Integrative and comparative genomic analyses identify clinically relevant pulmonary carcinoid groups and unveil the supra-carcinoids.

The worldwide incidence of pulmonary carcinoids is increasing, but little is known about their molecular characteristics. Through machine learning and multi-omics factor analysis, we compare and contrast the genomic profiles of 116 pulmonary carcinoids (including 35 atypical), 75 large-cell neuroendocrine carcinomas (LCNEC), and 66 small-cell lung cancers. Here we report that the integrative analyses on 257 lung neuroendocrine neoplasms stratify atypical carcinoids into two prognostic groups with a 10-year overall survival of 88% and 27%, respectively. We identify therapeutically relevant molecular groups of pulmonary carcinoids, suggesting DLL3 and the immune system as candidate therapeutic targets; we confirm the value of OTP expression levels for the prognosis and diagnosis of these diseases, and we unveil the group of supra-carcinoids. This group comprises samples with carcinoid-like morphology yet the molecular and clinical features of the deadly LCNEC, further supporting the previously proposed molecular link between the low- and high-grade lung neuroendocrine neoplasms.

Changing trends in diagnosis, staging, treatment and survival in lung cancer: comparison of three consecutive cohorts in an Australian lung cancer centre.

BACKGROUND: Lung cancer accounts for significant morbidity and mortality worldwide. The effect of recent changes in demographics and management on outcomes in Australia has not been clearly defined. AIMS: To compare three consecutive lung cancer cohorts to evaluate emergent differences in diagnosis, management and mortality. METHODS: For comparative analysis, 2119 lung cancer patients were divided into three successive cohorts. Current death data were sought from the Victorian Cancer Registry. RESULTS: Age at diagnosis, mode of presentation and pathology did not significantly differ between the groups. Significantly more females were diagnosed with lung cancer in the most recent cohort (P = 0.04). Amongst non-small-cell lung cancer patients, there were more adenocarcinomas and less large cell carcinomas in the latest cohort (P = <0.01). More patients from the most recent cohort were staged pathologically and via positron emission tomography and fewer were clinically staged (P = <0.01). The most recent cohort had a greater proportion of Stage IV disease (P = <0.01) and more curative surgical or combined modality radiotherapy and chemotherapy versus palliative radiotherapy or supportive care (P = <0.01). Overall 5-year survival improved significantly in the most recent cohort, even after adjustment for age, gender and stage (P = <0.01). CONCLUSION: Comparison of three lung cancer patient cohorts diagnosed between 2001 and 2013 highlights emergent changes in lung cancer demographics, management and outcomes. These include recent increases in proportion of females, pathological and positron emission tomography staging, and Stage IV disease, as well as improved survival despite later stage disease.

Associations between the IASLC/ATS/ERS lung adenocarcinoma classification and EGFR and KRAS mutations.

We sought to investigate the frequency of mutations in epidermal growth factor receptor (EGFR) and Kirsten-RAS (KRAS) by each pathological subtype for patients with resected pulmonary adenocarcinoma as defined by the IASLC/ATS/ERS classification. Histological examination determined the predominant subtype according to the IASLC/ATS/ERS classification. EGFR and KRAS mutations were determined by high-resolution melting and Sanger sequencing. Clinical data were collected from medical records and clinicians. The 178 consecutive patients consisted of 48% males, median age 68 years (range 20-87) and smoking history 78%. The tumour stage was I in 62%, II in 18% and III in 20%. The mutation rates were: EGFR 30%; KRAS 28%. The rate of EGFR mutations in the acinar predominant reference group (n=76), was 37%. The solid predominant subtype showed significantly fewer EGFR mutations [3/33 (9%), odds ratio 0.17 (0.05-0.61), p=0.007]. No differences in mutation rate were observed in other subtypes. No association was found between KRAS mutations and predominant histological subtype. Advanced stage and solid predominant subtype were negative prognostic factors. EGFR mutations can be present in adenocarcinoma of any predominant subtype, however rarely in solid predominant tumours. No association was found between KRAS mutation and the predominant histological subtype.

Frequent loss of BRCA1 mRNA and protein expression in sporadic ovarian cancers.

Germline mutations in the BRCA1 gene cause inherited susceptibility to breast and ovarian cancers. However, somatic mutations of BRCA1 are rare in sporadic breast and ovarian tumours. To establish whether BRCA1 is altered during the development of sporadic ovarian cancer by mechanisms other than somatic mutation, we have analysed 57 sporadic epithelial ovarian tumours for BRCA1 protein and RNA expression. Reduced or absent protein expression was observed in 90% of tumours. Decreased protein expression was significantly associated with a reduction in the levels of RNA expression. Somatic mutations of BRCA1 and LOH at the BRCA1 locus were detected in 3.5% and 44% of informative tumours, respectively; there was no significant correlation between the levels of protein and RNA expression and the DNA mutation and/or LOH status. Together, these data suggest that expression of BRCA1 is down-regulated at the level of transcription during the development of sporadic ovarian cancers.

Knowledge of display rules in prelingually deaf and hearing children.

Deaf children of elementary and secondary school age participated in a study designed to examine their understanding of display rules, the principles governing the expression and concealment of emotion in social situations. The results showed that deaf children's knowledge of display rules, as measured by their reported concealment of emotion, was comparable to that of hearing children of the same age. However, deaf children were less likely to report that they would conceal happiness and anger. They were also less likely to produce reasons for concealing emotion and a smaller proportion of their reasons were prosocial, that is, relating to the feelings of others. The results suggest that the understanding of display rules (which function to protect the feelings of other people) may develop more gradually in deaf children raised in a spoken language environment than it does in hearing children.

The aesthetics of rectangle proportion: effects of judgment scale and context.

Two experiments examined preference for rectangle proportion, using a method that allowed participants to adjust 1 dimension of a rectangle to achieve the most preferred proportion. Instructing participants to use an interestingness response scale resulted in a preference for rectangles having more extreme sides ratios, compared with pleasingness or preferability scales. Instructing participants to produce a rectangle representing the preferred proportions of a painting or a kitchen tile shifted the preferred sides ratio toward a less extreme value than did a no-context rectangle instruction. Implications of the results for the findings of experiments that seek evidence for the special significance of particular ratios, such as the golden section, are discussed.

Testing the aesthetic significance of the golden-section rectangle.

The aesthetic significance of the golden-section rectangle was tested in two studies designed to obviate some of the criticisms of earlier experiments. In the first, employing the method of use, the mean sides-ratios of samples of paintings from five subject-matter categories (landscape, still life, head-and-shoulders portrait, upper-body portrait, full-length portrait) provided no evidence for the significance of the golden section. However, the sides ratio of portraits varied between categories in ways that were consistent with the requirements of the proportions of the subject matter. In the second study, using the method of production, participants produced the most pleasing four-sided shape, under four instruction conditions. Under a 'portrait painting' condition and a 'landscape painting' condition, the mean sides-ratios differed significantly from the golden section. Under two 'context free' geometric shape conditions--horizontal rectangle and vertical rectangle--the mean sides-ratio approximated the golden section. The results are discussed in terms of the methodological requirements for a valid test of the aesthetic significance of the golden section and the possibility that this ratio may indeed have special significance.

The development of theory of mind in deaf children.

Deaf children aged 4 to 16 years were given a false-belief test of theory of mind. Although the children experienced difficulty with the test, relative to hearing children, confirming a report by Peterson and Siegal (1995), performance was age-related, with a significantly higher proportion of 13- to 16-year-olds passing the test. It was concluded that deaf children raised in a spoken language environment show a developmental delay in theory of mind acquisition. This delay is consistent with the assumption that their early opportunities for learning about mental states are relatively restricted and that the normal development of theory of mind is dependent upon such opportunities.

Psychiatric disturbance and acute stress responses in surgical patients.

BACKGROUND: A number of reports have appeared of post-traumatic stress symptoms occurring in physically ill patients. This study sought to measure the extent of psychiatric disturbance and acute post-traumatic stress reactions occurring in surgical inpatients, and to examine their relationship with the stress of illness and hospitalization and the personal coping style of the patient. METHODS: Thirty-seven admissions to a general surgical unit were assessed on admission and immediately prior to discharge. Measures were made of depression, anxiety, cognitive impairment, post-traumatic stress symptoms, severity of illness, level of physical functioning, degree of hospital stress and coping style. RESULTS: There was a significant reduction in anxiety scores postoperatively. Twenty-seven per cent of patients developed high levels of acute post-traumatic stress symptoms and these correlated with depression at admission and intra-hospital stress. Depression at discharge was related to depression at admission, physical functioning and coping style. In general, avoidance and acceptance-resignation were associated with a poorer psychiatric outcome. CONCLUSIONS: Postoperative psychiatric disturbance, including acute stress symptoms, can be understood as a reaction to the 'trauma' of illness and hospitalization, predisposed to by pre-existing depression. Interventions could be directed at screening for at-risk patients, minimizing stress, and encouraging adaptive mechanisms of coping in patients.

Germline mutations of the BRCA1 gene in breast and ovarian cancer families provide evidence for a genotype-phenotype correlation.

Mutations in the BRCA1 gene, discovered in 1994, are associated with an 80-90% lifetime risk of breast cancer. We have analysed 60 families with a history of breast and/or ovarian cancer for germline mutations in BRCA1. Twenty-two different mutations were detected in 32 families (53%), of which 14 are previously unreported. We observed a significant correlation between the location of the mutation in the gene and the ratio of breast to ovarian cancer incidence within each family. Our data suggest a transition in risk such that mutations in the 3' third of the gene are associated with a lower proportion of ovarian cancer. Haplotype analysis supports previous data which suggest some BRCA1 mutation carriers have common ancestors; however, we have found at least two examples where recurrent mutations appear to have arisen independently.

Randomized controlled trial of prophylactic antiarrhythmic therapy in patients with inducible ventricular tachyarrhythmias after recent myocardial infarction.

Survivors of acute myocardial infarction who had inducible sustained ventricular tachyarrhythmias at programmed stimulation 1-4 weeks after infarction were recruited to a randomized pilot trial of Class I antiarrhythmic drugs, in an attempt to determine whether their mortality and risk of spontaneous ventricular tachycardia and fibrillation could be reduced by treatment. Of 136 eligible patients, 96 (71%) joined the trial and 47 were randomized to 'no treatment' and 49 were randomized to 'treatment' (quinidine, disopyramide or mexiletine given to attain 'therapeutic' serum levels). During follow-up, the two groups fared similarly. For the 'treatment' and 'no treatment' groups, the respective 3-year probabilities of remaining incident-free were:cardiac death, 0.91 vs 0.89; instantaneous death + non-fatal ventricular tachyarrhythmias, 0.87 vs 0.87; cardiac death + non-fatal ventricular tachyarrhythmias, 0.83 vs 0.85. The highest risk patients with inducible ventricular tachycardia fared similarly in the 'treatment' and 'no treatment' groups. The respective probabilities of remaining incident-free were: cardiac death, 0.89 vs 0.88; instantaneous death + non-fatal ventricular tachyarrhythmias, 0.79 vs 0.84; cardiac death + non-fatal ventricular tachyarrhythmias, 0.76 vs 0.77. We conclude that prophylactic Class I antiarrhythmic drug therapy with quinidine, disopyramide or mexiletine given to achieve a 'therapeutic' serum level does not appear to alter the prognosis of patients with inducible ventricular tachyarrhythmias after myocardial infarction.

Correlation between signal-averaged electrocardiogram and programmed stimulation in patients with and without spontaneous ventricular tachyarrhythmias.

This study examined the incidence of delayed ventricular activation on signal-averaged electrocardiograms and the incidence of inducible sustained ventricular tachycardia (VT) at programmed stimulation (1 or 2 extrastimuli) in patients with and patients without spontaneous ventricular tachyarrhythmias. The correlation between delayed ventricular activation and inducible VT was investigated in 371 patients with acute myocardial infarction (AMI). In 32 patients with no ventricular disease and no spontaneous arrhythmias (group I), ventricular activation time averaged 115 +/- 2 ms, compared with 166 +/- 3 ms (p less than 0.001) for 65 patients with spontaneous ventricular tachyarrhythmias late after AMI (group II). In AMI patients with no spontaneous arrhythmias, ventricular activation time averaged 133 +/- 2 ms for 306 patients studied 1 to 4 weeks after AMI (group III) and 130 +/- 2 ms for 67 patients studied 3 to 12 months after AMI (group IV). The values for group III and group IV patients were each significantly higher than for group I (p less than 0.001), but lower than that for group II (p less than 0.001). The incidence of delayed ventricular activation was 89% for group II, 26% for group III and 18% for group IV. Sustained VT was not inducible in group I patients, but was inducible in 78% of group II (p less than 0.001 vs group I) and 20% of group III (p less than 0.05 vs group I; p less than 0.001 vs group II) (group IV was not studied).(ABSTRACT TRUNCATED AT 250 WORDS)

Prognostic significance of ventricular tachycardia and fibrillation induced at programmed stimulation and delayed potentials detected on the signal-averaged electrocardiograms of survivors of acute myocardial infarction.

The relative prognostic significance of ventricular tachycardia and ventricular fibrillation inducible at programmed stimulation within 1 month of acute myocardial infarction was compared in a prospective study of 403 clinically well survivors of transmural infarction who were 65 years old or younger. The prognostic significance of delayed potentials on the signal-averaged electrocardiogram was also examined in a subset of 306 patients without bundle branch block. Among the study patients, 20% had inducible ventricular tachycardia, 14% had inducible ventricular fibrillation, and 66% had no inducible arrhythmias. The 2 year probability of remaining free from cardiac death or nonfatal ventricular tachycardia or fibrillation was 0.73 for those with inducible ventricular tachycardia, 0.93 for those with inducible ventricular fibrillation, and 0.92 for those with no inducible arrhythmias. The cycle length of inducible ventricular tachycardia was 230 msec or more in 70% of the patients with inducible tachycardia who died. Of the patients studied by signal-averaged electrocardiography, 26% had delayed potentials. At 2 years, the probability of remaining free from cardiac death or nonfatal ventricular tachycardia or fibrillation was 0.73 for patients with delayed potentials and 0.95 for patients with no delayed potentials. There was a significant correlation (p less than .001) between the presence of delayed potentials and the ability to induce ventricular tachycardia. In conclusion, in survivors of recent infarction who have not had spontaneous ventricular tachycardia or fibrillation, inducible tachycardia (but not inducible fibrillation) at programmed stimulation predicts a significant risk of death or spontaneous tachycardia or fibrillation. A similar risk is found for patients with delayed potentials on the signal-averaged electrocardiogram.

Effect of antiarrhythmic therapy on delayed potentials detected by the signal-averaged electrocardiogram in patients with ventricular tachycardia after acute myocardial infarction.

The ability of class I and class II antiarrhythmic drugs to either abolish delayed potentials or modify their timing was investigated in 39 patients with spontaneous ventricular tachycardia (VT) after myocardial infarction. Before the study all patients had delayed potentials on the signal-averaged electrocardiogram and inducible VT with programmed stimulation. These investigations were repeated during 67 trials of oral antiarrhythmic therapy (mexiletine 25, quinidine 24, metoprolol 13, disopyramide 2, procainamide 1, drug combinations 2). Delayed potentials were abolished in only 5 trails (7%), which was within the baseline variability of 8.5% for detection of delayed potentials. In the 7 trials in which VT inducibility was suppressed, delayed potentials persisted in 6 and mean ventricular activation time was virtually unchanged (151 ms before drug therapy, 152 ms after). Quinidine, mexiletine and metoprolol caused no consistent change in ventricular activation time. There was also no change in mean ventricular activation time (164 ms before and 163 ms after drug treatment) in patients in whom spontaneous VT did not recur with drug therapy during follow-up. Thus, the tested antiarrhythmic drugs had no consistent effects on presence or timing of delayed potentials on the signal-averaged electrocardiogram, even when VT inducibility was suppressed or recurrence of spontaneous VT was prevented.

Value of programmed stimulation and exercise testing in predicting one-year mortality after acute myocardial infarction.

The ability of programmed ventricular stimulation and exercise testing to predict 1-year mortality after acute myocardial infarction (AMI) was investigated in 228 clinically well survivors of AMI. Patients with inducible ventricular tachycardia (VT) or ventricular fibrillation (VF) had a higher mortality rate than those without inducible arrhythmias (26% vs 6%, p less than 0.001). Exercise-induced ST-segment change of 2 mm or more was associated with a higher mortality rate than ST change of less than 2 mm (11% vs 4%, 0.05 less p less than 0.10). Of patients who had both tests, 62% had no inducible ventricular tachycardia or ventricular fibrillation and ST change of less than 2 mm, and only 1% died during the first year. Thus, in clinically well survivors of AMI, programmed stimulation is a powerful predictor of first-year mortality; programmed stimulation and exercise testing together predict virtually all deaths within the first year, and they can identify a large group of patients with a very low mortality rate.

A new protocol of programmed stimulation for assessment of predisposition to spontaneous ventricular arrhythmias.

We have devised a simple method for identifying predisposition to spontaneous sustained ventricular fibrillation (VF) and tachycardia (VT). A standardized protocol of programmed stimulation was applied to 111 control subjects without ventricular disease and with no history of VF or VT (Group I) and to 27 patients with previous myocardial infarction and documented spontaneous (in the absence of evidence of further acute myocardial ischaemia) VF or VT (Group II). The stimulation protocol consisted of single and paired ventricular extra stimuli introduced during ventricular drive at the right ventricular apex and outflow tract, at twice diastolic threshold current intensity and at 20 mA. None of the Group I subjects exhibited VF or sustained (more than 10 s) VT. In contrast sustained arrhythmias were induced in 24 (89%) of Group II patients. We conclude: In our study population, initiation of a sustained ventricular tachyarrhythmia at programmed stimulation was both a sensitive (89%) and specific (100%) indicator for predisposition to spontaneous VF and VT.

Ventricular electrical instability: a predictor of death after myocardial infarction.

The results of a prospective study of ventricular electrical instability after myocardial infarction (MI) are presented. Ventricular electrical stability was assessed using a standardized protocol of programmed stimulation in 165 hemodynamically stable patients 6 to 28 days after acute MI. Ventricular electrical instability was defined as induction at programmed stimulation of ventricular fibrillation (VF) or ventricular tachycardia (VT) lasting at least 10 seconds. Of 165 MI survivors, 38 (23%) had ventricular electrical instability. No significant differences were noted between stable and unstable patients in terms of coronary prognostic index, elevation of serum creatine phosphokinase, coronary anatomy, site of MI, or frequency of VT within 48 hours of MI. The mean follow-up period was 8 months (range 0 to 12). There were 7 deaths in stable patients (5 from cardiogenic shock, 1 from septicemia, and 1 unwitnessed) and 10 deaths in unstable patients (8 instantaneous, 1 from cardiogenic shock, and 1 unwitnessed) during the subsequent year. In addition, 2 of 127 stable patients and 4 of 38 unstable patients had spontaneous VT from which they were satisfactorily resuscitated. Thus, the sensitivity of ventricular electrical instability as a predictor of instantaneous death or spontaneous VT was 86% and the specificity 83%. The predictive accuracy of the absence of ventricular electrical instability as an indicator for the absence of instantaneous death or spontaneous VT was 98%. The predictive accuracy of the presence of ventricular electrical instability as a predictor of instantaneous death or spontaneous VT was 32%. Thus, patients with ventricular electrical instability after MI have a high risk of instantaneous death within 1 year; patients without ventricular electrical instability after MI have a low risk of instantaneous death within 1 year; prospective studies of antiarrhythmic therapy and measures to prevent reinfarction and optimize left ventricular performance are required to determine whether instantaneous death can be prevented in unstable patients; and therapy to prevent reinfarction and optimize left ventricular performance may offer the best chance to improve prognosis in stable patients.

Measurement of the activation time for platelet adhesion to foreign surfaces.

An apparatus is described which permitted a perfusant (lactated Ringer's solution) to be passed through a porous sample in a pulsatile manner with a square wave pressure profile. The "on" time, "off" time, number of cycles and pressure amplitude were separately controllable. Using this apparatus and immersing the sample in stirred, heparinized, human blood, there was a certain "off" time below which platelet adhesion to the sample abruptly ceased. The values of this "off" time, termed the activation time ta for platelet adhesion were approximately 0.5 sec for 0.2 micrometers pore size cellulose diacetate/nitrate (millipore filter) and approximately 0.3 sec for 0.2 micrometers polycarbonated (nuclepore filter). After a single cycle with a 5 sec "off" time, adhered platelets on both these materials showed pseudopodia, varying degrees of spreading and membrane perforation.

Blood-compatible materials by fluid perfusion.

The feasibility of preventing platelet adhesion to porous foreign surfaces in contact with blood by passing (perfusing) a physiologic fluid through the pores into the blood was tested. Porous-walled tubes of Teflon (Gore-tex) and aluminosilicate ceramic were perfused with lactated Ringer's solution at rates between 3.13 and 0.3 cc/min per cm2 of perfused surfaced and exposed to heparinized and unheparinized flowing human whole blood for periods of 3-6 min. Under these conditions, with 0.159 cm I.D. tubes and a mean blood flow rate of 8.3 cm/sec, the adhesion of all blood cells was prevented, compared with the adhesion of 1 to 8 X 10(6) platelets/cm2 on the nonperfused controls. The adhesion of plasma proteins was also markedly reduced as determined by bromophenol blue staining. The critical perfusion rate to prevent platelet adhesion to Gore-tex (0.5 micron pore size, 60% pore volume) was found to be between 0.04 and 0.3 cc/(min-cm2). The boundary layer produced by a perfused segment of porous tubing prevented platelet adhesion for several centimeters downstream from the perfusing segment under experimental conditions used.