.8-3.1; p < 0.0001) in PNH negative cases, both in univariate and multivariable analysis. Our data suggest systematic PNH testing in AA/MDS, as it might allow better prediction/prognostication and consequent clinical/laboratory follow-up timing.
In ARDS patients, mechanical ventilation should minimize ventilator-induced lung injury. The mechanical power which is the energy per unit time released to the respiratory system according to the ...applied tidal volume, PEEP, respiratory rate, and flow should reflect the ventilator-induced lung injury. However, similar levels of mechanical power applied in different lung sizes could be associated to different effects. The aim of this study was to assess the role both of the mechanical power and of the transpulmonary mechanical power, normalized to predicted body weight, respiratory system compliance, lung volume, and amount of aerated tissue on intensive care mortality.
Retrospective analysis of ARDS patients previously enrolled in seven published studies. All patients were sedated, paralyzed, and mechanically ventilated. After 20 min from a recruitment maneuver, partitioned respiratory mechanics measurements and blood gas analyses were performed with a PEEP of 5 cmH
O while the remaining setting was maintained unchanged from the baseline. A whole lung CT scan at 5 cmH
O of PEEP was performed to estimate the lung gas volume and the amount of well-inflated tissue. Univariate and multivariable Poisson regression models with robust standard error were used to calculate risk ratios and 95% confidence intervals of ICU mortality.
Two hundred twenty-two ARDS patients were included; 88 (40%) died in ICU. Mechanical power was not different between survivors and non-survivors 14.97 11.51-18.44 vs. 15.46 12.33-21.45 J/min and did not affect intensive care mortality. The multivariable robust regression models showed that the mechanical power normalized to well-inflated tissue (RR 2.69 95% CI 1.10-6.56, p = 0.029) and the mechanical power normalized to respiratory system compliance (RR 1.79 95% CI 1.16-2.76, p = 0.008) were independently associated with intensive care mortality after adjusting for age, SAPS II, and ARDS severity. Also, transpulmonary mechanical power normalized to respiratory system compliance and to well-inflated tissue significantly increased intensive care mortality (RR 1.74 1.11-2.70, p = 0.015; RR 3.01 1.15-7.91, p = 0.025).
In our ARDS population, there is not a causal relationship between the mechanical power itself and mortality, while mechanical power normalized to the compliance or to the amount of well-aerated tissue is independently associated to the intensive care mortality. Further studies are needed to confirm this data.
The human lung tissue microbiota remains largely uncharacterized, although a number of studies based on airway samples suggest the existence of a viable human lung microbiota. Here we characterized ...the taxonomic and derived functional profiles of lung microbiota in 165 non-malignant lung tissue samples from cancer patients.
We show that the lung microbiota is distinct from the microbial communities in oral, nasal, stool, skin, and vagina, with Proteobacteria as the dominant phylum (60 %). Microbiota taxonomic alpha diversity increases with environmental exposures, such as air particulates, residence in low to high population density areas, and pack-years of tobacco smoking and decreases in subjects with history of chronic bronchitis. Genus Thermus is more abundant in tissue from advanced stage (IIIB, IV) patients, while Legionella is higher in patients who develop metastases. Moreover, the non-malignant lung tissues have higher microbiota alpha diversity than the paired tumors.
Our results provide insights into the human lung microbiota composition and function and their link to human lifestyle and clinical outcomes. Studies among subjects without lung cancer are needed to confirm our findings.
Interpersonal conflicts at workplace are increasing in relation to high competitiveness and pressures at work, mainly connected with labor market globalization. Their manifestation is multifaceted in ...relation to different working conditions and they not only hinder health, performance, and job satisfaction, but can also harm people's rights and dignity. The study analyses issues related to work conflicts and adverse health consequences in 1,493 workers who approached a hospital service for work-related stress and harassment over a 3-year period. The subjects were examined according to a broad protocol covering working conditions, sources of conflict and negative actions suffered, and resulting impact on health status. Many critical conditions were reported in all occupational sectors with some differentiation in relation to gender (women more at risk) and employment status. Higher qualified levels were more exposed to experiencing severe personal adversities aimed at their progressive expulsion or resignation, with consequent higher risk of chronic adjustment disorders, while lower levels reported more stressful conditions in terms of interpersonal disputes and greater interference in the home-work interface. The study can provide useful indications for a better understanding of workplace conflicts in order to set up the most appropriate actions to manage and prevent them.
Hemolytic uremic syndrome associated with Shiga toxin-producing Escherichia coli (STEC-HUS) is a severe acute illness without specific treatment except supportive care; fluid management is ...concentrated on preventing fluid overload for patients, who are often oligoanuric. Hemoconcentration at onset is associated with more severe disease, but the benefits of volume expansion after hemolytic uremic syndrome (HUS) onset have not been explored.
All the children with STEC-HUS referred to our center between 2012 and 2014 received intravenous infusion targeted at inducing an early volume expansion (+10% of working weight) to restore circulating volume and reduce ischemic or hypoxic tissue damage. The short- and long-term outcomes of these patients were compared with those of 38 historical patients referred to our center during the years immediately before, when fluid intake was routinely restricted.
Patients undergoing fluid infusion soon after diagnosis showed a mean increase in body weight of 12.5% (vs 0%), had significantly better short-term outcomes with a lower rate of central nervous system involvement (7.9% vs 23.7%, P = .06), had less need for renal replacement therapy (26.3% vs 57.9%, P = .01) or intensive care support (2.0 vs. 8.5 days, P = .02), and needed fewer days of hospitalization (9.0 vs 12.0 days, P = .03). Long-term outcomes were also significantly better in terms of renal and extrarenal sequelae (13.2% vs 39.5%, P = .01).
Patients with STEC-HUS had great benefit from early volume expansion. It is speculated that early and generous fluid infusions can reduce thrombus formation and ischemic organ damage, thus having positive effects on both short- and long-term disease outcomes.
In January 2020, Novel Coronavirus Disease 2019 (COVID‐19) resulted in a global pandemic, creating uncertainty toward the management of liver transplantation (LT) programs. Lombardy has been the most ...affected region in Italy: the current mortality rate of COVID‐19 patients is 18.3% (10 022 deaths; April 10th) with hospitals in Lombardy having to expand the total number of ICU beds from 724 to 1381 to accommodate infected patients. There has been a drastic decrease in liver donors. From February 23rd until April 10th, 17 LTs were performed in Lombardy. Mean donor age was 49 years (range 18‐74) whereas mean recipient age was 55 (13‐69); mean MELD score was 12 (6‐24). All donors underwent screening for SARS‐CoV‐2 prior to LT. Two patients tested positive after LT, and one patient died for COVID on POD 30. Sixteen patients are alive after an average of 30 days post‐LT (range 3‐46). 10 patients have been discharged. This study has found no specific reason concerning the safety of recipients, to stop LT programs. Several key lessons from our experience are reported. However, due to the complex circumstances which surround the viral outbreak, the cessation or a reduction in LT activity is a pragmatic requirement.
Authors report key lessons and results of 17 liver transplantations performed in 4 liver transplantation centers in Northern
Data concerning the efficacy of SARS-CoV-2 vaccines in patients with non-oncological hematologic conditions are lacking. These include autoimmune cytopenias (autoimmune hemolytic anemia AIHA, immune ...thrombocytopenia ITP, and autoimmune neutropenia), and bone marrow failure syndromes (aplastic anemia, low risk myelodysplastic syndromes, and paroxysmal nocturnal hemoglobinuria). These conditions may relapse/reactivate after COVID-19 infection and vaccine. Moreover, they are mainly handled with immunosuppressive drugs that may hamper the response to vaccine. In this study, we prospectively evaluated the rate of seroconversion after mRNA SARS-CoV-2 vaccines in patients with autoimmune cytopenias or bone marrow failure syndrome after 2 ± 1 months from the last vaccine dose. Overall, 149 patients were tested and 135 (91%) seroconverted. The highest proportion of non-responders was observed in Evans syndrome (association of ITP and AIHA) and warm AIHA patients (p = 0.001), in those with lower levels of baseline serum IgG (p = 0.008), and in patients on active therapy with steroids (p = 0.03) who also had lower anti-Spike titers. The latter were inversely related with age, and a positively with lymphocyte counts. Additionally, patients who had received rituximab within 12 months from vaccination showed higher rates of non-response (p = 0.03) as compared to those treated before. Contrarily, cyclosporine alone, complement inhibitors, and bone marrow stimulating agents had no detrimental effect on seroconversion. These data suggest maintaining high vigilance and adherence to preventive/protective measures in this population since a proportion of cases may not respond or exhibit low anti-Spike titers.
Lung cancer in never smokers (LCINS) is a common cause of cancer mortality but its genomic landscape is poorly characterized. Here high-coverage whole-genome sequencing of 232 LCINS showed 3 subtypes ...defined by copy number aberrations. The dominant subtype (piano), which is rare in lung cancer in smokers, features somatic UBA1 mutations, germline AR variants and stem cell-like properties, including low mutational burden, high intratumor heterogeneity, long telomeres, frequent KRAS mutations and slow growth, as suggested by the occurrence of cancer drivers' progenitor cells many years before tumor diagnosis. The other subtypes are characterized by specific amplifications and EGFR mutations (mezzo-forte) and whole-genome doubling (forte). No strong tobacco smoking signatures were detected, even in cases with exposure to secondhand tobacco smoke. Genes within the receptor tyrosine kinase-Ras pathway had distinct impacts on survival; five genomic alterations independently doubled mortality. These findings create avenues for personalized treatment in LCINS.
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