Citations

Pegfilgrastim (Neulasta) is a recombinant filgrastim (human granulocyte colony-stimulating factor (G-CSF)) attached to a polyethylene glycol (PEG) molecule and is given as part of chemotherapy regimens that are associated with significant myelosuppression and risk for febrile neutropenia. Prescribing information available on manufacturer’s website for the drug warns us about possible severe sickle cell crises related to the medication but does not report the actual incidence or the use in patients with sickle cell trait. Caution is advised when using it in patients with sickle cell disease. Here we present a case of a Caucasian female with known sickle cell trait (SCT) with no prior complications who developed a presumed sickle cell crisis after getting Neulasta, as a part of the chemotherapy regimen used to treat her breast cancer. Based on our literature review, this appears to be the first case report of a patient with SCT developing a sickle cell crisis with the pegylated form of recombinant filgrastim. Given the dearth of literature regarding the use of G-CSF and its related pegylated forms in patients with sickle cell anemia and sickle cell trait, a discussion of potential mechanisms and review of current literature and guidelines is also presented.

Abstract Autoimmune pancreatitis (AIP) is a form of chronic pancreatitis characterised clinically by frequent presentation with obstructive jaundice, histologically by a lymphoplasmacytic infiltrate with fibrosis, and therapeutically by a dramatic response to steroids. When so defined, AIP can be sub-classified into two subtypes, 1 and 2. Recent international consensus diagnostic criteria for AIP have been developed for diagnosis of both forms of AIP. Type 1 AIP is the pancreatic manifestation of a multiorgan disease, recently named IgG4-related disease. Little is known about the pathogenesis of either form of AIP. Despite frequent association of type 1 AIP with elevated serum IgG4 levels and infiltration with IgG4-positive plasma cells, it is unlikely that IgG4 plays a pathogenic role in AIP. Type 1 AIP responds to steroids, but there needs to be consensus on treatment regimens for induction and therapeutic end points. Relapses are common, but can be reduced by long-term use of low-dose steroids. Recent reports suggest that immunomodulators (azathioprine, 6-mercaptopurine and mycophenolate mofetil), as well biological agents (the antibody to CD20, rituximab) may have a role in maintaining remission in relapsing type 1 AIP. Future studies should clarify the best management options for treatment of relapses and maintenance of remission. Type 2 AIP is a pancreas-specific disorder not associated with IgG4. It presents in younger individuals equally with obstructive jaundice and pancreatitis. The inflammatory process responds to steroid therapy; relapses are uncommon. The clinical spectrum and long-term outcomes of medically treated type 2 AIP are still being evaluated.

Patient compliance is important when assessing movement, particularly in a free-living environment when patients are asked to don their own accelerometers. Reducing the number of accelerometers could increase patient compliance. The aims of this study were (1) to determine and compare the validity of different accelerometer combinations and placements for a previously developed posture and dynamic movement identification algorithm. Custom-built activity monitors, each containing one tri-axial accelerometer, were placed on the ankles, right thigh, and waist of 12 healthy adults. Subjects performed a protocol in the laboratory including static orientations of standing, sitting, and lying down, and dynamic movements of walking, jogging, transitions between postures, and fidgeting to simulate free-living activity. When only one accelerometer was used, the thigh was found to be the optimal placement to identify both movement and static postures, with a misclassification error of 10%, and demonstrated the greatest accuracy for walking/fidgeting and jogging classification with sensitivities and positive predictive value (PPVs) greater than 93%. When two accelerometers were used, the waist-thigh accelerometers identified movement and static postures with greater accuracy than the thigh-ankle accelerometers (with a misclassification error of 11% compared to 17%). However, the thigh-ankle accelerometers demonstrated the greatest accuracy for walking/ fidgeting and jogging classification with sensitivities and PPVs greater than 93%. Movement can be accurately classified in healthy adults using tri-axial accelerometers placed on one or two of the following sites: waist, thigh, or ankle. Posture and transitions require an accelerometer placed on the waist and an accelerometer placed on the thigh.

BackgroundWe sought to determine the utility of a magnetic navigation system (MNS) in treating a variety of coronary artery lesions including those that could not be revascularized with standard percutaneous coronary intervention (PCI). MNS may add value in the treatment of tortuous arteries and bifurcation lesions; however its widespread adoption has lagged because of cost and a lack of clear advantage over conventional PCI. We performed a retrospective analysis to determine whether MNS improved procedural success for highly complex lesions.Methods and ResultsOne hundred and forty‐eight patients underwent treatment with MNS at Mayo Clinic, Rochester. Clinical data, angiographic and procedural characteristics, lesion crossing success and outcomes were reviewed. Overall 133 patients underwent successful revascularization with 87% (143) of 164 lesions crossed using MNS alone. Another six lesions required a combination of MNS and conventional devices resulting in overall success of 91% (149/164). Eighteen complex lesions had previously failed PCI and 12 (67%) were successfully treated with MNS. Success after failed PCI was higher (88%) when a frequent user operated MNS, but occasional users also noted incremental success (30%). Twenty‐five chronic total occlusions were included amongst these 164 lesions, with observed antegrade MNS lesion crossing rates of 78% for regular and 14% for occasional users.ConclusionsMNS is a useful adjunct to performance of PCI. This specialized technology has a clear learning curve and can facilitate treatment of highly complex lesions. © 2013 Wiley Periodicals, Inc.

Background— Regenerative cell-based therapies are associated with limited myocardial retention of delivered stem cells. The objective of this study is to develop an endocardial delivery system for enhanced cell retention. Methods and Results— Stem cell retention was simulated in silico using 1- and 3-dimensional models of tissue distortion and compliance associated with delivery. Needle designs, predicted to be optimal, were accordingly engineered using nitinol, a nickel and titanium alloy displaying shape memory and superelasticity. Biocompatibility was tested with human mesenchymal stem cells. Experimental validation was performed with species-matched cells directly delivered into Langendorff-perfused porcine hearts or administered percutaneously into the endocardium of infarcted pigs. Cell retention was quantified by flow cytometry and real-time quantitative polymerase chain reaction methodology. Models, computing optimal distribution of distortion calibrated to favor tissue compliance, predicted that a 75°-curved needle featuring small-to-large graded side holes would ensure the highest cell retention profile. In isolated hearts, the nitinol curved needle catheter (C-Cath) design ensured 3-fold superior stem cell retention compared with a standard needle. In the setting of chronic infarction, percutaneous delivery of stem cells with C-Cath yielded a 37.7±7.1% versus 10.0±2.8% retention achieved with a traditional needle without effect on biocompatibility or safety. Conclusions— Modeling-guided development of a nitinol-based curved needle delivery system with incremental side holes achieved enhanced myocardial stem cell retention.

Abstract Abundant epidemiologic evidence indicates that regular and long-term use of aspirin is associated with a significant reduction in the incidence of colorectal cancer. The long duration of aspirin needed to prevent colorectal cancer is believed to be due to inhibition of precursor lesions known as adenomas, the recurrence of which is inhibited by aspirin in randomized trials. Aspirin intake has also been associated with a statistically significant improvement in patient survival after curative resection of colorectal cancer in large observational studies. In these cohorts, the survival benefit of aspirin was shown to depend upon the level of COX-2 expression in the primary colorectal cancer. More recent analysis of patient tumors from these observational cohorts suggests that the benefit of aspirin may be limited to specific molecular subtypes. Aspirin intake following colorectal cancer resection was associated with a significant improvement of survival in patients whose tumors carried mutant, but not wild-type, copies of the phosphoinositide 3-kinase (PI3KCA) gene, especially tumors that overexpressed COX-2. A mechanistic explanation is suggested by the finding that inhibition of COX-mediated prostaglandin E2 synthesis by aspirin attenuates PI3K signaling activity that is known to regulate cancer cell proliferation and survival. Aspirin has also been shown to reduce the incidence of colorectal cancers bearing wild-type, but not mutant alleles of the BRAFV600E oncogene. Although provocative, the potential utility of these molecular markers for predicting aspirin efficacy awaits prospective evaluation in clinical trials. If validated, these findings may support a personalized approach to using aspirin for the therapy of colorectal cancer. Clin Cancer Res; 20(5); 1087–94. ©2013 AACR.

Abstract Glycogen synthase kinase-3 (GSK-3), a constitutively active serine/threonine kinase, is a key regulator of numerous cellular processes ranging from glycogen metabolism to cell-cycle regulation and proliferation. Consistent with its involvement in many pathways, it has also been implicated in the pathogenesis of various human diseases, including type II diabetes, Alzheimer disease, bipolar disorder, inflammation, and cancer. Consequently, it is recognized as an attractive target for the development of new drugs. In the present study, we investigated the effect of both pharmacologic and genetic inhibition of GSK-3 in two different renal cancer cell lines. We have shown potent antiproliferative activity of 9-ING-41, a maleimide-based GSK-3 inhibitor. The antiproliferative activity is most likely caused by G0–G1 and G2–M phase arrest as evident from cell-cycle analysis. We have established that inhibition of GSK-3 imparted a differentiated phenotype in renal cancer cells. We have also shown that GSK-3 inhibition induced autophagy, likely as a result of imbalanced energy homeostasis caused by impaired glucose metabolism. In addition, we have demonstrated the antitumor activity of 9-ING-41 in two different subcutaneous xenograft renal cell carcinoma tumor models. To our knowledge, this is the first report describing autophagy induction due to GSK-3 inhibition in renal cancer cells. Mol Cancer Ther; 13(2); 285–96. ©2013 AACR.