Precision Oncology in Surgery: Patient Selection for Operable Pancreatic Cancer.

OBJECTIVE: We aimed to define preoperative clinical and molecular characteristics that would allow better patient selection for operative resection. BACKGROUND: Although we use molecular selection methods for systemic targeted therapies, these principles are not applied to surgical oncology. Improving patient selection is of vital importance for the operative treatment of pancreatic cancer (pancreatic ductal adenocarcinoma). Although surgery is the only chance of long-term survival, 80% still succumb to the disease and approximately 30% die within 1 year, often sooner than those that have unresected local disease. METHOD: In 3 independent pancreatic ductal adenocarcinoma cohorts (total participants = 1184) the relationship between aberrant expression of prometastatic proteins S100A2 and S100A4 and survival was assessed. A preoperative nomogram based on clinical variables available before surgery and expression of these proteins was constructed and compared to traditional measures, and a postoperative nomogram. RESULTS: High expression of either S100A2 or S100A4 was independent poor prognostic factors in a training cohort of 518 participants. These results were validated in 2 independent patient cohorts (Glasgow, n = 198; Germany, n = 468). Aberrant biomarker expression stratified the cohorts into 3 distinct prognostic groups. A preoperative nomogram incorporating S100A2 and S100A4 expression predicted survival and nomograms derived using postoperative clinicopathological variables. CONCLUSIONS: Of those patients with a poor preoperative nomogram score, approximately 50% of patients died within a year of resection. Nomograms have the potential to improve selection for surgery and neoadjuvant therapy, avoiding surgery in aggressive disease, and justifying more extensive resections in biologically favorable disease.

Fiber-Optic Confocal Laser Endomicroscopy of Small Renal Masses: Toward Real-Time Optical Diagnostic Biopsy.

PURPOSE: The incidental detection of small renal masses is increasing. However, not all require aggressive treatments as up to 20% are benign and the majority of malignant tumors harbor indolent features. Improved preoperative diagnostics are needed to differentiate tumors requiring aggressive treatment from those more suitable for surveillance. We evaluated and compared confocal laser endomicroscopy with standard histopathology in ex vivo human kidney tumors as proof of principle towards diagnostic optical biopsy. MATERIALS AND METHODS: Patients with a solitary small renal mass scheduled for partial or radical nephrectomy were enrolled in study. Two kidneys were infused with fluorescein via intraoperative intravenous injection and 18 tumors were bathed ex vivo in dilute fluorescein prior to confocal imaging. A 2.6 mm confocal laser endomicroscopy probe was used to image tumors and surrounding parenchyma from external and en face surfaces after specimen bisection. Confocal laser endomicroscopy images were compared to standard hematoxylin and eosin analysis of corresponding areas. RESULTS: Ex vivo confocal laser endomicroscopy imaging revealed normal renal structures that correlated well with histology findings. Tumor tissue was readily distinguishable from normal parenchyma, demonstrating features unique to benign and malignant tumor subtypes. Topical fluorescein administration provided more consistent confocal laser endomicroscopy imaging than the intravenous route. Additionally, en face tumor imaging was superior to external imaging. CONCLUSIONS: We report what is to our knowledge the first feasibility study using confocal laser endomicroscopy to evaluate small renal masses ex vivo and provide a preliminary atlas of images from various renal neoplasms with corresponding histology. These findings serve as an initial and promising step toward real-time diagnostic optical biopsy of small renal masses.

Clinical Experience With Pharmacological Venous Thromboembolism Prophylaxis in the Underweight and Critically Ill.

BACKGROUND: The optimal regimen for pharmacological prophylaxis of venous thromboembolism (VTE) in underweight, critically ill patients is unknown. OBJECTIVE: To describe prescribing patterns for VTE prophylaxis in underweight (≤50 kg or body mass index ≤18.5 kg/m(2)), critically ill patients and identify the prevalence of VTE and bleeding. METHODS: This was a retrospective cohort study that included patients who received standard- or reduced-dose VTE prophylaxis for ≥48 hours. RESULTS: A total of 295 individuals were included in the study. The majority of underweight patients in this study (79.7%) received unfractionated heparin, 5000 units 3 times daily. No statistically significant difference in the prevalence of clinically relevant VTEs between the reduced- and standard-dose groups was observed (4.4% vs 5.6%, P = 1.00), but a higher proportion of bleeding events was identified within the standard-dose group (6.7% vs 11.2%, P = 0.4). CONCLUSIONS: Empirical dose reductions of VTE prophylaxis are infrequently used in underweight, critically ill patients. Further studies need to be conducted that assess the safety and efficacy of reduced-dose VTE prophylactic regimens in this population to determine if acceptable efficacy can be achieved, with lower risks of bleeding.

The effect of ultrafiltration with cardiopulmonary bypass on the removal of dabigatran from the circulation of adult pigs.

OBJECTIVE: Dabigatran etexilate is a direct thrombin inhibitor approved for use in patients with non-valvular atrial fibrillation. There is no currently available pharmacological therapy to reverse this renally cleared anticoagulant. Dabigatran has a low level of plasma protein binding and has been considered dialyzable. We used a pig model with renal artery ligation to exclude intrinsic drug excretion to examine the efficacy of ultrafiltration (UF) during cardiopulmonary bypass (CPB) for dabigatran removal. METHOD: Dabigatran was intravenously infused (20 mg) in Yorkshire pigs (male, n=7, 70±1 kg) following renal artery ligation. CPB with UF was initiated after heparinization and continued until a total volume of 6 liters of UF effluent was removed. Serial labs, including dabigatran concentration, activated coagulation times (ACT), hematocrit and creatinine were drawn at intervals before the start of CPB and then incrementally during UF (0, 2, 4 and 6 L removed). Hemodialysis (HD) was performed on one animal following UF. RESULTS: Dabigatran concentration (ng/mL) rose from undetectable levels at baseline to 296±70 (p<0.05) at the conclusion of infusion, but dropped significantly upon administration of heparin (178±40, p<0.05). A further decrement in dabigatran concentration was observed from the administration of heparin to the start of CPB (to 135±28, p<0.05). Once on CPB, dabigatran remained stable, with the end UF (eUF) dabigatran concentration being 133±34. Dabigatran concentration in the UF effluent was measured in one animal and was 98.8, with 6 L of effluent having been removed. The total recovery of dabigatran was calculated to be less than 5%. Dabigatran concentrations also did not decrease appreciably with HD on CPB following UF. CONCLUSIONS: UF in conjunction with CPB was ineffective at removing dabigatran. Heparin demonstrated a dabigatran-lowering effect, suggesting a possible drug interaction or assay impairment. Based on these findings, emergent cardiac surgery with UF on cardiopulmonary bypass to remove dabigatran is not advisable. Alternative forms of drug removal or reversal must be identified.

MALDI Mass Spectrometry Imaging Reveals Decreased CK5 Levels in Vulvar Squamous Cell Carcinomas Compared to the Precursor Lesion Differentiated Vulvar Intraepithelial Neoplasia.

Vulvar cancer is the fourth most common gynecological cancer worldwide. However, limited studies have been completed on the molecular characterization of vulvar squamous cell carcinoma resulting in a poor understanding of the disease initiation and progression. Analysis and early detection of the precursor lesion of HPV-independent vulvar squamous cell carcinoma (VSCC), differentiated vulvar intraepithelial neoplasia (dVIN), is of great importance given dVIN lesions have a high level of malignant potential. Here we present an examination of adjacent normal vulvar epithelium, dVIN, and VSCC from six patients by peptide Matrix-assisted laser desorption/ionization Mass Spectrometry Imaging (MALDI-MSI). The results reveal the differential expression of multiple peptides from the protein cytokeratin 5 (CK5) across the three vulvar tissue types. The difference observed in the relative abundance of CK5 by MALDI-MSI between the healthy epithelium, dVIN, and VSCC was further analyzed by immunohistochemistry (IHC) in tissue from eight VSCC patients. A decrease in CK5 immunostaining was observed in the VSCC compared to the healthy epithelium and dVIN. These results provide an insight into the molecular fingerprint of the vulvar intraepithelial neoplasia that appears to be more closely related to the healthy epithelium than the VSCC.

Expression of a retinoic acid receptor (RAR)-like protein in the embryonic and adult nervous system of a protostome species.

The vitamin A metabolite, retinoic acid, is an important molecule in nervous system development and regeneration in vertebrates. Retinoic acid signaling in vertebrates is mediated by two classes of nuclear receptors, the retinoid X receptors (RXRs) and the retinoic acid receptors (RARs). Recently, evidence has emerged to suggest that many effects of retinoic acid are conserved between vertebrate and invertebrate nervous systems, even though the RARs were previously thought to be a vertebrate innovation and to not exist in non-chordates. We have cloned a full-length putative RAR from the CNS of the mollusc Lymnaea stagnalis (LymRAR). Immunoreactivity for the RAR protein was found in axons of adult neurons in the central nervous system and in growth cones of regenerating neurons in vitro. A vertebrate RAR antagonist blocked growth cone turning induced by exogenous all-trans retinoic acid, possibly suggesting a role for this receptor in axon guidance. We also provide immunostaining evidence for the presence of RAR protein in the developing, embryonic CNS, where it is also found in axonal processes. Using qPCR, we determined that LymRAR mRNA is detectable in the early veliger stage embryo and that mRNA levels increase significantly during embryonic development. Putative disruption of retinoid signaling in Lymnaea embryos using vertebrate RAR antagonists resulted in abnormal eye and shell development and in some instances completely halted development, resembling the effects of all-trans retinoic acid. This study provides evidence for RAR functioning in a protostome species.

A potentially novel nicotinic receptor in Aplysia neuroendocrine cells.

Nicotinic receptors form a diverse group of ligand-gated ionotropic receptors with roles in both synaptic transmission and the control of excitability. In the bag cell neurons of Aplysia, acetylcholine activates an ionotropic receptor, which passes inward current to produce a long-lasting afterdischarge and hormone release, leading to reproduction. While testing the agonist profile of the cholinergic response, we observed a second current that appeared to be gated only by nicotine and not acetylcholine. The peak nicotine-evoked current was markedly smaller in magnitude than the acetylcholine-induced current, cooperative (Hill value of 2.7), had an EC50 near 500 µM, readily recovered from desensitization, showed Ca(2+) permeability, and was blocked by mecamylamine, dihydro-ß-erythroidine, or strychnine, but not by α-conotoxin ImI, methyllycaconitine, or hexamethonium. Aplysia transcriptome analysis followed by PCR yielded 20 full-length potential nicotinic receptor subunits. Sixteen of these were predicted to be cation selective, and real-time PCR suggested that 15 of the 16 subunits were expressed to varying degrees in the bag cell neurons. The acetylcholine-induced current, but not the nicotine current, was reduced by double-strand RNA treatment targeted to both subunits ApAChR-C and -E. Conversely, the nicotine-evoked current, but not the acetylcholine current, was lessened by targeting both subunits ApAChR-H and -P. To the best of our knowledge, this is the first report suggesting that a nicotinic receptor is not gated by acetylcholine. Separate receptors may serve as a means to differentially trigger plasticity or safeguard propagation by assuring that only acetylcholine, the endogenous agonist, initiates large enough responses to trigger reproduction.

The Current Role of Analytical Psychology in Maintaining Fictitious Boundaries that are Promoted through the Race Lie: A call to dismantle the virtual wall that exists through attitudes of white supremacy.

In 1928, the American Anthropological Association declared that "Anthropology provided no scientific basis for discrimination against any people on the ground of racial inferiority, religious affiliation, or linguistic heritage" (Guthrie, 1976/1998/2004, p. 30). In 1945, Jung denounced race theory as a pseudo-science. In 1950, UNESCO released its statement denouncing race. Long discredited as scientifically invalid, the race concept still holds uncanny value and significance for Americans and Europeans. In effect, the concept seems to be mysteriously linked to the limited accessibility and the limited economic support that is allotted to people of colour, internationally. This paper will explore the global implications of Jung's expressed attitude towards people of colour prior to 1945, which I identify as an attitude of white supremacy, an attitude that stands in direct contrast to the analytical ethos, as expressed by the International Association for Analytical Psychology (IAAP). This attitude may promote the continuance of racialized beliefs and behaviours within the planning and provision of care to individuals in need of medical and mental health services. It is requested that a written acknowledgment of harm be added to the works of C. G. Jung.

En 1928, l'American Anthropological Association a déclaré que « l'anthropologie ne fournissait aucun fondement scientifique pour la discrimination contre toute personne sur la base de l'infériorité raciale, de l'affiliation religieuse ou de l'héritage linguistique ¼ (Guthrie, 2004, p. 30). En 1945, Jung a dénoncé la théorie de la race comme une pseudoscience. En 1950, l'UNESCO a publié une déclaration dénonçant la notion de race. Longtemps discrédité comme scientifiquement invalide, le concept de race a toujours une valeur et une signification étranges pour les Américains et les Européens. En effet, le concept semble être mystérieusement lié à l'accessibilité limitée et au soutien économique limité qui est accordé aux personnes de couleur, à l'échelle internationale. Cette présentation explorera les implications globales de l'attitude exprimée par Jung envers les personnes de couleur avant 1945, que j'identifie comme une attitude de suprématie blanche, une attitude qui contraste directement avec l'esprit analytique, tel qu'exprimé par l'Association Internationale de Psychologie Analytique. Cette attitude risque de favoriser le maintien de croyances et de comportements racialisés dans la planification et la dispensation de soins aux personnes qui ont besoin de services médicaux et de santé mentale. Il est demandé qu'une reconnaissance écrite du préjudice causé soit ajoutée aux travaux de C. G. Jung.

En 1928, la Asociación Americana de Antropología declaró que "la antropología no proporcionaba ninguna base científica para discriminar a un pueblo sobre la base de inferioridad racial, afiliación religiosa o herencia lingüística" (Guthrie, 2004, p. 30). En 1945, Jung denunció la teoría racial como pseudociencia. En 1950, la UNESCO publicó su declaración denunciando la raza. Desacreditado hace tiempo como científicamente inválido, el concepto de raza sigue teniendo un valor y un significado sorprendente para estadounidenses y europeos. En efecto, el concepto parece estar misteriosamente vinculado a la limitada accesibilidad y al limitado apoyo económico que se asigna a las personas de color, a escala internacional. Esta presentación explorará las implicancias globales de la actitud expresada por Jung hacia la gente de color antes de 1945, la cual identifico como una actitud de supremacía blanca, una actitud que contrasta directamente con el ethos analítico, tal y como lo expresa la Asociación Internacional de Psicología Analítica. Esta actitud puede promover la continuidad de creencias y comportamientos raciales en la planificación y provisión de cuidados a individuos que necesitan servicios médicos y de salud mental. Se solicita que se añada por escrito a las obras de C. G. Jung un reconocimiento del daño.

Impact of Pharmacist Intervention on Inappropriate Continuations of Antipsychotics upon ICU Discharge.

Background: Transitions of care (TOC) are important to best practices as they are at times prone to medication errors. The intensive care unit (ICU) is an essential location needing effective TOC due to many reasons, but an important one being that certain medications are only indicated there. One example is antipsychotics used for agitation, delirium, and sedation. Objective: To design, implement, and analyze the benefit of a pharmacist intervention on inappropriate antipsychotic continuation from the ICU to another point in care at a small community hospital. Secondary outcomes include patients discharged from the hospital on antipsychotics inappropriately and accepted pharmacist interventions. Methods: This standard of care, prospective with historical control study included adult patients who were ordered a formulary antipsychotic for delirium, agitation, or sedation during their ICU-level of care admission at SSM Health: St. Clare Hospital- Fenton. Results: There were 33 patients in the historical period and 24 in the intervention period. Those in the intervention period were less likely to have a continuation of antipsychotics beyond 72 hours compared to patients in the historical period (16.7% vs 57.6%, P = 0.002). In addition, patients in the intervention period were less likely to have continuation of antipsychotics when discharged to home (12.5% vs 36.4%, P = 0.04). Conclusions: A pharmacist-driven intervention led to a significant decrease in patients continuing antipsychotics upon ICU discharge. This decrease was seen at both 72 hours from patients leaving the ICU and at hospital discharge.