Inhibition of ligand-mediated HER2 activation in androgen-independent prostate cancer

Hormone-independent tumor growth and metastasis are associated with increased mortality in human prostate cancer. In this study, we evaluate a potential role for ligand-mediated activation of HER2 receptor tyrosine kinase in androgen-independent prostate cancers. HER2, HER3, and epidermal growth factor receptor were detected in the androgen-independent cell line 22Rv1. Heregulin stimulation results in receptor phosphorylation and cell proliferation that is inhibited by increasing concentrations of anti-HER2 recombinant humanized monoclonal antibody (rhuMAb) 2C4. Furthermore, inhibition of tumor growth was observed in xenografts derived from 22Rv1 cells when treated with rhuMAb 2C4 in a dose-dependent manner. These studies provide a framework, both in vitro and in vivo, to examine the molecular mechanisms of ligand-driven HER2 activation in androgen-independent tumorigenesis.     

When should determination of ketonemia be recommended?

Diabetic ketoacidosis is a serious complication of type diabetes. beta-Hydroxybutyrate (beta-OHB) accounts for about 75% of ketones, and blood concentration can be determined with a sensor. The aim of this study was to investigate the frequency and degree of ketonemia in daily life of children with diabetes and to make a base for recommendations for determination of ketonemia in clinical practice. During 3 months 45 patients with type 1 diabetes since 1-10 years old (mean 4.4 +/- 3.3 years old) at the pediatric clinic in Link?ping, Sweden, performed 24-h profiles (eight determinations) in 2 weeks with blood glucose and beta-OHB. The children performed 11,189 blood glucose and 7,057 beta-OHB measurements. Only 0.3% (n = 21) of beta-OHB measurements were > or = 1.0 mmol/L. An beta-OHB concentration > 0.2 mmol/L was more common in the morning than during the rest of the day (p < 0.001). Young children (4-7 years old) had values > or = 0.2 mmol/L more often than adolescents (p < 0.001). Blood glucose values > 15 mmol/L were more often accompanied by beta-OHB > 0.2 mmol/L (p < 0.001). High beta-OHB concentrations are rare in diabetic children with reasonably good metabolic control. Already a value > 0.4 mmol/L seems abnormal, and we recommend that patients retest glucose and ketones with beta-OHB > 0.4 mmol/L. Furthermore, we recommend that diabetic children and adolescents measure beta-OHB when symptoms like nausea or vomiting occur to differentiate ketoacidosis from gastroenteritis, and during infections, during periods with high blood glucose (> 15 mmol/L), and if they notice ketonuria. Monitoring beta-OHB should be routine for patients on pump therapy.     

Refractory status epilepticus: frequency, risk factors, and impact on outcome

BACKGROUND: Refractory status epilepticus (RSE) is a life-threatening condition in which seizures do not respond to first- and second-line anticonvulsant drug therapy. How often RSE occurs, risk factors that predispose to this condition, and the effect of failure to control seizures on clinical outcome are poorly defined. OBJECTIVE: To determine the frequency, risk factors, and impact on outcome of RSE. DESIGN: Retrospective cohort study. SETTING: Large academic teaching hospital. PATIENTS: Consecutive sample of 83 episodes of status epilepticus in 74 patients (mean age, 63 years). MAIN OUTCOME MEASURES: Refractory status epilepticus was defined as seizures lasting longer than 60 minutes despite treatment with a benzodiazepine and an adequate loading dose of a standard intravenous anticonvulsant drug. Factors associated with RSE were identified using univariate and backward stepwiselogistic regression analyses. RESULTS: In 57 episodes (69%), seizures occurred after treatment with a benzodiazepine, and in 26 (31%), seizures occurred after treatment with a second-line anticonvulsant drug (usually phenytoin), fulfilling our criteria for RSE. Nonconvulsive SE (P=.03) and focal motor seizures at onset (P=.04) were identified as independent risk factors for RSE. Eleven (42%) of 26 patients with RSE had seizures after receiving a third-line agent (usually phenobarbital). Although mortality was not increased (17% overall), RSE was associated with prolonged hospital length of stay (P<.001) and more frequent functional deterioration at discharge (P=.02). CONCLUSIONS: Refractory status epilepticus occurs in approximately 30% of patients with SE and is associated with increased hospital length of stay and functional disability. Nonconvulsive SE and focal motor seizures at onset are risk factors for RSE. Randomized controlled trials are needed to define the optimal treatment of RSE.     

The use of ex vivo gene transfer based on muscle-derived stem cells for cardiovascular medicine

Cell transplantation is a potential therapy for patients suffering from congestive heart failure. Many cell types have been experimentally tested for their ability to improve cardiac function. In this review, we discuss the potential of cell transplantation into the heart using various cell sources and introduce an attractive new cell source: Muscle-derived stem cells (MDSCs) are capable of delivering therapeutic genes and potentially differentiating toward a cardiomyocyte lineage within an injected heart. MDSCs are an attractive, alternate cell source because in addition to being multipotent (i.e., capable of differentiating into various lineages), they are easily accessible via simple biopsy of the patient's own muscle. This review will describe the isolation and unique characteristics of MDSCs and outline their potential use in regenerative medicine.     

Comparison of two superparamagnetic viral-sized iron oxide particles ferumoxides and ferumoxtran-10 with a gadolinium chelate in imaging intracranial tumors

BACKGROUND AND PURPOSE: Ultrasmall superparamagnetic iron oxide particles result in shortening of T1 and T2 relaxation time constants and can be used as MR contrast agents. We tested four hypotheses by evaluating MR images of intracranial tumors after infusion of two iron oxide agents in comparison with a gadolinium chelate: 1) Ferumoxtran in contrast to ferumoxides can be used as an intravenous MR contrast agent in intracranial tumors; 2) ferumoxtran enhancement, albeit delayed, is similar to gadolinium enhancement; 3) ferumoxtran-enhanced MR images in contrast to gadolinium-enhanced MR images may be compared with histologic specimens showing the cellular location of iron oxide particles; 4) ferumoxtran can serve as a model for viral vector delivery. METHODS: In 20 patients, ferumoxides and ferumoxtran were intravenously administered at recommended clinical doses. MR imaging was performed 30 minutes and 4 hours after ferumoxides infusion (n = 3), whereas ferumoxtran-enhanced MR imaging (n = 17) was performed 6 and 24 hours after infusion in the first five patients and 24 hours after infusion in the remaining 12. MR sequences were spin-echo (SE) T1-weighted, fast SE T2- and proton density-weighted, gradient-recalled-echo T2*-weighted, and, in four cases, echo-planar T2-weighted sequences. Representative regions of interest were chosen on pre- and postcontrast images to compare each sequence and signal intensity. RESULTS: Despite some degree of gadolinium enhancement in all tumors, no significant T1 or T2 signal intensity changes were seen after ferumoxides administration at either examination time. Fifteen of 17 patients given ferumoxtrans had T1 and/or T2 shortening consistent with iron penetration into tumor. Histologic examination revealed minimal iron staining of the tumor with strong staining at the periphery of the tumors. CONCLUSION: 1) Ferumoxtran can be used as an intravenous MR contrast agent in intracranial tumors, mostly malignant tumors. 2) Enhancement with ferumoxtran is comparable to but more variable than that with the gadolinium chelate. 3) Histologic examination showed a distribution of ferumoxtran particles similar to that on MR images, but at histology the cellular uptake was primarily by parenchymal cells at the tumor margin. 4) Ferumoxtran may be used as a model for viral vector delivery in malignant brain tumors.     

Treatment of aggressive fibromatosis: a retrospective study of 72 patients followed for 1-27 years

We evaluated prognostic factors for local recurrence-free survival, including expression of estrogen receptors, after surgical treatment of aggressive fibromatosis in 72 patients (53 women) having primary tumors between 1970 and 1998. Their median age at diagnosis was 31(1 month-77 years) years. 50 patients had extraabdominal and 22 abdominal fibromatosis. Median tumor size was 4 (1-27) cm. 8 patients were treated with an intralesional resection, 32 with marginal, 31 with wide and with radical resection. They were followed for a median of 8 (1-27) years. The overall and local recurrence-free 5-year survival rates were 98% and 73%, respectively. Univariate analysis identified age, compartmentalization and tumor size as prognostic factors for local recurrence-free survival as well as radiotherapy in extraabdominal tumors. In the multivariate analysis, tumor size > 4 cm, extracompartmental location, inadequate margin and age < 32 years were independent negative prognostic factors for local recurrence. None of the tumors expressed estrogen receptors. In conclusion, aggressive fibromatosis as a high local recurrence rate, but a good prognosis, since almost no patients die of their tumor.     

Internal jugular vein patency after lateral neck dissection: a prospective study

In spite of anatomical preservation of the internal jugular vein (IJV), an occlusion rate of the vessel of up to 30% has been documented after selective or modified radical neck dissections. The aim of the present prospective study was to evaluate the patency of the IJV following selective lateral neck dissection (LND) in 34 patients affected by squamous cell carcinoma of the upper aerodigestive tract who underwent surgery concomitantly on the primary site and the neck. Eighteen patients received unilateral and 16 bilateral LND, for a total of 50 IJVs. Postoperative radiotherapy on the neck was delivered in four patients with histologic evidence of micro-extracapsular spread; the impact of this variable on IJV patency was assessed by the Fisher test. A preoperative baseline study of vein patency and flow by ultrasonography (US) was obtained. Postoperative controls were scheduled at 1 week, 1 month and 3 months following surgery. No patient developed either wound infection or a pharyngocutaneous fistula, and no signs or symptoms of IJV occlusion were observed during the postoperative course. At the first US control, 25 IJVs (50%) did not present any alteration in patency, and 23 (46%) and 2 (4%) had a reduced or absent flow, respectively. At the second and third controls, 33 (66%) and 45 (90%) of the IJVs presented with normal flow, respectively. At the end of the study, none of the patients showed evidence of occlusion. Postoperative radiotherapy did not have a statistically significant impact on IJV patency ( P=0.09). In conclusion, long-term IJV occlusion after LND has to be considered an exceedingly rare event with negligible morbidity. However, alterations of IJV flow frequently occur in the immediate postoperative course.     

Tumor suppressive role of a 2.4 Mb 9q33-q34 critical region and DEC1 in esophageal squamous cell carcinoma

The key genes involved in the development of esophageal squamous cell carcinoma (ESCC) remain to be elucidated. Previous studies indicate extensive genomic alterations occur on chromosome 9 in ESCC. Using a monochromosome transfer approach, this study provides functional evidence and narrows down the critical region (CR) responsible for chromosome 9 tumor suppressing activity to a 2.4 Mb region mapping to 9q33-q34 between markers D9S1798 and D9S61. Interestingly, a high prevalence of allelic loss in this CR is also observed in primary ESCC tumors by microsatellite typing. Allelic loss is found in 30/34 (88%) tumors and the loss of heterozygosity (LOH) frequency ranges from 67 to 86%. Absent to low expression of a 9q32 candidate tumor suppressor gene (TSG), DEC1 (deleted in esophageal cancer 1), is detected in four Asian ESCC cell lines. Stably expressing DEC1 transfectants provide functional evidence for inhibition of tumor growth in nude mice and DEC1 expression is decreased in tumor segregants arising after long-term selection in vivo. There is 74% LOH in the DEC1 region of ESCC primary tumors. This study provides the first functional evidence for the presence of critical tumor suppressive regions on 9q33-q34. DEC1 is a candidate TSG that may be involved in ESCC development.     

Supraorbital craniotomy for parasellar lesions. Technical note

The authors present a modification to a previously reported supraorbital craniotomy procedure that is smaller, simpler, safe, and cosmetically pleasing. Minimal brain retraction is used without compromising the surgical exposure of the orbital roof, floor of the anterior fossa, and the parasellar region to treat tumoral lesions that are located medial to the ipsilateral optic nerve as well as aneurysms of the anterior communicating artery.     

The patient safety institute demonstration project: a model for implementing a local health information infrastructure

The increasing focus on patient safety has uncovered many unsafe conditions in the current US. healthcare system. One of the most glaring problems is the inability of a fragmented healthcare system to provide critical and timely clinical information at the point of care. The Institute of Medicine has called for the development of a National Health Information Infrastructure to rectify this deficiency. This NHII will be built on Local Health Information Infrastructures, or LHIIs. The Patient Safety Institute is a potential model for an LHII that was developed and implemented in Seattle using the Swedish Medical Centers and associated ambulatory clinics. This model was piloted and evaluated among 365 clinical users across three hospitals, three clinics, and family practice residency programs involving access of records of more than 5300 distinct patients within a five-month period and involved the collection of more than 23 million clinical data results. User responses revealed the technology was intuitive to learn, easy to use, easy to navigate, and helpful in clinical care. The PSI demonstration project has developed an approach to the creation and implementation of LHIIs that is potentially transferable to other local communities.