Cancer Mortality Among Solid Organ Transplant Recipients in the United States During 1987-2018.

BACKGROUND: Solid organ transplant recipients (ie, "recipients") have elevated cancer risk and reduced survival after a cancer diagnosis. Evaluation of cancer mortality among recipients can facilitate improved outcomes from cancers arising before and after transplantation. METHODS: We linked the US transplant registry to the National Death Index to ascertain the causes of 126 474 deaths among 671 127 recipients (1987-2018). We used Poisson regression to identify risk factors for cancer mortality and calculated standardized mortality ratios to compare cancer mortality in recipients with that in the general population. Cancer deaths verified with a corresponding cancer diagnosis from a cancer registry were classified as death from pretransplant or posttransplant cancers. RESULTS: Thirteen percent of deaths were caused by cancer. Deaths from lung cancer, liver cancer, and non-Hodgkin lymphoma (NHL) were the most common. Heart and lung recipients had the highest mortality for lung cancer and NHL, whereas liver cancer mortality was highest among liver recipients. Compared with the general population, cancer mortality was elevated overall (standardized mortality ratio 2.33; 95% confidence interval, 2.29-2.37) and for most cancer sites, with large increases from nonmelanoma skin cancer (23.4, 21.5-25.5), NHL (5.17, 4.87-5.50), kidney cancer (3.40, 3.10-3.72), melanoma (3.27, 2.91-3.68), and, among liver recipients, liver cancer (26.0, 25.0-27.1). Most cancer deaths (93.3%) were associated with posttransplant cancer diagnoses, excluding liver cancer deaths in liver recipients (of which all deaths were from pretransplant diagnoses). CONCLUSIONS: Improved posttransplant prevention or screening for lung cancer, NHL, and skin cancers and management of liver recipients with prior liver cancer may reduce cancer mortality among recipients.

Diagnostic performance of a faecal immunochemical test for patients with low-risk symptoms of colorectal cancer in primary care: an evaluation in the South West of England.

BACKGROUND: The faecal immunochemical test (FIT) was introduced to triage patients with low-risk symptoms of possible colorectal cancer in English primary care in 2017, underpinned by little primary care evidence. METHODS: All healthcare providers in the South West of England (population 4 million) participated in this evaluation. 3890 patients aged ≥50 years presenting in primary care with low-risk symptoms of colorectal cancer had a FIT from 01/06/2018 to 31/12/2018. A threshold of 10 µg Hb/g faeces defined a positive test. RESULTS: Six hundred and eighteen (15.9%) patients tested positive; 458 (74.1%) had an urgent referral to specialist lower gastrointestinal (GI) services within three months. Forty-three were diagnosed with colorectal cancer within 12 months. 3272 tested negative; 324 (9.9%) had an urgent referral within three months. Eight were diagnosed with colorectal cancer within 12 months. Positive predictive value was 7.0% (95% CI 5.1-9.3%). Negative predictive value was 99.8% (CI 99.5-99.9%). Sensitivity was 84.3% (CI 71.4-93.0%), specificity 85.0% (CI 83.8-86.1%). The area under the ROC curve was 0.92 (CI 0.86-0.96). A threshold of 37 µg Hb/g faeces would identify patients with an individual 3% risk of cancer. CONCLUSIONS: FIT performs exceptionally well to triage patients with low-risk symptoms of colorectal cancer in primary care; a higher threshold may be appropriate in the wake of the COVID-19 crisis.

The response of relativistic outflowing gas to the inner accretion disk of a black hole.

The brightness of an active galactic nucleus is set by the gas falling onto it from the galaxy, and the gas infall rate is regulated by the brightness of the active galactic nucleus; this feedback loop is the process by which supermassive black holes in the centres of galaxies may moderate the growth of their hosts. Gas outflows (in the form of disk winds) release huge quantities of energy into the interstellar medium, potentially clearing the surrounding gas. The most extreme (in terms of speed and energy) of these-the ultrafast outflows-are the subset of X-ray-detected outflows with velocities higher than 10,000 kilometres per second, believed to originate in relativistic (that is, near the speed of light) disk winds a few hundred gravitational radii from the black hole. The absorption features produced by these outflows are variable, but no clear link has been found between the behaviour of the X-ray continuum and the velocity or optical depth of the outflows, owing to the long timescales of quasar variability. Here we report the observation of multiple absorption lines from an extreme ultrafast gas flow in the X-ray spectrum of the active galactic nucleus IRAS 13224-3809, at 0.236 ± 0.006 times the speed of light (71,000 kilometres per second), where the absorption is strongly anti-correlated with the emission of X-rays from the inner regions of the accretion disk. If the gas flow is identified as a genuine outflow then it is in the fastest five per cent of such winds, and its variability is hundreds of times faster than in other variable winds, allowing us to observe in hours what would take months in a quasar. We find X-ray spectral signatures of the wind simultaneously in both low- and high-energy detectors, suggesting a single ionized outflow, linking the low- and high-energy absorption lines. That this disk wind is responding to the emission from the inner accretion disk demonstrates a connection between accretion processes occurring on very different scales: the X-ray emission from within a few gravitational radii of the black hole ionizing the disk wind hundreds of gravitational radii further away as the X-ray flux rises.

Flows of X-ray gas reveal the disruption of a star by a massive black hole.

Tidal forces close to massive black holes can violently disrupt stars that make a close approach. These extreme events are discovered via bright X-ray and optical/ultraviolet flares in galactic centres. Prior studies based on modelling decaying flux trends have been able to estimate broad properties, such as the mass accretion rate. Here we report the detection of flows of hot, ionized gas in high-resolution X-ray spectra of a nearby tidal disruption event, ASASSN-14li in the galaxy PGC 043234. Variability within the absorption-dominated spectra indicates that the gas is relatively close to the black hole. Narrow linewidths indicate that the gas does not stretch over a large range of radii, giving a low volume filling factor. Modest outflow speeds of a few hundred kilometres per second are observed; these are below the escape speed from the radius set by variability. The gas flow is consistent with a rotating wind from the inner, super-Eddington region of a nascent accretion disk, or with a filament of disrupted stellar gas near to the apocentre of an elliptical orbit. Flows of this sort are predicted by fundamental analytical theory and more recent numerical simulations.

Measuring cancer clinical trial understanding.

Researchers, practitioners, and participants in cancer clinical trials must have a clear understanding of clinical trials if participation in them is to be solicited ethically and effectively. A valid and reliable measure of cancer clinical trial understanding did not exist prior to a 2005 study conducted for the Coalition of Cooperative Cancer Groups. This report outlines a measure derived from that study, discusses the rationale for its component items, examines its psychometric properties, and demonstrates the relationship of this measure to the enrollment decision. Data from national samples of cancer survivors and the general public demonstrate the measure's validity and reliability. Results are discussed as they relate to patient understanding of clinical trials, informed decision making, and health communication processes.

The tissue diagnostic instrument.

Tissue mechanical properties reflect extracellular matrix composition and organization, and as such, their changes can be a signature of disease. Examples of such diseases include intervertebral disk degeneration, cancer, atherosclerosis, osteoarthritis, osteoporosis, and tooth decay. Here we introduce the tissue diagnostic instrument (TDI), a device designed to probe the mechanical properties of normal and diseased soft and hard tissues not only in the laboratory but also in patients. The TDI can distinguish between the nucleus and the annulus of spinal disks, between young and degenerated cartilage, and between normal and cancerous mammary glands. It can quantify the elastic modulus and hardness of the wet dentin left in a cavity after excavation. It can perform an indentation test of bone tissue, quantifying the indentation depth increase and other mechanical parameters. With local anesthesia and disposable, sterile, probe assemblies, there has been neither pain nor complications in tests on patients. We anticipate that this unique device will facilitate research on many tissue systems in living organisms, including plants, leading to new insights into disease mechanisms and methods for their early detection.

Eicosanoid actions in insect immunity.

Insects express 3 lines of protection from infections and invasions. Their cuticles and peritrophic membranes are physical barriers. Infections and invasions are quickly recognized within insect bodies, and recognition launches 2 lines of innate immune reactions. Humoral reactions involve induced synthesis of antimicrobial peptides, the bacteriolytic enzyme lysozyme and activation of the prophenoloxidase system. Cellular immune reactions include phagocytosis, nodulation and encapsulation. These reactions entail direct interactions between circulating hemocytes and the invaders. Cellular immune reactions begin immediately after an invasion is detected while antimicrobial peptides typically appear in the hemolymph some hours after infection. Microaggregation is a step in the nodulation process, which is responsible for clearing the bulk of bacterial infections from circulation. Coordinated cellular actions lead to encapsulation of invaders, such as parasitoid eggs, that are very much larger than individual hemocytes. In this paper, we review the roles of eicosanoids as central mediators of insect immune reactions, particularly cellular reactions. We briefly describe insect immune functions, outline eicosanoid biosynthesis and treat eicosanoid actions in cellular immunity of insects. Eicosanoids act in several cellular defense functions, including phagocytosis, microaggregation, nodulation, encapsulation, cell spreading and hemocyte migration toward a source of a bacterial peptide. We also describe our most recent work on the influence of one group of eicosanoids, prostaglandins, on gene expression in an established insect cell line.

Physician-related factors involved in patient decisions to enroll onto cancer clinical trials.

The development of new cancer therapies requires additional, and more complex, clinical trials. But only approximately 3% to 5% of adult cancer patients participate in cancer clinical trials. This study seeks to identify and understand the attitudes of the public and cancer survivors toward health-related decisions and cancer clinical trials to identify the key factors that must be addressed to increase that percentage.

Eicosanoids mediate insect hemocyte migration.

Hemocyte migration toward infection and wound sites is an essential component of insect defense reactions, although the biochemical signal mechanisms responsible for mediating migration in insect cells are not well understood. Here we report on the outcomes of experiments designed to test the hypotheses that (1) insect hemocytes are able to detect and migrate toward a source of N-formyl-Met-Leu-Phe (fMLP), the major chemotactic peptide from Escherichia coli and (2) that pharmaceutical modulation of eicosanoid biosynthesis inhibits hemocyte migration. We used primary hemocyte cultures prepared from fifth-instar tobacco hornworms, Manduca sexta in Boyden chambers to assess hemocyte migration toward buffer (negative control) and toward buffer amended with fMLP (positive control). Approximately 42% of negative control hemocytes migrated toward buffer and about 64% of positive control hemocytes migrated toward fMLP. Hemocyte migration was inhibited (by >40%) by treating hornworms with pharmaceutical modulators of cycloxygenase (COX), lipoxygenase and phospholipase A2 (PLA2) before preparing primary hemocyte cultures. The influence of the COX inhibitor, indomethacin, and the glucocorticoid, dexamethasone, which leads to inhibition of PLA2, was expressed in a dose-dependent way. The influence of dexamethasone was reversed by injecting arachidonic acid (precursor to eicosanoid biosynthesis) into hornworms before preparing primary hemocyte cultures. The saturated fatty acid, palmitic acid, did not reverse the inhibitor effect. These findings support both our hypotheses, first that insect hemocytes can detect and respond to fMLP, and second, that insect hemocyte migration is mediated by eicosanoids.

Eicosanoids influence in vitro elongation of plasmatocytes from the tobacco hornworm, Manduca sexta.

Nodule formation is the predominant insect cellular defense reaction to bacterial challenges, responsible for clearing the largest proportion of infecting bacteria from hemolymph circulation. Hemocyte spreading behavior is a critical step in the nodulation process. It has been suggested that eicosanoids mediate several steps in the process. However, the influence of eicosanoids on hemocyte spreading has not been investigated in detail. To test the hypothesis that eicosanoids mediate hemocyte spreading behavior, I treated larvae of the tobacco hornworm, Manduca sexta, with eicosanoid biosynthesis inhibitors and later assessed plasmatocyte elongation on glass slides. Plasmatocytes from larvae treated with dexamethasone did not elongate to the extent of plasmatocytes from untreated control larvae. The dexamethasone effect on plasmatocyte elongation was expressed in a dose-dependent manner and was reversed by injecting dexamethasone-treated larvae with the eicosanoid-precursor fatty acid, arachidonic acid. Palmitic acid, which is not substrate for eicosanoid biosynthesis, did not reverse the influence of dexamethasone on plasmatocyte elongation. Finally, plasmatocytes from larvae treated with a range of eicosanoid biosynthesis inhibitors did not elongate to the extent of plasmatocytes from control larvae. Plasmatocyte width did not appear to be influenced in this study. These findings strongly support the idea that insect plasmatocyte elongation is influenced by eicosanoids.

Lipopolysaccharide evokes microaggregation reactions in hemocytes isolated from tobacco hornworms, Manduca sexta.

Insect cellular immune reactions to bacterial infection include nodule formation. Eicosanoids mediate several cellular actions in the nodulation process, including formation of hemocyte microaggregates, an early step. In previous work, we reported that isolated hemocytes produce and secrete eicosanoids that influence hemocyte behavior in response to bacterial challenge. We also reported that microaggregate formation in response to challenge was mediated by prostaglandins (PGs), but not by products of the lipoxygenase (LOX) pathways. In this paper we describe experiments designed to test the idea that exposing isolated hemocytes to lipopolysaccharide (LPS) evokes formation of hemocyte microaggregates and this cellular action is mediated by PGs. Results show that isolated hemocyte preparations challenged with LPS formed more hemocyte microaggregates than unchallenged preparations (6.9x10(3) microaggregates/ml hemolymph vs. 2.5x10(3) microaggregates/ml hemolymph). LPS challenge stimulated formation of hemocyte microaggregates in a dose dependent manner. Experimental groups pretreated with cyclooxygenase inhibitors produced fewer hemocyte microaggregates in response to LPS challenge than untreated control groups. The formation of hemocyte microaggregates was not influenced by LOX inhibitors. Furthermore, the influence of dexamethasone was reversed by supplementing the experimental groups with the eicosanoid precursor fatty acid molecule, arachidonic acid and PGH(2). Palmitic acid, which is not substrate for eicosanoid biosynthesis, did not reverse the effects of dexamethasone on the formation of microaggregates. The LOX product 5(S)hydroperoxyeicosa-6E,8Z,11Z,14Z-tetraenoic acid also did not reverse the effects of dexamethasone. These results are consistent with similar investigations performed with bacterial suspensions. We infer that isolated hemocyte preparations recognize and react to LPS by forming microaggregates and this reaction is mediated by PGs, but not products of the LOX pathway.

Prostaglandins, not lipoxygenase products, mediate insect microaggregation reactions to bacterial challenge in isolated hemocyte preparations.

Nodulation is the predominant cellular defense reaction to bacterial challenge in insects. Eicosanoids mediate several steps in the nodulation process, including formation of hemocyte microaggregations. Isolated hemocyte preparations synthesize and secrete eicosanoids, which mediate hemocytic immune reactions. Two major groups of eicosanoids are prostaglandins (products of cyclooxygenase pathways) and various products of lipoxygenase pathways. In this study, we test the hypothesis that prostaglandins, but not lipoxygenase products, mediate hemocyte microaggregation reactions in response to bacterial challenge. Our results indicate that isolated hemocyte preparations pretreated with the cyclooxygenase inhibitors indomethacin and naproxen yielded fewer microaggregates than untreated control groups (3.7 x 10(5) microaggregates/ml hemolymph vs. 11.0 x 10(5) microaggregates/ml hemolymph). These inhibitors influence hemocyte microaggregate formation in a dose-dependent manner in treatments ranging from 0 to 200 microM. The lipoxygenase inhibitors esculetin and caffeic acid did not impact the formation of microaggregates in this system. The influence of the phospholipase A(2) inhibitor dexamethasone was reversed by amending experimental (dexamethasone-treated) preparations with prostaglandin H(2), but not prostaglandin D(2), prostaglandin E(2), nor 5(S)-hydroperoxy-6E,8Z,11Z,14Z-eicosatetraenoic acid, a product of the lipoxygenase pathway. We infer that prostaglandins are the primary mediators of microaggregation reactions to bacterial challenge in insect hemocyte preparations.

Public attitudes toward participation in cancer clinical trials.

PURPOSE: The objective of this study is to understand the attitudes of American adults toward participation in cancer clinical trials. METHODS: A national probability sample of 1,000 adults aged 18 and older living in noninstitutional settings was interviewed by telephone by Harris Interactive during March and April 2000. One participant was selected from each household selected for the study. The resulting data were weighted to reflect the full adult population of the United States as reported in Current Population Reports. An Index of Participation in a Cancer Clinical Trial was computed, using a confirmatory factor analysis and converting the factor scores into a 0-to-100 scale. RESULTS: Approximately 32% of American adults (64 million individuals) indicate that they would be very willing to participate in a cancer clinical trial if asked to do so. An additional 38% of adults (76 million individuals) scored in a range that indicates that they are inclined to participate in a cancer clinical trial if asked, but hold some questions or reservations about participation. Projected rates of diagnosis, eligibility, and recruitment indicate that substantially more patients are willing to participate than are actually accrued. CONCLUSION: These results indicate that the primary problem with accrual is not the attitudes of patients, but rather that the loss of potential participants is the result of the unavailability of an appropriate clinical trial and the disqualification of large numbers of patients. The pool of willing patients is further reduced by the reluctance of some physicians to engage in accrual.