Role of insulin-like growth factor binding proteins in 1alpha,25-dihydroxyvitamin D(3)-induced growth inhibition of human prostate cancer cells

BACKGROUND: The mechanisms underlying 1alpha,25-dihydroxyvitamin D(3) (1,25D)-induced growth inhibition of human prostate cancer cells have not been fully elucidated. To determine whether alterations in the insulin-like growth factor (IGF) signaling axis are associated with 1,25D-induced growth inhibition, we examined the ability of 1,25D to regulate expression of IGF binding proteins (IGFBPs) in human prostate cancer cell lines. METHODS: Northern and Western blot analyses were used to detect 1,25D-induced alterations in IGFBP expression. Additional in vitro studies were performed to determine the role of IGFBP-3 in 1,25D-induced growth inhibition. RESULTS: 1,25D decreased mRNA levels of the growth stimulatory IGFBP-2 and induced IGFBP-3 mRNA in LNCaP and C4-2 cells. 1,25D treatment also increased secreted IGFBP-3 protein levels in prostate cancer cell lines sensitive to 1,25D growth inhibition but had little effect on IGFBP-3 expression in 1,25D-resistant DU145 cells. However, recombinant IGFBP-3 had only a minor effect on LNCaP cell growth in the presence of serum. Furthermore, siRNA duplexes that reduced IGFBP-3 expression did not alter 1,25D growth inhibition in either LNCaP or PC-3 cell lines grown in serum-containing media. CONCLUSIONS: Our studies indicate 1,25D-induced up-regulation of IGFBP-3 is not required for the growth inhibitory effects of 1,25D in prostate cancer cells grown in serum-containing media.     

Platelet function profiles in patients with type 2 diabetes and coronary artery disease on combined aspirin and clopidogrel treatment

To assess platelet function profiles in diabetic and nondiabetic patients on aspirin and clopidogrel therapy, two patient populations were included to investigate the 1) acute effects of a 300-mg clopidogrel loading dose (group 1, n = 52) and 2) long-term effects of clopidogrel (group 2, n = 120) on platelet function in diabetic compared with nondiabetic patients already on aspirin treatment. Patients were stratified according to the presence of type 2 diabetes. Platelet aggregation was assessed using light transmittance aggregometry (groups 1 and 2). Platelet activation (P-selectin expression and PAC-1 binding) was determined using whole-blood flow cytometry (group 2). Clopidogrel response was also assessed. In group 1, platelet aggregation was significantly increased in diabetic (n = 16) compared with nondiabetic (n = 36) patients at baseline and up to 24 h following a 300-mg loading dose (P = 0.005). In group 2, platelet aggregation and activation were increased in diabetic (n = 60) compared with nondiabetic (n = 60) subjects (P < 0.05 for all platelet function assays). Diabetic subjects had a higher number of clopidogrel nonresponders (P = 0.04). Diabetic patients have increased platelet reactivity compared with nondiabetic subjects on combined aspirin and clopidogrel treatment. Reduced sensitivity to antiplatelet drugs may contribute to the increased atherothombotic risk in diabetic patients.     

Sentinel lymph node biopsy: a rational approach for staging T2N0 oral cancer

OBJECTIVES/HYPOTHESIS: For oral cancer patients, the presence of neck nodal metastases is the most important disease prognosticator. However, a significant proportion of clinically N0 patients harbor occult microscopic nodal metastasis. Our objective was to determine the feasibility and accuracy of sentinel node biopsy (SNB) in the staging of T2N0 oral carcinoma patients. STUDY DESIGN: Prospective analysis. METHODS: Twenty patients with previously untreated N0 oral cavity squamous cell carcinoma were studied. Each patient had an SNB performed using preoperative technetium sulfur colloid lymphoscintigraphy, intraoperative gamma probe guidance, and intraoperative peritumoral injection of 1% isosulfan blue. All patients underwent neck dissection.The sentinel lymph nodes (SLNs) were sectioned in 2- to 3-mm intervals, formalin fixed, and sectioned at three levels. The non-SLNs were sectioned in a routine manner for histologic examination. RESULTS: SLNs were identified in all patients (100%) and accurately predicted the pathologic nodal status in 18 of 20 patients (90%). Tumor was found exclusively in the SLNs in six patients (30%). Two patients had positive SLNs at multiple neck levels. Two patients had a negative SLN and a positive non-SLN (false-negative findings). Occult nodal metastases were present in 60% of the cohort. CONCLUSIONS: SNB is a technically feasible and accurate procedure for staging the neck in oral carcinoma patients. However, SNB accuracy is lower for floor of the mouth lesions. The rate of occult nodal metastases identified in this cohort is higher than previously reported in the literature. These results suggest that SNB warrants further multi-institutional studies.     

Management and outcome of children with skin and soft tissue abscesses caused by community-acquired methicillin-resistant Staphylococcus aureus

BACKGROUND: Although the epidemiology of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) has been explored in many investigations, management of this emerging infection has not been well-studied. For non-methicillin-resistant Staphylococcus aureus skin and soft tissue abscesses, incision and drainage is generally adequate therapy without the use of antibiotics, but this has not been established for CA-MRSA. METHODS: Children presenting to Children's Medical Center of Dallas for management of skin and soft tissue abscesses caused by culture-proved CA-MRSA were prospectively followed. We analyzed data from the initial evaluation and from two follow-up visits that focused on the management and outcome of CA-MRSA infection. Retrospective chart review was performed 2 to 6 months after the initial visit. RESULTS: Sixty-nine children were identified with culture-proved CA-MRSA skin and soft tissue abscess. Treatment consisted of drainage in 96% of patients and wound packing in 65%. All children were treated with antibiotics. Five patients (7%) were prescribed an antibiotic to which their CA-MRSA isolate was susceptible before culture results were known. Four patients (6%) required hospital admission on the first follow-up; none of these patients had received an antibiotic effective against CA-MRSA. A significant predictor of hospitalization was having a lesion initially >5 cm (P = 0.004). Initial ineffective antibiotic therapy was not a significant predictor of hospitalization (P = 1.0). Of the 58 patients initially given an ineffective antibiotic and managed as outpatients, an antibiotic active against CA-MRSA was given to 21 (36%) patients after results of cultures were known. No significant differences in response were observed in those who never received an effective antibiotic than in those who did. CONCLUSIONS: Incision and drainage without adjunctive antibiotic therapy was effective management of CA-MRSA skin and soft tissue abscesses with a diameter of <5 cm in immunocompetent children.     

Extremely High Body Mass Index is not a Contraindication to Laparoscopic Gastric Bypass

Background: Laparoscopic Roux-en-Y gastric bypass (LRYGBP) is an effective operation for morbidly obese patients who have failed conservative weight loss treatments. It is currently indicated for patients with BMI >40 kg/m² or >35 with significant co-morbidities. Controversy exists whether there is an upper limit to BMI beyond which this operation should not be performed. Methods: Between April 1999 and February 2001, 82 patients (19 male, 63 female) underwent LRYGBP. Average age was 43.6, and average BMI was 56 kg/m². These patients were divided into those with BMI <60 and those with BMI ≥60 kg/m². Results:There were 61 patients with BMI <60 and 21 patients with BMI ≥60. The groups were similar in age, gender, distribution or incidence of co-morbid conditions (diabetes, coronary artery disease, hypertension, sleep apnea, asthma) between the groups. The BMI ≥60 group had a significantly longer length of stay (6.6 days vs 5.3 days, P <0.05), and only 1 patient (BMI 85) developed an anastomotic leak and died. 2 patients in this group (BMI 62 and 73) developed small bowel obstruction requiring lysis of adhesions. 1 patient in the BMI <60 group developed a gastrojejunal stricture requiring balloon dilatation. Conclusion: While patients with a BMI ≥60 are at higher risk for postoperative complications, they are also at higher risk from continued extreme obesity. In our series, 85% of these patients had an uneventful postoperative course and began shedding excess weight. BMI ≥60 should not be a contraindication for LRYGBP.     

Internal mammary lymph node (IMN) coverage by standard radiation tangent fields in patients showing IMN drainage on lymphoscintigraphy: therapeutic implications

The purpose of this report is to evaluate the variability in coverage of the internal mammary nodal chain (IMN) by standard radiation tangential fields in those patients with medial drainage on lymphoscintigraphy. Twenty-two patients who showed lymphoscintigraphic IMN drainage underwent radiation simulation planned with computed tomography (CT). Standard tangent fields were placed and CT scans were reviewed to assess IMN inclusion and correlation with presternal fat thickness. Of the 22 patients who showed IMN drainage on lymphoscintigraphy, 10 (45%) had lateral primary lesions, 9 (41%) had medial lesions and 3 (14%) had subareolar lesions. Of these 22 women, 4 (19%) had the IMN completely within the standard tangent fields. Twelve women (55%) had only partial coverage of the IMN and the remaining 6 women (27%) had the IMN region completely outside. Presternal fat thickness greater than 10 mm was less likely associated with complete IMN coverage than fat thickness 10 mm or less, P = 0.001. Lymphoscintigram drainage to the IMN in breast cancer patients may suggest an increased risk of IMN involvement. Our data show that a majority (73%) of these patients had complete or partial incidental inclusion of the IMNs with standard tangents, which may in part explain the historically low IMN failure rate.     

Treatment of pain syndromes with venlafaxine

Major depressive disorder (MDD) and anxiety disorders such as generalized anxiety disorder (GAD) are often accompanied by chronic painful symptoms. Examples of such symptoms are backache, headache, gastrointestinal pain, and joint pain. In addition, pain generally not associated with major depression or an anxiety disorder, such as peripheral neuropathic pain (e.g., diabetic neuropathy and postherpetic neuralgia), cancer pain, and fibromyalgia, can be challenging for primary care providers to treat. Antidepressants that block reuptake of both serotonin and norepinephrine, such as the tricyclic antidepressants (e.g., amitriptyline), have been used to treat pain syndromes in patients with or without comorbid MDD or GAD. Venlafaxine, a serotonin and norepinephrine reuptake inhibitor, has been safe and effective in animal models, healthy human volunteers, and patients for treatment of various pain syndromes. The use of venlafaxine for treatment of pain associated with MDD or GAD, neuropathic pain, headache, fibromyalgia, and postmastectomy pain syndrome is reviewed. Currently, no antidepressants, including venlafaxine, are approved for the treatment of chronic pain syndromes. Additional randomized, controlled trials are necessary to fully elucidate the role of venlafaxine in the treatment of chronic pain.     

Single dose of the antivascular agent, ZD6126 (N-acetylcolchinol-O-phosphate), reduces perfusion for at least 96 hours in the GH3 prolactinoma rat tumor model

Tumor vasculature is an attractive therapeutic target as it differs structurally from normal vasculature, and the destruction of a single vessel can lead to the death of many tumor cells. The effects of antivascular drugs are frequently short term, with regrowth beginning less than 24 hours posttreatment. This study investigated the duration of the response to the vascular targeting agent, ZD6126, of the GH3 prolactinoma, in which efficacy and dose-response have previously been demonstrated. GH3 prolactinomas were grown in the flanks of eight Wistar Furth rats. All animals were treated with 50 mg/kg ZD6126. The tumors were examined with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) 24 hours pretreatment and posttreatment, and at a single time between 48 and 96 hours posttreatment. No evidence of recovery of perfusion was observed even at the longest (96-hour) time point. Involvement of a statistician at the project planning stage and the use of DCE-MRI, which permits noninvasive quantitation of parameters related to blood flow in intact animals, allowed this highly significant result to be obtained using only eight rats.