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Reclassification of a tubal leiomyosarcoma as an eGIST by molecular evaluation of c-KIT

Thu, 03/19/2015 - 3:27pm

BACKGROUND: Extragastrointestinal stromal tumors (eGISTs) are rare mesenchymal-derived tumors arising outside of the GI tract. eGISTs are often histologically confused with leiomyosarcoma. Distinction between eGIST and leiomyosarcoma is critical because of the unique responsiveness of eGISTs to the molecularly targeted agent imatinib.

CASE: A woman presented with a history of tubal spindle cell tumor that was initially diagnosed and treated as a leiomyosarcoma. Because of minimal response to sarcoma directed chemotherapy, the possibility that the tumor was in fact an eGIST was investigated and supported by immunohistochemical and mutational analyses of the c-Kit receptor tyrosine kinase. The patient currently has stable disease control on imatinib for the last 18 months.

CONCLUSIONS: The possibility of eGIST should be considered in the differential diagnosis of tumors with a spindle cell morphology in the gynecologic tract especially when involving the ovary, fallopian tube, or uterine serosa.

Comparative effects of unfractionated heparin and low molecular weight heparin on vascular endothelial cell tissue factor pathway inhibitor release: a model for assessing intrinsic thromboresistance

Thu, 03/19/2015 - 3:27pm

OBJECTIVES: The purpose of our study was to characterize tissue factor pathway inhibitor (TFPI) release from human vascular endothelial cells following daily exposure to varying concentrations of unfractionated heparin (UFH) and low molecular weight heparin (LMWH).

BACKGROUND: A "rebound" increase in ischemic/thrombotic events, including myocardial infarction and cardiovascular death, has been observed after the abrupt cessation of UFH. In a single center pilot study of patients with acute coronary syndromes (ACS) we reported that thrombin generation was evident within one (1) hour of UFH cessation, increased progressively over the subsequent 24 hours, correlated directly with factor VII activity and inversely with TFPI (concentration and activity). METHODS: Human umbilical vein endothelial cells were grown to confluence and incubated with varying concentrations of UFH or dalteparin, a low molecular weight haparin, for up to 144 hours. Daily samples of the cells supernatant were obtained and assayed for TFPI. Cellular reserve and responsiveness to recombinant endothelial cell growth factor (rEGF) stimulation were determined at 168 hours.

RESULTS: In low concentrations (0.5 U/mL) UFH caused a progressive rise in TFPI concentration with a peak level of 6.36 +/- 0.5 ng/10(5) cells at 24 hours. By 72 hours of daily exposure, the levels declined to below control values and TFPI release following rEGF stimulation was reduced by approximately 60% compared to control (1.93 +/- 0.42 vs 4.3 +/- 0.78 ng/10(5) cells; p = 0.001). Initial endothelial cell release and rate of decline were more robust with high concentrations of UFH (5.0 U/ml). TFPI levels were above control values at each sampling time point up to 120 hours and cellular responsiveness to stimulation was preserved with dalteparin (compared to UFH) (p < 0.001).

CONCLUSIONS: Thrombin generation and clinical events that occur during treatment with UFH and following its abrupt cessation may represent an acquired state of transiently impaired thromboresistance to the tissue factor-VIIa complex. The differing effects of UFH and LMWH on vascular endothelial cell TFPI synthesis, release and reserve with prolonged administration require further investigation.

Analysis of axillary coverage during tangential radiation therapy to the breast

Thu, 03/19/2015 - 3:27pm

PURPOSE: To evaluate the percent of the prescribed radiation dose to the breast delivered to the axillary tissue and to evaluate the volume of the axilla receiving 95% of the prescribed dose with normal and with high tangential fields.

METHODS AND MATERIALS: Computed tomographic scan images with 5-mm sections were retrospectively analyzed for 35 patients who had undergone three-dimensional (3D) planning for whole-breast radiation. The axillary nodal region was identified and divided into Levels I to III and Rotter's nodes (RN). Digitally reconstructed radiographs were created, and two plans were developed: (a) the standard clinical opposed tangential irradiation fields and (b) the high-tangential irradiation fields. Axillary coverage was examined by use of dose-volume histograms (DVH), and the average coverage for the four nodal groups was obtained.

RESULTS: The data show that with the standard tangential irradiation fields, the average dose delivered to Levels I, II, III, and RN is 66% (standard deviation, or SD = 13%), 44% (SD = 18%), 31% (SD = 20%), and 70% (SD = 19%) of the prescribed dose, respectively. The coverage increases to 86% (SD = 9%), 71% (SD = 19%), 73% (SD = 17%), and 94% (SD = 8%) of the prescribed dose, respectively, for Levels I, II, III, and RN when the high tangential irradiation fields are used. 51% of Level I, 26% of Level II, and 15% of Level III receive 95% of the prescribed dose with normal tangents. The volume increases to 79%, 51%, and 49% of Levels I, II, and III, respectively, with high tangents.

CONCLUSION: The tangential fields designed to treat only the breast do not adequately cover the axillary region and, therefore, cannot be relied upon for prophylactic therapy of the axilla. The high tangential irradiation fields increase the dosages received by the axillary region, but the average dosages received by the lower axillary regions are still less than 90% of the prescribed dose.

Delta opiates increase ischemic tolerance in isolated rabbit jejunum

Thu, 03/19/2015 - 3:27pm

Mammalian hibernation is mediated by humoral agonists of the delta opioid receptor (DOR). Moreover, transfer of either humoral or synthetic DOR agonists to non-hibernators reportedly induces a state of improved myocardial ischemic tolerance.

OBJECTIVE: To determine whether the DOR agonist D-Ala 2, D-Leu 5, enkephalin (DADLE) similarly elicits protection in noncardiac-i.e., mesenteric-tissue.

METHODS: In Protocols 1 and 2, the authors developed and characterized an in vitro model of mesenteric ischemia/reperfusion in isolated rabbit jejunum by documenting the effect of increasing ischemic duration (0 to 120 minutes) and the relative importance of glucose and/or oxygen deprivation on the evolution of jejunal injury. In Protocol 3, jejunal segments were randomized to receive either no treatment (controls) or 15 minutes of pretreatment with 1 microM DADLE, followed by 60 minutes of simulated ischemia and 30 minutes of reperfusion. Jejunal injury was quantified by repeated, time-matched assessment of peak contractile force evoked by 1 microM acetylcholine (all protocols) and delineation of tissue necrosis (Protocol 1).

RESULTS: Development of significant jejunal injury required combined oxygen/glucose deprivation. Moreover, there was a direct relationship between ischemic duration and tissue injury, and a significant inverse correlation between reperfusion contractile force (% of baseline) and the extent of smooth muscle necrosis (r(2) = 0.87; p < 0.01). Most notably, mesenteric ischemia/reperfusion injury was attenuated by DADLE: reperfusion contractile force was 47 +/- 5% versus 36 +/- 5% in DADLE-treated versus control segments (p < 0.01).

CONCLUSIONS: Treatment with the delta opioid agonist DADLE increases ischemic tolerance of isolated rabbit jejunum.

Astrocytes interact intimately with degenerating motor neurons in mouse amyotrophic lateral sclerosis (ALS)

Thu, 03/19/2015 - 3:27pm

Astrocytic proliferation and hypertrophy (astrogliosis) are associated with neuronal injury. However, neither the temporal nor the spatial relationship between astrocytes and injured neurons is clear, especially in neurodegenerative diseases. We investigated these questions in a mouse amyotrophic lateral sclerosis (ALS) model. The initial increase in astrogliosis coincided with the onset of clinical disease and massive mitochondrial vacuolation in motor neurons. After disease onset, astrogliosis increased further in parallel with the number of degenerating motor neurons. Examination of individual astrocytes by three-dimensional reconstruction revealed that astrocytes extended their processes toward, wrapped around, and sometimes penetrated vacuoles derived from neuronal mitochondria. These results show a close temporal correlation between the onset of neuronal degeneration and the beginning of astrogliosis in this neurodegenerative disease and reveal a novel spatial relationship that is consistent with the view that astrocytes play an active role in the neuronal degeneration process.

Polyplex-mediated gene transfer into human retinal pigment epithelial cells in vitro

Thu, 03/19/2015 - 3:27pm

The human retinal pigment epithelium (RPE) is a potential target tissue for directed transfer of candidate genes to treat age-related macular degeneration (AMD). The RPE is uniquely suited to gene therapy protocols that use liposome-mediated DNA transfer because of its high intrinsic phagocytic function in vivo. In these studies, we examined the efficacy of human RPE cell uptake and expression of the green fluorescent protein (GFP) and neomycin resistance marker genes by polyplex-mediated gene transfer in vitro. The effects of varying DNA and polyplex concentration and ratios on GFP transgene expression were examined. A narrow range of experimental conditions were found to maximize transgene expression; most important were the DNA concentration and the DNA:polyplex ratio. The transfection efficiency for human RPE cells was reproducibly 20% in vitro by this method and reached a maximum level of expression after 48 h. There was a rapid decline in gene expression over 2 weeks following polyplex-mediated gene transfer, but stable integration does occur at low frequencies with and without selection.

Use of meperidine in patient-controlled analgesia and the development of a normeperidine toxic reaction

Thu, 03/19/2015 - 3:27pm

HYPOTHESIS: Intravenous patient-controlled analgesia (IV PCA) meperidine hydrochloride can be used with a reasonable margin of safety. DESIGN: A retrospective review was performed of 355 medical records of patients receiving IV PCA meperidine treatment. Four groups of patients were defined, based on daily meperidine dose and the presence or absence of central nervous system excitation adverse effects. Use of more than 600 mg/d of meperidine hydrochloride was considered a high dose. SETTING: University tertiary care hospital. PARTICIPANTS: Postoperative patients from general, orthopedic, neurosurgical, gynecological, and urologic procedures receiving IV PCA. INTERVENTIONS: If patients were judged to have consumed significant amounts of meperidine, the analgesic regimen was modified to (1) discontinue meperidine therapy, (2) substitute hydromorphone hydrochloride, or (3) decrease the use of meperidine by adding oral methadone hydrochloride or transdermal fentanyl citrate to the regimen. MAIN OUTCOME MEASURES: Patients who received less than 10 mg/kg per day of IV PCA meperidine hydrochloride therapy were unlikely to experience central nervous system excitatory adverse effects and maintain adequate analgesia. RESULTS: The mean meperidine hydrochloride consumption for those patients classified as high dose, asymptomatic was 13.3 mg/kg per day (95% confidence interval, 12.1-14.4 mg/kg per day). This differed statistically significantly (P<.05) from the mean meperidine hydrochloride dose in patients classified as high dose, symptomatic, which was 16.9 mg/kg per day (95% confidence interval, 14.7-19.2 mg/kg per day). The duration of meperidine use did not differ among the 4 patient groups. The incidence of a central nervous system toxic reaction associated with IV PCA meperidine therapy was 2%. CONCLUSIONS: We recommend 10 mg/kg per day as a maximum safe meperidine hydrochloride dose by an IV PCA device for no longer than 3 days. Daily patient evaluation is mandatory. Care must also be taken when using this dose to ensure the absence of renal dysfunction or enhanced hepatic metabolism of meperidine.

Cervical Cancer

Thu, 03/19/2015 - 9:55am

This chapter in Cancer Concepts: A Guidebook for the Non-Oncologist presents provides an overview of cervical cancer. The etiology, pathology, staging, and principles of treatment will be reviewed.

Cognitive status in patients hospitalized with acute decompensated heart failure

Sun, 03/15/2015 - 10:06pm

BACKGROUND: Cognitive impairment is highly prevalent in patients with heart failure and is associated with adverse outcomes. However, whether specific cognitive abilities (eg, memory vs executive function) are impaired in heart failure has not been fully examined. We investigated the prevalence of impairment in 3 cognitive domains in patients hospitalized with acute decompensated heart failure (ADHF) and the associations of impairment with demographic and clinical characteristics.

METHODS: The sample included 744 patients hospitalized with ADHF (mean age 72 years, 46% female) at 5 medical centers. Impairment was assessed in 3 cognitive domains (memory, processing speed, executive function) using standardized measures. Demographic and clinical characteristics were obtained from a structured interview and medical record review.

RESULTS: A total of 593 (80%) of 744 patients were impaired in at least 1 cognitive domain; 32%, 31%, and 17% of patients were impaired in 1, 2, or all 3 cognitive domains, respectively. Patients impaired in more than 1 cognitive domain were significantly older, had less formal education, and had more noncardiac comorbidities (all P values < .05). In multivariable adjusted analyses, patients with older age and lower education had higher odds of impairment in 2 or more cognitive domains. Depressed patients had twice the odds of being impaired in all 3 cognitive domains (odds ratio 1.98, 95% CI 1.08-3.64).

CONCLUSION: Impairments in executive function, processing speed, and memory are common among patients hospitalized for ADHF. Recognition of these prevalent cognitive deficits is critical for the clinical management of these high-risk patients.

Oncologic Emergencies and Urgencies

Fri, 03/13/2015 - 11:50am

This chapter in Cancer Concepts: A Guidebook for the Non-Oncologist presents a discussion of the risks to cancer patients for oncologic and metabolic crises. These effects may be caused by the cancer, the treatment provided to cure or palliate the cancer, and/or other medical conditions. They may occur at initial presentation, as a first sign of disease or during the disease course. Oncologists divide these crises into emergencies and urgencies, depending on the severity of the consequences of delay in treatment. Every health care provider should be aware of the signs and symptoms of oncologic urgencies and emergencies and initial management.

Building a Community of Practice to Support Young Adults with Serious Mental Health Conditions

Fri, 03/13/2015 - 9:15am

A Community of Practice brings together groups of people who share a concern, a set of problems, a passion about a topic, and who deepen their knowledge and expertise in this area by interacting on an ongoing basis. The Transitions Research and Training Center assisted in the development of a Community of Practice on supporting Transition Age Youth and Young Adults with Serious Mental Health Conditions. The Northeast Massachusetts Community of Practice was composed of local stakeholders seeking to enhance services for this group.

UMCCTS Newsletter, March 2015

Thu, 03/12/2015 - 9:11pm

This is the March 2015 issue of the UMass Center for Clinical and Translational Science Newsletter containing news and events of interest.