What's Current and What's New in Mesothelioma?

Malignant mesothelioma is a rare disease with limited treatment options. In malignant pleural mesothelioma (MPM), radical trimodality approaches, including surgery, radiotherapy and systemic chemo- and immunotherapy, have been delivered in some countries but remain controversial due to a lack of randomised evidence. Even in the unresectable scenario, surgery and radiotherapy play an important role in managing pleural effusions and pain, which may optimise wellbeing and maintain performance status. From the systemic treatment point of view, the recent incorporation of anti-angiogenics and, more importantly, immunotherapy has changed the standard of care in a space where chemotherapy with platinum and pemetrexed was the only therapeutic intervention with demonstrated benefits in overall survival. Histology is essential in determining an initial treatment plan as non-epithelioid MPMs may have a higher substantial survival improvement with dual immunotherapy compared with chemotherapy, whereas chemotherapy remains an option for epithelioid MPM; however, predictive biomarkers for systemic therapy are not entirely validated to guide the selection, as a subgroup of MPM patients might not benefit from immunotherapy. This overview approaches how the overall management of mesothelioma is evolving to incorporate the recent changes in the standards of care.

Polypharmacy Rates among Patients over 45 years

Polypharmacy, defined as receipt of ≥5 medications in any one month, is often associated with potentially inappropriate prescribing and adverse drug interactions. High levels of polypharmacy have been observed internationally and in Ireland. The Health Service Executive Primary Care Reimbursement Services (HSE-PCRS) pharmacy claims database for the GMS eligible population was used. We conducted Chi-square tests to determine the statistical significance of perceived differences in medication use among patients aged ³ 45 years. Our results establish a national benchmark for polypharmacy in gender and various age categories in the HSE-PCRS. Of the 794,628 individuals aged ≥45 years with at least one claim in 2013, 64.3% (510,946) had polypharmacy, with higher rates among women (67.0% - 293,886 - compared to 60.8% of men - 216,444). Patients aged 45-54 years were less likely to have polypharmacy (38.6% - 69,934) compared to those aged 75 years old (82.6% - 197,565). The high levels of polypharmacy are of interest, and suggest that monitoring and evaluation of patients' medication regimes may be required to ensure appropriateness.

Infective endocarditis.

BACKGROUND: Infective endocarditis continues to pose a therapeutic challenge to treating clinicians. We believe that the successful management of endocarditis mandates a thorough understanding of the risk factors for adverse outcomes and a co-ordinated team approach. METHODS: Between the years 2000 and 2009, 85 patients required surgery for infective endocarditis, with a total of 112 infected valves being treated surgically. Data was analysed to determine factors significantly associated with morbidity and mortality. RESULTS: The mean age was 50.5 years. Nine (10.5%) of these patients had Prosthetic Valve Endocarditis, the remaining 76 (89.5%) had Native Valve Endocarditis. Twenty-nine percent of patients were NYHA 4 pre-operatively, 15% of patients were haemodynamically unstable requiring inotropic support, 34% were persistently febrile despite antibiotic therapy, and 48% had suffered any embolic event, 20% suffered cerebral emboli. The commonest causative organism in our series was Staphylococcus Aureus (54.1%) with 2.3% of cases being due to MRSA. The second commonest organism isolated was Streptococcus spp. at 21.1%. Operative mortality was 12.9%, of which on-table mortality was 2.2%. Mean follow-up was 56 months (range 1-151). Early recurrence rates (<3 months) were 2.3%. Late recurrence was 7.0%. The pre-operative factors associated with increased mortality were age over 65, inotropic requirement, uncontrolled sepsis and cerebral emboli. We summarise our experience and recommendations for a team approach to the management of infective endocarditis.

Aortic root replacement for ascending aortic disease: a 10 year review.

BACKGROUND: Bentall's procedure and its modifications have been used for over 40 years for the treatment of ascending aortic disease. This study reviewed 10 years of experience with Aortic Root Replacement (ARR) in a major cardiac surgical centre. METHODS: Eighty-nine patients underwent ARR between 1999 and 2009. The records were scrutinised by retrospective chart review. RESULTS: The mean age was 54 years. Seventy-nine percent of patients were male and 21% female. The indications for the procedure were Aortic Root Aneurysm (ARA) (65%), type A dissection (28%), infective endocarditis (4.4%) and prosthetic valve regurgitation (2.2%). Fifty-seven percent of these were performed electively and 43% as an emergency. A bicuspid aortic valve was present in 37%. Arch surgery was required in 15.7%, bypass grafting in 12.3% and mitral valve surgery in 5.6%. The descending aorta was involved in 16.8%. Operative mortality was 3.3% and in-hospital mortality 12.3%. Mean follow-up was 67.05 months (range 2-143). No patients required re-operation. CONCLUSIONS: The factors associated with increased in-hospital mortality were pre-operative haemodynamic instability, concommitant coronary artery disease and acute renal failure. The presence of a bicuspid valve may be associated with lower rates of complications, but no difference in mortality.

Perioperative diagnosis of the positive axilla in breast cancer: a safe, time efficient algorithm.

BACKGROUND: This study evaluates the combined role of axillary ultrasound (Ax US), fine needle aspiration (FNAC) and intraoperative frozen section analysis of the sentinel node (FS SN) in a practical, time efficient algorithm to reduce the requirement for reoperation for axillary clearance in breast cancer in a busy tertiary unit. METHODS: Between October 2007 and June 2009 188 women underwent Ax US as a first investigation for nodal status. Suspicious nodes were biopsied, negative axillae proceeded to FS SN at time of primary breast surgery. All confirmed positive cases proceeded to immediate axillary clearance. RESULTS: 93 women had positive axillary nodes at final histology. Ax US + FNAC identified 59 positive axillae and had a sensitivity of 63.4% and specificity of 100%. FS SN identified a further 26 cases with a sensitivity of 76.5% and specificity of 100%. Overall, only 8 women required reoperation for axillary clearance. Sensitivity for the combined procedures was 91.4%. Commencement of adjuvant therapy was significantly less in those women identified earlier compared to those requiring a second operation (23.3 days vs 49.0 days, p < 0.005). CONCLUSION: 95.7% of cases were diagnosed accurately in the perioperative period, preventing delay to triage to definitive oncological care and reducing requirement for costly reoperation.

Interns as teachers of medical students: a pilot programme.

BACKGROUND: In recent years, rising numbers of medical students and an increasingly demanding clinical workload has put pressures on the educational systems for medical students in the hospital. Bedside teaching remains central to education, but tutorial delivery by registrars, tutors and consultants has proven to be increasingly difficult with the greater numbers of students now in the undergraduate system. AIMS: We have performed a pilot study to determine the feasibility of developing a Junior Tutor Programme, to assist in the delivery of tutorials to undergraduate medical students. METHODS: This was designed and delivered by interns under the supervision of the academic staff in the Departments of Medicine and Surgery in Connolly Hospital. The programme was evaluated by a questionnaire filled in by the students anonymously. RESULTS: A supervised programme of tutorials delivered by interns is a potentially useful way to ensure delivery of clinical teaching to undergraduate medical students.

Consciousness, information, and living systems.

The possibility of a proactive role for consciousness in the establishment of physical reality has been addressed via an extensive 26-year program investigating physical anomalies in human/machine interactions and non-sensory acquisition of information about remote geographical locations. Empirical databases comprising many hundreds of millions of random events confirm that information can be introduced into, or extracted from, otherwise random physical processes solely through the agencies of human intention and subjective resonance. Much of the evidence mitigates the likelihood that the anomalies are manifestations of neo-cortical cognitive activity. Rather, they may be expressions of a deeper information organizing capacity of biological origin that emerges from the uncertainty inherent in the complexity of all living systems.

Correlations of random binary sequences with pre-stated operator intention: a review of a 12-year program.

Strong correlations between output distribution means of a variety of random binary processes and pre-stated intentions of some 100 individual human operators have been established over a 12-year experimental program. More than 1000 experimental series, employing four different categories of random devices and several distinctive protocols, show comparable magnitudes of anomalous mean shifts from chance expectation, with similar distribution structures. Although the absolute effect sizes are quite small, of the order of 10(-4) bits deviation per bit processed, over the huge databases accumulated, the composite effect exceeds 7sigma (p approximately 3.5 x 10(-13)). These data display significant disparities between female and male operator performances, and consistent serial position effects in individual and collective results. Data generated by operators far removed from the machines and exerting their efforts at times other than those of machine operation show similar effect sizes and structural details to those of the local, on-time experiments. Most other secondary parameters tested are found to have little effect on the scale and character of the results, with one important exception: studies performed using fully deterministic pseudorandom sources, either hard-wired or algorithmic, yield null overall mean shifts, and display no other anomalous features.

Information and uncertainty in remote perception research.

This article has four purposes: 1) to present for the first time in archival form all results of some 25 years of remote perception research at this laboratory; 2) to describe all of the analytical scoring methods developed over the course of this program to quantify the amount of anomalous information acquired in the experiments; 3) to display a remarkable anti-correlation between the objective specificity of those methods and the anomalous yield of the experiments; and 4) to discuss the phenomenological and pragmatic implications of this complementarity. The formal database comprises 653 experimental trials performed over several phases of investigation. The scoring methods involve various arrays of descriptor queries that can be addressed to both the physical targets and the percipients' description thereof, the responses to which provide the basis for numerical evaluation and statistical assessment of the degree of anomalous information acquired. Twenty-four such recipes have been employed, with queries posed in binary, ternary, quaternary, and ten-level distributive formats. Thus treated, the database yields a composite z-score against chance of 5.418 (p = 3 x 10(-8), one-tailed). Numerous subsidiary analyses agree that these overall results are not significantly affected by any of the secondary protocol parameters tested, or by variations in descriptor effectiveness, possible participant response biases, target distance from the percipient, or time interval between perception effort and agent target visitation. However, over the course of the program there has been a striking diminution of the anomalous yield that appears to be associated with the participants' growing attention to, and dependence upon, the progressively more detailed descriptor formats and with the corresponding reduction in the content of the accompanying free-response transcripts. The possibility that increased emphasis on objective quantification of the phenomenon somehow may have inhibited its inherently subjective expression is explored in several contexts, ranging from contemporary signal processing technologies to ancient divination traditions. An intrinsic complementarity is suggested between the analytical and intuitive aspects of the remote perception process that, like its more familiar counterpart in quantum science, brings with it an inescapable uncertainty that limits the extent to which such anomalous effects can be simultaneously produced and evaluated.

FieldREG II: consciousness field effects: replications and explorations.

Based on formal analysis of 18 exploratory applications, 12 of which have been reported previously, a testable general hypothesis for FieldREG experiments has been postulated, namely that data taken in environments fostering relatively intense or profound subjective resonance will show larger deviations of the mean relative to chance expectation than those generated in more pragmatic assemblies. The 61 subsequent FieldREG applications reported here comprise 21 hypothesis-based formal replications, along with 40 further explorations designed to learn more about the circumstances that favor anomalous deviations. The results of the formal replications strongly confirm the general hypothesis, yielding a composite probability against chance for the resonant subset of 2.2 x 10(-6) compared to 0.91 for the mundane subset. The exploratory work suggests other venues in which anomalous effects of group consciousness can be expected, and also identifies a number of situations that do not appear to be conducive to such responses.

A modular model of mind/matter manifestations (M5).

While ongoing empirical research into anomalous mind/matter interactions continues to reaffirm the reality of such phenomena, it has heretofore failed to stimulate viable theoretical models, or even to suggest effective strategies for more productive experimentation. In contrast to prevalent presumption, re-examination of several large databases from this laboratory raises doubt that such effects are produced by direct attention of the conscious mind to the observable physical processes addressed. Rather, an alternative route is indicated wherein unconscious mind and intangible physical mechanisms are invoked to achieve anomalous acquisition of mental information about, or anomalous mental influence upon, otherwise inaccessible material processes. Implications for more effective experiments include subtler feedback schemes that facilitate submission of conscious intention to unconscious mental processing; physical target systems that provide a richness of intangible potentialities; operators who are amenable to such interactions; and an environmental ambience that supports the composite strategy. Theoretical requisites include better understanding of the information dialogue between conscious and unconscious aspects of mind; more pragmatic formulations of the relations between tangible and intangible physical processes; and most importantly, cogent representation of the merging of mental and material dimensions into indistinguishability at their deepest levels.

The PEAR proposition.

For more than a quarter century, the Princeton Engineering Anomalies Research (PEAR) laboratory has engaged in a broad range of experiments on consciousness-related physical anomalies and has proposed a corresponding selection of theoretical models that have combined to illuminate the fundamental nature of the provocative phenomena that emerge. Productive pursuit of this topic has inescapably involved a spectrum of political, cultural, personal, and interpersonal factors that are normally not encountered in more conventional scientific scholarship, but have both enriched and complicated the enterprise in many ways. Some of the insights gleaned from the work are objectively specifiable, such as the scale and structural character of the anomalous effects; their relative insensitivity to objective physical correlates, including distance and time; the oscillating sequential patterns of performance they display; the major discrepancies between male and female achievements; and their irregular replicability at all levels of experience. But many others relate to subjective issues, such as the responsiveness of the effects to conscious and unconscious intention and to individual and collective resonance; the relevance of ambience and attitude in their generation; and the importance of intrinsic uncertainty as a source of the anomalies. This blend of empirical features predicates radical excursions of the dedicated models, and hence of the more general scientific paradigms, to allow consciousness and its subjective information processing capacities a proactive role in the establishment of objective reality, with all of the complications of specificity, causality, and reproducibility that entails. The attendant complexities of conceptualization, formulation, and implementation notwithstanding, pragmatic applications of these phenomena in many sectors of public endeavor now can be foreseen.

Endophysical models based on empirical data.

Any proposed endophysical models need to acknowledge a number of subjective correlates that have been well established in such objectively quantifiable experimental contexts as anomalous human/machine interactions and remote perception information acquisition. Most notable of these factors are conscious and unconscious intention; gender disparities; serial position effects; intrinsic uncertainties; elusive replicability; and emotional resonance between the participants and the devices, process, and tasks. Perhaps even more pertinent are the insensitivities of the anomalous effects to spatial and temporal separations of the participants form the physical targets. Inclusion of subjective coordinates in the models, and exclusion of physical distance and time, raise formidable issues of specification, quantification, and dynamical formulation from both the physical and psychological perspectives. A few primitive examples of possible approaches are presented.

Science of the subjective.

Over the greater portion of its long scholarly history, the particular form of human observation, reasoning, and technical deployment we properly term "science" has relied at least as much on subjective experience and inspiration as it has on objective experiments and theories. Only over the past few centuries has subjectivity been progressively excluded from the practice of science, leaving an essentially secular analytical paradigm. Quite recently, however, a compounding constellation of newly inexplicable physical evidence, coupled with a growing scholarly interest in the nature and capability of human consciousness, are beginning to suggest that this sterilization of science may have been excessive and could ultimately limit its epistemological reach and cultural relevance. In particular, an array of demonstrable consciousness-related anomalous physical phenomena, a persistent pattern of biological and medical anomalies, systematic studies of mind/brain relationships and the mechanics of human creativity, and a burgeoning catalogue of human factors effects within contemporary information processing technologies, all display empirical correlations with subjective aspects that greatly complicate, and in many cases preclude, their comprehension on strictly objective grounds. However, any disciplined re-admission of subjective elements into rigorous scientific methodology will hinge on the precision with which they can be defined, measured, and represented, and on the resilience of established scientific techniques to their inclusion. For example, any neo-subjective science, while retaining the logical rigor, empirical/theoretical dialogue, and cultural purpose of its rigidly objective predecessor, would have the following requirements: acknowledgment of a proactive role for human consciousness; more explicit and profound use of interdisciplinary metaphors; more generous interpretations of measurability, replicability, and resonance; a reduction of ontological aspirations; and an overarching teleological causality. Most importantly, the subjective and objective aspects of this holistic science would have to stand in mutually respectful and constructive complementarity to one another if the composite discipline were to fulfill itself and its role in society.

Sensors, filters, and the source of reality.

The failure of contemporary scientific theory to correlate and explicate anomalous consciousness-related physical phenomena may trace to inadequate comprehension of the process of information exchange between the mind and its ultimate source. Elevation of the subjective capacities of consciousness to complementary status with the more objective physical senses, along with recognition of the bi-directional capabilities of both categories, allows establishment of resonant channels of communication between the mind and its source environment that can exceed conventional expectations. In this manner, order can be introduced into randomnicity, and self-consistent realities can be extracted from transcendent chaos. The key elements in tuning these channels to amplify such information creation are the physiological and psychological filters imposed upon them, some of which can be enhanced or altered by conscious or unconscious attention. Specifically, such attitudinal tactics as openness to alternative perspectives, utilization of transdisciplinary metaphors, self-sacrificial resonance, tolerance of uncertainty, and replacement of dualistic rigor by mental complementarity can enable experiential realities that are responsive to intention, desire, or need, to an extent consistent with prevailing empirical evidence.

Observer variation in immunohistochemical analysis of protein expression, time for a change?

AIM: Immunohistochemical analysis of protein expression is central to most clinical translational studies and defines patient treatment or selection criteria for novel drugs. Interobserver variation is rarely analysed despite recognition that this is a key area of potential inaccuracy. Therefore our aim was to examine observer variation and suggest the revision of current standards. METHODS AND RESULTS: We analysed inter- and intra-observer variation, by interclass correlation coefficient (ICCC) and kappa statistics, in 8661 samples. Intra-observer assessment of nuclear, cytoplasmic and membrane staining for seven proteins in 1323 samples resulted in an ICCC of 0.94 and a kappa-value of 0.787. Interobserver reproducibility, assessed on 28 proteins by seven observer pairs in 8661 carcinomas, gave an ICCC of 0.90 and a kappa-value of 0.70. No significant effect of either antibody or cellular compartmentalization was observed. CONCLUSION: We have demonstrated that ICCC is a consistent method to assess observer variation when a continuous scoring system is used, compared with kappa statistics, which depends on a categorical system. Given the importance of accurate assessment of protein expression in diagnostic and experimental medicine, we suggest raising thresholds for observer variation: ICCC of 0.7 should be regarded as the minimum acceptable standard, ICCC of 0.8 as good and ICCC of > or = 0.9 as excellent.

Consciousness, information, and living systems.

The possibility of a proactive role for consciousness in the establishment of physical reality has been addressed via an extensive 26-year program investigating physical anomalies in human/machine interactions and non-sensory acquisition of information about remote geographical locations. Empirical databases comprising many hundreds of millions of random events confirm that information can be introduced into, or extracted from, otherwise random physical processes solely through the agencies of human intention and subjective resonance. Much of the evidence mitigates the likelihood that the anomalies are manifestations of neo-cortical cognitive activity. Rather, they may be expressions of a deeper information organizing capacity of biological origin that emerges from the uncertainty inherent in the complexity of all living systems.

IHC for Her2 with CBE356 antibody is a more accurate predictor of Her2 gene amplification by FISH than HercepTest in breast carcinoma.

BACKGROUND: Her2 (c-erbB-2/neu) overexpression in breast carcinoma predicts response to the anti-Her2 monoclonal antibody, trastuzumab, and is associated with a poor prognosis. When considering patients for trastuzumab treatment, Her2 protein expression is measured by imunohistochemistry (IHC) and, where staining is equivocal, by fluorescence in situ hybridisation (FISH) detection of Her2 gene amplification. AIMS: To compare IHC using CBE356 with IHC using the Food and Drug Administration approved HercepTesttrade mark. METHODS: CBE356 and HercepTest were analysed using 167 FISH characterised breast carcinomas. Immunohistochemical expression of Her2 was measured semiquantitatively. Sensitivity, specificity, predictive values, and overall accuracy were calculated for both IHC methods using gene amplification by FISH as the end point, and IHC and FISH assays were tested in Kaplan-Meier survival analysis. RESULTS: The accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of CBE356 positive (2+ and 3+) cases were 94%, 89%, 95%, 84%, and 97%, respectively, and of HercepTest positive (2+ and 3+) cases were 91%, 66%, 98%, 92%, and 91%, respectively. A positive result with CBE356, HercepTest, or FISH was associated with significantly decreased overall survival (log rank p = 0.005, p = 0.0017, and p = 0.0005, respectively). CONCLUSIONS: Positive IHC staining for Her2 using CBE356 is 3% more accurate and 23% more sensitive at predicting Her2 gene amplification by FISH than positive staining with HercepTest. Negative IHC using CBE356 antibody is 6% more likely to represent a truly negative result than negative staining with HercepTest. Overall, CBE356 was a more accurate predictor of Her2 gene amplification by FISH than HercepTest.