Ashley Wysong

Dexmedetomidine and the Reduction of Postoperative Delirium after Cardiac Surgery

BACKGROUND Delirium is a neurobehavioral syndrome caused by the transient disruption of normal neuronal activity secondary to systemic disturbances. OBJECTIVE The authors investigated the effects of postoperative sedation on the development of delirium in patients undergoing cardiac-valve procedures. METHODS Patients underwent elective cardiac surgery with a standardized intraoperative anesthesia protocol, followed by random assignment to one of three postoperative sedation protocols: dexmedetomidine, propofol, or midazolam. RESULTS The incidence of delirium for patients receiving dexmedetomidine was 3%, for those receiving propofol was 50%, and for patients receiving midazolam, 50%. Patients who developed postoperative delirium experienced significantly longer intensive-care stays and longer total hospitalization. CONCLUSION The findings of this open-label, randomized clinical investigation suggest that postoperative sedation with dexmedetomidine was associated with significantly lower rates of postoperative delirium and lower care costs.

An investigator-initiated open-label clinical trial of vismodegib as a neoadjuvant to surgery for high-risk basal cell carcinoma

BACKGROUND Vismodegib is an oral hedgehog-pathway inhibitor approved for advanced basal cell carcinoma (BCC). Although most BCCs are amenable to surgery, excision of large tumors in aesthetically sensitive sites may compromise function or cosmesis. OBJECTIVE We sought to evaluate the reduction in BCC surgical defect area after 3 to 6 months of neoadjuvant vismodegib. METHODS This was an open-label, single-arm intervention trial with a primary outcome of change in target-tumor surgical defect area pre- and post-vismodegib (150 mg/d). Secondary outcomes were change in tumor area and tolerability. RESULTS Eleven of 15 enrolled patients, aged 39 to 100 years, completed the trial. Thirteen target tumors were excised after a mean of 4±2 months of vismodegib. In all, 29% (4 of 14 patients) could not complete more than 3 months because of vismodegib-related side effects. The mean baseline target-tumor diameter was 3.2 cm, and 10 of 13 tumors occurred on the face. Overall, vismodegib reduced the surgical defect area by 27% (95% confidence interval -45.7% to -7.9%; P=.006) from baseline. Vismodegib was not effective in patients who received less than 3 months. Over a mean follow-up of 11.5 (range 4-21) months for all tumors, only 1 tumor recurred at 17 months post-Mohs micrographic surgery. LIMITATIONS Short follow-up time and no placebo control are limitations. CONCLUSION Neoadjuvant vismodegib appears to reduce surgical defect area when taken for 3 months or longer for nonrecurrent BCCs in functionally sensitive locations. Further studies with larger sample sizes and long-term follow-up are warranted.

Update on Metastatic Basal Cell Carcinoma: A Summary of Published Cases From 1981 Through 2011

While basal cell carcinoma (BCC) is the most common cancer in the United States,1 metastasis (mBCC) is extremely rare, with an incidence of 0.0028% to 0.55%.2 The most recent review of mBCC cases from 1894 through 1980 by von Domarus and Stevens2 is now 30 years old. We conducted a retrospective systematic evaluation of all published mBCC cases from 1981 through 2011 to update patient demographics and tumor characteristics associated with mBCC and to determine whether adjuvant therapy was associated with improved survival.

NF-κB Inhibition Protects against Tumor-Induced Cardiac Atrophy in Vivo

Cancer cachexia is a severe wasting syndrome characterized by the progressive loss of lean body mass and systemic inflammation. It occurs in approximately 80% of patients with advanced malignancy and is the cause of 20% to 30% of all cancer-related deaths. The mechanism by which striated muscle loss occurs is the tumor release of pro-inflammatory cytokines, such as IL-1, IL-6, and TNF-α. These cytokines interact with their cognate receptors on muscle cells to enhance NF-κB signaling, which then mediates muscle loss and significant cardiac dysfunction. Genetic inhibition of NF-κB signaling has demonstrated its predominant role in skeletal muscle loss. Therefore, we tested two novel drugs designed to specifically inhibit NF-κB by targeting the IκB kinase (IKK) complex: Compound A and NEMO binding domain (NBD) peptide. Using an established mouse model of cancer cachexia (C26 adenocarcinoma), we determined how these drugs affected the development of tumor-induced cardiac atrophy and function. Echocardiographic and histological analysis revealed that both Compound A and NBD inhibit cardiac NF-κB activity and prevent the development of tumor-induced systolic dysfunction and atrophy. This protection was independent of any effects of the tumor itself (Compound A) or tumor-secreted cytokines (NBD). This study identifies for the first time, to our knowledge, that drugs targeting the IKK complex are cardioprotective against cancer cachexia-induced cardiac atrophy and systolic dysfunction, suggesting therapies that may help reduce cardiac-associated morbidities found in patients with advanced malignancies.

New Onset of Keratoacanthomas After Vismodegib Treatment for Locally Advanced Basal Cell Carcinomas: A Report of 2 Cases

While keratoacanthomas (KAs) and squamous cell carcinomas (SCCs) have been reported in response to a number of systemic drugs such as vemurafenib, sorafenib, or voriconazole, 1–3 their association with Smoothened inhibitors has not been previously noted. Herein, we report 2 cases of new KAs developing within 2 months of starting vismodegib therapy in individuals with no history of KAs or SCCs.

Metabolomic analysis of cancer cachexia reveals distinct lipid and glucose alterations

Cancer cachexia remains a challenging clinical problem with complex pathophysiology and unreliable diagnostic tools. A blood test to detect this metabolic derangement would aid in early treatment of these patients. A 1H NMR-based metabolomics approach was used to determine the unique metabolic fingerprint of cachexia and to search for biomarkers in serum samples taken from an established murine model of cancer cachexia. Male CD2F1 mice received a subcutaneous flank injection of C26 adenocarcinoma cells to induce experimental cancer-related cachexia. Two molecular markers of muscle atrophy, upregulation of the E3 ubiquitin ligase Muscle Ring Finger 1 (MuRF1) and aberrant glycosylation of β-dystroglycan (β-DG), were used to confirm muscle wasting in the tumor-bearing mice. Serum samples were collected for metabolomic analysis during the development of the cachexia: at baseline, when the tumor was palpable, and when the mice demonstrated cachexia. The unsupervised statistical analysis demonstrated a distinct metabolic profile with the onset of cachexia. The critical metabolic changes associated with cachexia included increased levels of very low density lipoprotein (VLDL) and low density lipoprotein (LDL), with decreased serum glucose levels. Regression analysis demonstrated a very high correlation of the presence of aberrant glycosylation of β-DG with the unique metabolic profile of cachexia. This study demonstrates for the first time that metabolomics has potential as a diagnostic tool in cancer cachexia, and in further elucidating simultaneous metabolic pathway alterations due to this syndrome. In addition, variations in VLDL and LDL deserve more investigation as surrogate serum biomarkers for cancer cachexia.

Metabolic derangements in the gastrocnemius and the effect of Compound A therapy in a murine model of cancer cachexia

BackgroundCancer cachexia is a severe wasting syndrome characterized by the progressive loss of lean body mass and systemic inflammation. Inhibiting the signaling of the transcription factor nuclear factor kappa B (NF-κB) largely prevents cancer-induced muscle wasting in murine models. We have previously shown the utility of Compound A, a highly selective novel NF-κB inhibitor that targets the IκB kinase complex, to provide clinical benefit in cancer-induced skeletal muscle and cardiac atrophy.MethodsUsing a metabolomics approach, we describe the changes found between cachectic and noncachectic gastrocnemius muscles before and after Compound A treatment at various doses.ResultsOf the 234 metabolites in the gastrocnemius, cachexia-induced changes in gastrocnemius metabolism reset the steady-state abundances of 42 metabolites (p < 0.05). These changes, not evenly distributed across biochemical categories, are concentrated in amino acids, peptides, carbohydrates and energetics intermediates, and lipids. The gastrocnemius glycolytic pathway is markedly altered—changes consistent with tumor Warburg physiology. This is the first account of a Warburg effect that is not exclusively restricted to cancer cells or rapidly proliferating nonmalignant cells. Cachectic gastrocnemius also displays tricarboxylic acid cycle disruptions, signs of oxidative stress, and impaired redox homeostasis. Compound A only partially rescues the phenotype of the cachectic gastrocnemius, failing to restore the gastrocnemius’ baseline metabolic profile.ConclusionsThe findings in the present manuscript enumerate the metabolic consequences of cachexia in the gastrocnemius and demonstrate that NF-kB targeted treatment only partly rescues the cachectic metabolic phenotype. These data strengthen the previous findings from metabolomic characterization of serum in cachectic animals, suggesting that many of the metabolic alterations observed in the blood originate in the diseased muscle. These findings provide significant insight into the complex pathophysiology of cancer cachexia and provide objective criteria for evaluating future therapeutics.

Quantifying soft tissue loss in facial aging: a study in women using magnetic resonance imaging.

BACKGROUND Facial aging involves changes in the facial skeleton and soft tissues. There is limited quantitative data on soft tissue aging of the face. OBJECTIVE Magnetic resonance imaging (MRI) was used to quantify and compare facial soft tissue loss over time. METHODS AND MATERIALS Two thousand thirty‐seven MRI scans from 58 women divided into young, middle‐aged, and older groups were screened. A blinded radiologist used MRI to measure the temporal, infraorbital, and medial and lateral cheek areas. RESULTS The mean thickness of the subcutaneous tissue in the temporal area was 12.3, 8.4, and 8.9 mm in the young, middle‐aged, and older groups, respectively (p < .001). A mean difference of 1.6 mm was seen between the young and middle‐aged groups and 2.2 mm between the young and older group (p < .001) in the infraorbital area, 3.3 mm between the young and middle‐aged groups and 3.2 mm between the young and older group in the medial cheeks (p < .001), and 2.4 mm between the young and middle‐aged groups and 2.4 mm between the young and older group in the lateral cheeks (p = .01). CONCLUSIONS Facial soft tissue undergoes significant deterioration over time, with the most dramatic changes between the ages of 30 and 60 in the temporal, infraorbital, and lateral and medial cheek areas. Soft tissue augmentation and volume correction in these areas may be an effective strategy for facial rejuvenation.

Quantifying soft tissue loss in the aging male face using magnetic resonance imaging

BACKGROUND Quantitative data on soft tissue aging of the face are scarce, particularly in men. OBJECTIVE Magnetic resonance imaging (MRI) was used to quantify and compare facial soft tissue loss in men. MATERIALS AND METHODS Two thousand thirty-seven MRIs were screened and 30 male subjects were divided into young, middle, and old-aged groups. A blinded radiologist measured temporal, infraorbital, and medial and lateral cheek areas. RESULTS The mean thickness of the subcutaneous tissue in the temporal area was 12.5, 10.9, and 9.6 mm in the young, middle, and older age groups, respectively (p < .001). A 40% reduction in the skin thickness was seen in the infraorbital areas. Finally, a decrease of 1.5 and 2.7 mm in medial cheeks (p < .001), and 0.9 and 1.6 mm (p = .03) in lateral cheeks were measured in middle and old age groups. CONCLUSION A steady and significant decline in the soft tissue thickness was noted at all measured sites in men over time. These findings are in contrast to our recently study in women showing dramatic loss of soft tissue between the ages of 30 and 60 with no significant differences between the middle and old-aged groups. These results have implications for volume correction and maintenance of a youthful appearance in the aging male face.

Nonmelanoma Skin Cancer Visits and Procedure Patterns in a Nationally Representative Sample: National Ambulatory Medical Care Survey 1995–2007

BACKGROUND The rising incidence of nonmelanoma skin cancer (NMSC) is well documented, but data are limited on the number of visits and treatment patterns of NMSC in the outpatient setting. OBJECTIVES To evaluate practice and treatment patterns of NMSC in the United States over the last decade and to characterize differences according to sex, age, race, insurance type, and physician specialty. METHODS AND MATERIALS Adults with an International Classification of Diseases, Ninth Revision, diagnosis of NMSC were included in this cross‐sectional survey study of the National Ambulatory Medical Care Survey between 1995 and 2007. Primary outcomes included population‐adjusted NMSC visit rates and odds ratios of receiving a procedure for NMSC using logistic regression. RESULTS Rates of NMSC visits increased between 1995 and 2007. The number of visits was significantly higher in men, particularly those aged 65 and older. Fifty‐nine percent of NMSC visits were associated with a procedure, and the individuals associated with that visit were more likely to be male, to be seen by a dermatologist, and to have private‐pay insurance. CONCLUSIONS Nonmelanoma skin cancer visit rates increased from 1995 to 2007 and were higher in men than women. Visits to a dermatologist are more likely to be associated with a procedure for NMSC, and there may be discrepancies in treatment patterns based on insurance type and sex.