Hidden in Plain Sight: Clinical Informaticians are the Oncology Subspecialists You Did Not Know You Needed.

Clinical informatics is a young, diverse and rapidly growing field. We asked eight clinical informaticians from a variety of oncology specialties, training pathways and careers for personal narratives to illustrate the wide spectrum of clinical informatics careers. Primary clinical specialties included radiation oncology, medical/haematology oncology and palliative care. Training pathways included fellowship, non-fellowship formal training and informal training. Careers included clinical care, research, operations and industry. We summarised common themes and advice for trainees. We hope to raise awareness of clinical informatics among trainees and oncologists to reveal new career opportunities and to avoid inadvertently taking clinical informatics and informaticians for granted.

The effect of the drying temperature on the properties of wet-extruded calcium stearate pellets: pellet microstructure, drug distribution, solid state and drug dissolution.

Although drying is widely applied during the manufacturing of solid dosage forms, its potential effect on the product's (key) properties is often underestimated. Hence, the present study addresses drying related modifications of wet-extruded pellets comprising calcium stearate (CaSt, matrix former) and ibuprofen (model drug). After spheronization, the pellets were tray dried at different temperatures. The dried pellets were evaluated regarding their microstructure, the ibuprofen distribution, solid state modifications and the resulting in-vitro dissolution profiles. The ibuprofen distribution profiles along the pellets' cross-sections varied for the different drying conditions. The profiles turned from inhomogeneous to uniform with increasing drying temperature. Temperatures above 20°C yielded solid state modifications, including ibuprofen transition into the amorphous state and the formation of eutectic compositions. As none of the batches exhibited a high specific surface area associated with an open, well-interconnected pore system, the dissolution profiles were a function of the ibuprofen distribution. Differences in the solid state did not contribute to the dissolution behavior, since the CaSt matrix did not swell or dissolve in the dissolution medium. These findings show that drying may considerably affect the final product properties even for moderate drying conditions.

Submicron polymeric particles prepared by vibrational spray-drying: Semisolid formulation and skin penetration/permeation studies.

Topical glucocorticoids (TG) such as dexamethasone (DEX) have been used for decades for the treatment of skin diseases. However, TG present well-documented side effects and their delivery to the skin is often insufficient. Therefore, many efforts have been undergone to improve the amount of drug delivered to the skin and to reduce side effects at the same time. In this work, the feasibility of DEX-submicron polymeric particles (SP) prepared by vibrational spray-drying as an approach to overcome the challenges associated with the topical administration of this drug class was evaluated. DEX was homogeneously dispersed in the SP matrix, according to confocal Raman microscopy analysis. Drug-loaded SP were incorporated into the oil phase of oil-in-water emulsions (creams). The formulation containing polymeric submicron particles (C-SP) showed controlled drug release kinetics and a significant drug accumulation in skin compared to formulations containing non-polymeric particles or free drug. DEX accumulation in the stratum corneum was evaluated by tape stripping and a depot effect over time was observed for C-SP, while the formulation containing the free drug showed a decrease over time. Similarly, C-SP presented higher drug retention in epidermis and dermis in skin penetration studies performed on pig skin in Franz diffusion cells, while drug permeation into the receptor compartment was negligible. It was demonstrated, for the first time, the advantageous application of submicron polymeric particles obtained by vibrational spray-drying in semisolid formulations for cutaneous administration to overcome challenges related to the therapy with TG such as DEX.

Label-free in vitro visualization of particle uptake into human oral buccal epithelial cells by confocal Raman microscopy.

In this study, we present confocal Raman microscopy for chemically selective analysis of a human buccal epithelial cell layer with a focus on label-free visualization of particle uptake into the cells. We demonstrate the suitability and benefit of this analytical technique in comparison to confocal fluorescence microscopy for three dimensional imaging of in vitro cell models.

Impact of drying on solid state modifications and drug distribution in ibuprofen-loaded calcium stearate pellets.

Drying is a common pharmaceutical process, whose potential to alter the final drug properties-even at relatively low temperatures-is often neglected. The present study addresses the impact of drying at 20 and 50 °C on wet-extruded calcium stearate (CaSt) pellets. Drying at 20 °C caused the majority of ibuprofen to accumulate at the pellet surface due to a strong convective flow from the pellet's center to the surface. In contrast, pellets dried at 50 °C still contained ibuprofen in the pellet's interior due to the higher drying rate and the associated film breakage during drying. Moreover, the higher drying temperature caused CaSt to form a second lamellar phase and ibuprofen to convert (partly) into its amorphous state. Overall, the drying process affected the solid state and the spatial ibuprofen distribution within the pellet. Knowledge of these effects can aid in tailoring advanced multipellet formulations.

Color-coded duplex endoscopic ultrasound of the adrenals.

Imaging of the adrenals by endoscopic ultrasound (EUS) is a valuable technique for detection and localization of adrenal lesions, but endosonomorphological tumor distinction remains difficult. In this single-center study, the amount of blood flow in common adrenal lesions, such as adrenal adenomas, adrenal hyperplasia, and pheochromocytomas, was visualized by color-coded duplex EUS (CD-EUS) and was retrospectively analysed. Therefore, we reviewed our EUS database to evaluate and correlate the perfusion patterns of common adrenal lesions with histologically confirmed diagnosis, possible malignancy, and endosonomorphological features such as echogeneity, echostructure, and tumor size. CD-EUS was performed using an endosonoscope Pentax FG 32 UA with a longitudinal 7.5 MHz sector array and Hitachi EUB 525 ultrasound system. In 38 consecutive patients (male=19; female=19; age: mean 53+/-16 yr SD), perfusion patterns of 46 histologically confirmed adrenal, para- or extra-adrenal lesions of adrenal origin (adenoma: no.=20; nodular hyperplasia: no.=11; pheochromocytoma: no.=15; diameter 26+/-15 mm, range 6-70 mm) were analyzed and classified semiquantitatively as "not" (no.=24), "slightly" (no.=12), "moderately" (no.=4) or "highly" (no.=6) hypervascularized. Compared to adenomas (p=0.003) and nodular hyperplasia (p=0.047), pheochromocytomas showed a significantly higher grade of perfusion. There was no relationship between perfusion patterns and localization of pheochromocytomas (adrenal: 8; paraadrenal: 3; extra-adrenal: 4). Vascularization was not statistically associated with tumor echogeneity, echostructure, malignancy or tumor size. CD-EUS is an additional tool for adrenal endosonographic tumor distinction and seems to improve the endosonographic detection of pheochromocytomas by visualization of hypervascularization. As an overlap of perfusion patterns exists, CD-EUS findings must be interpreted in the context of clinical, laboratory and chemical results.

Small neuroendocrine pancreatic tumors in multiple endocrine neoplasia type 1 (MEN1): least significant change of tumor diameter as determined by endoscopic ultrasound (EUS) imaging.

Endosonography enables detection and localization of small pancreatic neuroendocrine tumors (PETs) which cannot be detected by computed tomography, magnetic resonance imaging, or somatostatin receptor scintigraphy. Knowledge about the prognosis of very small PETs in MEN1 is limited, and if there are no clinical symptoms, endocrine activity or mechanical problems and thus no clear indication for surgical therapy, an appropriate decision for the management of such patients might be to control their follow-up by endosonographic imaging. Therefore, the reproducibility of the measurement of the diameter of very small PETs by endosonographic imaging was investigated in this prospective study. We included 33 PETs smaller than 15 mm in their largest diameter detected by endosonographic imaging (Pentax FG 32 UA) in ten patients with genetically confirmed MEN1-disease. Three repeated measurements of each tumor were performed. Reproducibility was expressed as mean coefficient of variation of intra-observer variability. Mean tumor diameter was 6.9 +/- 3.4 mm (range 2.8 - 14.2 mm). Mean coefficient of variation was 5.5 +/- 4.6 % (range 0.0 - 19.4 %): in tumors < 5 mm (n = 13) 7.1 +/- 6.3 %, in tumors > 5 mm (n = 20) 4.4 +/- 2.6 %. Least significant change (p < 0.05) was calculated as 15.4 % (tumors < 5 mm: 19.9 %; tumors > 5 mm: 12.3 %). In conclusion, endosonographic imaging enables the measurement of small PETs with an acceptable reproducibility. Changes of tumor diameter of more than 20 % have to be taken as statistically significant.

Harmful drinking in military veterans with post-traumatic stress disorder: association with the D2 dopamine receptor A1 allele.

AIMS: The frequency of the Taq I A alleles (A1 and A2) of the D2 dopamine receptor (DRD2) gene was examined in Caucasian post-traumatic stress disorder (PTSD) patients and controls. RESULTS: In 91 PTSD patients, the frequency of the A1 allele was higher (P = 6.12 x 10(-3)) than in the 51 controls. In the 38 PTSD harmful drinkers (>or=60 g alcohol/day), A1 allelic frequency was higher (P = 3.91 x 10(-2)) than in the 53 non-harmful drinkers (<60 g alcohol/day), the former being also higher (P = 3.76 x 10(-4)) than in controls. However, there was no difference between non-harmful drinkers and controls. Based on DRD2 allelic association, the 35 PTSD patients with the A1(+) (A1A1, A1A2) allele consumed more than twice the daily amount of alcohol than the 56 patients with the A1(-) (A2A2) allele (P = 1.94 x 10(-3)). When the hourly rate of alcohol consumed was compared, A1(+) allelic patients consumed twice the rate of the A1(-) allelic patients (P < 10(-7)). CONCLUSION: The DRD2 A1 allele was associated with PTSD. However, this association was found only in the harmful drinkers. PTSD patients with the A1(+) allele consumed more alcohol than patients with the A1(-) allele. The importance of determining alcohol consumption in DRD2 association studies with PTSD is suggested.

GABA(A) receptor beta 3 subunit gene and psychiatric morbidity in a post-traumatic stress disorder population.

GABAergic systems have been implicated in the pathogenesis of anxiety, depression and insomnia. These symptoms are part of the core and comorbid psychiatric disturbances in post-traumatic stress disorder (PTSD). In a sample of Caucasian male PTSD patients, dinucleotide repeat polymorphisms of the GABA(A) receptor beta 3 subunit gene were compared to scores on the General Health Questionnaire-28 (GHQ). As the major allele at this gene locus (GABRB3) was G1, the alleles were divided into G1 and non-G1 groups. On the total score of the GHQ, which comprises the somatic symptoms, anxiety/insomnia, social dysfunction and depression subscales, patients with the G1 non-G1 genotype had a significantly higher score when compared to either the G1G1 genotype (alpha=0.01) or the non-G1 non-G1 genotype (alpha=0.05). No significant difference was found between the G1G1 and non-G1 non-G1 genotypes. When the G1 non-G1 heterozygotes were compared to the combined G1G1 and non-G1 non-G1 homozygotes, a significantly higher total GHQ score was found in the heterozygotes (P=0.002). These observations suggest a heterosis effect. Further analysis of GHQ subscale scores showed that heterozygotes compared to the combined homozygotes had higher scores on the somatic symptoms (P=0.006), anxiety/insomnia (P=0.003), social dysfunction (P=0.054) and depression (P=0.004) subscales. In conclusion, the present study indicates that in a population of PTSD patients, heterozygosity of the GABRB3 major (G1) allele confers higher levels of somatic symptoms, anxiety/insomnia, social dysfunction and depression than found in homozygosity.

Nicotine induces endothelial TNF-alpha expression, which mediates growth retardation in vitro.

PURPOSE: Atherosclerosis is understood as the common pathologic manifestation of arterial injury caused by a variety of etiologies. One well-established etiologic agent is nicotine. We hypothesized that cytokines of endothelial origin are involved with the pathologic changes found in atherosclerosis associated with smoking. We chose to assay for TNF-alpha due to its many biologic actions that are similar to those found in peripheral vascular disease. METHODS: Human umbilical vein endothelial cells (HUVEC) were plated in endothelial growth medium (EGM-2) on plastic coverslips until 75% confluent. Free base nicotine (FBN) was diluted in EGM-2 to a concentration of 10(-8) M and added to experimental cells. At 1, 3, and 24 h, coverslips were removed and fixed. Immunohistochemical staining was performed using anti-TNF-alpha. Digital image analysis (DIA) was performed to quantify expression of TNF-alpha. An intensity stain index measuring area and intensity of stain/total cellular area was determined for each time point (n = 5). Additional HUVEC were plated in 12-well plates in EGM-2 at 2 x 10(3) cells/cm(2) on T(-2) day. FBN was diluted in medium to 10(-9) M and added to wells with and without 0.9 microg/ml anti-TNF-alpha on T(0) day. Cell counts were performed in triplicate on days T(2-5) utilizing hemocytometry. Data was analyzed using Student's t test and ANOVA, with a 95% confidence interval. RESULTS: Dose response determinations showed that the minimal concentration required to show statistically significant cell retardation is 10 (-9) M. Accordingly, this concentration was used for subsequent proliferation studies. DIA showed a threefold increase in TNF-alpha activity at 1 h and a twofold increase at 3 h. Activity returned to baseline by 24 h. Cell growth was significantly decreased in cells exposed to nicotine when compared to controls on days T(2)-T(5) (P < 0.05). In cells exposed to anti-TNF-alpha and nicotine there was inhibition of the growth retardation seen in the cells containing nicotine alone. Differences between the control group and the anti-TNF-alpha group were not statistically significant. CONCLUSION: These data demonstrate the ability of endothelial cells to secrete TNF-alpha in response to nicotine at levels found in serum after smoking and also shows that endothelial cell growth retardation as a consequence of nicotine exposure may be TNF-alpha mediated.

BioGlue surgical adhesive for thoracic aortic repair during coagulopathy: efficacy and histopathology.

BACKGROUND: We hypothesized that induction of coagulopathy in sheep would model clinical needle hole and surgical bleeding from synthetic graft anastomoses, and that a new tissue bioadhesive (BioGlue) would control postoperative blood loss during surgical repair of the thoracic aorta. METHODS: Sheep were anticoagulated with aspirin and heparin. A bypass was made using end-to-side anastomoses of a graft to a partially occluded descending thoracic aorta. Experimental anastomoses (EXP, n = 9) were treated with BioGlue, and control anastomoses (CON, n = 5) were treated with Surgicel to gain intraoperative hemostasis. RESULTS: EXP animals exhibited significantly reduced postsurgical bleeding (CON median 955 mL versus EXP median 470 mL, p < 0.003), a reduced rate of blood loss over the first 2 postoperative hours (CON median 210 mL/hr versus EXP median 92.5 mL/hr, p < 0.006), and over the entire recovery period (CON median 158 mL/hr versus EXP median 86 mL/hr, p < 0.05), and reduced total blood loss (CON mean 1,497 +/- 691 mL versus EXP mean 668 +/- 285 mL, p < 0.008). On histologic examination of tissues explanted after 3 months, BioGlue was relatively inert and demonstrated a minimal inflammatory response. CONCLUSIONS: The use of BioGlue significantly reduced the volume and rate of postsurgical bleeding in a coagulopathic sheep model for thoracic aortic operations. Histopathologically, BioGlue generated only a minimal inflammatory response. This new surgical tissue bioadhesive should prove extremely beneficial for coagulopathic patients undergoing thoracic aortic or vascular procedures.

Hemangioma of the right ventricular outflow tract.

Obstruction of the right ventricular outflow tract by a primary cardiac tumor is rare. Six cases of right ventricular outflow tract obstruction by a primary cardiac hemangioma have been reported; all but one were detected before the age of 25 years. In this report, we review the literature and describe what we believe to be only the second reported case of right ventricular outflow tract obstruction produced by a cardiac hemangioma that presented in late adulthood.

Past, present, and future research in the field of composite tissue allotransplantation.

In September 1998, a surgical team in Lyon, France, performed the first successful hand transplant. After this historic event, in January 1999, the University of Louisville performed the first hand transplant in the United States. These events sparked interest and debate concerning the justification of performing limb allotransplantation. The field of composite tissue allotransplantation (CTA) has made significant advances in the past two decades, yet advancement of the applications of CTA into the clinical arena had been fairly limited to this point. The most inherent controversy in CTA involves the fact that the clinical applications for the most part involve restoration of function and/or structural integrity. These procedures are done essentially for quality-of-life concerns, not life-saving issues. Present concern involves subjecting CTA recipients to a lifetime of postoperative immunosuppressive therapy. We cannot fully understand where we stand at present and in what future directions the field is heading unless we have an understanding of where we have been in composite tissue transplantation. This article reviews the historical aspects of CTA, discusses the present state of CTA, and speculates on potential future applications of CTA.

Age-adjusted outcomes in traumatic flail chest injuries in the elderly.

Severe chest trauma does not independently predict poor outcome in elderly patients. We chose a specific injury, flail chest, to determine whether age factored into outcome of these patients. A retrospective chart review of all trauma admissions to our Level I trauma center between January 1994 and January 1998 sustaining flail chest was undertaken. Sixty-eight patients were identified, but ten patients were excluded because of death on arrival. Fifty-eight patients were included in the study and separated into groups. The first group comprised those under the age of 55 (n = 32) and the second comprised those over age 55 (n = 26). Parameters evaluated were age, Injury Severity Score (ISS), neurologic injury, the need for mechanical ventilation, need for tracheostomy, length of stay, and death. Statistical analysis was performed with Wilcoxon t test, chi2, and logistic regression where appropriate. A 95 per cent confidence interval was sought as determinant of significance. Of the 58 surviving patients analyzed there was no significant difference between the groups regarding ISS, length of stay, days on the ventilator, head injury, tracheostomy, or development of pneumonia or adult respiratory distress syndrome. The likelihood of death was shown to increase by 132 per cent for every 10 years starting at the second decade and continuing to the eighth decade of life. The likelihood of death also increased by 30 per cent for each unit increase in ISS. The likelihood of death decreased by 23 per cent for every day survived in the hospital. Blunt chest trauma directly impacts respiratory mechanics. Elderly patients are more likely to have comorbid conditions and less likely to tolerate traumatic respiratory compromise. Age (and its effects on the body) is the strongest predictor of outcome with flail chest and is associated with an increased mortality (P < or = 0.05).

Safety of carotid endarterectomy associated with small intracranial aneurysms.

BACKGROUND: The incidence and outcome of combined carotid artery disease and intracranial aneurysm (ICA) are not well reported. METHODS: Ten patients with combined disease, ICA and symptomatic carotid artery disease, were identified in 209 consecutive angiograms. Five men and five women with a mean age of 68 years and the risk factors of diabetes, hypertension, smoking, cardiac disease, peripheral vascular disease, and hypercholesterolemia formed the basis for this study. RESULTS: Five patients with carotid endarterectomy (CEA) and arterial aneurysms less than 5 mm and five with carotid stenosis and ICA less than 6 mm were treated with Coumadin; one with combined disease left the hospital without treatment; and one with combined disease died preoperatively of a myocardial infarction. One patient with a 2 cm x 3 cm ICA and carotid had both operated on successfully. CONCLUSIONS: In this group of patients, CEAs were done safely in patients with ICAs less than 6 mm.